Studies showed that resveratrol increased life span in lower organisms by activating the NAD
(+)-dependent histone deacetylase Sirt1. And, it was found that that resveratrol promoted longevity and
improved glucose homeostasis in mice by stimulating the Sirt1-mediated deacetylation of the
transcriptional coactivator PGC-1alpha. [7] Researchers are interested to diabetes. The following is a
summary of a few interesting research studies about the potential benefits of resveratrol on chronic
diseases, such as diabetes.

In 2001, Naderali EK and co-workers from University of Liverpool found resveratrol (5-35 micromol/l)
induced concentration-dependent relaxation of mesenteric arteries preconstricted with noradrenaline (8
micromol/l) or KCl (125 mmol/l) from both lean and dietary-obese rats. [1]

Hyperglycemia, a symptom of diabetes mellitus, induces hyperosmotic responses, including apoptosis, in
vascular endothelial cells and leukocytes. Hyperosmotic shock elicits a stress response in mammalian
cells, often leading to apoptotic cell death. Moreover, resveratrol was found to attenuate high
glucose-induced apoptotic changes by virtue of its antioxidant property. [2]

Diabetic nephropathy is a serious vascular complication and one of the main causes of end-stage renal
disease. Increased oxidative stress plays an important role in the etiology of diabetic nephropathy. In a
study, researchers found treatment with resveratrol significantly attenuated renal dysfunction and
oxidative stress in diabetic rats. [3]

Most of type 2 diabetes mellitus patients eventually become insulin dependent because insulin secretion
by the islets of Langerhans becomes exhausted. In the present study, researchers from Chang Gung
University, Taiwan, showed that resveratrol (3,5,4'-trihydroxylstilbene) possesses hypoglycemic and
hypolipidemic effects in streptozotocin-induced diabetes rats. In resveratrol-treated diabetic rats, the
plasma glucose concentration on day 14 was reduced by 25.3%, and the triglyceride concentration was
reduced by 50.2% compared with the placebo-treated rats. In nicotinamide-treated diabetic rats, the
plasma glucose oncentration on day 14 was reduced only by 20.3 %, and the triglyceride concentration
was reduced by 33 %. Resveratrol administration ameliorates common DM symptoms, such as body
weight loss, polyphagia, and polydipsia. In STZ-nicotinamide DM rats, resveratrol administration
significantly decreased insulin secretion and delayed the onset of insulin resistance. [4]

Usually, diabetic rats exhibited a significant thermal hyperalgesia and cold allodynia along with increased
plasma glucose and decreased body weights. Allodynia means other pain. It is a painful response to a
usually non-painful stimulus. Hyperalgesia is an increased sensitivity to pain, which may be caused by
damage to nociceptors or peripheral nerves. [Wikipedia] Sharma S and co-workers from Panjab
University, India, reported treatment with resveratrol (10mg/kg orally) from week 4 to week 6 significantly
attenuated the cold allodynia and thermal hyperalgesia, suggesting the application of resveratrol in
diabetes, especially for diabetic neuropathy. [5]

Researchers, at Boston University Medical Center, revealed inactivation of hepatic AMP-activated protein
kinase was a key event in the pathogenesis of hyperlipidemia in diabetes (based on a study of in type 1
diabetic LDL receptor-deficient mice). They showed that resveratrol could lower lipid levels by activating
AMP-activated protein kinase. It was about 200 times the potency of Metformin! [6]

Recent Research Studies of Resveratrol on Diabetes

Schmatz R and co-workers from Universidade Federal de Santa Maria, Brazil, found that treatment with
resveratrol prevented the increase in acetylcholinesterase activity and consequently memory impairment
in diabetic rats. [8]

Palsamy P and other India researchers found daily oral treatment of resveratrol to diabetic rats for 30
days demonstrated a significant decline in blood glucose and glycosylated hemoglobin levels and a
significant increase in plasma insulin level. The administration of resveratrol also reverted the altered
activities of the key enzymes of carbohydrate metabolism such as hexokinase, pyruvate kinase, lactate
dehydrogenase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glucose-6-phosphate
dehydrogenase, glycogen synthase and glycogen phosphorylase in liver and kidney tissues of diabetic
rats to near normal levels. [9]

Researchers from New York Medical College observed that resveratrol increased mitochondrial mass and
mtDNA content, up-regulated protein expression of electron transport chain constituents and induced
mitochondrial biogenesis factors (PGC-1alpha, Nrf-1, Tfam) in cultured human coronary arterial
endothelial cells. They found resveratrol treatment normalized impaired mitochondrial biogenesis in aortas
of type 2 diabetic mice. This suggests the potential benefits of resveratrol on diabetes or metabolic
diseases. [10]

Researchers from Dortmund University of Technology, Germany, observed that resveratrol could inhibit
the formation of islet amyloid polypeptide (IAPP) fibril. Following preferential partitioning of IAPP into the
fluid lipid phase, the membrane of beta-cells suffered irreversible damage and predominantly
circularly-shaped lipid-containing IAPP amyloid was formed. Deposition of amyloid in the extracellular
matrix of beta-cells commonly occurs in type II diabetes mellitus. Thus, resveratrol may benefit animals
suffered from diabetes. [11]

Rodella LF and co-workers from University of Brescia, Italy, found resveratrol and cobalt protoporphyrin
administration increased heme oxygenase-1 protein expression and heme oxygenase activity in the aorta
and significantly increased serum adiponectin levels, compared to untreated diabetic rats. Increased
heme oxygenase-1 expression usually improves vascular function. [12]

Resveratrol decreased blood glucose, glycosylated hemoglobin, blood urea, serum uric acid, serum
creatinine and diminished activities of pathophysiological enzymes such as aspartate transaminase (AST),
alanine transaminase (ALT) and alkaline phosphatase (ALP) in diabetic rats after 30 days of treatment.

