The Role of Levodopa-induced Glycemic Disturbance in PD

1. Cortisol levels in PWP peak in morning and evening.
2. Glucose levels in diabetics peak morning and evening.
3. Glucose and insulin metabolism in a large number of PWP resembles a low-level form of diabetes in which Sinemet interferes with glucose absorption by skeletal muscle. This prompts an increase in insulin levels as the body attempts to overcome this action. A study noted below found insulin levels tripled after a year of ldopa.
4. Hyperglycemia can quickly trigger hypoglycemia via overproduction of insulin. Sensitivity to this abrupt switch instead of its magnitude can be a problem.
5. There is also a reference below to the destruction of catechalomines by insulin. That raises the possibility of a cycle wherein Sinemet increases insulin which destroys dopamine leading to a need for more Sinemet.

Normal response to glucose in the blood includes insulin-stimulated muscle absorption and storage, thus lowering the glycemic levels. But this study seems to indicate that Sinemet stops that protective action.

Smith 2004: We hypothesized that levodopa with carbidopa, a common therapy for patients with Parkinson’s disease, might contribute to the high prevalence of insulin resistance reported in patients with Parkinson’s disease. We examined the effects of levodopa-carbidopa on glycogen concentration, glycogen synthase activity, and insulin-stimulated glucose transport in skeletal muscle, the predominant insulin-responsive tissue. In isolated muscle, levodopa-carbidopa completely prevented insulin-stimulated glycogen accumulation and glucose transport…..

A separate set of rats was treated intragastrically twice daily for 4 wk with levodopa-carbidopa. After 4 wk of treatment, oral glucose tolerance was reduced in rats treated with drugs compared with control animals. Muscles from drug-treated rats contained at least 15% less glycogen and ~50% lower glycogen synthase activity compared with muscles from control rats. The data demonstrate {beta}-adrenergic-dependent inhibition of insulin action by levodopa-carbidopa and suggest that unrecognized insulin resistance may exist in chronically treated patients with Parkinson’s disease….

Several investigators have reported high rates of glucose intolerance among patients with PD (2, 3, 27). For example, in two separate studies of 30 and 57 patients with PD, respectively, ~50% of the patients displayed abnormal oral glucose tolerance (2, 27). Similarly, abnormal intravenous glucose tolerance was found in four of eight patients with PD (3). Notably, hyperglycemic effects of levodopa and dopamine have been documented in humans and laboratory animals (3, 17, 18, 33). The decarboxylase inhibitor carbidopa is given with levodopa to prevent the conversion of levodopa to dopamine in peripheral tissues, because dopamine does not cross the blood-brain barrier (4). However, carbidopa does not prevent accumulation of dopamine in skeletal muscle in animals treated with levodopa (9, 30)……

Chronic levodopa-carbidopa treatment decreased oral glucose tolerance and led to lower muscle glycogen concentration and GS activity. These findings are consistent with previous reports of hyperglycemic effects of levodopa (3, 17, 18, 33). The levodopa-related peripheral insulin resistance we found (i.e., inhibition of insulin-stimulated glucose transport into and storage by muscle) could contribute to hyperglycemia in animals treated with levodopa. It appears that levodopa impinges on muscle glucose metabolism despite the presence of carbidopa, a decarboxylase inhibitor…..

Levodopa and its metabolite dopamine have been shown to cause hyperglycemia in humans in a number of studies (17, 18). In one study, a 1.0-g dose of levodopa given orally to seven patients with PD caused an increase in fasting plasma glucose level from 87 to 99 mg/dl within 30 min (3). Four and five hours after a 100-g glucose load, plasma glucose concentrations were still elevated (133 and 122 mg/dl) in subjects who had ingested levodopa before consuming glucose compared with plasma glucose concentrations (83 and 78 mg/dl) in subjects for whom the oral glucose load was administered without levodopa (3). In a separate study, 1.0 g of levodopa caused hyperglycemia in patients with PD who had been treated for 3 mo with levodopa (33). Furthermore, 12 mo of chronic levodopa treatment reduced oral glucose tolerance in these patients, such that mean peak plasma glucose concentrations during oral glucose tolerance tests increased from ~165 to ~190 mg/dl (33). The year of chronic levodopa treatment was associated with a threefold increase in mean peak circulating insulin concentration and a twofold increase in insulin area under the curve during an OGTT (33). Thus in the absence of a decarboxylase inhibitor, acute and chronic levodopa treatment both appear to cause hyperglycemia (3, 17, 18, 33). The current study indicates that even in the presence of a decarboxylase inhibitor, levodopa can inhibit insulin action and impair glycogen metabolism in skeletal muscle. However, similar studies need to be done in humans…..

We found that levodopa-carbidopa impairs insulin-stimulated glucose transport and glycogen accumulation in muscle. Because normally ~90% of plasma glucose that is absorbed in response to insulin is stored as glycogen in skeletal muscle (22, 32), it appears possible that disruption of insulin action by levodopa may contribute to glucose intolerance reported for patients with PD…

Hornykiewicz 2002:
The article traces the development of research on the naturally occurring amino acid L-3,4-dihydroxyphenylalanine (L-dopa), from the first synthesis of its D,L racemate in 1911, and the isolation of its L-isomer from seedling of Vicia faba beans to the amino acid’s successful application, from 1961 onward, as the most efficacious drug treatment of Parkinson’s disease (PD). Upon its isolation from legumes in 1913, L-dopa was declared to be biologically inactive. However, two early pharmacological studies, published in 1927 and 1930 respectively, proved (in the rabbit) that D,L-dopa exerted significant effects on glucose metabolism (causing marked hyperglycemia) and on arterial blood pressure. Interest in L-dopa’s biological activity increased considerably following the discovery, in 1938, of the enzyme L-dopa decarboxylase and the demonstration that in the animal and human body L-dopa was enzymatically converted to dopamine (DA), the first biologically active amine in the biosynthetic chain of tissue catecholamines. This prompted, in the 1940s, many studies, both in animals and in humans, especially concerned with the vasopressor potential of L-dopa/DA. In the 1950s, the focus of L-dopa research shifted to its potential for replenishing the experimentally depleted (by insulin or reserpine) peripheral and brain catecholamine stores and the concomitant restoration of normal function. During that period, of special interest were the observations that L-dopa reversed the reserpine-induced state of “tranquilisation” and that its decarboxylation product DA occurred in high amounts in animal and human brain, with a preferential localization in the basal ganglia. These observations set the stage for the beginning of DA studies in PD brain. In 1960, the severe brain DA deficit, confined to patients with PD was discovered, and a year later L-dopa’s strong therapeutic effect in patients with PD was demonstrated. In 1967, the chronic high-dose oral L-dopa regimen was successfully introduced into clinical practice. Despite some initial doubts about L-dopa’s mechanism of action in PD, it is now generally recognized that L-dopa use in PD is a classic example of a brain neurotransmitter replacement therapy. However, the DA replacement potential of L-dopa may not be its sole action of interest, as suggested by recent evidence that L-dopa may also have its own biological activity in the CNS, independent of DA.

Here we learn of the tie to mitochondrial impairment and oxidation as a result of hyperglycemia.

Rollo 2006:
1: Toxicol Appl Pharmacol. 2006 Apr 15;212(2):167-78. Epub 2006 Feb 20.

Diabetes and mitochondrial function: role of hyperglycemia and oxidative stress.

Rolo AP, Palmeira CM.

Center for Neurosciences and Cell Biology of Coimbra, Department of Zoology,
University of Coimbra, 3004-517 Coimbra, Portugal.

Hyperglycemia resulting from uncontrolled glucose regulation is widely
recognized as the causal link between diabetes and diabetic complications. Four
major molecular mechanisms have been implicated in hyperglycemia-induced tissue
damage: activation of protein kinase C (PKC) isoforms via de novo synthesis of
the lipid second messenger diacylglycerol (DAG), increased hexosamine pathway
flux, increased advanced glycation end product (AGE) formation, and increased
polyol pathway flux. Hyperglycemia-induced overproduction of superoxide is the
causal link between high glucose and the pathways responsible for hyperglycemic
damage. In fact, diabetes is typically accompanied by increased production of
free radicals and/or impaired antioxidant defense capabilities, indicating a
central contribution for reactive oxygen species (ROS) in the onset,
progression, and pathological consequences of diabetes. Besides oxidative
stress, a growing body of evidence has demonstrated a link between various
disturbances in mitochondrial functioning and type 2 diabetes. Mutations in
mitochondrial DNA (mtDNA) and decreases in mtDNA copy number have been linked to
the pathogenesis of type 2 diabetes. The study of the relationship of mtDNA to
type 2 diabetes has revealed the influence of the mitochondria on
nuclear-encoded glucose transporters, glucose-stimulated insulin secretion, and
nuclear-encoded uncoupling proteins (UCPs) in beta-cell glucose toxicity. This
review focuses on a range of mitochondrial factors important in the pathogenesis
of diabetes. We review the published literature regarding the direct effects of
hyperglycemia on mitochondrial function and suggest the possibility of
regulation of mitochondrial function at a transcriptional level in response to
hyperglycemia. The main goal of this review is to include a fresh consideration
of pathways involved in hyperglycemia-induced diabetic complications.

PMID: 16490224 [PubMed - indexed for MEDLINE]

Sandyk 1993
1: Int J Neurosci. 1993 Mar-Apr;69(1-4):125-30.

The relationship between diabetes mellitus and Parkinson’s disease.

Sandyk R.

NeuroCommunication Research Laboratories, Danbury, CT.

It has been reported that 50% to 80% of patients with Parkinson’s disease have
abnormal glucose tolerance which may be further exacerbated by levodopa therapy.
Little is known about the impact of chronic hyperglycemia on the severity of the
motor manifestations and the course of the disease as well as its impact on the
efficacy of levodopa or other dopaminergic drugs. This issue, which has been
largely ignored, is of clinical relevance since animal studies indicate that
chronic hyperglycemia decreases striatal dopaminergic transmission and increases
the sensitivity of postsynaptic dopamine receptors. In addition, evidence from
experimental animal studies indicates that diabetic rats are resistant to the
locomotor and behavioral effects of the dopamine agonist amphetamine. The
resistance to the central effects of amphetamine is largely restored with
chronic insulin therapy. In the present communication, I propose that in
Parkinson’s disease diabetes may exacerbate the severity of the motor disability
and attenuate the therapeutic efficacy of levodopa or other dopaminergic agents
as well as increase the risk of levodopa-induced motor dyskinesias. Thus, it is
advocated that Parkinsonian patients should be routinely screened for evidence
of glucose intolerance and that if found aggressive treatment of the
hyperglycemia may improve the response to levodopa and potentially diminish the
risk of levodopa-induced motor dyskinesias.

PMID: 8082998 [PubMed - indexed for MEDLINE]

What I have observed thus far in my own case resembles fasting hyperglycemia in that it occurs even without eating. If I am, indeed, experiencing intermittent diabetic patterns, even at low glucose levels, then that may not only contribute to symptoms but also to damage over the long term.

1: Diabetes Technol Ther. 2004 Aug;6(4):525-33.

Fasting hyperglycemia: etiology, diagnosis, and treatment.

Sheehan JP.

