GLP-1 (9–36) Amide Metabolite Suppression of Glucose Production in Isolated Mouse Hepatocytes

Abstract

The glucoincretin hormone glucagon-like peptide-1 (GLP-1) augments glucose-stimulated insulin secretion and is in use as an effective treatment for diabetes. However, after its secretion from the intestine, the insulinotropic GLP-1 (7-36) amide hormone is rapidly inactivated by enzymatic cleavage by the diaminopeptidyl peptidase-4 giving rise to GLP-1 (9-36) amide. Inasmuch as most of the circulating GLP-1 is in the form of the metabolite GLP-1 (9-36) amide it has been suggested that it has insulin-like actions on peripheral insulin-sensitive tissues. In earlier studies, infusions of GLP-1 (9-36) amide in obese insulin-resistant subjects showed a marked suppression of hepatic glucose production. However, it remained uncertain whether the effects on glucose production were due to direct effects on hepatocytes, involved central or portal vein-mediated actions, or were mediated by insulin secretion. Here we show that GLP-1 (9-36) amide directly suppresses glucose production in isolated mouse hepatocytes ex vivo independent of the GLP-1 receptor. These findings support direct insulinomimetic actions of the GLP-1 metabolite on gluconeogenesis in hepatocytes that are independent of insulin action and the GLP-1 receptor, and suggest that GLP-1 (9-36) amide-based peptides might present a novel therapy for the treatment of excessive hepatic glucose production in individuals with insulin-resistant diabetes.

The peptide-hormone glucagon-like peptide-1 activates cAMP and inhibits growth of breast cancer cells

“…GLP-1R is not expressed in fat tissue, but treatment with GLP-1 elicited insulinomimentic effects in 3T3-L1 cells, and exendin-(9-39) enhanced the effect [27]. GLP-1(9-36) amide, a GLP-1 cleaved product, directly suppressed glucose production in isolated mouse hepatocytes ex vivo independent of the GLP-1R, an effect augmented by exendin-(9-39) [43]. Finally, we have recently shown that treatment of human primary liver cultures (negative to GLP-1R) with exendin-4 increased cell proliferation and enhanced PDX-1-induced liver to pancreas trans-differentiation process [44].…”

Infliximab treatment prevents hyperglycemia and the intensification of hepatic gluconeogenesis in an animal model of high fat diet-induced liver glucose overproduction

“…Since in situ perfused livers reflected the in vivo conditions of the animal immediately before the liver isolation (Galende et al 2009;OliveiraYamashita et al, 2009) and considering that mice treated with a HFD were a suitable experimental model to induce the liver glucose overproduction (Tomas et al 2010;Wu et al 2010), this experimental approach was used. As showed by Table 1, the treatment with infliximab prevented the glucose overproduction during the infusion of L-alanine in the liver from HFD mice (p<0.05: HFD + Infliximab vs. HFD + Saline).…”

“…However, metformin shows several adverse effects, including nausea, vomiting, diarrhea, flatulence (Florez et al 2010) and is contraindicated in conditions that could increase the risk of lactic acidosis, including kidney disorders, lung disease and liver disease (Friesecke et al 2010). Considering that except metformin there are only a few pharmacological alternatives to reduce the liver glucose overproduction (ADA 2010;Tomas et al 2010), the development of new drugs, which influences this metabolic process must be investigated. In this context, the anti-TNF-alpha monoclonal antibody infliximab showed beneficial effects not only for the diseases such as rheumatoid arthritis, Crohn's disease, and psoriatic arthritis (Karampetsou et al 2010) but also for type 2 diabetic patients (Ursini 2009;Ursini et al 2010;Yazdani-Biuki et al 2006).…”

Pharmacological Effects of EGLP-1, a Novel Analog of Glucagon-Like Peptide-1, on Carbohydrate and Lipid Metabolism

“…These results indicated that EGLP-1 reduced blood glucose by improving the function of β-cells. It has been reported that GLP-1 possesses a number of anti-diabetic actions, including glucose-dependent insulin secretion (insulinotropic action) dependent on GLP-1R [9] and an insulin-like (insulinomimetic) action independent on GLP-1R [38][39][40][41] in addition to its insulinotropic action. This suggests that EGLP-1 may have a new role in improving β-cell function independently of GLP-1R.…”