Long-Term AICAR Administration Reduces Metabolic Disturbances and Lowers Blood Pressure in Rats Displaying Features of the Insulin Resistance Syndrome

Buhl, Esben S.; Jessen, Niels; Pold, Rasmus; Ledet, Thomas; Flyvbjerg, Allan; Pedersen, Steen; Pedersen, Oluf; Schmitz, O.; Lund, Sten

doi:10.2337/diabetes.51.7.2199

Cited by 221 publications

(188 citation statements)

References 45 publications

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“…This is an important finding, in view of the fact that long-term exposure to other AMPK activators, such as AICAR, produces a moderate increase in the liver weight of animals [35,36] that has been considered a potential side-effect of this kind of molecule, and which has not been observed in the chronic treatment with resveratrol.…”

Section: Discussionmentioning

confidence: 79%

Long-term resveratrol administration reduces metabolic disturbances and lowers blood pressure in obese Zucker rats

Rivera

Morón

Zarzuelo

et al. 2009

Biochemical Pharmacology

355

251

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Section: Discussionmentioning

confidence: 79%

Long-term resveratrol administration reduces metabolic disturbances and lowers blood pressure in obese Zucker rats

Rivera

Morón

Zarzuelo

et al. 2009

Biochemical Pharmacology

355

251

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“…These studies demonstrate that AMPK activation by AICAR stimulates glucose uptake [2-4, 6, 7] and inhibits hepatic glucose output [5] in an insulin-independent manner. In obese and/or insulin-resistant rodent models, glucose tolerance is improved after long-term AICAR administration [10][11][12]. Ex vivo studies in human skeletal muscle tissue samples have yielded similar results, demonstrating that AICAR increases glucose transport [13] and fatty acid oxidation [14], which is accompanied by an increase in AMPK phosphorylation and/or activity [13,14] and ACC phosphorylation [13,14].…”

Section: Discussionmentioning

confidence: 82%

“…Importantly, AMPK regulates these processes in an insulin-independent manner. The AMPK pathway appears largely intact in obese and/or type 2 diabetic rodents [3,[9][10][11][12] and humans [5,[13][14][15][16]. Consequently, AMPK is regarded as a potential target for the treatment of type 2 diabetes.…”

Section: Introductionmentioning

confidence: 99%

Intravenous AICAR administration reduces hepatic glucose output and inhibits whole body lipolysis in type 2 diabetic patients

et al. 2008

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Aims/hypothesis The 5′-AMP-activated protein kinase (AMPK) pathway is intact in type 2 diabetic patients and is seen as a target for diabetes treatment. In this study, we aimed to assess the impact of the AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR) on both glucose and fatty acid metabolism in vivo in type 2 diabetic patients.Methods Stable isotope methodology and blood and muscle biopsy sampling were applied to assess blood glucose and fatty acid kinetics following continuous i.v. infusion of AICAR (0.75 mg kg −1 min −1 ) and/or NaCl (0.9%) in ten male type 2 diabetic patients (age 64±2 years; BMI 28±1 kg/m 2 ). Results Plasma glucose rate of appearance (R a ) was reduced following AICAR administration, while plasma glucose rate of disappearance (R d ) was similar in the AICAR and control test. Consequently, blood glucose disposal (R d expressed as a percentage of R a ) was increased following AICAR infusion (p<0.001). Accordingly, a greater decline in plasma glucose concentration was observed following AICAR infusion (p<0.001). Plasma NEFA R a and R d were both significantly reduced in response to AICAR infusion, and were accompanied by a significant decline in plasma NEFA concentration. Although AMPK phosphorylation in skeletal muscle was not increased, we observed a significant increase in acetyl-CoA carboxylase phosphorylation (p<0.001). Conclusions/interpretation The i.v. administration of AICAR reduces hepatic glucose output, thereby lowering blood glucose concentrations in vivo in type 2 diabetic patients. Furthermore, AICAR administration stimulates hepatic fatty acid oxidation and/or inhibits whole body lipolysis, thereby reducing plasma NEFA concentration.