Case Western Reserve University, Cleveland, Ohio, USA. ncide1@aol.com

Suboptimal glycemic control in individuals with type 1 and type 2 diabetes
mellitus is associated with an increased risk of microvascular and macrovascular
complications. Even brief periods of hyperglycemia increase the risk of
complications. Fasting hyperglycemia is a phenomenon that has been observed in
essentially all individuals with diabetes and may be due to dysregulation of the
normal circadian hormonal patterns resulting in increased hepatic glucose
output. Controlling hepatic glucose output and disposal is essential for
effectively managing fasting hyperglycemia. Fasting hyperglycemia generally can
be attributed to inadequate or inappropriate hepatic insulinization or the dawn
phenomenon (fasting hyperglycemia occurring in the absence of antecedent
hypoglycemia). Less commonly, the Somogyi effect (marked fasting hyperglycemia
following antecedent hypoglycemia) can cause fasting hyperglycemia. Accurate
diagnosis with overnight home blood glucose monitoring is important in
developing an appropriate treatment strategy. Manipulation of the individual’s
diet or oral agent therapy may be all that is required in some individuals to
reduce fasting hyperglycemia. Hepatic glucose output and disposal in the fasting
state may be controlled via bedtime administration of either an
intermediate-acting insulin such as NPH or a long-acting true basal insulin such
as insulin glargine. Attention to fasting hyperglycemia coupled with appropriate
individualization of treatment should improve the long-term outcome of
individuals with type 1 and type 2 diabetes by reducing the risk of
complications. Normalization of the fasting blood glucose, through whatever
strategy, minimizes glucotoxicity and insulin resistance, profoundly influences
daytime glycemic control, and profoundly reduces the risk of the complications
of diabetes.

PMID: 15321011 [PubMed - indexed for MEDLINE]

Diabetics, at least, show a rhythm in their glucose production that is not present in normal folk and which increases morning levels, at least when fasting, which then dissipate as the day goes on. This is similar to the pattern I found in my own case and would explain the increase in blood sugar readings when fasting.

1: Diabetologia. 2006 Jul;49(7):1619-28. Epub 2006 May 16.

Diurnal rhythm in endogenous glucose production is a major contributor to
fasting hyperglycaemia in type 2 diabetes. Suprachiasmatic deficit or limit
cycle behaviour?

Radziuk J, Pye S.

Diabetes and Metabolism Research Unit, Ottawa Hospital (Civic Campus), 1053
Carling Avenue, Ottawa, ON, K1Y 4E9, Canada.

AIMS/HYPOTHESIS: An increase in endogenous glucose production (EGP) is a major
contributor to fasting morning hyperglycaemia in type 2 diabetes. This increase
is dissipated with fasting, later in the day. To understand its origin, EGP,
gluconeogenesis and hormones that regulate metabolism were measured over 24 h.
We hypothesised that EGP, and therefore glycaemia, would demonstrate a centrally
mediated circadian rhythm in type 2 diabetes. SUBJECTS AND METHODS: Seven
subjects with type 2 diabetes and six age- and BMI-matched control subjects,
fasting after breakfast (08.00 h), underwent a further 24-h fast, with the
infusion of [U-(13)C]glucose and [3-(14)C]lactate, starting at 14.00 h. The MCR
and production of total and gluconeogenic glucose were determined from the
tracer concentrations using compartmental analysis. RESULTS: MCR was near
constant: 1.73+/-0.10 in control and 1.40+/-0.14 ml kg(-1) min(-1) in diabetic
subjects (p=0.04). EGP in diabetes rose gradually overnight from 8.2+/-0.7 to
11.3+/-0.5 mumol kg(-1) min(-1) at 06.00 h (p<0.05). Glucose utilisation lagged
EGP, rising from 8.5+/-0.6 to 10.5+/-0.4 mumol kg(-1) min(-1) (p<0.05), inducing
a fall in glycaemia from a peak of 8.0+/-0.5 mmol/l to 6.3+/-0.4 mmol/l
(p<0.05). Cortisol and melatonin showed diurnal variations, whereas insulin,
glucagon and leptin did not. Melatonin was most closely related to EGP, but its
secretion was attenuated in diabetes (p<0.05). CONCLUSIONS/INTERPRETATION: In
type 2 diabetes, EGP and gluconeogenesis display diurnal rhythms that drive the
fasting hyperglycaemia and are absent in healthy control subjects. The rise in
EGP may be related to a deficit in suprachiasmatic nucleus activity in diabetes,
or result from non-linear behaviour plus a transition from a normal steady state
to a limit cycle pattern in diabetes, or both.

PMID: 16752180 [PubMed - in process]

The following report speculates that this pattern may be caused by growth-hormone impact on glucose related function of muscle and liver.

1: Endocr Pract. 2005 Jan-Feb;11(1):55-64.

The dawn phenomenon revisited: implications for diabetes therapy.

Carroll MF, Schade DS.

Endocrinology and Metabolism Clinic, Eastern New Mexico Medical Center, Roswell,
New Mexico, USA.

OBJECTIVE: To summarize current data on the magnitude, prevalence, variability,
pathogenesis, and management of the dawn phenomenon in patients with diabetes
mellitus. METHODS: On the basis of the pertinent available literature and
clinical experience, we propose a quantitative definition of the dawn
phenomenon, discuss potential pathogenic mechanisms, and suggest management
options. RESULTS: The “dawn phenomenon” is a term used to describe hyperglycemia
or an increase in the amount of insulin needed to maintain normoglycemia,
occurring in the absence of antecedent hypoglycemia or waning insulin levels,
during the early morning hours. To be clinically relevant, the magnitude of the
dawn increase in blood glucose level should be more than 10 mg/dL or the
increase in insulin requirement should be at least 20% from the overnight nadir.
Controversy exists regarding the frequency, reproducibility, and pathogenesis of
the dawn phenomenon. Approximately 54% of patients with type 1 diabetes and 55%
of patients with type 2 diabetes experience the dawn phenomenon when the
foregoing quantitative definition is used. The most likely pathogenic mechanism
underlying the dawn phenomenon is growth hormone-mediated impairment of insulin
sensitivity at the liver and muscles. The exact biochemical pathways involved
are unknown. Therapeutic decisions aimed at correcting fasting hyperglycemia
should take into account the variability and magnitude of the dawn phenomenon
within individual patients. Successful insulinization appears to minimize the
effects of the dawn phenomenon. Currently, no subcutaneous depot preparation of
insulin exists that is capable of mimicking the basal insulinsecretion of the
healthy pancreas. CONCLUSION: Increases in the bedtime doses of hypoglycemic
agents with nighttime peaks in action may correct early morning hyperglycemia
but be associated with undesirable nocturnal hypoglycemia. Targeted continuous
subcutaneous insulin infusion programming can facilitate the prevention of early
morning hyperglycemia in selected patients.

PMID: 16033737 [PubMed - indexed for MEDLINE]

The following establishes the pattern of higher levels of glucose in the morning and evenings. This is the same pattern as for cortisol, so their interaction would be of major importance.

1: Diabetes Res Clin Pract. 2006 May 25; [Epub ahead of print]

Daytime variations in glucose tolerance in people with impaired glucose
tolerance.

Santos ML, Aragon FF, Padovani CR, Pimenta WP.

Medicine School, University of Sao Paulo State, Botucatu, Sao Paulo, Brazil.

To determine whether glucose tolerance varies throughout the day in people with
impaired glucose tolerance (IGT). We studied 15 healthy IGT, and 18 matched
normal glucose tolerant (NGT) individuals. Blood samples were taken every
30-120min during a 24h period in which all individuals had three mixed meals and
nocturnal sleep. We measured glucose, free fatty acids, specific insulin, intact
proinsulin, cortisol and growth hormone. Variable responses were considered as
concentrations and areas under the curves. Comparison between the groups was by
Student’s t-test, Mann-Whitney, and analysis of variance. Higher total glucose
response, inappropriate normal total insulin response, and unproportionally
increased proinsulin total response were observed in the IGT group. Lower
glucose tolerance occurred in IGT after dinner, as in the NGT, and after
breakfast associated with increased insulin response after breakfast, and
similar proinsulin response after all three meals. IGT had higher glucose
response than NGT after breakfast and lunch, similar insulin responses, and
increased proinsulin-insulin ratio after all three meals. Data from this study
demonstrate that IGT individuals present lower glucose tolerance in the evening,
as those with NGT, and in the morning, as reported in patients with type 2
diabetes.

PMID: 16730846 [PubMed - as supplied by publisher]

Evidence that high cortisol could be a causal factor of glucose problems:

1: Neuroendocrinology. 2005;81(3):200-4. Epub 2005 Jul 11.

Activity of the hypothalamus-pituitary-adrenal system and oral glucose tolerance
in depressed patients.

Weber-Hamann B, Kopf D, Lederbogen F, Gilles M, Heuser I, Colla M, Deuschle M.

Central Institute of Mental Health, Mannheim, Campus Benjamin Franklin,
Department of Psychiatry, Berlin, Germany.

We hypothesized that the activity of the hypothalamus-pituitary-adrenal system
in depressed patients is related to oral glucose tolerance. In 70 moderately
depressed inpatients, we measured morning saliva cortisol for 6 days and
assessed oral glucose tolerance. We found glucose concentrations to be
positively associated with mean morning cortisol concentrations (F3,236 = 2.86,
p < 0.05). Also, the ISI, a measure of insulin receptor sensitivity, was
negatively associated with mean morning cortisol concentrations (r = -0.25, p <
0.04). These findings support the hypothesis that hypercortisolemia may lead to
disturbed glucose utilization in depressed patients. (c) 2005 S. Karger AG,
Basel

PMID: 16020929 [PubMed - indexed for MEDLINE]

Is neuromalignant syndrome related to blood sugar?

1: Nippon Ronen Igakkai Zasshi. 1998 Feb;35(2):139-44.

[Malignant syndrome associated with disseminated intravascular coagulation and a
high level of amylase in serum, followed by diabetic coma in an elderly patient
with Parkinson's disease during L-dopa therapy]
[Article in Japanese]

Saeki H, Muneta S, Kobayashi T.

Department of Internal Medicine, Matsuyama Red Cross Hospital.

A 66-year-old woman with a 7-year history of Parkinsons’ disease was admitted to
our hospital because of a high fever and disturbance of consciousness. She had
been treated with levodopa/benserazide hydrochloride and trihexyphenidyl
hydrochloride until admission. On admission, the patient was comatose, her
temperature was 40.5 degrees C, her blood pressure was 54/-mmHg, and her pulse
rate was 130 beats/min. Laboratory tests showed leukocytosis, a high level of
creatine kinase in serum and evidence of hyperosmolar non-ketotic diabetic coma
(blood glucose, 1,080 mg/dl) and of disseminated intravascular coagulation
(DIC). A continuous insulin infusion, antibiotics, nafamostat mesilate, and
urinastatin were given, after which the DIC, hyperglycemia, and the level of
consciousness were improved. However, levels of creatine kinase, myoglobin,
transaminase, and amylase in serum continued to increase, and multiple organ
failure was suspected. Furthermore, she became less responsive, diaphoretic, and
tremulous; fever and mild rigidity developed. The peak creatine kinase and
myoglobin were 11,095 U/l and 12,520 ng/ml, respectively. A diagnosis of
malignant syndrome was made, and treatment with levodopa/carbidopa and
dantrolene was begun. Within several days, the clinical and laboratory findings
improved. We report here a rare case of malignant syndrome associated with DIC
followed by diabetic coma in an elderly patient with Parkinsons’ disease during
L-dopa therapy. Timely diagnosis and treatment of malignant syndrome are
important in the management of elderly patients with Parkinsons’ disease,
because DIC and multiple organ failure may occur in the early stages of
malignant syndrome.

PMID: 9584493 [PubMed - indexed for MEDLINE]

Could there be a role for our friend LPS? Sure seems likely.

1: Am J Physiol Endocrinol Metab. 2006 Jul;291(1):E108-14. Epub 2006 Feb 7.

Influence of TNF-alpha and IL-6 infusions on insulin sensitivity and expression
of IL-18 in humans.

Krogh-Madsen R, Plomgaard P, Moller K, Mittendorfer B, Pedersen BK.

