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Endocr J 2021 Apr 6. 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 Mar 15. 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, patients with type 2 and type 1 diabetes. Read More

Mol Metab 2021 Feb 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 Feb 2. 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

Front Endocrinol (Lausanne) 2020 16;11:606264. Epub 2020 Dec 16.

ENETS Centre of Excellence, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom.

Introduction: In the UK, the fasting plasma concentrations of a panel of gut hormones (comprising vasoactive intestinal peptide (VIP), gastrin, pancreatic polypeptide (PP), glucagon, somatostatin and chromogranin A) are measured to evaluate patients who have or who (due to unexplained and compatible symptoms) are suspected of having neuroendocrine tumors (NETs). False positive elevated hormone concentrations are sometimes found.

Objective: To evaluate the frequency and implications of false positive fasting gut hormone results. Read More

J Clin Med 2020 Dec 15;9(12). Epub 2020 Dec 15.

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

A key criterion for the most common chronic liver disease-non-alcoholic fatty liver disease (NAFLD)-is an intrahepatic fat content above 5% in individuals who are not using steatogenic agents or having significant alcohol intake. Subjects with NAFLD have increased plasma concentrations of glucagon, and emerging evidence indicates that subjects with NAFLD may show hepatic glucagon resistance. For many years, glucagon has been thought of as the counterregulatory hormone to insulin with a primary function of increasing blood glucose concentrations and protecting against hypoglycemia. Read More

Diabetes 2021 02 25;70(2):477-491. Epub 2020 Nov 25.

Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, Miller School of Medicine, University of Miami, Miami, FL

Elevation of glucagon levels and increase in α-cell mass are associated with states of hyperglycemia in diabetes. Our previous studies have highlighted the role of nutrient signaling via mTOR complex 1 (mTORC1) regulation that controls glucagon secretion and α-cell mass. In the current studies we investigated the effects of activation of nutrient signaling by conditional deletion of the mTORC1 inhibitor, TSC2, in α-cells (αTSC2). Read More

Genes Dev 2020 Dec 12;34(23-24):1650-1665. Epub 2020 Nov 12.

Division of Endocrinology, Diabetes, Nutrition, and Patient Education, Department of Medicine, University of Geneva, 1211 Geneva, Switzerland.

Circadian clocks in pancreatic islets participate in the regulation of glucose homeostasis. Here we examined the role of these timekeepers in β-cell regeneration after the massive ablation of β cells by doxycycline-induced expression of diphtheria toxin A (DTA) in Insulin-rtTA/TET-DTA mice. Since we crossed reporter genes expressing α- and β-cell-specific fluorescent proteins into these mice, we could follow the fate of α- and β cells separately. Read More

Hepatol Commun 2020 Nov 1;4(11):1610-1623. Epub 2020 Sep 1.

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

Nonalcoholic fatty liver disease (NAFLD) is associated with impaired hepatic actions of glucagon and insulin. Glucagon and amino acids are linked in an endocrine feedback circuit, the liver-alpha cell axis, that may be disrupted by NAFLD. We investigated how NAFLD severity affects glucagon and insulin resistance in individuals with obesity and whether bariatric surgery improves these parameters. Read More

Curr Drug Saf 2020 Nov 5. Epub 2020 Nov 5.

Department of Endocrinology & Metabolism, Eastbourne Hospital. United Kingdom.

A large proportion of persons with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) do not reach the glycosylated haemoglobin (HbA1c) target of < 7% (53 mmol/mol) with an increasing proportion of them being overweight or obese. In both T1DM and T2DM, there is accelerated gastric emptying and postprandial hyperglucagonemia. Furthermore, insulin therapy itself is associated with risk of hypoglycemia and weight-gain both of which are barriers to achieving good control. Read More

Can J Diabetes 2021 Apr 7;45(3):249-254. Epub 2020 Sep 7.

Department of Diabetes, Imakiire General Hospital, Kagoshima, Japan.

Objectives: In this study, we used a double-antibody sandwich enzyme-linked immunosorbent assay to assess the association between blood glucagon levels and indices of obesity, glycemic control and renal function in patients with type 2 diabetes mellitus (T2DM).

Methods: This investigation was a cross-sectional study on inpatients with T2DM who had plasma glucagon levels measured during hospitalization. Associations of fasting glucagon levels (G), 120-minute postbreakfast plasma glucagon (G), fasting glucagon/C-peptide ratio (G/CPR) and postbreakfast glucagon/C-peptide ratio (G/CPR) with clinical data were evaluated using multiple regression analysis. Read More

Heliyon 2020 Sep 15;6(9):e04951. Epub 2020 Sep 15.

Chulabhorn Graduate Institute, Chulabhorn Royal Academy, Bangkok, Thailand.

β-cell dedifferentiation has been accounted as one of the major mechanisms for β-cell failure; thus, is a cause to diabetes. We study direct impacts of liraglutide treatment on human dedifferentiated islets, and its effects on genes important in endocrine function, progenitor states, and epithelial mesenchymal transition (EMT). Human islets from non-diabetic donors, were purified and incubated until day 1 and day 4, and were determined insulin contents, numbers of insulin (INS) and glucagon (GCG) cells. Read More

Mol Metab 2020 12 13;42:101080. Epub 2020 Sep 13.

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department for Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Objective: Glucagon is well known to regulate blood glucose but may be equally important for amino acid metabolism. Plasma levels of amino acids are regulated by glucagon-dependent mechanism(s), while amino acids stimulate glucagon secretion from alpha cells, completing the recently described liver-alpha cell axis. The mechanisms underlying the cycle and the possible impact of hepatic steatosis are unclear. Read More

Endocr J 2021 Jan 10;68(1):95-102. Epub 2020 Sep 10.

