Long-Term AICAR Administration and Exercise Prevents Diabetes in ZDF Rats

Abstract

Lifestyle interventions including exercise programs are cornerstones in the prevention of obesity-related diabetes. The AMP-activated protein kinase (AMPK) has been proposed to be responsible for many of the beneficial effects of exercise on glucose and lipid metabolism. The effects of long-term exercise training or 5-aminoimidazole-4-carboxamide-1-␤-D-riboruranoside (AICAR) treatment, both known AMPK activators, on the development of diabetes in male Zucker diabetic fatty (ZDF) rats were examined. Five-week-old, prediabetic ZDF rats underwent daily treadmill running or AICAR treatment over an 8-week period and were compared with an untreated group. In contrast to the untreated, both the exercised and AICAR-treated rats did not develop hyperglycemia during the intervention period. Whole-body insulin sensitivity, as assessed by a hyperinsulinemic-euglycemic clamp at the end of the intervention period, was markedly increased in the exercised and AICAR-treated animals compared with the untreated ZDF rats (P < 0.01). In addition, pancreatic ␤-cell morphology was almost normal in the exercised and AICAR-treated animals, indicating that chronic AMPK activation in vivo might preserve ␤-cell function. Our results suggest that activation of AMPK may represent a therapeutic approach to improve insulin action and prevent a decrease in ␤-cell function associated with type 2 diabetes. Diabetes 54:928 -934, 2005

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

“…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].…”

“…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.…”

Endurance Training Activates Pancreatic Islets Amp-Activated Kinase-Uncoupling Protein 2 Pathway and Reduces Insulin Secretion

“…According to this proposal, treatment with AICAR prevented hyperinsulinemia and preserved b-cell mass in fat Zucker rats (Pold et al 2005). In contrast, it was also demonstrated that AICAR activation of AMPK in isolated b-cells increased apoptosis (Kefas et al 2003), whereas AMPK inhibition protected b-cell toxicity and apoptosis (Riboulet-Chavey et al 2008).…”

The anti-diabetic AMPK activator AICAR reduces IL-6 and IL-8 in human adipose tissue and skeletal muscle cells

“…Chronic treatment of obese rodents with AICAR has been shown to improve insulin sensitivity, reduce blood pressure, improve lipid profiles, and prevent the development of diabetes (Buhl et al, 2002;Pold et al, 2005;Yu et al, 2004). Thus, stimulation of the AMPK by AICAR seems to ameliorate several of the clinical features of the metabolic syndrome.…”