Rigshospitalet, Section 7641, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
krogh-madsen@inflammation-metabolism.dk

Inflammation is associated with insulin resistance, and both tumor necrosis
factor (TNF)-alpha and interleukin (IL)-6 may affect glucose uptake. TNF induces
insulin resistance, whereas the role of IL-6 is controversial. High plasma
levels of IL-18 are associated with insulin resistance in epidemiological
studies. We investigated the effects of TNF and IL-6 on IL-18 gene expression in
skeletal muscle and adipose tissue. Nine human volunteers underwent three
consecutive interventions, receiving an infusion of recombinant human (rh)IL-6,
rhTNF, and saline. Insulin sensitivity was assessed by measurement of whole body
glucose uptake with the stable isotope tracer method during a euglycemic
hyperinsulinemic clamp (20 mU.min(-1).kg(-1)), which was initiated 1 h after the
IL-6-TNF-saline infusion. Cytokine responses were measured in plasma, muscle,
and fat biopsies. Plasma concentrations of TNF and IL-6 increased 10- and
38-fold, respectively, during the cytokine infusions. Whole body
insulin-mediated glucose uptake was significantly reduced during TNF infusion
but remained unchanged during IL-6 infusion. TNF induced IL-18 gene expression
in muscle tissue, but not in adipose tissue, whereas IL-6 infusion had no effect
on IL-18 gene expression in either tissue. We conclude that TNF-induced insulin
resistance of whole body glucose uptake is associated with increased IL-18 gene
expression in muscle tissue, indicating that TNF and IL-18 interact, and both
may have important regulatory roles in the pathogenesis of insulin resistance.

PMID: 16464907 [PubMed - indexed for MEDLINE]

This one would indicate that far from being doomed to live for our blood sugar, that we have found a major tool to manage our symptoms at a minimum.

1: Metabolism. 2006 Feb;55(2):243-51.

The metabolic response to a high-protein, low-carbohydrate diet in men with type
2 diabetes mellitus.

Nuttall FQ, Gannon MC.

The Metabolic Research Laboratory, Endocrinology, Metabolism, and Nutrition
Section, Department of Veterans Affairs Medical Center, Minneapolis, MN 55417,
USA. nutta001@umn.edu

We recently reported that in subjects with untreated type 2 diabetes mellitus, a
5-week diet of 20:30:50 carbohydrate-protein-fat ratio resulted in a dramatic
decrease in 24-hour integrated glucose and total glycohemoglobin compared with a
control diet of 55:15:30. Body weight, total cholesterol, low-density
lipoprotein cholesterol, high-density lipoprotein cholesterol, and serum ketones
were unchanged; insulin and nonesterified fatty acids were decreased. We now
present data on other hormones and metabolites considered to be affected by
dietary macronutrient changes. The test diet resulted in an elevated fasting
plasma total insulin-like growth factor 1, but not growth hormone. Urinary
aldosterone was unchanged; free cortisol was increased, although not
statistically. Urinary pH and calcium were unchanged. Blood pressure, creatinine
clearance, serum vitamin B12, folate, homocysteine, thyroid hormones, and uric
acid were unchanged. Serum creatinine was modestly increased. Plasma alpha-amino
nitrogen and urea nitrogen were increased. Urea production rate was increased
such that a new steady state was present. The calculated urea production rate
accounted for 87% of protein ingested on the control diet, but only 67% on the
test diet, suggesting net nitrogen retention on the latter. The lack of negative
effects, improved glucose control, and a positive nitrogen balance suggest
beneficial effects for subjects with type 2 diabetes mellitus at risk for loss
of lean body mass.

PMID: 16423633 [PubMed - indexed for MEDLINE]

Another reason exercise is so important.

1: Am J Physiol Endocrinol Metab. 2005 Aug;289(2):E241-50. Epub 2005 Mar 1.

Contraction activates glucose uptake and glycogen synthase normally in muscles
from dexamethasone-treated rats.

Ruzzin J, Jensen J.

Dept. of Physiology, National Institute of Occupational Health, PO Box 8149
Dep., N-0033, Oslo, Norway.

Glucocorticoids cause insulin resistance in skeletal muscle. The aims of the
present study were to investigate the effects of contraction on glucose uptake,
insulin signaling, and regulation of glycogen synthesis in skeletal muscles from
rats treated with the glucocorticoid analog dexamethasone (1 mg x kg(-1) x
day(-1) ip for 12 days). Insulin resistance in dexamethasone-treated rats was
confirmed by reduced insulin-stimulated glucose uptake (approximately 35%),
glycogen synthesis (approximately 70%), glycogen synthase activation
(approximately 80%), and PKB Ser(473) phosphorylation (approximately 40%).
Chronic dexamethasone treatment did not impair glucose uptake during contraction
in soleus or epitrochlearis muscles. In epitrochlearis (but not in soleus), the
presence of insulin during contraction enhanced glucose uptake to similar levels
in control and dexamethasone-treated rats. Contraction also increased glycogen
synthase fractional activity and dephosphorylated glycogen synthase at Ser(645),
Ser(649), Ser(653), and Ser(657) normally in muscles from dexamethasone-treated
rats. After contraction, insulin-stimulated glycogen synthesis was completely
restored in epitrochlearis and improved in soleus from dexamethasone-treated
rats. Contraction did not increase insulin-stimulated PKB Ser(473) or glycogen
synthase kinase-3 (GSK-3) phosphorylation. Instead, contraction increased
GSK-3beta Ser(9) phosphorylation in epitrochlearis (but not in soleus) in
muscles from control and dexamethasone-treated rats. In conclusion, contraction
stimulates glucose uptake normally in dexamethasone-induced insulin resistant
muscles. After contraction, insulin’s ability to stimulate glycogen synthesis
was completely restored in epitrochlearis and improved in soleus from
dexamethasone-treated rats.

PMID: 15741240 [PubMed - indexed for MEDLINE]

So ldopa in the blood caused an increase of glucose from the liver without a compensatory rise in insulin nor uptake from the blood. What is the significance of the growth hormone increase yet no increase in cortisol? Does this mean that ldopa causes increased liver output of glucose each time we take it? Lopa <up>; glucose<up>; insulin <no change>; growth hormone <up>; cortisol <no change>.  This reports that carbidopa prevents the hyperglycemia induced by ldopa’s effect on the liver but does not address the skeletal muscles mentioned in the 2004 study above.

1: Pharmacology. 1978;17(3):138-48.

On the mechanism of hyperglycemia and stimulation of growth hormone secretion by
L-dopa.

Hampshire J, Moraru E, Altszuler N.

The mechanism of hyperglycemia produced by L-dopa was studied in normal trained
dogs with 3-3H-glucose infusion to measure rates of hepatic glucose output
(production) and overall glucose uptake (utilization). Infusion of L-dopa (20
mg/kg/h) increased glucose production causing hyperglycemia. Despite the
hyperglycemia plasma insulin did not increase nor did glucose uptake, indicating
a relative inhibition of glucose utilization. These effects resemble those
produced by epinephrine infusion. Pretreatment with a decarboxylase inhibitor,
carbidopa, prevented the L-dopa effect to increase glucose production and no
hyperglycemia occurred. Hyperglycemia was not prevented by pimozide, a dopamine
receptor blocker, nor by propranolol but was prevented by phentolamine. L-Dopa
also increased plasma growth hormone levels without affecting plasma cortisol.
The effect on growth hormone was prevented by carbidopa and by phentolamine but
not by pimozide; propranolol potentiated the rise in growth hormone. The data
suggest that the L-dopa-induced hyperglycemia is due to a peripheral action,
whereas stimulation of growth hormone secretion may be due to a central action
of a L-dopa metabolite.

PMID: 704657 [PubMed - indexed for MEDLINE]

Nialamide is an MAO inhibitor and phentolamine is an adrenoloic blocker. So an MAOI made the hyperglycemia worse and if an AB was added to that hypo- was the result.

1: Eur J Pharmacol. 1979 May 1;55(3):241-6.

The effects of levodopa on plasma glucose in two strains of rat.

Furman BL, Wilson GA.

The effects of levodopa on plasma glucose were examined in two strains of rats.
In fasted Wistar rats levodopa produced a dose-dependent hyperglycaemic response
which was augmented by pretreatment with nialamide. This response in
nialamide-treated rats was prevented by pretreatment with phentolamine and
converted to a hypoglycaemic response. Phentolamine increased the plasma
concentration of immunoreactive insulin (IRI). In phentolamine-pretreated rats
levodopa produced a further marked increase in the plasma IRI concentration. It
is suggested that the prevention of levodopa hyperglycaemia by phentolamine is
due to the marked increase in the plasma IRI concentration produced by
pretreatment with phentolamine. Moreover the fall in the plasma glucose
concentration produced by levodopa in phentolamine-pretreated rats is likely to
be due, at least in part, to the additional increase in the plasma IRI
concentration produced by levodopa under these conditions. In contrast, in
fasted Sprague-Dawley rats pretreated with nialamide, levodopa produced either
no effect on plasma glucose, or in larger doses, a marked hypoglycaemic effect
followed by death. This hypoglycaemic effect was accompanied by a decrease in
the plasma IRI concentration.

PMID: 456422 [PubMed - indexed for MEDLINE]

Two points stand out: the hypo- was prevented by dopamine agonists and also did not seem to be triggered by insulin as in diabetes. What did trigger it then?

1: Eur J Pharmacol. 1977 Feb 21;41(4):351-60.

Effects of levodopa and dopamine of plasma glucose concentration in mice.

Darwish SA, Furman BL.

In nialamide-treated, fasted mice levodopa produced a dose-dependent
hypoglycaemic response. The response was also seen in pargyline-treated mice but
not in animals which were not treated with a monoamine oxidase inhibitor.
Dopamine did not affect plasma glucose under these conditons. In doses which
were ineffective when injected i.v., both levodopa and dopamine produced
hypoglycemia when injected intracerebroventriculary (i.c.v.). The hypoglycaemic
response to levodopa was prevented by the dopamine antagonists, haloperidol and
pimozide. The possible involvement of 5HT in the hypoglycaemic response to
levodopa was suggested by the blockade of the response by cyproheptadine and
methysergide together with the observations that hypoglycaemia is produced by
5HTP and by i.c.v. 5HT. p-Chlorophenylalanine (PCPA) also reduced the response
to levodopa but the usefulness of PCPA as an inhibitor of 5HT synthesis in these
experiments in doubtful since it also inhibited the hypoglycaemic effects of
5HTP and i.c.v. 5HT. Hypoglycaemia produced by levodopa did not appear to involve stimulation of insulin secretion since plasma IRI levels were not increased by levodopa and the hypoglycaemia was accompanied by a elevation of plasma FFA and no significant change in the liver glycogen content. It is
suggested that the hypoglycaemic effect of levodopa is mediated through dopamine
acting in the brain, although the involvement of 5HT in the response and the
mechanisms involved remain to be determined.

PMID: 139316 [PubMed - indexed for MEDLINE]

1: J Clin Endocrinol Metab. 1989 Jun;68(6):1013-8.

Fasting alters pulsatile and rhythmic cortisol release in normal man.

Vance ML, Thorner MO.

Department of Internal Medicine, University of Virginia Medical Center,
Charlottesville 22908.

