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GLP-1 (9-36)amide is the cleavage product of GLP-1(7-36) amide, formed by the action of diaminopeptidyl peptidase-4 (Dpp4), and is the major circulating form in plasma. Whereas GLP-1(7-36)amide stimulates glucose-dependent insulin secretion, GLP-1(9-36)amide has only weak partial insulinotropic agonist activities on the GLP-1 receptor, but suppresses hepatic glucose production, exerts antioxidant cardioprotective actions and reduces oxidative stress in vasculature tissues. These insulin-like activities suggest a role for GLP-1 (9-36)amide in the modulation of mitochondrial functions by mechanisms independent of the GLP-1 receptor. In this paper, we discuss the current literature suggesting that GLP-1(9-36)amide is an active peptide with important insulin-like actions. These findings have implications in nutrient assimilation, energy homeostasis, obesity, and the use of Dpp4 inhibitors for the treatment of diabetes., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)

Exercise improves insulin sensitivity. As AMP-activated protein kinase (AMPK) plays an important role in muscle metabolism during exercise, we investigated the effects of the AMPK activator 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) on insulin action in insulin-resistant high-fat-fed (HF) rats. Rats received a subcutaneous injection of 250 mg/kg AICAR (HF-AIC) or saline (HF-Con). The next day, euglycemic-hyperinsulinemic clamp studies were performed. Glucose infusion rate during the clamp was enhanced (50%) in HF-AIC compared with HF-Con rats. Insulin-stimulated glucose uptake was improved in white but not in red quadriceps, whereas glycogen synthesis was improved in both red and white quadriceps of HF-AIC rats. HF-AIC rats also showed increased insulin suppressibility of hepatic glucose output (HGO). AICAR-induced responses in both liver and muscle were accompanied by reduced malonyl-CoA content. Clamp HGO correlated closely with hepatic triglyceride content (r = 0.67, P < 0.01). Thus, a single dose of AICAR leads to an apparent enhancement in whole-body, muscle, and liver insulin action in HF rats that extends beyond the expected time of AMPK activation. Whether altered tissue lipid metabolism mediates AICAR effects on insulin action remains to be determined. Follow-up studies suggest that at least some of the post-AICAR insulin-enhancing effects also occur in normal rats. Independent of this, the results suggest that pharmacological activation of AMPK may have potential in treating insulin-resistant states and type 2 diabetes.

FGF21 is a key metabolic regulator modulating physiological processes and its pharmacological administration improves metabolic profile in preclinical species and humans. We used native-FGF21 and a long-acting FGF21 (PF-05231023), to determine the contribution of liver and brown adipose tissue (BAT) towards metabolic improvements in Zucker rats and DIO mice (DIOs). FGF21 improved glucose tolerance and liver insulin sensitivity in Zuckers without affecting BW and improved liver function by decreased lipogenesis, increased fatty acid oxidation and improved insulin signaling. Through detailed lipidomic analyses of liver metabolites in DIOs, we demonstrate that FGF21 favorably alters liver metabolism. We observed a dose-dependent increase of [18F]-FDG-glucose uptake in interscapular BAT (iBAT) of DIOs upon FGF21 administration. Upon excision of iBAT (X-BAT) and administration of FGF21 to mice housed at 80 °F or 72 °F, the favorable effects of FGF21 on BW and glucose excursion were fully retained in both sham and X-BAT animals. Taken together, we demonstrate the liver as an organ that integrates the actions of FGF21 and provide metabolic benefits of FGF21 in Zucker rats and DIOs. Finally, our data demonstrates iBAT does not play a role in mediating favorable metabolic effects of FGF21 administration in DIOs housed at 80 °F or 72 °F. [ABSTRACT FROM AUTHOR]