Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage

Abstract

Intestinal glucagon-like peptide-1 (GLP-1) is a hormone released into the hepatoportal circulation that stimulates pancreatic insulin secretion. GLP-1 also acts as a neuropeptide to control food intake and cardiovascular functions, but its neural role in glucose homeostasis is unknown. We show that brain GLP-1 controlled wholebody glucose fate during hyperglycemic conditions. In mice undergoing a hyperglycemic hyperinsulinemic clamp, icv administration of the specific GLP-1 receptor antagonist exendin 9-39 (Ex9) increased muscle glucose utilization and glycogen content. This effect did not require muscle insulin action, as it also occurred in muscle insulin receptor KO mice. Conversely, icv infusion of the GLP-1 receptor agonist exendin 4 (Ex4) reduced insulin-stimulated muscle glucose utilization. In hyperglycemia achieved by i.v. infusion of glucose, icv Ex4, but not Ex9, caused a 4-fold increase in insulin secretion and enhanced liver glycogen storage. However, when glucose was infused intragastrically, icv Ex9 infusion lowered insulin secretion and hepatic glycogen levels, whereas no effects of icv Ex4 were observed. In diabetic mice fed a high-fat diet, a 1-month chronic i.p. Ex9 treatment improved glucose tolerance and fasting glycemia. Our data show that during hyperglycemia, brain GLP-1 inhibited muscle glucose utilization and increased insulin secretion to favor hepatic glycogen stores, preparing efficiently for the next fasting state.

The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men

“…Studies in two MODY genotypes, HNF-1α/β (also known as HNF1A/B), have reported differential effects of HNF-1β and HNF-1α on hepatic insulin sensitivity, with normal plasma glucagon levels and unaffected peripheral insulin sensitivity, and it has been proposed that the site of defect is located in the regulation of insulin action by HNF-1β and its effect on gluconeogenesis [36]. Intra-cerebral administration of a GLP-1 receptor agonist caused a fourfold increase in insulin secretion and enhanced liver glycogen storage in mice [37]. It remains to be determined whether TCF7L2 exerts a direct or indirect (via the central nervous system) influence on hepatic gluconeogenesis, glycogenolysis and/or glycogen synthesis, explaining its effect on EGP in the basal state as well as during insulin infusion.…”

Metabolic Endotoxemia Initiates Obesity and Insulin Resistance

“…The pumps were filled either with NaCl (0.9%) or LPS (from Escherichia coli 055:B5; Sigma, St. Louis, MO) to infuse 300 g ⅐ kg Ϫ1 ⅐ day Ϫ1 for 4 weeks. For the clamp studies, an intrafemoral catheter was indwelled as previously described (18). Insulin sensitivity was assessed by the euglycemic-hyperinsulinemic clamp as described (19).…”

Coenzyme Q10 supplementation lowers hepatic oxidative stress and inflammation associated with diet-induced obesity in mice

“…An oral glucose tolerance test was performed 7 weeks after the beginning of the feeding period [7,28,29]. Six-hour-fasted mice received an oral load of glucose (Fluka, Buchs, Switzerland) of 3 g/kg body wt with a 660 g/l glucose solution.…”