The effect of a 5-day fast on integrated, pulsatile, and periodic cortisol
release was studied in 10 normal men by measuring serum cortisol concentrations
every 20 min for 24 h before (day 0) and during the fifth day of fasting (day
5). Serum concentration profiles were analyzed for integrated cortisol release
(area under the curve), pulsatile hormone release by an objective, statistically
based pulse detection algorithm (cluster analysis), and periodic hormone release
(circadian and ultradian rhythms) by Fourier expansion time series analysis.
Urinary cortisol excretion per 24 h was measured in 5 men. The mean 24-h
integrated serum cortisol concentration increased 1.7-fold during fasting (P =
0.0006). This increase resulted from a 2-fold increase in the serum cortisol
concentrations between pulses (valley mean; P = 0.0004), an increase in the
pulse height (P = 0.001), and an increase in pulse increment above baseline (P =
0.01). There were no changes in the number of pulses per 24 h, the interval
between pulses, the width of the pulses, or the area of the pulses during
fasting. Twenty-four-hour urinary cortisol excretion increased in all men, and
the mean urinary cortisol (nanomoles per L)/creatinine clearance (milliliters
per s) ratio increased from 119 on day 0 to 187 on day 5 (n = 5; P = 0.05). The
pattern of periodic hormone release also changed during fasting; the mean (+/-
SE) circadian rhythm (24-h) amplitude decreased from 160 +/- 14 nmol/L on day 0
to 102 +/- 105 nmol/L on day 5 (P = 0.06), and the amplitude of the 12-h rhythm
increased from 68 +/- 11 to 99 +/- 11 nmol/L. There also were significant
increases in the amplitudes of rhythms with periodicities of 8.1, 4.1, 2.4, 1.6,
and 1.3 h (P = 0.02-0.008). Fasting in normal men results in distinct changes in
the amount and pattern of pulsatile, circadian, and ultradian cortisol release.

PMID: 2723024 [PubMed - indexed for MEDLINE]

The pattern was Group 1 eats at 0000; everyone has meds at 0030; Group 2 eats at 0230. Group 1 had delayed response. This is not necessarily a bad thing.

1: Eur J Clin Pharmacol. 1998 Jun;54(4):303-8.

Erratum in:
Eur J Clin Pharmacol 1998 Sep;54(7):577.

Effect of meal timing on the kinetic-dynamic profile of levodopa/carbidopa
controlled release [corrected] in parkinsonian patients.

Contin M, Riva R, Martinelli P, Albani F, Baruzzi A.

Institute of Neurology, University of Bologna, Italy.
tis1848@iperbole.bologna.it

OBJECTIVE: The aim of the study was to assess the effect of the time of
ingestion of a meal on the pharmacokinetics and pharmacodynamics of a
levodopa/carbidopa controlled-release formulation in parkinsonian patients on
chronic levodopa therapy. METHODS: The kinetic-dynamic profile of one tablet of
controlled-release levodopa/carbidopa 200/50 mg was monitored in eight patients,
according to an intrasubject randomized cross-over design in two different
sessions. A standard meal was consumed by the patients after they had fasted for
15-17 h, on one occasion 30 min before the ingestion of the test dose, and on
the other occasion 2 h after the ingestion of the same drug dose. Blood venous
samples for analysis of plasma levodopa and its metabolite 3-O-methyldopa were
drawn at 20-min intervals up to 6 h after dosing. Motor response to the levodopa
test dose was assessed by the finger tapping and walking speed tests at the same
times as blood was drawn. RESULTS: Controlled release [corrected] levodopa
intake after meals resulted in a significant delay in drug absorption, with an
almost twofold increase in time of initial appearance of levodopa in plasma and
time to peak plasma concentration. Peak plasma drug concentrations were not
significantly different in the two experimental conditions; the area under the
6-h plasma concentration-time curve showed an average reduction of 24% in the
fed condition, partly reflecting the incomplete assessment of levodopa
absorption, within the 6 h of examination, due to 5-h delayed peak plasma
levodopa concentration in two patients. With reference to levodopa
pharmacodynamics, time to onset of motor response was significantly delayed and
duration of motor response significantly curtailed in the fed condition, while
the magnitude and overall extent of motor effect were unchanged. CONCLUSIONS: In
keeping with previous findings on levodopa standard-release preparations, these
data show that time of meal ingestion is an important determinant of levodopa
disposition, even from controlled-release preparations in parkinsonian patients.
From a clinical point of view, these results help to explain some of the
delayed, curtailed and even lacking responses that often complicate afternoon
motor performances in patients at the more advanced stages of the disease.

PMID: 9696954 [PubMed - indexed for MEDLINE]

1: Neurobiol Aging. 1988 Sep-Dec;9(5-6):730-2.

Glucose effects on firing rate of neurons of the locus coeruleus: another
attempt to put memory back in the brain.

Sara SJ.

Department de Psychophysiologie, Laboratoire de Physiologie Nerveuse, C.N.R.S.,
Gif sur Yvette, France.

After a generation of research into the biological mechanisms of memory, the
essential nature of the engram remains as elusive as ever. Many investigators
have reorganized their conceptual framework to emphasize the role of
physiological responses elicited by a learning experience in modulating memory
for that event. This approach has generated a long list of correlations between
physiological functions and memory performance. The papers comprising the
present section have the common theme of contributing to that list, but the
remarkable fact which they emphasize is that these correlations are much greater
in the aged rat than in young animals, suggesting that it is a parallel
degeneration of several physiological functions which mediate deficits in memory
performance.

PMID: 3211269 [PubMed - indexed for MEDLINE]

These areas need to be compared to Braak’s findings to check for overlaps.

1: Synapse. 1989;4(1):80-7.

Alterations in local cerebral glucose utilization following central
administration of corticotropin-releasing factor in rats.

Sharkey J, Appel NM, De Souza EB.

Neuroscience Branch, National Institute on Drug Abuse, Baltimore, Maryland
21224.

We have examined the effects of intracerebroventricular administration of
corticotropin-releasing factor (CRF) (5.25 nmol in 10 microliters of saline) on
glucose utilization, an index of cerebral function, in 65 anatomically discrete
regions of rat brain by using the 14C-2-deoxyglucose quantitative
autoradiographic technique. CRF administration increased plasma glucose
concentrations with a temporal onset and magnitude of response similar to those
previously reported. CRF differentially affected glucose utilization (GU) in
discrete regions of rat brain. Consonant with the hypophysiotropic role for CRF,
pronounced increases in GU were seen in median eminence and lateral nucleus of
the hypothalamus. CRF also increased GU in brain regions implicated in mediating
responses to stress including locus coeruleus and median raphe nucleus. In
contrast, reductions in GU were observed in prefrontal cortex and nucleus
accumbens. Punctate increases in GU were noted in the cerebellar cortex.
Furthermore, large increases in GU occurred in vermis, inferior olive, and red
nucleus substantiating a neurotransmitter role for CRF in the olivocerebellar
pathway. Additional brain areas showing significant alterations in GU in
response to CRF included anteroventral, anterior pretectal, and posterolateral
nuclei of the thalamus, fornix, dorsal tegmental nucleus, spinal trigeminal
nucleus, and cuneate nucleus. These data demonstrating regional changes in GU in
response to CRF administration further elucidate the neuroanatomical substrates
underlying the actions of CRF in brain and support the role of this neuropeptide
in coordinating responses to stress.

PMID: 2788932 [PubMed - indexed for MEDLINE]

So protein does indeed flatten the profile and lessen the extremes. In fact, the differences in the two groups were not very marked.

1: Clin Neurol Neurosurg. 1993 Sep;95(3):215-9.

The influence of a standard meal on Sinemet CR absorption in patients with
Parkinson’s disease.

Roos RA, Tijssen MA, van der Velde EA, Breimer DD.

Department of Neurology, Academic Hospital, Leiden, The Netherlands.

We studied the influence of dietary protein intake on the plasma level profile
of levodopa, carbidopa, and 3-O-methyldopa and clinical efficacy in 12 patients
with idiopathic Parkinson’s disease after intake of one levodopa-carbidopa
200/50 controlled release tablet (Sinemet CR; LC-CR). The tablet was given 1 h
before the protein rich meal on one day (fasted) and together with the meal on
an other day (non-fasted). Higher levodopa and carbidopa concentrations were
reached when the LC-CR was taken 1 h before the meal, but the plasma level
profile for levodopa was flatter in the non-fasted state. The area under the
curve for levodopa was slightly higher in the fasted condition. For the clinical
variables walking and tapping slightly better clinical results (P = 0.08) were
found in the fasted condition with the higher levodopa levels. If the patient on
levodopa is in a clinically satisfactory condition, then non-fasted condition
could be preferred because of the smooth plasma level profile demonstrated.
However, if the initial levodopa concentrations are not in the critical range to
be effective for the patient, the advice should be to take the drug in a fasted
condition.

PMID: 8242964 [PubMed - indexed for MEDLINE]

Again, must compare to Braak.

1: Brain Res. 1995 Jun 26;684(1):47-55.

Four-day hyperinsulinemia in euglycemic conditions alters local cerebral glucose
utilization in specific brain nuclei of freely moving rats.

Doyle P, Cusin I, Rohner-Jeanrenaud F, Jeanrenaud B.

Faculty of Medicine, University of Geneva, Switzerland.

Although insulin is a well known regulator of peripheral tissue glucose
metabolism, there is little agreement over its effects on brain glucose
metabolism. Several investigators report that peripheral insulin may enter the
brain via several routes. The presence of insulin receptors specific to brain,
coupled to diverse reports of the effect of acute insulin administration on
brain glucose use, led us to carry out a 4-day hyperinsulinemic euglycemic clamp
in freely moving rats with subsequent labelled 2-deoxyglucose metabolic mapping
studies. It was found that after 4 days of peripheral insulin infusion, several
brain regions (Anterior Hypothalamic area, Suprachiasmatic nucleus, Basolateral
Amygdaloid nucleus, Supramammillary bodies, Medial Geniculate nucleus and Locus
Coeruleus) had an altered local cerebral glucose utilization. Upon subsequent
analysis of their anatomical and functional connections it is proposed that
insulin may regulate an integrated circuit of pathways within the central
nervous system.

PMID: 7583203 [PubMed - indexed for MEDLINE]

Is hypoglycemia an action or a reading? That is, is the spike and drop a hypoglycemic action? Even if the values stay within the norm?

1: Pancreas. 2005 Aug;31(2):142-7.

Maintaining euglycemia prevents insulin-induced Fos expression in brain
autonomic regulatory circuits.

Ao Y, Wu S, Go VL, Toy N, Yang H.

Department of Medicine, Division of Digestive Diseases and Brain Research
Institute, UCLA, Los Angeles, CA 90073, USA.

OBJECTIVE: Insulin-induced hypoglycemia activates neurons in hypothalamic and
brain medullary nuclei involved in central autonomic regulation. We investigated
whether these central neuronal activations relates to a deficiency of glucose
supply. METHODS: Three groups of non-fasted, conscious rats received intravenous
(iv) saline infusion (control), a hyperinsulinemic/hypoglycemic clamp, or a
hyperinsulinemic/euglycemic clamp for 120 minutes and then the brains were
collected for Fos immunohistochemistry. RESULTS: The number of Fos positive
cells significantly increased in the paraventricular nucleus of the hypothalamus
(PVN, 191 +/- 63 versus 66 +/- 18), pontine locus coeruleus (LC, 53 +/- 19
versus 5 +/- 2), brain medullary dorsal motor nucleus of the vagus (DMV, 26 +/-
4 versus 1 +/- 0), and nucleus tractus solitarii (NTS, 38 +/- 3 versus 10 +/-
35) in rats with hyperinsulinemic/hypoglycemic clamp compared with the controls.
Maintaining blood glucose levels within physiological range by
hyperinsulinemic/euglycemic clamp prevented insulin infusion-induced Fos
expression in the PVN, DMV, and NTS. The numbers of Fos positive cells in these
nuclei were significantly lower (-87%, -75%, and -51%, respectively) than that
in the hypoglycemic rats. CONCLUSION: These results indicate that neuronal
activation in hypothalamic and medullary autonomic regulatory nuclei induced by insulin administration is caused by hypoglycemia rather than a direct action of insulin. In addition, certain neurons in the medullary DMV and NTS respond to declines in glucose levels within physiological range.

