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J Assoc Physicians India 2022 Apr;70(4):11-12

Sms Medical College, Jaipur.

Apart from defects in insulin secretion and insulin resistance, hyperglucagonemia is a major factor affecting diabetes development and progression. Diabetic patients show relatively higher fasting and postprandial glucagon levels due to alpha cell resistance or dysfunction. As glucagon secretion is highly affected by insulin, it is better to consider glucagon relative to insulin as a glucagon insulin ratio instead of assessing each absolute value seperately. Read More

Metabolism 2022 Jun 4;131:155199. Epub 2022 Apr 4.

Division of Diabetes, University of Texas at San Antonio, San Antonio, TX, United States.

Aims/hypothesis: Roux-en Y gastric bypass surgery (GB) and sleeve gastrectomy (SG) alter prandial glucose metabolism, producing lower nadir glucose values and predisposing susceptible individuals to prandial hypoglycemia. The glycemic phenotype of GB or SG is associated with prandial hyperinsulinemia and hyperglucagonemia along with an increased influx of ingested glucose. Following insulin-induced hypoglycemia, glucagon is the most important stimulus for hepatic glucose production (HGP). Read More

J Clin Endocrinol Metab 2022 May;107(6):1569-1576

Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Context: In adults, hyperglucagonemia is associated with type 2 diabetes, impaired glucose tolerance, and obesity. The role of glucagon in pediatric overweight/obesity remains unclear.

Objective: We examined whether fasting concentrations of glucagon are elevated in youth with overweight/obesity and whether this associates with cardiometabolic risk profiles. Read More

J Nutr Biochem 2022 04 2;102:108952. Epub 2022 Feb 2.

Service of Bone Diseases, Department of Rehabilitation and Geriatrics, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.

The need to consume adequate dietary protein to preserve physical function during ageing is well recognized. However, the effect of protein intakes on glucose metabolism is still intensively debated. During age-related estrogen withdrawal at the time of the menopause, it is known that glucose homeostasis may be impaired but the influence of dietary protein levels in this context is unknown. Read More

Front Physiol 2021 23;12:710652. Epub 2021 Dec 23.

Department of Ecology and Evolutionary Biology, University of Toronto, Toronto, ON, Canada.

Metabolic homeostasis requires the precise regulation of circulating sugar titers. In mammals, homeostatic control of circulating sugar titers requires the coordinated secretion and systemic activities of glucagon and insulin. Metabolic homeostasis is similarly regulated in through the glucagon-like adipokinetic hormone (AKH) and the insulin-like peptides (DILPs). Read More

Diabetes 2021 Oct 21. Epub 2021 Oct 21.

Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark.

Hyperglucagonemia is a common observation in both obesity and type 2 diabetes, and the etiology is primarily thought to be hypersecretion of glucagon. We investigated whether altered elimination kinetics of glucagon could contribute to the hyperglucagonemia in type 2 diabetes and obesity. Individuals with type 2 diabetes and preserved kidney function (8 with and 8 without obesity) and matched control individuals (8 with and 8 without obesity) were recruited. Read More

Islets 2022 12;14(1):40-57

Department of Pathology and Laboratory Medicine, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada.

Glucagon hypersecretion from the pancreatic α-cell is a characteristic sign of diabetes, which exacerbates fasting hyperglycemia. Thus, targeting glucagon secretion from α-cells may be a promising approach for combating hyperglucagonemia. We have recently identified stathmin-2 as an α-cell protein that regulates glucagon secretion by directing glucagon toward the endolysosomal system in αTC1-6 cells. Read More

Eur J Endocrinol 2022 Jan 6;186(2):207-221. Epub 2022 Jan 6.

Clinical Research, Copenhagen University Hospital - Steno Diabetes Center Copenhagen, Herlev, Denmark.

Objective: Type 2 diabetes (T2D) pathophysiology includes fasting and postprandial hyperglucagonemia, which has been linked to hyperglycemia via increased endogenous glucose production (EGP). We used a glucagon receptor antagonist (LY2409021) and stable isotope tracer infusions to investigate the consequences of hyperglucagonemia in T2D.

