Long-term AICAR administration and exercise prevents diabetes in ZDF rats.

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-beta-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, pre-diabetic 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 beta-cell morphology was almost normal in the exercised and AICAR-treated animals, indicating that chronic AMPK activation in vivo might preserve beta-cell function. Our results suggest that activation of AMPK may represent a therapeutic approach to improve insulin action and prevent a decrease in beta-cell function associated with type 2 diabetes.

Evidence against a role for insulin-signaling proteins PI 3-kinase and Akt in insulin resistance in human skeletal muscle induced by short-term GH infusion.

Prolonged growth hormone (GH) excess is known to be associated with insulin resistance, but the underlying mechanisms remain unknown. The aim of this study was to assess the impact of GH on insulin-stimulated glucose metabolism and insulin signaling in human skeletal muscle. In a cross-over design, eight healthy male subjects (age 26.0 +/- 0.8 yr and body mass index 24.1 +/- 0.5 kg/m2) were infused for 360 min with either GH (Norditropin, 45 ng.kg(-1).min(-1)) or saline. During the final 180 min of the infusion, a hyperinsulinemic euglycemic clamp was performed (insulin infusion rate: 1.2 mU.kg(-1).min(-1)). Muscle biopsies from vastus lateralis were taken before GH/saline administration and after 60 min of hyperinsulinemia. GLUT4 content and insulin signaling, as assessed by insulin receptor substrate (IRS)-1-associated phosphatidylinositol 3-kinase and Akt activity were determined. GH levels increased to a mean (+/-SE) level of 20.0 +/- 2.3 vs. 0.5 +/- 0.2 microg/l after saline infusion (P < 0.01). During GH infusion, the glucose infusion rate during hyperinsulinemia was reduced by 38% (P < 0.01). In both conditions, free fatty acids were markedly suppressed during hyperinsulinemia. Despite skeletal muscle insulin resistance, insulin still induced a similar approximately 3-fold rise in IRS-1-associated PI 3-kinase activity (269 +/- 105 and 311 +/- 71% compared with baseline, GH vs. saline). GH infusion did not change Akt protein expression, and insulin caused an approximately 13-fold increase in Akt activity (1,309 +/- 327 and 1,287 +/- 173%) after both GH and saline infusion. No difference in total GLUT4 content was noted (114.7 +/- 7.4 and 107.6 +/- 16.7 arbitrary units, GH vs. saline, compared with baseline). In conclusion, insulin resistance in skeletal muscle induced by short-term GH administration is not associated with detectable changes in the upstream insulin-signaling cascade or reduction in total GLUT4. Yet unknown mechanisms in insulin signaling downstream of Akt may be responsible.

Effects of AICAR and exercise on insulin-stimulated glucose uptake, signaling, and GLUT-4 content in rat muscles.

Physical activity is known to increase insulin action in skeletal muscle, and data have indicated that 5'-AMP-activated protein kinase (AMPK) is involved in the molecular mechanisms behind this beneficial effect. 5-Aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) can be used as a pharmacological tool to repetitively activate AMPK, and the objective of this study was to explore whether the increase in insulin-stimulated glucose uptake after either long-term exercise or chronic AICAR administration was followed by fiber-type-specific changes in insulin signaling and/or changes in GLUT-4 expression. Wistar rats were allocated into three groups: an exercise group trained on treadmill for 5 days, an AICAR group exposed to daily subcutaneous injections of AICAR, and a sedentary control group. AMPK activity, insulin-stimulated glucose transport, insulin signaling, and GLUT-4 expression were determined in muscles characterized by different fiber type compositions. Both exercised and AICAR-injected animals displayed a fiber-type-specific increase in glucose transport with the most marked increase in muscles with a high content of type IIb fibers. This increase was accompanied by a concomitant increase in GLUT-4 expression. Insulin signaling as assessed by phosphatidylinositol 3-kinase and PKB/Akt activity was enhanced only after AICAR administration and in a non-fiber-type-specific manner. In conclusion, chronic AICAR administration and long-term exercise both improve insulin-stimulated glucose transport in skeletal muscle in a fiber-type-specific way, and this is associated with an increase in GLUT-4 content.