PMID: 16025001 [PubMed - indexed for MEDLINE]

Levodopa is not our friend.

1: Brain. 1996 Dec;119 ( Pt 6):2121-32.

Acute effects of levodopa on neuropsychological performance in stable and
fluctuating Parkinson’s disease patients at different levodopa plasma levels.

Kulisevsky J, Avila A, Barbanoj M, Antonijoan R, Berthier ML, Gironell A.

Department of Neurology, Sant Pau Hospital, Autonomous University of Barcelona,
Spain.

The contribution of dopaminergic systems to cognitive defects in Parkinson’s
disease and the cognitive effects of levodopa remain controversial. The levodopa
plasma levels and the neuropsychological performance of 10 parkinsonian patients
with a stable motor response to the drug and 10 matched parkinsonian patients
with a ‘wearing-off’ phenomenon were studied 12 h after levodopa was withdrawn
(time zero), and at 1 h and 4 h after an oral dose of levodopa (i.e. at ‘+1H’
and ‘+4H’), to investigate whether discrete cognitive domains are more sensitive
to levodopa in parkinsonian patients with the wearing-off phenomenon.
Considering the 20 patients as a whole, levodopa significantly diminished the
response time in verbal and visuospatial memory tests, the extradimensional
matching test and the Wisconsin card sorting test (WCST), without significantly
improving or worsening the patient’s accuracy. A significant group-by-time
effect was only evident in the WCST; while in stable patients levodopa produced
no changes, wearing-off patients significantly reduced the number of categories
achieved and had more perseverative errors at +1H, recovering at +4H. These
results confirm previous findings of selective adverse effects of levodopa on
highly demanding executive tasks in Parkinson’s disease and additionally suggest that some previous discrepancies between studies may be accounted for by lack of
differentiation between stable and wearing-off conditions. ‘Frontal’
disturbances on neuropsychological tests with levodopa may become evident only
after massive degeneration of the dopamine systems has occurred.

PMID: 9010015 [PubMed - indexed for MEDLINE]

Food and ldopa

But the question remains as to whether this is a plus or a minus. And these are not particularly overwhelming results, either. Fifteen percent?

1: Clin Neuropharmacol. 1987 Dec;10(6):527-37.

Influence of meal ingestion time on pharmacokinetics of orally administered
levodopa in parkinsonian patients.

Baruzzi A, Contin M, Riva R, Procaccianti G, Albani F, Tonello C, Zoni E,
Martinelli P.

Institute of Neurology, University of Bologna, Italy.

The influence of meal ingestion time on rate and extent of oral levodopa
absorption was evaluated in a group of 17 patients, after administration of
their usual second daily dose of levodopa plus carbidopa (Sinemet 10:1) or
benserazide (Madopar 4:1). Standard meals were consumed by the patients after
they had fasted 15-17 h, on one occasion 30 min before ingestion of the levodopa
“study dose” and, at another time, 2 h after ingestion of the same dose. This
study dose, ranging from 50 to 250 mg levodopa, was given to the patients at 11
a.m., 4 h after their first morning dose. Time to peak plasma levodopa
concentration increased threefold (from 45 +/- 23 to 134 +/- 76 min, p less than
0.001), when levodopa was administered after meals. Area under the 6-h plasma
concentration-time curve for levodopa was decreased in 10 subjects, unchanged in
three and higher in four after ingestion of meals, the latter finding probably
resulting from an erratic absorption even at fasting. On the whole, levodopa
absorption proved significantly lower (p less than 0.01), on the average 15%.
Similarly, peak plasma levodopa concentrations were lower in 12 patients,
unchanged in two, and higher in three, with an overall significant decrease (p
less than 0.001) of 30% on the average. The data confirm the importance of meal
ingestion time in relation to levodopa dose as a determinant of drug absorption.

PMID: 3427559 [PubMed - indexed for MEDLINE]

Growth Hormone must be investigated.

1: Arch Neurol. 1976 Feb;33(2):131-4.

Modification of the actions of some neuroactive drugs by growth hormone.

Tang LC, Cotzias GC.

The flat serum growth hormone (GH) patterns of untreated parkinsonian patients
develop diurnal rises during treatment with levodopa. This chronic exposure to
excesses of GH might lead to the eventual emergence of the “on-off” phenomenon,
which would indicate a need for animal experiments. Pretreatment of mice with GH
increased (1) cerebral dopa and dopamine concentrations in levodopa-treated
mice, (2) cerebral accumulation of injected tritiated apomorphine and tritiated
thymidine, and (3) behavioral responses to levodopa, L-m-tyrosine, apomorphine
hydrochloride, and oxotremorine.

PMID: 1252146 [PubMed - indexed for MEDLINE]

Potential therapies

What could be simpler? What else does it affect besides bread? Anything? Everything? And it seems to be dose dependent!

1: Eur J Clin Nutr. 2005 Sep;59(9):983-8.

Vinegar supplementation lowers glucose and insulin responses and increases
satiety after a bread meal in healthy subjects.

Ostman E, Granfeldt Y, Persson L, Bjorck I.

Applied Nutrition and Food Chemistry, Department of Food Technology, Engineering
and Nutrition, Lund University, Lund, Sweden. Elin.Ostman@inl.ith.se

OBJECTIVE: To investigate the potential of acetic acid supplementation as a
means of lowering the glycaemic index (GI) of a bread meal, and to evaluate the
possible dose-response effect on postprandial glycaemia, insulinaemia and
satiety. SUBJECTS AND SETTING: In all, 12 healthy volunteers participated and
the tests were performed at Applied Nutrition and Food Chemistry, Lund
University, Sweden. INTERVENTION: Three levels of vinegar (18, 23 and 28 mmol
acetic acid) were served with a portion of white wheat bread containing 50 g
available carbohydrates as breakfast in randomized order after an overnight
fast. Bread served without vinegar was used as a reference meal. Blood samples
were taken during 120 min for analysis of glucose and insulin. Satiety was
measured with a subjective rating scale. RESULTS: A significant dose-response
relation was seen at 30 min for blood glucose and serum insulin responses; the
higher the acetic acid level, the lower the metabolic responses. Furthermore,
the rating of satiety was directly related to the acetic acid level. Compared
with the reference meal, the highest level of vinegar significantly lowered the
blood glucose response at 30 and 45 min, the insulin response at 15 and 30 min
as well as increased the satiety score at 30, 90 and 120 min postprandially. The
low and intermediate levels of vinegar also lowered the 30 min glucose and the
15 min insulin responses significantly compared with the reference meal. When GI
and II (insulinaemic indices) were calculated using the 90 min incremental area,
a significant lowering was found for the highest amount of acetic acid, although
the corresponding values calculated at 120 min did not differ from the reference
meal. CONCLUSION: Supplementation of a meal based on white wheat bread with
vinegar reduced postprandial responses of blood glucose and insulin, and
increased the subjective rating of satiety. There was an inverse dose-response
relation between the level of acetic acid and glucose and insulin responses and
a linear dose-response relation between acetic acid and satiety rating. The
results indicate an interesting potential of fermented and pickled products
containing acetic acid.

PMID: 16015276 [PubMed - indexed for MEDLINE]

Sugar and dopamine

1: Neuroreport. 2001 Nov 16;12(16):3549-52.

Excessive sugar intake alters binding to dopamine and mu-opioid receptors in the
brain.

Colantuoni C, Schwenker J, McCarthy J, Rada P, Ladenheim B, Cadet JL, Schwartz
GJ, Moran TH, Hoebel BG.

Department of Psychology, Green Hall, Princeton University, Princeton, NJ 08544,
USA.

Palatable food stimulates neural systems implicated in drug dependence; thus
sugar might have effects like a drug of abuse. Rats were given 25% glucose
solution with chow for 12 h followed by 12 h of food deprivation each day. They
doubled their glucose intake in 10 days and developed a pattern of excessive
intake in the first hour of daily access. After 30 days, receptor binding was
compared to chow-fed controls. Dopamine D-1 receptor binding increased
significantly in the accumbens core and shell. In contrast, D-2 binding
decreased in the dorsal striatum. Binding to dopamine transporter increased in
the midbrain. Opioid mu-1 receptor binding increased significantly in the
cingulate cortex, hippocampus, locus coeruleus and accumbens shell. Thus,
intermittent, excessive sugar intake sensitized D-1 and mu-1 receptors much like
some drugs of abuse.

PMID: 11733709 [PubMed - indexed for MEDLINE]

Effects of chronic ldopa/dopamine exposure

“Exposed to a non-physiologic shift in dopamine level” somehow just doesn’t make me comfortable.

1: Clin Neuropharmacol. 1994;17 Suppl 2:S7-13.

Clinical implications of sustained dopaminergic stimulation.

Stocchi F, Patsalos PN, Berardelli A, Barbato L, Bonamartini A, Manfredi M,
Ruggieri S.

Department of Neurosciences, University La Sapienza, Rome, Italy.

Fluctuations in motor performance are the major problems in chronic management
of Parkinson’s disease. Most of these fluctuations reflect the decline of
levodopa availability. As a consequence, levodopa dosage might be increased and
the interdose interval progressively shortened. The postsynaptic dopamine
receptors at this point are exposed to a nonphysiologic shift in dopamine level,
which may induce changes at the receptor site and contribute to the appearance
of “on-off” phenomena and dyskinesias. We compared a group of 18 patients
treated for 60 consecutive months with continuous subcutaneous lisuride infusion
with a group of 20 patients treated with conventional oral levodopa treatment.
The clinical evaluations performed during the study showed in the lisuride group
only a worsening of dyskinesias, whereas the other symptoms remained unchanged.
In the other group the evaluation scores showed a significant worsening of all
long-term treatment complications. The slow-release preparations of levodopa may
ensure a more continuous dopaminergic stimulation than standard formulations.
However, the use of these compounds is difficult in severely fluctuating
patients because the lack of a plasma peak level usually leads to a very long
delay before patients turn “on.” We studied the pharmacokinetic and clinical
effects of the two slow-release preparations of levodopa [Madopar HBS and
Sinemet controlled-release (CR)] and a combination of Sinemet CR plus standard
Sinemet in 13 fluctuating parkinsonian patients. The results of this study show
that the combination of standard Sinemet and Sinemet CR ensures a more prolonged
clinical effect with a very short latency to the “on” phase.

PMID: 9358190 [PubMed - indexed for MEDLINE]

“reduced the effect without reducing plasma concentrations”? Does this mean that there is no correlation between the two?

1: N Engl J Med. 1984 Feb 23;310(8):483-8.

The “on-off” phenomenon in Parkinson’s disease. Relation to levodopa absorption
and transport.

Nutt JG, Woodward WR, Hammerstad JP, Carter JH, Anderson JL.

To determine whether the oscillating clinical response to levodopa in
Parkinson’s disease (the “on-off” phenomenon) reflects fluctuations in
absorption and transport of the drug, we investigated this phenomenon in nine
patients with an oscillating motor state. We studied the response to continuous
infusion of levodopa and the effects of meals on the plasma levodopa
concentrations and on the clinical response during oral and intravenous
administration of the drug. Meals reduced peak plasma levodopa concentrations by
29 per cent and delayed absorption by 34 minutes. Bypassing absorption by
constant infusion of the drug produced a stable clinical state lasting for 12
hours in all of six patients and for up to 36 hours in some. High-protein meals
or oral phenylalanine, leucine, or isoleucine (100 mg per kilogram of body
weight) reversed the therapeutic effect of infused levodopa without reducing
plasma levodopa concentrations. Glycine and lysine at identical doses had no
effect. We conclude that interference with absorption of levodopa by food and by
competition between large neutral amino acids and levodopa for transport from
plasma to the brain may be partly responsible for the fluctuating clinical
response in patients with Parkinson’s disease.

