These authors suggest that the glucagonostatic and insulinotropic effects of GLP-1 equally contribute to its hypoglycemic efficacy
These authors suggest that the glucagonostatic and insulinotropic effects of GLP-1 equally contribute to its hypoglycemic efficacy. of glucagon secretion and its participation in T2D pathogenesis are summarized. role of insulin signaling in the modulation of alpha-cell function was provided by the conditional alpha-cell specific insulin receptor knock-out (IRKO) mice, which exhibited up to 50% higher glucose levels compared to control animals in the fed state, as well as hyperglucagonemia . Unger and Orci  have recently introduced the term paracrinopathy to designate the loss of tonic restraint normally exerted by a high local concentration of insulin on alpha-cells; beta-cell destruction and beta-cell failure to secrete the first phase of insulin associated with alpha-cells insulin resistance would be the main mechanistic factors in type 1 and type 2 diabetes, respectively. Besides the lack of inhibitory tone exerted by insulin on glucagon release, other mechanisms have been investigated to explain the inappropriate increased alpha-cell function in T2D. Motivated by the findings of some studies showing that T2D patients, in contrast to their improper glucagon response to oral glucose, are able to suppress glucagon release after an isoglycemic intravenous glucose infusion (IIGI) similarly to nondiabetic subjects, Lund et al. evaluated the role of GIP, GLP-1 and glucagon-like peptide-2 (GLP-2) in this discrepant response. Therefore, plasmatic glucagon concentrations were measured during a 3-h, 50-g oral glucose BETd-260 overload or an IIGI in ten T2D patients; four additional IIGI were performed in which GIP, GLP-1, GLP-2 or a combination of the three were intravenously infused. While no suppression of glucagon was observed during the initial phase BETd-260 of the oral glucose overload, significantly lower plasmatic concentrations of this hormone were observed during the first 30?min of the IIGI. The glucagon response during the IIGI performed with infusion of GIP?+?GLP-1?+?GLP-2 was inappropriate and mimicked the one observed after the oral glucose overload; infusion of GIP alone promoted significant hypersecretion of glucagon, whereas infusion of GLP-1 alone enhanced glucagon suppression during the IIGI. These authors suggested that the improper hyperglucagonemic response to oral glucose could be dependent on the release of the intestinal hormones, especially GIP, which seems to play an important role in this pathophysiological feature . In the pathophysiology of T2D a disbalance in beta-to-alpha-cell ratio, mainly due to beta-cell apoptosis, has also been suggested as a mechanism contributing to a decreased insulin-to-glucagon ratio. However, a new possible mechanism has been put forward in an animal model, suggesting that, under stress demand, beta-cell dedifferentiation to progenitor pluripotent cells takes place. These cells may begin to express, and eventually Rabbit Polyclonal to TAZ release, glucagon and somatostatin , further contributing to decreased insulin-to-glucagon ratio. Addressing glucagon in T2D treatment Unger and Cherrington  have proposed BETd-260 a glucagonocentric vision of diabetes pathophysiology, and their arguments for defending this point of view include the following facts: glucagon augments the catabolic processes occurring BETd-260 in the absence of insulin; hyperglucagonemia is present in all forms of poorly controlled diabetes and leptin and somatostatin, known glucagon suppressors, abrogate the catabolic manifestations of diabetes during total insulin deficiency. Perhaps the most astonishing fact had been the finding that glucagon receptorCnull mice do not develop diabetes following complete beta-cell destruction . More recently, Omar et al. suggested that the explanation for the absence of hyperglycemia in this mice model may not only be the lack of glucagon effects, but also the presence of high concentrations of fibroblast growth factor 21 (FGF-21) and GLP-1 exhibited by these mice. They demonstrated that the concurrently neutralization of FGF-21 (with a FGF-21 antibody) and GLP-1 (with its antagonist Exendin 9C39) actions resulted in hyperglycemia in those insulin.