Glucagon – the new ‘insulin’ in the pathophysiology of diabetes

Abstract

Purpose of review Autoimmune destruction of the b cells is considered the key abnormality in type 1 diabetes mellitus and insulin replacement the primary therapeutic strategy. However, a lack of insulin is accompanied by disturbances in glucagon release, which is excessive postprandially, but insufficient during hypoglycaemia. In addition, replacing insulin alone appears insufficient for adequate glucose control. This review focuses on the growing body of evidence that glucagon abnormalities contribute significantly to the pathophysiology of diabetes and on recent efforts to target the glucagon axis as adjunctive therapy to insulin replacement. Recent findingsThis review discusses recent (since 2013) advances in abnormalities of glucagon regulation and their link to the pathophysiology of diabetes; new mechanisms of glucagon action and regulation; manipulation of glucagon in diabetes treatment; and analytical and systems biology tools to study glucagon regulation. SummaryRecent efforts 'resurrected' glucagon as a key hormone in the pathophysiology of diabetes. New studies target its abnormal regulation and action that is key for improving diabetes treatment. The progress is promising, but major questions remain, including unravelling the mechanism of loss of glucagon counterregulation in type 1 diabetes mellitus and how best to manipulate glucagon to achieve more efficient and safer glycaemic control. adequate glucose control. Thus, recent efforts have been focused on manipulating glucagon either alone or as adjunctive therapy to insulin replacement. This work reviews recent advances in abnormal glucagon regulation and its link to the pathophysiology of diabetes; novel mechanisms of glucagon action and regulation; glucagon manipulation in diabetes treatment; and analytical and systems biology tools to study glucagon regulation.

The feedback cycles between glucose, amino acids and lipids and alpha cell secretion and their role in metabolic fatty liver disease

“…Glucagon contributes to hyperglycemia in diabetes by increasing hepatic glucose output, and antagonizing glucagon's actions has been an appealing strategy to reduce glycemia [7,8]. Indeed, glucagon receptor antagonists lower blood glucose in clinical and experimental diabetes [9,10], and deletion of the gene for glucagon or the glucagon receptor, globally or liver-specific, results in slightly lower blood glucose levels in mice [11][12][13].…”

The feedback cycles between glucose, amino acids and lipids and alpha cell secretion and their role in metabolic fatty liver disease

“…Glucagon contributes to hyperglycemia in diabetes by increasing hepatic glucose output, and antagonizing glucagon's actions has been an appealing strategy to reduce glycemia [7,8]. Indeed, glucagon receptor antagonists lower blood glucose in clinical and experimental diabetes [9,10], and deletion of the gene for glucagon or the glucagon receptor, globally or liver-specific, results in slightly lower blood glucose levels in mice [11][12][13].…”

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.…”

Tripartite cell networks for glucose homeostasis

“…Furthermore, some diabetic patients show abnormally high concentrations of insulin in the blood, insulinaemia, since more insulin is required to stimulate desensitized insulin receptors undergoing insulin resistance. In addition, a paradoxically high concentration of glucagon in the blood, glucagonaemia, is also observed in hyperglycaemia under diabetes [167][168][169]. However, beyond the absolute levels of physiological quantities, rhythmic processes and their synchronization must have additional information in physiology [170].…”

“…However, later research became insulin-centric with an emphasis on β cells. Nevertheless, the importance of the balance between insulin and glucagon or a glucagonocentric view has been continuously mentioned with the abnormal functions of α cells in diabetes [167][168][169][184][185][186]. Recently, islet biologists have resumed emphasizing the role of δ cells in glucose control [187][188][189], which was reported 40 years ago [190,191].…”

The feedback cycles between glucose, amino acids and lipids and alpha cell secretion and their role in metabolic fatty liver disease

“…Glucagon contributes to hyperglycemia in diabetes by increasing hepatic glucose output, and antagonizing glucagon's actions has been an appealing strategy to reduce glycemia [7,8]. Indeed, glucagon receptor antagonists lower blood glucose in clinical and experimental diabetes [9,10], and deletion of the gene for glucagon or the glucagon receptor, globally or liver-specific, results in slightly lower blood glucose levels in mice [11][12][13].…”

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.…”

Tripartite cell networks for glucose homeostasis

“…Furthermore, some diabetic patients show abnormally high concentrations of insulin in the blood, insulinaemia, since more insulin is required to stimulate desensitized insulin receptors undergoing insulin resistance. In addition, a paradoxically high concentration of glucagon in the blood, glucagonaemia, is also observed in hyperglycaemia under diabetes [167][168][169]. However, beyond the absolute levels of physiological quantities, rhythmic processes and their synchronization must have additional information in physiology [170].…”

“…However, later research became insulin-centric with an emphasis on β cells. Nevertheless, the importance of the balance between insulin and glucagon or a glucagonocentric view has been continuously mentioned with the abnormal functions of α cells in diabetes [167][168][169][184][185][186]. Recently, islet biologists have resumed emphasizing the role of δ cells in glucose control [187][188][189], which was reported 40 years ago [190,191].…”

The feedback cycles between glucose, amino acids and lipids and alpha cell secretion and their role in metabolic fatty liver disease

“…Glucagon contributes to hyperglycemia in diabetes by increasing hepatic glucose output, and antagonizing glucagon's actions has been an appealing strategy to reduce glycemia [7,8]. Indeed, glucagon receptor antagonists lower blood glucose in clinical and experimental diabetes [9,10], and deletion of the gene for glucagon or the glucagon receptor, globally or liver-specific, results in slightly lower blood glucose levels in mice [11][12][13].…”

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.…”

Tripartite cell networks for glucose homeostasis

“…Furthermore, some diabetic patients show abnormally high concentrations of insulin in the blood, insulinaemia, since more insulin is required to stimulate desensitized insulin receptors undergoing insulin resistance. In addition, a paradoxically high concentration of glucagon in the blood, glucagonaemia, is also observed in hyperglycaemia under diabetes [167][168][169]. However, beyond the absolute levels of physiological quantities, rhythmic processes and their synchronization must have additional information in physiology [170].…”

“…However, later research became insulin-centric with an emphasis on β cells. Nevertheless, the importance of the balance between insulin and glucagon or a glucagonocentric view has been continuously mentioned with the abnormal functions of α cells in diabetes [167][168][169][184][185][186]. Recently, islet biologists have resumed emphasizing the role of δ cells in glucose control [187][188][189], which was reported 40 years ago [190,191].…”