PMID: 6694694 [PubMed - indexed for MEDLINE]

Hormones in PD

Cortisol levels in plasma lower during day for PWP??? Runs counter to everything I have read thus far, must confirm.

1: J Neurol. 1991 Feb;238(1):19-22.

Plasma profiles of adrenocorticotropic hormone, cortisol, growth hormone and
prolactin in patients with untreated Parkinson’s disease.

Bellomo G, Santambrogio L, Fiacconi M, Scarponi AM, Ciuffetti G.

II Department of Internal Medicine, University of Perugia Medical School, Italy.

Plasma profiles of prolactin, growth hormone, adrenocorticotropic hormone (ACTH)
and cortisol were evaluated in a group of untreated patients with idiopathic
Parkinson’s disease and a group of healthy age-matched controls. Plasma
integrated concentrations of all hormones except prolactin were significantly
lower in the patients as compared with the controls; however, prolactin
nocturnal peak concentration was significantly elevated in the patients;
nocturnal growth hormone levels were significantly reduced in the Parkinson
group; ACTH and cortisol plasma concentrations were also consistently lower
during most of the day in the patients with Parkinson’s disease. These data
confirm the presence of a hypothalamic disturbance in patients with idiopathic
Parkinson’s disease, which can affect pituitary function.

PMID: 1851513 [PubMed - indexed for MEDLINE]

Milk both increases glucose problems and is linked to increased chance of PD.

1: Eur J Clin Nutr. 2001 Nov;55(11):994-9.

Milk as a supplement to mixed meals may elevate postprandial insulinaemia.

Liljeberg Elmstahl H, Bjorck I.

Department of Applied Nutrition and Food Chemistry, Center for Chemistry and
Chemical Engineering, Lund University, PO Box 124, SE-221 00 Lund, Sweden.
Helena.Elmstahl@inl.lth.se

OBJECTIVE: The objective was to evaluate the impact of milk added to a
high-glycaemic index (GI) white bread meal vs a low-GI spaghetti meal,
respectively, on postprandial glucose and insulin responses in healthy subjects.
DESIGN: The volunteers were served the bread or spaghetti meals with either milk
(200 or 400 ml, respectively) or water (400 ml) following an overnight fast.
Capillary blood samples were collected before and during 3 h after the meals.
SETTING: The study was performed at the Department of Applied Nutrition and Food
Chemistry, Lund University, Sweden. SUBJECTS: Ten healthy volunteers, seven men
and three women, aged 22-30 y, with normal body mass indices, were recruited.
RESULTS: There was no difference in postprandial glucose area under curve (AUC)
with and without added milk in the case of the high-GI bread meals. As could be
expected, glucose AUC after the bread meal+water was higher than after the
spaghetti meal+water. Milk added at 200 or 400 ml to the spaghetti meal did not
affect glucose AUC. However, a significantly higher insulin AUC was seen with
the bread meal with 400 ml milk (+65%) and the spaghetti meal with 200 ml or 400
ml milk (+300%), respectively, compared with corresponding test meal with water
CONCLUSIONS: The addition of milk to a low-GI spaghetti meal may significantly
increase the postprandial insulinaemia. Even an ordinary amount of milk (200 ml)
increased the insulin AUC to a low-GI spaghetti meal to the same level as seen
with white bread. The mechanism for the insulinotrophic effect of milk is not
known, and the potential long-term metabolic consequences need to be elucidated.
SPONSORSHIP: Swedish Dairy Association.

PMID: 11641749 [PubMed - indexed for MEDLINE]

1: Neurology. 2005 Mar 22;64(6):1047-51.

Consumption of milk and calcium in midlife and the future risk of Parkinson
disease.

Park M, Ross GW, Petrovitch H, White LR, Masaki KH, Nelson JS, Tanner CM, Curb
JD, Blanchette PL, Abbott RD.

Korea University Genomic Institute, College of Medicine, Korea University,
Ansan-Si, Republic of Korea.

OBJECTIVE: To examine the relation between milk and calcium intake in midlife
and the risk of Parkinson disease (PD). METHODS: Findings are based on dietary
intake observed from 1965 to 1968 in 7,504 men ages 45 to 68 in the Honolulu
Heart Program. Men were followed for 30 years for incident PD. RESULTS: In the
course of follow-up, 128 developed PD (7.1/10,000 person-years). Age-adjusted
incidence of PD increased with milk intake from 6.9/10,000 person-years in men
who consumed no milk to 14.9/10,000 person-years in men who consumed >16 oz/day
(p = 0.017). After further adjustment for dietary and other factors, there was a
2.3-fold excess of PD (95% CI 1.3 to 4.1) in the highest intake group (>16
oz/day) vs those who consumed no milk. The effect of milk consumption on PD was
also independent of the intake of calcium. Calcium from dairy and nondairy
sources had no apparent relation with the risk of PD. CONCLUSIONS: Findings
suggest that milk intake is associated with an increased risk of Parkinson
disease. Whether observed effects are mediated through nutrients other than
calcium or through neurotoxic contaminants warrants further study.

PMID: 15781824 [PubMed - indexed for MEDLINE]

Hypoglycemia

This article is a copy of a freely distributable article from the United States National Institutes of Health.
Carbohydrates are the main dietary source of the glucose that is manufactured in the liver and absorbed into the bloodstream to fuel the body’s cells and organs. Glucose concentration is controlled by hormones, primarily insulin and glucagon. Glucose concentration is also controlled by epinephrine (adrenalin) and norepinephrine, as well as growth hormone. If these regulators are not working properly, levels of blood sugar can become either excessive (as in hyperglycemia) or inadequate (as in hypoglycemia). If a person has a blood sugar level of 50 mg/dl or less, he or she is considered hypoglycemic, although glucose levels vary widely from one person to another.

Hypoglycemia can occur in several ways.

Ideopathic or reactive hypoglycemia (also called postprandial hypoglycemia) occurs when some people eat. A number of reasons for this reaction have been proposed, but no single cause has been identified.

In some cases, this form of hypoglycemia appears to be associated with malfunctions or diseases of the liver, pituitary, adrenals, liver, or pancreas. These conditions are unrelated to diabetes. Children intolerant of a natural sugar (fructose) or who have inherited defects that affect digestion may also experience hypoglycemic attacks. Some children with a negative reaction to aspirin also experience reactive hypoglycemia. It sometimes occurs among people with an intolerance to the sugar found in milk (galactose), and it also often begins before diabetes strikes later on.
Fasting hypoglycemia

Fasting hypoglycemia sometimes occurs after long periods without food, but it also happens occasionally following strenuous exercise, such as running in a marathon.

When carbohydrates are eaten, they are converted to glucose that goes into the bloodstream and is distributed throughout the body. Simultaneously, a combination of chemicals that regulate how our body’s cells absorb that sugar is released from the liver, pancreas, and adrenal glands. These chemical regulators include insulin, glucagon, epinephrine (adrenalin), and norepinephrine. The mixture of these regulators released following digestion of carbohydrates is never the same, since the amount of carbohydrates that are eaten is never the same.

Interactions among the regulators are complicated. Any abnormalities in the effectiveness of any one of the regulators can reduce or increase the body’s absorption of glucose. Gastrointestinal enzymes such as amylase and lactase that break down carbohydrates may not be functioning properly. These abnormalities may produce hyperglycemia or hypoglycemia, and can be detected when the level of glucose in the blood is measured.

Cell sensitivity to these regulators can be changed in many ways. Over time, a person’s stress level, exercise patterns, advancing age, and dietary habits influence cellular sensitivity. For example, a diet consistently overly rich in carbohydrates increases insulin requirements over time. Eventually, cells can become less receptive to the effects of the regulating chemicals, which can lead to glucose intolerance.

Diet is both a major factor in producing hypoglycemia as well as the primary method for
Early symptoms of severe hypoglycemia, particularly in the drug-induced type of hypoglycemia, resemble an extreme shock reaction. Symptoms include:

* cold and pale skin
* numbness around the mouth
* apprehension
* heart palpitations
* emotional outbursts
* hand tremors
* mental cloudiness
* dilated pupils
* sweating
* fainting

Mild attacks, however, are more common in reactive hypoglycemia and are characterized by extreme tiredness. Patients first lose their alertness, then their muscle strength and coordination. Thinking grows fuzzy, and finally the patient becomes so tired that he or she becomes “zombie-like,” awake but not functioning. Sometimes the patient will actually fall asleep. Unplanned naps are typical of the chronic hypoglycemic patient, particularly following meals.

Additional symptoms of reactive hypoglycemia include headaches, double vision, staggering or inability to walk, a craving for salt and/or sweets, abdominal distress, premenstrual tension, chronic colitis, allergies, ringing in the ears, unusual patterns in the frequency of urination, skin eruptions and inflammations, pain in the neck and shoulder muscles, memory problems, and sudden and excessive sweating.

Unfortunately, a number of these symptoms mimic those of other conditions. For example, the depression, insomnia, irritability, lack of concentration, crying spells, phobias, forgetfulness, confusion, unsocial behavior, and suicidal tendencies commonly seen in nervous system and psychiatric disorders may also be hypoglycemic symptoms. It is very important that anyone with symptoms that may suggest reactive hypoglycemia see a doctor.

Because all of its possible symptoms are not likely to be seen in any one person at a specific time, diagnosing hypoglycemia can be difficult. One or more of its many symptoms may be due to another illness. Symptoms may persist in a variety of forms for long periods of time. Symptoms can also change over time within the same person. Some of the factors that can influence symptoms include physical or mental activities, physical or mental state, the amount of time passed since the last meal, the amount and quality of sleep, and exercise patterns.

Diagnosis
Drug-induced hypoglycemia

Reactive hypoglycemia

Reactive hypoglycemia can only be diagnosed by a doctor. Symptoms usually improve after the patient has gone on an appropriate diet. Reactive hypoglycemia was diagnosed more frequently 10–20 years ago than today. Studies have shown that most people suffering from its symptoms test normal for blood sugar, leading many doctors to suggest that actual cases of reactive hypoglycemia are quite rare. Some doctors think that people with hypoglycemic symptoms may be particularly sensitive to the body’s normal postmeal release of the hormone epinephrine, or are actually suffering from some other physical or mental problem. Others doctors believe reactive hypoglycemia is actually the early onset of diabetes that occurs after a number of years. There continues to be disagreement about the cause of reactive hypoglycemia.

A common test to diagnose hypoglycemia is the extended oral glucose tolerance test. Following an overnight fast, a concentrated solution of glucose is drunk and blood samples are taken hourly for five to six hours. Though this test remains helpful in early identification of diabetes, its use in diagnosing chronic reactive hypoglycemia has lost favor because it can trigger hypoglycemic symptoms in people with otherwise normal glucose readings. Some doctors now recommend that blood sugar be tested at the actual time a person experiences hypoglycemic symptoms.

There are a variety of diet recommendations for the reactive hypoglycemic. Patients should:

* avoid overeating
* never skip breakfast
* include protein in all meals and snacks, preferably from sources low in fat, such as the white meat of chicken or turkey, most fish, soy products, or skim milk
* restrict intake of fats (particularly saturated fats, such as animal fats), and avoid refined sugars and processed foods
* be aware of the differences between some vegetables, such as potatoes and carrots. These vegetables have a higher sugar content than others (like squash and broccoli). Patients should be aware of these differences and note any reactions they have to them.
* be aware of differences found in grain products. White flour is a carbohydrate that is rapidly absorbed into the bloodstream, while oats take much longer to break down in the body.
* keep a “food diary.” Until the diet is stabilized, a patient should note what and how much he/she eats and drinks at every meal. If symptoms appear following a meal or snack, patients should note them and look for patterns.
* eat fresh fruits, but restrict the amount they eat at one time. Patients should remember to eat a source of protein whenever they eat high sources of carbohydrate like fruit. Apples make particularly good snacks because, of all fruits, the carbohydrate in apples is digested most slowly.
* follow a diet that is high in fiber. Fruit is a good source of fiber, as is oatmeal and oat bran, which slows the buildup of sugar in the blood during digestion.

