Glucagon is the key factor in the development of diabetes

Abstract

Glucagon plays important roles in normal glucose homeostasis and in metabolic abnormalities, particularly diabetes. Glucagon excess, rather than insulin deficiency, is essential for the development of diabetes for several reasons. Glucagon increases hepatic glucose and ketone production, the catabolic features of insulin deficiency. Hyperglucagonaemia is present in every form of diabetes. Beta cell destruction in glucagon receptor null mice does not cause diabetes unless mice are administered adenovirus encoding the glucagon receptor. In rodent studies the glucagon suppressors leptin and glucagon receptor antibody suppressed all catabolic manifestations of diabetes during insulin deficiency. Insulin prevents hyperglycaemia; however, insulin monotherapy cannot cure diabetes such that non-diabetic glucose homeostasis is achieved. Glucoseresponsive beta cells normally regulate alpha cells, and diminished insulin action on alpha cells will favour hypersecretion of glucagon by the alpha cells, thus altering the insulin:glucagon ratio. Treating diabetes by suppression of glucagon, with leptin or antibody against the glucagon receptor, normalised glucose level (without glycaemic volatility) and HbA 1c . Glucagon suppression also improved insulin sensitivity and glucose tolerance. If these results can be translated to humans, suppression of glucagon action will represent a step forward in the treatment of diabetes. This review summarises a presentation given at the 'Novel data on glucagon' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by

Chronic fractalkine administration improves glucose tolerance and pancreatic endocrine function

“…Moreover, in vitro incubation of primary mouse islets with FKN suppressed low-glucose-induced glucagon release, without interfering insulin effects ( Figure 5A). Since insulin suppresses α cell glucagon release (30,31), we hypothesized that FKN treatment could decrease glucagon release from α cells, contributing to the improved glucose tolerance (6). Surprisingly, FKN also directly suppressed glucagon release in αTC1 mouse α cells ( Figure 5B), raising the possibility that FKN can act on α cells to inhibit glucagon secretion.…”

“…One component of insulin's action to suppress postprandial hyperglycemia is to counteract the effects of glucagon (5,6). In T2DM, insulin resistance potentiates α cell glucagon secretion and hepatic glucagon action, which stimulates hepatic glucose production (7,8).…”

“…Chronic fractalkine administration improves glucose tolerance and pancreatic endocrine function Matthew Riopel, 1 Jong Bae Seo, 1,2 Gautam K. Bandyopadhyay, 1 Pingping Li, 1,3 Joshua Wollam, 1 Heekyung Chung, 1 Seung-Ryoung Jung, 2 Anne Murphy, 4 Maria Wilson, 5 Ron de Jong, 5 Sanjay Patel, 5 Deepika Balakrishna, 5 James Bilakovics, 5 Andrea Fanjul, 5 Artur Plonowski, 5 Duk-Su Koh, 2 Christopher J. Larson, 5,6 Jerrold M. Olefsky, 1 and Yun Sok Lee glucose tolerance in HFD WT mice ( Figure 1G), but not in HFD CX3CR1-KO mice ( Figure 1H), showing that these beneficial effects of FKN-Fc are CX3CR1-dependent. Interestingly, chronic FKN-Fc administration decreased fasting plasma insulin level ( Figure 1I), similarly to what has been reported in chronic GLP-1 analog-treated animals (29).…”

Anti-Obesity Therapy: from Rainbow Pills to Polyagonists

“…Subsequent studies showed that somatostatin-induced inhibition of postprandial glucagon secretion ameliorates hyperglycemia in patients with T2D (Gerich et al, 1974;Dinneen et al, 1995;Shah et al, 2000), and more recently that blocking glucagon action decreases hyperglycemia in a variety of species, including rodents (Mu et al, 2011;Kim et al, 2012b;Okamoto et al, 2017), rabbits (Brand et al, 1996), dogs (Rivera et al, 2007), nonhuman primates (Xiong et al, 2012;Okamoto et al, 2015), and humans (Petersen and Sullivan, 2001;Kelly et al, 2015;van Dongen et al, 2015;Kazda et al, 2016;Kostic et al, 2018). The virtues and limitations of antagonizing glucagon signaling for the treatment of diabetes have recently been highlighted in several review articles (Unger and Cherrington, 2012;Farhy and McCall, 2015;Lee et al, 2016b;Müller et al, 2017), with the implication that excess glucagon action can serve a greater role in the pathology of T2D than impaired insulin action (Unger and Cherrington, 2012). In summary, there is substantial evidence directing inhibition of glucagon action as opposed to enhancing it for the treatment of T2D.…”

Hyperlipidemia-Induced MicroRNA-155-5p Improves β-Cell Function by TargetingMafb

“…[180][181][182] Hence, Mir155 knockout may lead to elevated plasma glucose levels in Ldlr -/-mice due to its effects on insulin and glucagon production in islets. Although chronic HFD feeding results in obesity and insulinresistance, the short-term effects of HFD feeding include enhanced β-cell proliferation and hyperinsulinemia.…”