Design: A double-blinded, randomized, placebo-controlled crossover study was conducted. Read More

Sci Rep 2021 11 17;11(1):22451. Epub 2021 Nov 17.

Department of Surgery, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea.

The present study aimed to investigate changes in glucose metabolism and incretin hormone response following longer intestinal bypass reconstruction after distal gastrectomy (DG) in low BMI patients with gastric cancer and type 2 diabetes. A total of 20 patients were prospectively recruited and underwent either conventional Billroth I (BI), Billroth II with long-biliopancreatic limb (BII), or Roux-en-Y anastomosis with long-Roux limb (RY) after DG. A 75g-oral glucose tolerance test (OGTT) was given preoperatively; and at 5 days, 3 months, and 6 months postoperatively. Read More

JCI Insight 2021 12 22;6(24). Epub 2021 Dec 22.

Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.

Glucagon, a hormone released from pancreatic α cells, plays a key role in maintaining euglycemia. New insights into the signaling pathways that control glucagon secretion may stimulate the development of novel therapeutic agents. In this study, we investigated the potential regulation of α cell function by G proteins of the Gq family. Read More

Diabetes 2021 Oct 26. Epub 2021 Oct 26.

Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark,

Hyperglucagonemia is a common observation in both obesity and type 2 diabetes, and the etiology is primarily thought to be hypersecretion of glucagon. We investigated whether altered elimination kinetics of glucagon could contribute to the hyperglucagonemia in type 2 diabetes and obesity. Individuals with type 2 diabetes and preserved kidney function (8 with and 8 without obesity) and matched control individuals (8 with and 8 without obesity) were recruited. Read More

Front Endocrinol (Lausanne) 2021 29;12:726368. Epub 2021 Sep 29.

Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.

Patients with diabetes mellitus exhibit hyperglucagonemia, or excess glucagon secretion, which may be the underlying cause of the hyperglycemia of diabetes. Defective alpha cell secretory responses to glucose and paracrine effectors in both Type 1 and Type 2 diabetes may drive the development of hyperglucagonemia. Therefore, uncovering the mechanisms that regulate glucagon secretion from the pancreatic alpha cell is critical for developing improved treatments for diabetes. Read More

Obesity (Silver Spring) 2021 11 21;29(11):1799-1801. Epub 2021 Sep 21.

Department of Molecular Biosciences, School of Veterinary Medicine and Department of Nutrition, University of California Davis, Davis, California, USA.

Dysregulation of hepatic glucose production (HGP) and glucose disposal leads to hyperglycemia and type 2 diabetes. Hyperglycemia results from the declining ability of insulin to reduce HGP and increase glucose disposal, as well as inadequate ß-cell compensation for insulin resistance. Hyperglucagonemia resulting from reduced suppression of glucagon secretion by insulin contributes to hyperglycemia by stimulating HGP. Read More

Int J Mol Sci 2021 Sep 1;22(17). Epub 2021 Sep 1.

Escuela de Nutrición y Dietética, Facultad de Medicina, Universidad Andres Bello, Sede Concepción 4260000, Chile.

Type 2 Diabetes Mellitus (T2DM) is one of the most prevalent chronic metabolic disorders, and insulin has been placed at the epicentre of its pathophysiological basis. However, the involvement of impaired alpha (α) cell function has been recognized as playing an essential role in several diseases, since hyperglucagonemia has been evidenced in both Type 1 and T2DM. This phenomenon has been attributed to intra-islet defects, like modifications in pancreatic α cell mass or dysfunction in glucagon's secretion. Read More

Mol Cell Endocrinol 2021 11 28;537:111445. Epub 2021 Aug 28.

Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China; Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, Shandong, China; Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, Shandong, China; Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, 250012, Shandong, China. Electronic address:

Background: α-cell dysregulation gives rise to fasting and postprandial hyperglycemia in type 2 diabetes mellitus(T2DM). Administration of Mesenchymal stem cells (MSCs) or their conditioned medium can improve islet function and enhance insulin secretion. However, studies showing the direct effect of MSCs on islet α-cell dysfunction are limited. Read More

Eur J Gastroenterol Hepatol 2021 12;33(1S Suppl 1):e818-e823

Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Objectives: Higher prevalence of progressive stages of nonalcoholic fatty liver disease (NAFLD) and hyperglucagonemia were observed in type 2 diabetes. We aim to investigate whether islet alpha cell dysfunction (evaluated by glucagon) associates with NAFLD progression in type 2 diabetic adults.