A doctor can recommend a proper diet, and there are many cookbooks available for For all of the reasons explained in the above paragraphs, deciding whether a blood glucose in the borderline range of 45-75 mg/dl (2.5-4.2 mM) represents clinically problematic hypoglycemia is not always simple. This leads people to use different “cutoff levels” of glucose in different contexts and for different purposes.

Pathophysiology: why low blood sugar primarily affects the brain

Like most animal tissues, brain metabolism depends primarily on glucose for fuel in most circumstances. A limited amount of glucose can be derived from glycogen stored in astrocytes, but it is consumed within minutes. For most practical purposes, the brain is dependent on a continual supply of glucose diffusing from the blood into the interstitial tissue within the central nervous system and into the neurons themselves.

Therefore, if the amount of glucose supplied by the blood falls, the brain is one of the first organs affected. In most people subtle reduction of mental efficiency can be observed when the glucose falls below 65 mg/dl (3.6 mM). Impairment of action and judgement usually becomes obvious below 40 mg/dl (2.2 mM). Seizures may occur as the glucose falls further. As blood glucose levels fall below 10 mg/dl (0.55 mM), most neurons become electrically silent and nonfunctional, resulting in coma. These brain effects are collectively referred to as neuroglycopenia.

The importance of an adequate supply of glucose to the brain is apparent from the number of nervous, hormonal and metabolic responses to a falling glucose. Most of these are defensive or adaptive, tending to raise the blood sugar via glycogenolysis and gluconeogenesis or provide alternative fuels.

Brief or mild hypoglycemia produces no lasting effects on the brain, though it can majority of symptomatic hypoglycemic episodes result in no detectable permanent harm.

Signs and symptoms of hypoglycemia

Hypoglycemic symptoms and manifestations can be divided into those produced by the counterregulatory hormones (adrenaline and glucagon) triggered by the falling glucose, and the neuroglycopenic effects produced by the reduced brain sugar.

Adrenergic Manifestations

* Shakiness, anxiety, nervousness, tremor
* Palpitations, tachycardia
* Sweating, feeling of warmth
* Pallor, coldness, clamminess
* Dilated pupils

Glucagon Manifestations

* Hunger, borborygmus
* Nausea, vomiting, abdominal discomfort

Neuroglycopenic Manifestations

* Abnormal mentation, impaired judgement
* Nonspecific dysphoria, anxiety, moodiness, depression, crying, fear of dying
* Negativism, irritability, belligerence, combativeness, rage
* Personality change, emotional lability
* Fatigue, weakness, apathy, lethargy, daydreaming, sleep
* Confusion, amnesia, dizziness, delirium
* Staring, “glassy” look, blurred vision, double vision
* Automatic behavior, also known as automatism
* Difficulty speaking, slurred speech
* Ataxia, incoordination, sometimes mistaken for “drunkenness”
* Focal or general motor deficit, paralysis, hemiparesis
* Paresthesias, headache
* Stupor, coma, abnormal breathing
* Generalized or focal seizures

Not all of the above manifestations occur in every case of hypoglycemia. There is no consistent order to the appearance of the symptoms. Specific manifestations vary by age and by severity of the hypoglycemia. In young children vomiting often accompanies morning hypoglycemia with ketosis. In older children and adults, moderately severe hypoglycemia can resemble mania, mental illness, drug intoxication, or drunkenness. In the elderly, hypoglycemia can produce focal stroke-like effects or a hard-to-define malaise. The symptoms of a single person do tend to be similar from episode to episode.

In newborns, hypoglycemia can produce irritability, jitters, myoclonic jerks, cyanosis, respiratory distress, apneic episodes, sweating, hypothermia, somnolence, hypotonia, refusal to feed, and seizures or “spells”. Hypoglycemia can resemble asphyxia, hypocalcemia, sepsis, or heart failure.

In both young and old patients, the brain may habituate to low glucose levels, with a reduction of noticeable symptoms despite neuroglycopenic impairment. In insulin-dependent diabetic patients this phenomenon is termed hypoglycemia unawareness and is a significant clinical problem when improved glycemic control is attempted. Another aspect of this phenomenon occurs in type I glycogenosis, when chronic hypoglycemia before diagnosis may be better tolerated than acute hypoglycemia after treatment is underway.

Nearly always, hypoglycemia severe enough to cause seizures or unconsciousness can be blood glucose is low, hormones which raise the glucose should be rising and insulin secretion should be completely suppressed.

The following is a brief list of hormones and metabolites which may be measured in a critical sample. Not all tests are checked on every patient. A “basic version” would include insulin, cortisol, and electrolytes, with C-peptide and drug screen for adults and growth hormone in children. The value of additional specific tests depends on the most likely diagnoses for an individual patient, based on the circumstances described above. Many of these levels change within minutes, especially if glucose is given, and there is no value in measuring them after the hypoglycemia is reversed. Others, especially those lower in the list, remain abnormal even after hypoglycemia is reversed, and can be usefully measured even if a critical specimen is missed. Although interpretation in difficult cases is beyond the scope of this article, for most of the tests, the primary significance is briefly noted.

* Glucose: needed to document actual hypoglycemia
* Insulin: any detectable amount is abnormal during hypoglycemia, but physician must know assay characteristics
* Cortisol: should be high during hypoglycemia if pituitary and adrenals are functioning normally
* Growth hormone: should rise after hypoglycemia if pituitary is functioning normally
* Electrolytes and total carbon dioxide: electrolyte abnormalities may suggest renal or adrenal disease; mild acidosis is normal with starvation hypoglycemia; usually no acidosis with hyperinsulinism
* Liver enzymes: elevation suggests liver disease
* Ketones: should be high during fasting and hypoglycemia; low levels suggest hyperinsulinism or fatty acid oxidation disorder
* Beta-hydroxybutyrate: should be high during fasting and hypoglycemia; low levels suggest hyperinsulinism or fatty acid oxidation disorder
* Free fatty acids: should be high during fasting and hypoglycemia; low levels suggest hyperinsulinism; high with low ketones suggests fatty acid oxidation disorder
* Lactic acid: high levels suggest sepsis or an inborn error of gluconeogenesis such as glycogen storage disease
* Ammonia: if elevated suggests hyperinsulinism due to glutamate dehydrogenase deficiency, Reye syndrome, or certain types of liver failure
* C-peptide: should be undetectable; if elevated suggests hyperinsulinism; low c-peptide with high insulin suggests exogenous (injected) insulin
* Proinsulin: detectable levels suggest hyperinsulinism; levels disproportionate to a detectabe insulin level suggest insulinoma
* Ethanol: suggests alcohol intoxication
* Toxicology screen: can detect many drugs causing hypoglycemia, especially for sulfonylureas
* Insulin antibodies: if positive suggests repeated insulin injection or antibody-mediated hypoglycemia
* Urine organic acids: elevated in various characteristic patterns in several types of organic aciduria
* Carnitine, free and total: low in certain disorders of fatty acid metabolism and certain types of drug toxicity and pancreatic disease
* Thyroxine and TSH: low T4 without elevated TSH suggests hypopituitarism or malnutrition
* Acylglycine: elevation suggests a disorder of fatty acid oxidation
* Epinephrine: should be elevated during hypoglycemia
* Glucagon: should be elevated during hypoglycemia
* IGF-1: low levels suggest hypopituitarism or chronic malnutrition
* IGF-2: low levels suggest hypopituitarism; high levels suggest non-pancreatic tumor hypoglycemia
* ACTH: should be elevated during hypoglycemia; unusually high ACTH with low cortisol suggests Addison’s disease
* Alanine or other plasma amino acids: abnormal patterns may suggest certain inborn errors of amino acid metabolism or gluconeogenesis

Further diagnostic steps depend on the initial evidence

lifestyle changes to reduce stress. See the following section of this article.

Hypoglycemia as American folk medicine

Hypoglycemia is also a term of contemporary American folk medicine which refers to a recurrent state of symptoms of altered mood and subjective cognitive efficiency, sometimes accompanied by adrenergic symptoms, but not necessarily by measured low blood glucose. Symptoms are primarily those of altered mood, behavior, and mental efficiency. This condition is usually treated by dietary changes which range from simple to elaborate.

reactive hypoglycemia

Reactive hypoglycemia is a medical term describing recurrent episodes of symptomatic hypoglycemia occurring 2-4 hours after a high carbohydrate meal (or oral glucose load). It is thought to represent a consequence of excessive insulin release triggered by the carbohydrate meal but continuing past the digestion and disposal of the glucose derived from the meal.

The prevalence of this condition is difficult to ascertain and controversial, because a number of stricter or looser definitions have been used, and because many healthy, asymptomatic people can have glucose tolerance test patterns said to be characteristic of reactive hypoglycemia. It has been proposed that the term reactive hypoglycemia be reserved for the pattern of postprandial hypoglycemia which meets the Whipple criteria (symptoms correspond to measurably low glucose and are relieved by raising the glucose), and that the term idiopathic postprandial syndrome be used for similar patterns of symptoms where abnormally low glucose levels at the time of symptoms cannot be documented.

Common Symptoms

Although symptoms vary according to individuals’ sensitivity to the elevation and decline of glucose levels, some of the more common symptoms are:

* fatigue
* headaches
* palpitations
* depression
* nervousness
* irritability
* tremors
* flushing
* cravings for sweets
* increased appetite
* rhinitis
* sweating

Causes and Treatment

To relieve reactive hypoglycemia, some health professionals recommend taking the following steps:

* eat small meals and snacks about every 3 hours
* exercise regularly
* eat a variety of foods, including meat, poultry, fish, or nonmeat sources of protein; foods such as whole-grain bread; fruits; vegetables; and dairy products
* choose high-fiber foods
* avoid or limit foods high in sugar, especially on an empty stomach
* avoid alcohol, caffeine, highly starchy foods such as white rice, potatoes (except sweet potatoes), corn, and popcorn

Your doctor can refer you to a registered dietitian for personalized meal planning advice. Although some health professionals recommend a diet high in protein and low in carbohydrates, studies have not proven the effectiveness of this kind of diet for reactive hypoglycemia.

This article is a copy of a freely distributable article from the United States National Institutes of Health.

1: Baillieres Best Pract Res Clin Endocrinol Metab. 1999 Dec;13(4):555-65.
Chronic inflammatory stress.

Harbuz MS.
University Research Centre for Neuroendocrinology, University of Bristol, UK.

A major mechanism involved in maintaining homeostasis in response to chronic inflammation is the hypothalamo-pituitary-adrenal (HPA) axis, resulting in the release of anti-inflammatory glucocorticoids from the adrenal cortex. An inadequate HPA axis response may result in the development of a pathology or an increase in susceptibility and/or severity of disease. Other neuroendocrine systems are also implicated. Increasingly considered important are circadian rhythms, not only of hormones, but also of components of the immune system. Recent evidence concerning changes in hypothalamic control of the HPA axis following development of disease, the implication of these for the response to stress and the use of the HPA axis as a predictor of susceptibility to disease will also be considered. Finally, the influence of stress on autoimmune disease will be discussed. This chapter will concentrate principally on rheumatoid arthritis, although other autoimmune diseases and animal models will be discussed.
PMID: 10903814 [PubMed - indexed for MEDLINE]

1: Ann N Y Acad Sci. 2005 Jun;1051:787-98.
Involvement of innate immunity in the development of inflammatory and autoimmune  diseases.