The prevalence of nonalcoholic fatty liver disease is high.nonalcoholic fatty liver disease is linked to
obesity, diabetes mellitus, and hypertriglyceridemia. Approximately 20% of patients with nonalcoholic fatty
liver disease will eventually develop cirrhosis. Resveratrol was found to decrease nonalcoholic fatty liver
disease severity in rats. This effect was mediated, at least in part, by tumor necrosis factor alpha
(TNF-alpha) inhibition and antioxidant activities. [14]

Resveratrol Benefits and Side Effects
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[1] Naderali EK, Smith SL, Doyle PJ, Williams G. The mechanism of resveratrol-induced vasorelaxation differs in the mesenteric resistance arteries of lean and obese rats. Clin Sci (Lond). 2001
Jan;100(1):55-60. [2] Chan WH. Effect of resveratrol on high glucose-induced stress in human leukemia K562 cells. J Cell Biochem. 2005 Apr 15;94(6):1267-79. [3] Sharma S, Anjaneyulu M, Kulkarni
SK, Chopra K. Resveratrol, a polyphenolic phytoalexin, attenuates diabetic nephropathy in rats. Pharmacology. 2006;76(2):69-75. Epub 2005 Nov 11. [4] Su HC, Hung LM, Chen JK. Resveratrol, a red
wine antioxidant, possesses an insulin-like effect in streptozotocin-induced diabetic rats. Am J Physiol Endocrinol Metab. 2006 Jun;290(6):E1339-46. Epub 2006 Jan 24. [5] Sharma S, Kulkarni SK,
Chopra K. Resveratrol, a polyphenolic phytoalexin attenuates thermal hyperalgesia and cold allodynia in STZ-induced diabetic rats. Indian J Exp Biol. 2006 Jul;44(7):566-9. [6] Zang M, Xu S,
Maitland-Toolan KA, Zuccollo A, Hou X, Jiang B, Wierzbicki M, Verbeuren TJ, Cohen RA. Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in
diabetic LDL receptor-deficient mice. Diabetes. 2006 Aug;55(8):2180-91. [7] Koo SH, Montminy M. In vino veritas: a tale of two sirt1s? Cell. 2006 Dec 15;127(6):1109-22. [8] Schmatz R, Mazzanti CM,
Spanevello R, Stefanello N, Gutierres J, Corrêa M, da Rosa MM, Rubin MA, Chitolina Schetinger MR, Morsch VM. Resveratrol prevents memory deficits and the increase in acetylcholinesterase
activity in streptozotocin-induced diabetic rats. Eur J Pharmacol. 2009 May 21;610(1-3):42-8. Epub 2009 Mar 19. [9] Palsamy P, Subramanian S. Modulatory effects of resveratrol on attenuating the key
enzymes activities of carbohydrate metabolism in streptozotocin-nicotinamide-induced diabetic rats. Chem Biol Interact. 2009 May 15;179(2-3):356-62. Epub 2008 Nov 19. [10] Csiszar A, Labinskyy
N, Pinto JT, Ballabh P, Zhang H, Losonczy G, Pearson KJ, de Cabo R, Pacher P, Zhang C, Ungvari ZI. Resveratrol induces mitochondrial biogenesis in endothelial cells. Am J Physiol Heart Circ
Physiol. 2009 May 8. [11] Radovan D, Opitz N, Winter R. Fluorescence microscopy studies on islet amyloid polypeptide fibrillation at heterogeneous and cellular membrane interfaces and its inhibition
by resveratrol. FEBS Lett. 2009 May 6;583(9):1439-45. Epub 2009 Apr 2. [12] Rodella LF, Vanella L, Peterson SJ, Drummond G, Rezzani R, Falck JR, Abraham NG. Heme oxygenase-derived carbon
monoxide restores vascular function in type 1 diabetes. Drug Metab Lett. 2008 Dec;2(4):290-300. [13] Palsamy P, Subramanian S. Resveratrol, a natural phytoalexin, normalizes hyperglycemia in
streptozotocin-nicotinamide induced experimental diabetic rats. Biomed Pharmacother. 2008 Nov;62(9):598-605. Epub 2008 Jul 9. [14] Bujanda L, Hijona E, Larzabal M, Beraza M, Aldazabal P,
García-Urkia N, Sarasqueta C, Cosme A, Irastorza B, González A, Arenas JI Jr. Resveratrol inhibits nonalcoholic fatty liver disease in rats. BMC Gastroenterol. 2008 Sep 9;8:40.
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