Methods: A total of 4937 diabetic participants were enrolled from seven communities in Shanghai, China. Read More

J Endocr Soc 2021 Sep 16;5(9):bvab084. Epub 2021 May 16.

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen,Denmark.

Context: Inhibitors of the protease neprilysin (NEP) are used for treating heart failure, but are also linked to improvements in metabolism. NEP may cleave proglucagon-derived peptides, including the glucose and amino acid (AA)-regulating hormone glucagon. Studies investigating NEP inhibition on glucagon metabolism are warranted. Read More

Front Immunol 2021 6;12:633540. Epub 2021 Jul 6.

Laboratory of Inflammation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil.

Sepsis is one of the most common comorbidities observed in diabetic patients, associated with a deficient innate immune response. Recently, we have shown that glucagon possesses anti-inflammatory properties. In this study, we investigated if hyperglucagonemia triggered by diabetes might reduce the migration of neutrophils, increasing sepsis susceptibility. Read More

Diabetes Metab Syndr 2021 Jul-Aug;15(4):102199. Epub 2021 Jul 6.

Department of Diabetology, M.V. Hospital for Diabetes and Prof. M. Viswanathan Diabetes Research Center (WHO Collaborating Center for Research Education and Training in Diabetes) (IDF Centre for Excellence in Diabetes Care), Royapuram, Chennai, Tamil Nadu, India. Electronic address:

Background And Aims: Glucagon levels and glucagon suppression in response to oral glucose load has not been elucidated at different stages of glucose intolerance in India.

Methods: A total of 81 subjects underwent OGTT and were classified into three groups as having normal glucose tolerance (NGT) (n = 23), prediabetes (PreDM) (n = 33), newly diagnosed diabetes (NDM) (n = 25). Insulin and glucagon at fasting, 30 and 120 min was measured by ELISA. Read More

J Nutr Biochem 2021 11 28;97:108811. Epub 2021 Jun 28.

Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan. Electronic address:

Dysregulation of glucagon is associated with the pathophysiology of type 2 diabetes. We previously reported that postprandial hyperglucagonemia is more obvious than fasting hyperglucagonemia in type 2 diabetes patients. However, which nutrient stimulates glucagon secretion in the diabetic state and the underlying mechanism after nutrient intake are unclear. Read More

Diabetes Care 2021 09 15;44(9):1961-1969. Epub 2021 Jun 15.

Kaiser Permanente Southern California, Pasadena, CA.

Objective: To determine whether β-cell hyperresponsiveness and insulin resistance in youth versus adults in the Restoring Insulin Secretion (RISE) Study are related to increased glucagon release.

Research Design And Methods: In 66 youth and 350 adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes (drug naive), we performed hyperglycemic clamps and oral glucose tolerance tests (OGTTs). From clamps we quantified insulin sensitivity (M/I), plasma fasting glucagon and C-peptide, steady-state glucagon and C-peptide at glucose of 11. Read More

Front Med 2021 Jun 28;15(3):372-382. Epub 2021 May 28.

Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.

Obesity increases the risk of type 2 diabetes through the induction of insulin resistance. The mechanism of insulin resistance has been extensively investigated for more than 60 years, but the essential pathogenic signal remains missing. Existing hypotheses include inflammation, mitochondrial dysfunction, hyperinsulinemia, hyperglucagonemia, glucotoxicity, and lipotoxicity. Read More

Probl Endokrinol (Mosk) 2021 03 30;67(2):28-39. Epub 2021 Mar 30.

Stavropol Regional Clinical Consultative and Diagnostic Center.

