Diabetes Mellitus, Insulin Sensitivity and Alpha-Lipoic Acid

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Diabetes Mellitus, Insulin Sensitivity and Alpha-Lipoic Acid

http://www.vitasearch.com/CP/experts/PKamenovaAT04-24-07.htm

Petya Kamenova, M.D., Ph.D.

Department of Diabetology

University Hospital of Endocrinology

Medical University

Sofia, Bulgaria

+359888343952 / +35929874145 (FAX)

kamenovap@...

" Improvement of Insulin Sensitivity in Patients with Type 2 Diabetes

Mellitus

After Oral Administration of Alpha-lipoic Acid, "

Hormones (Athens), 2006; 5(4): 251-8. 45077 (6/2007)

Kirk Hamilton: Can you please share with us your educational

background and current position?

Petya Kamenova: I graduated from the Medical Academy, Sofia,

Bulgaria and I received the qualification of Medical Doctor in 1984. I

have been working as an assistant after passing the relevant examination

at the Department of Diabetology, University Hospital of Endocrinology,

Medical University, Sofia since 1985. I am a specialist of internal

diseases, and endocrinology and metabolism diseases. My activities

include treatment of patients with diabetes mellitus and endocrine

diseases; practical teaching of medical students, trainee-doctors and

specializing physicians in the field of diabetes mellitus and

endocrinology; and research activities with main topics on treatment of

type 2 diabetes mellitus, novel agents, insulin resistance and metabolic

syndrome. In 2004 I defended my dissertation ”Insulin Sensitivity and

Cardiovascular Risk Factors in Type 2 Diabetes Mellitus” and earned my

PhD degree. My current position is an Assistant Professor at the

Department of Diabetology, University Hospital of Endocrinology

(currently named University Specialized Hospital for active treatment in

Endocrinology “Acad.Iv. Penchev”).

KH: What got you interested in studying the role of alpha-lipoic acid

(ALA) and insulin resistance?

PK: My interest on studying the role of alpha-lipoic acid (ALA) and

insulin resistance was

based on the significant importance of treating insulin resistance as a

major pathogenic factor of type 2 diabetes mellitus and as a

cardiovascular risk factor, in order to achieve good glycemic control

and improve the cardiovascular prognosis of patients with type 2

diabetes. I established that patients treated with ALA for diabetic

polyneuropathy, were getting better glycemic control without changing

the dose of insulin or oral hypoglycemic drugs and with no influence on

endogenous insulin secretion. Consequently, the better glycemic control

could be from improving insulin sensitivity.

KH: What is the biochemistry of ALA that might effect insulin

resistance positively?

PK: Like biological antioxidants and free radical scavengers, ALA

can enhance insulin sensitivity via reducing oxidative stress and

improving endothelial function and blood flow to the skeletal muscles,

which represent the major site of insulin resistance. Experimental data,

however, has shown a direct effect of ALA on insulin sensitivity,

affecting the insulin signaling pathway. Several potential mechanisms

have been discussed to explain the positive effect of ALA on insulin

resistance: stimulation of the tyrosine phosphorylation of the insulin

receptor; activation of two important molecules of insulin signaling -

pathway-insulin-receptor substrate-1 (IRS-1) protein and

phosphatidylinositol 3-kinase (PI 3-kinase) with subsequent enhancement

of glucose uptake via the glucose transport system, inducing

redistribution and activation of glucose transporters (GLUT1 and GLUT4)

on the plasma membrane; and increasing both glucose oxidation and

glycogen synthesis. Clinical studies have confirmed experimental data

regarding the direct effect of ALA on insulin resistance since this

effect has not been associated with change in fasting plasma insulin,

body mass index and has been independent of glycemic control.

KH: Where did you come up with a dose of ALA of 600 mg twice daily?

Was the ALA given with meals or away from meals?

PK: I came up with a dose of ALA of 600 mg twice daily because

improvement in insulin sensitivity has been reported by acute parenteral

administration of 600 mg and 1000 mg and chronic parenteral

administration of 500 mg for 10 days. Data about the effect of oral

administration of ALA on insulin sensitivity were not convincing. Oral

administration of ALA (600 mg twice daily for 4 weeks) has been

associated with an increase in insulin sensitivity defined by

intravenous glucose tolerance testing (minimal model analysis) in lean

type 2 diabetic patients. On the other hand a 4-week oral ALA treatment

at varying doses - 600 mg, 1200 mg and 1800 mg has not resulted in

significant increases in insulin sensitivity. ALA was given 30 minutes

before meals, because of the interaction with food, one 600 mg tablet in

the morning and the other in the evening, with a time interval of 12 h

apart over a 4 week period.

KH: Can you tell us about your study and the basic results?

PK: Having in mind the treatment strategy of type 2 diabetes

mellitus to reduce cardiovascular risk, the aim of the study was to

assess the effect of oral administration of alpha-lipoic acid on insulin

sensitivity in patients with type 2 diabetes mellitus. Well controlled

on diet and metformin patients and subjects with normal glucose

tolerance, served as controls in terms of insulin sensitivity, took part

in an open label study. Insulin sensitivity was measured with the gold

standard-manual hyperinsulinemic euglycemic clamp technique, expressed

as a glucose disposal rate (M), and insulin sensitivity index (ISI),

before and after a 4- week period of ALA treatment, and in controls. At

study entry, insulin sensitivity, expressed as a glucose disposal rate

(M) and ISI in the diabetic patients was significantly lower compared to

that of the control subjects. A 4-week treatment with ALA significantly

improved glucose utilization in type 2 diabetic patients. M and ISI were

remarkably enhanced by 85.9 % and 63 %, respectively. After 1200 mg/day

of ALA administration, there was no significant difference in insulin

sensitivity between type 2 diabetic patients and the control subjects.

Body mass index, systolic and diastolic blood pressure, serum lipids and

uric acid were not affected by the treatment.

KH: Were there any side effects to the ALA?

PK: ALA was well tolerated and no adverse effects were observed.

Only one patient treated with 3 tablets of Metformin (850mg) experienced

mild hypoglycemia. There were no changes in biochemical parameters as well.

KH: How might ALA be used clinically? For short-term use or long-term

use?

PK: According to the results of this study, a-4-week treatment of

ALA improved insulin sensitivity, measured with the most accurate method

- hyperinsulinemic euglycemic clamp technique. I have not observed side

effects in longer ALA treatment for diabetic polyneuropathy in my

clinical practice. Bearing in mind the good tolerability of the drug, in

my opinion, it could be used for long term as well.

KH: Is there any way to assess for the functional need of ALA?

PK: Alpha-lipoic acid is synthesized by the liver and exists as two

different enantiomers: the biologically active ® - isomer and the (S)

- isomer, which is part of a synthetic racemic mixture, but is found

minimally in biological tissues. In this study the patients were treated

with ALA - a synthetic racemic mixture, and I could say according to the

results, that a dose of 1200 mg/ day improved insulin sensitivity.

KH: Do you have any further comments you would like to make regarding

this interesting topic?

PK: In my opinion, the results of this study and some other

pre-clinical and clinical studies, encourage further research and reveal

a new perspective of alpha-lipoic acid in the complex treatment strategy

of type 2 diabetes mellitus which is beyond it’s use in the treatment of

diabetic polyneuropathy.

--

ne Holden, MS, RD < fivestar@... >

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