Tlaskalová-Hogenová H, Tucková L, Stepánková R, Hudcovic T, Palová-Jelínková L, Kozáková H, Rossmann P, Sanchez D, Cinová J, Hrncír T, Kverka M, Frolová L, Uhlig H, Powrie F, Bland P.  Department of Immunology and Gnotobiology, Institute of Microbiology, Academy of  Sciences of the Czech Republic, 1st Faculty of Medicine, Charles University, Víde-ská 1083, Prague 4, Czech Republic. tlaskalo@biomed.cas.cz

Initial events and effector mechanisms of most inflammatory and autoimmune diseases remain largely unknown. Dysfunction of the innate and adaptive immune systems associated with mucosae (the major interface between the organism and its environment, e.g., microbiota, food) can conceivably cause impairment of mucosal  barrier function and development of localized or systemic inflammatory and autoimmune processes. Animal models help in elucidating the etiology and pathogenetic mechanisms of human diseases, such as the inflammatory bowel diseases, Crohn’s disease and ulcerative colitis, severe chronic diseases affecting the gut. To study the role of innate immunity and gut microbiota in intestinal inflammation, colitis was induced by dextran sulfate sodium (DSS) in mice with severe combined immunodeficiency (SCID). Conventionally reared (microflora-colonized) SCID mice displayed severe inflammation like that seen in  immunocompetent Balb/c mice, whereas only minor changes appeared in the intestinal mucosa of DSS-fed gnotobiotic germ-free SCID mice. The presence of microflora facilitates the inflammation in DSS-induced colitis that develops in immunodeficient SCID mice, that is, in the absence of T and B lymphocytes. Celiac disease, a chronic autoimmune small bowel disorder, afflicts genetically susceptible individuals with wheat gluten intolerance. We showed that, in contrast with any other food proteins, wheat gliadin and its peptic fragments activate mouse macrophages and human monocytes to produce proinflammatory cytokines through the nuclear factor-kappaB signaling pathway. Activation of innate immunity cells by food proteins or components from gut microbiota thus could participate in the impairment of intestinal mucosa and the development of intestinal and/or systemic inflammation.

PMID: 16127016 [PubMed - indexed for MEDLINE]

1. FASEB J. 2005 Apr;19(6):533-42.  Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease.

Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, Wilson B, Zhang W, Zhou Y, Hong JS, Zhang J.  Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina, USA.

A growing body of evidence indicates that an inflammatory process in the substantia nigra, characterized by activation of resident microglia, likely either initiates or aggravates nigral neurodegeneration in Parkinson’s disease (PD). To study the mechanisms by which nigral microglia are activated in PD, the  potential role of alpha-synuclein (a major component of Lewy bodies that can cause neurodegeneration when aggregated) in microglial activation was investigated. The results demonstrated that in a primary mesencephalic neuron-glia culture system, extracellular aggregated human alpha-synuclein indeed activated microglia; microglial activation enhanced dopaminergic neurodegeneration induced by aggregated alpha-synuclein. Furthermore, microglial  enhancement of alpha-synuclein-mediated neurotoxicity depended on phagocytosis of alpha-synuclein and activation of NADPH oxidase with production of reactive oxygen species. These results suggest that nigral neuronal damage, regardless of  etiology, may release aggregated alpha-synuclein into substantia nigra, which activates microglia with production of proinflammatory mediators, thereby leading to persistent and progressive nigral neurodegeneration in PD. Finally, NADPH oxidase could be an ideal target for potential pharmaceutical intervention, given that it plays a critical role in alpha-synuclein-mediated microglial activation and associated neurotoxicity.  PMID: 15791003 [PubMed - indexed for MEDLINE]

I have not posted for a bit but am very much alive with a great deal still to be said. I have been on an involuntary voyage of exploration and discovery that has included stops at stress, periodic paralysis, potassium, vitamin D, hyperthyroidism, and various other ports of call.

While I will have to allow the details to filter in with time, I will try to begin the process with this post. Do remember, however, that the experience is still being processed and research is ongoing.

The story begins with stress, the least appreciated of the foundations of Parkinson’s Disease. Between the Thanksgiving and Christmas holidays a “perfect storm” began to build as currents from life, money, health, family, etc. all converged on Ground Zero – yours truly.

As the new year advanced the pressures increased until by early Spring cognition began to slip. At least, that is the only explanation that I can offer for the final actions that sent me spiraling away for a few weeks. For any Tolkien fans out there, I held my breath and jumped into the Abyss with the Balrog and have returned clad in white. For those who need an interpreter, I made a major mistake, recovered, and have figured some things out that I will share as they develop.

The mistake lay in deciding that it was time to have a patch of pine trees removed from around my home. They had gotten to a stage where they were falling more and more and were increasingly dangerous. And so, a local contractor began to remove them, one by one. There were about three acres of them and my house was near the center. The job was expected to take two weeks but weather stretched it to seven. Seven weeks of hell.

The crew of four, in addition to chainsaws and other mundane tools, depended very much on a sort of modified bulldozer called a “skidder”. The skidder was what moved the logs around. It emitted a deep, low rumble of a sound that, because of the weight and solid contact with the ground, penetrated deep into the bones which seemed to then vibrate as well.

This rich spectrum of sound frequencies dropped below the levels that the human can normally hear and into the range called “subsonic”. Subsonic sound is very powerful and not normally encountered in nature. One of the few places that our ancestor’s would encounter it is in the roar of a big cat, such as a tiger, as it sprang. The subsonic portion of the roar triggers a brief paralysis and the tiger dines.

So, my inner reptile found itself trapped in my house as the roar of predators came from all directions. Fight or flight triggers were pulled again and again until one evening I found myself curled like a fetus in the floor unable to move even enough to open my eyes. And, while this state passed in about an hour’s time, I had an opportunity to think. In fact, I had several such opportunities.  I will take up my tale again from this point.

But I would like to point out something here. In nature, subsonics are rare and are always a sign of great danger. In modern society, they are common. But the primitive part of our brain has no reason to see them as benign.

In fact, they can be deadly as studies of populations living near airports, for example, have shown. Is it possible that there is a role for this in the maladies of our modern society? (to be continued)

Botanical Phenolics and Brain Health ; Sun et al, 2009

This is a review of the research on treating PD and similar disorders by means of the use of the complex chemicals produced by plants. It provides numerous links to specific studies and deserves a bookmark.

Note- If links have not carried over properly, the original post complete with working links is at

http://parkinsonsonline.org/blog1/?p=666

_____________________________________________

…its main catechin polyphenol constituent (-)-epigallocatechin-3-gallate has been shown to exert neuroprotective/neurorescue activities in a wide array of cellular and animal models of neurological disorders.  (Mandel 2008) PMID: 18641210

The results of the study demonstrated that GTE significantly attenuated LPS-induced sickness behavior as well as hepatic damage either by its antioxidant activity or by inhibiting LPS induced cytokine production in rats.  (Singal 2006) PMID: 16444665

Microglial activation is believed to play a pivotal role in the selective neuronal injury associated with several neurodegenerative disorders, including Parkinson’s disease (PD) and Alzheimer’s disease. We provide evidence that (-)-epigallocatechin gallate (EGCG), a major monomer of green tea polyphenols, potently inhibits lipopolysaccharide (LPS)-activated microglial secretion of nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha)  (Li 2004) PMID: 15478178

tea drinking may decrease the incidence of dementia, AD and Parkinson’s disease. In particular, its main catechin polyphenol constituent (-)-epigallocatechin-3-gallate (EGCG) has been shown to exert neuroprotective/neurorescue activities in a wide array of cellular and animal models of neurological disorders.  (Mandel 2008) PMID: 18953110

The neuronal activity of dopaminergic neurons is closely linked to dopamine release. When neurons switch from a single-spike firing to bursts of action potentials, the release of dopamine increases. The above experimental results suggest that EGCG increases the neuronal activity…  (Park 2007) PMID: 17174286

…pretreatment with L-theanine significantly attenuated the down-regulation of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) production in SH-SY5Y cells. These results suggest that L-theanine directly provide neuroprotection against PD-related neurotoxicants….  (Cho 2008) PMID: 18452993

The B-vitamins, including vitamins B12, B6, B1, B2, niacin (B3) and folate (B9), have been implicated as protective risk factors against cognitive decline and Alzheimer’s disease. (Morris 2006) PMID: 16917152

Raised plasma total homocysteine is a strong prognostic marker of future cognitive decline, and is common in world populations. Low-normal concentrations of the B vitamins, the main determinant of homocysteine concentrations, are also common and occur in particularly vulnerable sections of the population, such as infants and elderly.  (Smith 2008) PMID: 18709889

Elevated plasma homocysteine (Hcy) concentrations have been reported in L-dopa treated Parkinson’s disease (PD) patients, suggesting that L-dopa treatment is an acquired cause of hyperhomocysteinemia.  (Zoccolella 2005) PMID: 15734674

Analysis of data revealed that Hcy levels were higher in L-dopa treated PD patients when compared with age- and sex-matched controls and that supplementation of the diet with cobalamin and folate is effective in reducing Hcy concentrations  (Lamberti 2005) PMID: 15804266

Elevated concentration of total homocysteine (Hcy) in plasma (> 12 micromol/l) is a risk factor for several diseases of the central nervous system. Epidemiological studies have shown a dose-dependent relationship between concentrations of Hcy and the risk for neurodegenerative diseases. Hcy is a marker for B-vitamin deficiency (folate, B12, B6).  (Herrmann 2007) PMID: 17729191

Vitamin B12 deficiency is an important nutritional disorder causing neurological manifestations of myelopathy, neuropathy and dementia. Sub-acute combined degeneration (SCD) with involvement of the posterior columns in the cervical and thoracic cord is a common presentation of this disorder.  (Puntambekkar 2009)  PMID: 19720386

PubMed Search: “Parkinson’s” + “Vitamin B”

In addition to the various toxins, problems arise over nutrient competition and absorption issues, B-vitamins in particular. And, of particular interest to me, it produces ammonia in its neutralizing of stomach acid. Ammonia goes to the liver which can get overloaded. When that happens, the ammonia can make it to the brain and that is very bad news, as we shall see.

We propose that IP is a systemic disorder resulting from a ubiquitous peripheral infection, and that only the tip of the iceberg comes to diagnosis. There is evidence for inflammatory/immune activation peripherally and in the brain.

The apparent importance of H. pylori in the etiology/pathogenesis of idiopathic parkinsonism is not confined to those with evidence of current infection.

Marked reversibility in both cachexia and disability of idiopathic parkinsonism followed Helicobacter heilmannii eradication in one case, Helicobacter pylori eradication in another, follow-up being > or = 3.5 years.

We challenge the concept of idiopathic parkinsonism (IP) as inevitably progressive neurodegeneration, proposing a natural history of sequential microbial insults with predisposing host response.

Chronic hepatic encephalopathy is a neuropsychiatric disorder with protean manifestations, the pathogenesis of which is poorly understood.2 It is generally under-diagnosed because, in most patients, the condition is subclinical….

Hepatic encephalopathy has been linked to H. pylori infection because of the ammonia produced by the organism in the stomach.

Among the plants that killed H. pylori, turmeric was the most efficient, followed by cumin, ginger, chilli, borage, black caraway, oregano and liquorice. Moreover, extracts of turmeric, borage and parsley were able to inhibit the adhesion of H. pylori strains to the stomach sections.

In particular, green tea extract (GTE) showed the strongest inhibition of H. pylori urease

EGCG pretreatment showed significant cytoprotective effects against H. pylori-induced gastric cytotoxicity via interference of the TLR-4 signaling induced by H. pylori. Thus, our result implies that continuous intakes of green tea could prevent the deleterious consequences of H. pylori infection.

B Vitamins and PD

Green Tea Extract

Helicobacter pylori