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“…33,34 Serum insulin level of 16-week-ZL rats (2.39 ng/ml) was significantly higher than that of ZDF, similar as reported previously in 12-to 16-week-ZL rats. [35][36][37] Serum insulin level of 16-week-ZF rats (6.30 ng/ml) was significantly higher than both ZDF and ZL rats. [38][39][40] The abnormally lower serum insulin level in ZDF rats is closely related to H 2 S metabolism.…”

Section: Discussionmentioning

confidence: 99%

Pancreatic islet overproduction of H2S and suppressed insulin release in Zucker diabetic rats

Yang

Jia

et al. 2009

Laboratory Investigation

199

156

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Hydrogen sulfide (H 2 S) has been traditionally known for its toxic effects on living organisms. The role of H 2 S in the homeostatic regulation of pancreatic insulin metabolism has been unclear. The present study is aimed at elucidating the effect of endogenously produced H 2 S on pancreatic insulin release and its role in diabetes development. Diabetes development in Zucker diabetic fatty (ZDF) rats was evaluated in comparison with Zucker fatty (ZF) and Zucker lean (ZL) rats. Pancreatic H 2 S production and insulin release were also assayed. It was found that H 2 S was generated in rat pancreas islets, catalyzed predominantly by cystathionine g-lyase (CSE). Pancreatic CSE expression and H 2 S production were greater in ZDF rats than in ZF or ZL rats. ZDF rats exhibited reduced serum insulin level, hyperglycemia, and insulin resistance. Inhibition of pancreatic H 2 S production in ZDF rats by intraperitoneal injection of DL-propargylglycine (PPG) for 4 weeks increased serum insulin level, lowered hyperglycemia, and reduced hemoglobin A1c level (Po0.05). Although in ZF rats it also reduced pancreatic H 2 S production and serum H 2 S level, PPG treatment did not alter serum insulin and glucose level. Finally, H 2 S significantly increased K ATP channel activity in freshly isolated rat pancreatic b-cells. It appears that insulin release is impaired in ZDF because of abnormally high pancreatic production of H 2 S. New therapeutic approach for diabetes management can be devised based on our observation by inhibiting endogenous H 2 S production from pancreas. KEYWORDS: diabetes; hydrogen sulfide; insulin release; K ATP channel; pancreas; type 2 diabetes mellitus Known as a swamp gas or 'rotten egg' gas, hydrogen sulfide (H 2 S) has yielded a public image of air pollutant for centuries. Physiological importance of H 2 S as a gasotransmitter has been realized for less than a decade. Endogenous production of H 2 S from L-cysteine is catalyzed by cystathionine b-synthase (CBS) and/or cystathionine g-lyase (CSE) with ammonium and pyruvate as co-products. 1 This process occurs in different organs and tissues, such as neuronal, vascular, and intestinal tissues. 2 Physiological concentrations of circulating H 2 S have been reported in the range of 45-300 mM. 1 At this physiological range, exogenous H 2 S has been shown to relax different vascular tissues, including isolated rat aortae and perfused mesenteric artery bed. 3-5 Altered cell proliferation or apoptosis induced by H 2 S has also been widely reported. [6][7][8][9][10] Endogenous production and physiological function of H 2 S in pancreas have been studied with identification of both CBS and CSE in rat pancreatic tissues or cloned rat pancreatic b-cell line. 11,12 In recent years, pathophysiological implications of the CSE/H 2 S system in diabetes have been reported. 12 CSE mRNA expression and H 2 S formation in rat pancreas was significantly increased after diabetes induction by streptozotocin injection. 12 CBS expression was reported in pancreatic acinar cells. 13 Y...

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Long-Term AICAR Administration Reduces Metabolic Disturbances and Lowers Blood Pressure in Rats Displaying Features of the Insulin Resistance Syndrome

Cited by 221 publications

References 45 publications

Long-term resveratrol administration reduces metabolic disturbances and lowers blood pressure in obese Zucker rats

Long-term resveratrol administration reduces metabolic disturbances and lowers blood pressure in obese Zucker rats

Intravenous AICAR administration reduces hepatic glucose output and inhibits whole body lipolysis in type 2 diabetic patients

Pancreatic islet overproduction of H2S and suppressed insulin release in Zucker diabetic rats

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