Glucose kinetics: an update and novel insights into its regulation by glucagon and GLP-1

Purpose of review Glucagon and GLP-1 share the same origin (i.e., proglucagon); primarily GLP-1 is generated from intestinal L-cells and glucagon from pancreatic &agr;-cell, but intestinal glucagon and pancreatic GLP-1 secretion is likely. Glucose kinetics are tightly regulated by pancreatic hormones insulin and glucagon, but other hormones, including glucagon-like peptide-1 (GLP-1), also play an important role. The purpose of this review is to describe the recent findings on the mechanisms by which these two hormones regulate glucose kinetics. Recent findings Recent findings showed new important mechanisms of action of glucagon and GLP-1 in the regulation of glucose metabolism. Knock out of glucagon receptors protects against hyperglycemia without causing hypoglycemia. GLP-1 not only stimulates insulin secretion, but it has also an independent effect on the liver and inhibits glucose production. Moreover, when coinfused with glucagon, GLP-1 limits the hyperglycemic effects. Both hormones have also central effects on gastric emptying (delayed), intestinal motility (reduced), and satiety (increased). Summary The implications of these findings are very important for the management of type 2 diabetes given that GLP-1 receptor agonist are currently approved for the treatment of hyperglycemia and glucagon receptor antagonists and GLP-1/glucagon dual agonists are under development.

[1]  R. Bergman,et al.  Hepatic portal vein denervation impairs oral glucose tolerance but not exenatide's effect on glycemia. , 2014, American journal of physiology. Endocrinology and metabolism.

[2]  A. Pocai.  Action and therapeutic potential of oxyntomodulin , 2013, Molecular metabolism.

[3]  N. Martin,et al.  Glucagon and GLP-1 inhibit food intake and increase c-fos expression in similar appetite regulating centres in the brainstem and amygdala , 2013, International Journal of Obesity.

[4]  A. Gastaldelli,et al.  Albiglutide for the treatment of type 2 diabetes. , 2014, Drugs of today.

[5]  M. Christensen,et al.  Glucagon and Type 2 Diabetes: the Return of the Alpha Cell , 2014, Current Diabetes Reports.

[6]  Rachel M. Brown,et al.  Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study , 2016, The Lancet.

[7]  G. Marchesini,et al.  Time for Glucagon like peptide-1 receptor agonists treatment for patients with NAFLD? , 2016, Journal of hepatology.

[8]  F. Rubino,et al.  Short-term Effects of Laparoscopic Adjustable Gastric Banding Versus Roux-en-Y Gastric Bypass , 2016, Diabetes Care.

[9]  H. Soni,et al.  Peptide-based GLP-1/glucagon co-agonists: A double-edged sword to combat diabesity. , 2016, Medical hypotheses.

[10]  R. Rizza,et al.  Pathogenesis of prediabetes: role of the liver in isolated fasting hyperglycemia and combined fasting and postprandial hyperglycemia. , 2013, The Journal of clinical endocrinology and metabolism.

[11]  D. D’Alessio,et al.  Mechanisms of surgical control of type 2 diabetes: GLP-1 is the key factor-Maybe. , 2016, Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery.

[12]  M. J. Charron,et al.  Hypothalamic glucagon signaling inhibits hepatic glucose production , 2013, Nature Medicine.

[13]  J. Holst,et al.  Insulin and Glucagon: Partners for Life , 2017, Endocrinology.

[14]  M. Birnbaum,et al.  Glucagon: acute actions on hepatic metabolism , 2016, Diabetologia.

[15]  E. Chambers,et al.  Coinfusion of Low-Dose GLP-1 and Glucagon in Man Results in a Reduction in Food Intake , 2014, Diabetes.

[16]  J. Holst,et al.  The biology of glucagon and the consequences of hyperglucagonemia. , 2016, Biomarkers in medicine.

[17]  I. Sporea,et al.  Bidirectional Relationship between Gastric Emptying and Plasma Glucose Control in Normoglycemic Individuals and Diabetic Patients , 2018, Journal of diabetes research.

[18]  Yan Jin,et al.  Anti-hyperglycemic and anti-hyperlipidemia effects of the alkaloid-rich extract from barks of Litsea glutinosa in ob/ob mice , 2018, Scientific Reports.

[19]  J. Holst,et al.  Glucagon-like Peptide-1 and the Central/Peripheral Nervous System: Crosstalk in Diabetes , 2017, Trends in Endocrinology & Metabolism.

[20]  J. Holst.  Enteroendocrine secretion of gut hormones in diabetes, obesity and after bariatric surgery. , 2013, Current opinion in pharmacology.

[21]  J. Holst,et al.  Acute disruption of glucagon secretion or action does not improve glucose tolerance in an insulin-deficient mouse model of diabetes , 2016, Diabetologia.

[22]  J. Romijn,et al.  Insulin resistance in obesity can be reliably identified from fasting plasma insulin , 2015, International Journal of Obesity.

[23]  T. Hansen,et al.  Insulin Resistance Is Accompanied by Increased Fasting Glucagon and Delayed Glucagon Suppression in Individuals With Normal and Impaired Glucose Regulation , 2016, Diabetes.

[24]  John B Buse,et al.  Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. , 2016, The New England journal of medicine.

[25]  J. Holst,et al.  Long-Term Effects of Bariatric Surgery on Meal Disposal and β-Cell Function in Diabetic and Nondiabetic Patients , 2013, Diabetes.