The cystic fibrosis transmembrane regulator (CFTR) gene encodes the synthesis of a protein of the same name, which functions as a direct activator of anionic transport. Chloride is the most abundant anion; as an antagonist of Na+ and K+, it provides electroneutrality of cell membranes at rest; together with cations, it serves as an important osmolyte and forms water flow across cell membranes for transepithelial secretion.Glandular cells in CF trap Cl- and Na+, and the prodused secretion is excessively viscous. Read More

Biosci Rep 2021 06;41(6)

School of Pharmacy, Fudan University, Shanghai 201203, China.

Glucagon plays an important role in glucose homeostasis and amino acid metabolism. It regulates plasma amino acid levels which in turn modulate glucagon secretion from the pancreatic α-cell, thereby establishing a liver-α-cell axis described recently. We reported previously that the knock-in mice bearing homozygous V369M substitution (equivalent to a naturally occurring mutation V368M in the human glucagon receptor, GCGR) led to hypoglycemia with improved glucose tolerance. Read More

Endocr J 2021 Aug 6;68(8):919-931. Epub 2021 Apr 6.

Department of Endocrinology and Metabolism, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan.

Gestational diabetes mellitus (GDM) is known to be a significant risk factor for the future development of type 2 diabetes. Here, we investigated whether a precise evaluation of β- and α-cell functions helps to identify women at high risk of developing glucose intolerance after GDM. Fifty-six women with GDM underwent a 75-g oral glucose tolerance test (OGTT) at early (6-12 weeks) postpartum. Read More

Diabetes 2021 06 15;70(6):1347-1356. Epub 2021 Mar 15.

Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark

Hyperglucagonemia is a well-known contributor to diabetic hyperglycemia, and glucagon-like peptide 1 (GLP-1) suppresses glucagon secretion. Reduced inhibitory effects of glucose and GLP-1 on glucagon secretion may contribute to the hyperglucagonemia in diabetes and influence the success of GLP-1 receptor agonist therapy. We examined the dose-response relationship for GLP-1 on glucose-induced glucagon suppression in healthy individuals and patients with type 2 and type 1 diabetes. Read More

Mol Metab 2021 07 19;49:101193. Epub 2021 Feb 19.

Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, The University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA; Department of Genetics, Perelman School of Medicine, The University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA. Electronic address:

Objective: While the molecular events controlling insulin secretion from β-cells have been documented in detail, the exact mechanisms governing glucagon release by α-cells are understood only partially. This is a critical knowledge gap, as the normal suppression of glucagon secretion by elevated glucose levels fails in type 2 diabetes (T2D) patients, contributing to hyperglycemia through stimulation of hepatic glucose production. A critical role of glycolytic flux in regulating glucagon secretion was supported by recent studies in which manipulation of the activity and expression of the glycolytic enzyme glucokinase altered the setpoint for glucose-suppression of glucagon secretion (GSGS). Read More

Cell Mol Gastroenterol Hepatol 2021 2;12(1):354-377.e3. Epub 2021 Feb 2.

Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada; Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario, Canada; Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada. Electronic address:

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is considered a health epidemic with potential devastating effects on the patients and the healthcare systems. Current preclinical models of NAFLD are invariably imperfect and generally take a long time to develop. A mouse model of survival motor neuron (SMN) depletion (Smn mice) was recently shown to develop significant hepatic steatosis in less than 2 weeks from birth. Read More

Front Cell Dev Biol 2020 14;8:605979. Epub 2021 Jan 14.

Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.

The glucagon receptor (GCGR) is activated by glucagon and is essential for glucose, amino acid, and lipid metabolism of animals. GCGR blockade has been demonstrated to induce hypoglycemia, hyperaminoacidemia, hyperglucagonemia, decreased adiposity, hepatosteatosis, and pancreatic α cells hyperplasia in organisms. However, the mechanism of how GCGR regulates these physiological functions is not yet very clear. Read More

Endocr Connect 2021 Feb;10(2):205-213

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Objective: Glucagon and glucagon-like peptide-1 (GLP-1) originate from the common precursor, proglucagon, and their plasma concentrations have been reported to be increased during inflammatory conditions. Increased blood glucose levels are frequently observed in septic patients, and therefore we hypothesized that glucagon, but not GLP-1, is increased in individuals with inflammation.

Design: Prospective longitudinal cohort study. Read More