[26]  B. Ahrén.  Glucagon – Early breakthroughs and recent discoveries , 2015, Peptides.

[27]  R. DeFronzo,et al.  The disposition index does not reflect β-cell function in IGT subjects treated with pioglitazone. , 2014, The Journal of clinical endocrinology and metabolism.

[28]  M. J. Charron,et al.  Metabolic manifestations of insulin deficiency do not occur without glucagon action , 2012, Proceedings of the National Academy of Sciences.

[29]  R. Unger,et al.  Glucagon is the key factor in the development of diabetes , 2016, Diabetologia.

[30]  A. Gastaldelli,et al.  The effect of chronic twice daily exenatide treatment on β‐cell function in new onset type 2 diabetes , 2014, Clinical endocrinology.

[31]  Lawrence A Leiter,et al.  Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. , 2016, The New England journal of medicine.

[32]  A. Scheen,et al.  Inhibiting or antagonizing glucagon: making progress in diabetes care , 2015, Diabetes, obesity & metabolism.

[33]  S. Madsbad.  The role of glucagon‐like peptide‐1 impairment in obesity and potential therapeutic implications , 2014, Diabetes, obesity & metabolism.

[34]  E. Ferrannini,et al.  Direct effect of GLP-1 infusion on endogenous glucose production in humans , 2012, Diabetologia.

[35]  M. Bednarek,et al.  A novel glucagon‐like peptide 1/glucagon receptor dual agonist improves steatohepatitis and liver regeneration in mice , 2017, Hepatology.

[36]  E. Chambers,et al.  Coadministration of Glucagon-Like Peptide-1 During Glucagon Infusion in Humans Results in Increased Energy Expenditure and Amelioration of Hyperglycemia , 2013, Diabetes.

[37]  Robert R. Henry,et al.  Type 2 diabetes mellitus , 2015, Nature Reviews Disease Primers.

[38]  A. Gastaldelli,et al.  Blockade of glucagon-like peptide 1 receptor corrects postprandial hypoglycemia after gastric bypass. , 2014, Gastroenterology.

[39]  D. Drucker,et al.  Islet α cells and glucagon—critical regulators of energy homeostasis , 2015, Nature Reviews Endocrinology.

[40]  G. Reaven,et al.  Dissecting the Relationship between Obesity and Hyperinsulinemia: Role of Insulin Secretion and Insulin Clearance , 2016, Obesity.

[41]  J. Lancaster,et al.  Exenatide Regulates Cerebral Glucose Metabolism in Brain Areas Associated With Glucose Homeostasis and Reward System , 2015, Diabetes.

[42]  D. D’Alessio,et al.  Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease. , 2015, Physiological reviews.

[43]  S. Gough,et al.  Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis , 2016, Journal of hepatology.

[44]  D. Drucker,et al.  Pharmacology, physiology, and mechanisms of incretin hormone action. , 2013, Cell metabolism.

[45]  P. Iozzo,et al.  Exenatide improves both hepatic and adipose tissue insulin resistance: A dynamic positron emission tomography study , 2016, Hepatology.

[46]  L. Bardram,et al.  GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. , 2014, Endocrinology.

[47]  J. Xie,et al.  Duodenal GLP-1 signaling regulates hepatic glucose production through a PKC-δ-dependent neurocircuitry , 2017, Cell Death & Disease.

[48]  M. Nauck,et al.  The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions. , 2016, The lancet. Diabetes & endocrinology.

[49]  M. J. Charron,et al.  Lack of glucagon receptor signaling and its implications beyond glucose homeostasis. , 2015, The Journal of endocrinology.

[50]  D. Sandoval,et al.  CNS Control of Glucose Metabolism: Response to Environmental Challenges , 2013, Front. Neurosci..

[51]  R. DeFronzo,et al.  Non-Alcoholic Fatty Liver Disease (NAFLD) and Its Connection with Insulin Resistance, Dyslipidemia, Atherosclerosis and Coronary Heart Disease , 2013, Nutrients.

[52]  A. Tura,et al.  Effect of exenatide on postprandial glucose fluxes, lipolysis, and ß‐cell function in non‐diabetic, morbidly obese patients , 2017, Diabetes, obesity & metabolism.

[53]  S. Madsbad.  Review of head‐to‐head comparisons of glucagon‐like peptide‐1 receptor agonists , 2015, Diabetes, obesity & metabolism.

[54]  G. Bray,et al.  Prediction of Diabetes Based on Baseline Metabolic Characteristics in Individuals at High Risk , 2013, Diabetes Care.

[55]  J. Romijn,et al.  Impaired insulin action in the liver, but not in adipose tissue or muscle, is a distinct metabolic feature of impaired fasting glucose in obese humans. , 2016, Metabolism: clinical and experimental.

[56]  P. Puigserver,et al.  Molecular pathophysiology of hepatic glucose production. , 2015, Molecular aspects of medicine.

[57]  J. Holst,et al.  Early Enhancements of Hepatic and Later of Peripheral Insulin Sensitivity Combined With Increased Postprandial Insulin Secretion Contribute to Improved Glycemic Control After Roux-en-Y Gastric Bypass , 2014, Diabetes.

[58]  J. Holst,et al.  Exaggerated Glucagon-Like Peptide 1 Response Is Important for Improved β-Cell Function and Glucose Tolerance After Roux-en-Y Gastric Bypass in Patients With Type 2 Diabetes , 2013, Diabetes.

[59]  John G. Jones.  Hepatic glucose and lipid metabolism , 2016, Diabetologia.