Department of Preventive Medicine for Diabetes and Lifestyle-related Diseases, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan.

Japanese Americans living in the United States are genetically identical to Japanese people, but have undergone a rapid and intense westernization of their lifestyle. This study investigated variability in glucagon secretion after glucose loading among Japanese Americans with normal glucose tolerance (NGT) according to obesity status. The 75-g oral glucose tolerance test (OGTT) was performed for 138 Japanese Americans (aged 40-75 years) living in Los Angeles. Read More

J Biol Chem 2020 10 12;295(42):14379-14390. Epub 2020 Aug 12.

Departments of Cellular and Molecular Physiology and Internal Medicine (Endocrinology), Yale School of Medicine, New Haven, Connecticut, USA

In a healthy person, the kidney filters nearly 200 g of glucose per day, almost all of which is reabsorbed. The primary transporter responsible for renal glucose reabsorption is sodium-glucose cotransporter-2 (SGLT2). Based on the impact of SGLT2 to prevent renal glucose wasting, SGLT2 inhibitors have been developed to treat diabetes and are the newest class of glucose-lowering agents approved in the United States. Read More

Mol Nutr Food Res 2021 03 13;65(5):e2000412. Epub 2020 Aug 13.

Department of Pharmacology, University of Alberta, Edmonton, T6G 2R3, Canada.

Scope: The aim of this study is to test whether the choice of the lipid emulsion in total parenteral nutrition (TPN), that is, n-3 fatty acid-based Omegaven versus n-6 fatty acid-based Intralipid, determines inflammation in the liver, the incretin profile, and insulin resistance.

Methods And Results: Jugular vein catheters (JVC) are placed in C57BL/6 mice and used for TPN for 7 days. Mice are randomized into a saline group (saline infusion with oral chow), an Intralipid group (IL-TPN, no chow), an Omegaven group (OV-TPN, no chow), or a chow only group (without JVC). Read More

Biochem J 2020 07;477(13):2581-2594

The National Center for Drug Screening and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China.

Glucagon is a peptide hormone secreted by islet α cells. It plays crucial roles in glucose homeostasis and metabolism by activating its cognate glucagon receptor (GCGR). A naturally occurring deleterious mutation V368M in the human GCGR leads to reduced ligand binding and down-regulation of glucagon signaling. Read More

J Diabetes Investig 2021 Feb 17;12(2):286-289. Epub 2020 Jul 17.

Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan.

Glucagon is detected in plasma even after total pancreatectomy, and it is debated whether this glucagon is derived from the gastrointestinal tract. Here, we applied sandwich enzyme-linked immunosorbent assay (ELISA) and liquid chromatography-high-resolution mass spectrometry to measure plasma glucagon levels in one patient after partial pancreatectomy (one-seventh of the pancreas remaining) and three patients after total pancreatectomy. Sandwich ELISA detected higher glucagon levels in pancreatectomy patients than in healthy individuals. Read More

Mol Metab 2020 10 21;40:101021. Epub 2020 May 21.

Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, Churchill Hospital, Oxford OX3 7LE, UK; Department of Computer Science, University of Oxford, Oxford OX1 3QD, UK. Electronic address:

Objectives: Elevated plasma glucagon is an early symptom of diabetes, occurring in subjects with impaired glucose regulation. Here, we explored alpha-cell function in female mice fed a high-fat diet (HFD).

Methods: Female mice expressing the Ca indicator GCaMP3 specifically in alpha-cells were fed a high-fat or control (CTL) diet. Read More

J Clin Endocrinol Metab 2020 07;105(7)

Division of Endocrinology, University of Virginia School of Medicine, Charlottesville, VA, US.

Context: The effect of physiological changes in night-time cortisol and glucagon on endogenous glucose production (EGP) and nocturnal glycemia are unknown.

Objective: To determine the effects of changes in cortisol and glucagon on EGP during the night.

Design: Two overnight protocols were conducted. Read More

Physiol Rep 2020 05;8(9):e14417

Institute of Pharmacology, Toxicology and Clinical Pharmacy, Technische Universität Braunschweig, Braunschweig, Germany.

Gestational diabetes mellitus (GDM) is a complex metabolic disease involving genetic and environmental factors. Recent studies have underlined its heterogeneity, so it is reasonable to divide patients into subpopulations depending on whether an insulin secretion or sensitivity defect is predominant. Since testing for GDM is usually performed in the second trimester, misinterpretation of prediabetes as gestational diabetes may occur. Read More

Clin Cosmet Investig Dermatol 2020 5;13:275-281. Epub 2020 Apr 5.

Department of Dermatology, Venereology and Leprosy, SN Medical College, Bagalkote 587102, Karnataka, India.

Necrolytic acral erythema (NAE) is now considered as a distinct clinical entity. It clinically presents as well demarcated hyperpigmented papules and plaques with thick adherent scales distributed symmetrically over dorsum of feet. It usually develops in patients with Hepatitis C virus (HCV) infection. Read More

Rev Cardiovasc Med 2020 Mar;21(1):41-56

Nephrology Division, Internal Medicine Department, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain.

The curve that describes the relationship between glomerular filtration rate (GFR) and cardiovascular risk is U-shaped, indicating that both reduced GFR (kidney failure) and elevated GFR (glomerular hyperfiltration) are equivalent cardiovascular risk factors. The elevated cardiovascular risk associated with abnormal GFR is not explained by standard cardiovascular risk factors. The relationship between GFR and all-cause mortality follows a similar pattern, so that altered GFR (either low or high) increases the risk for overall mortality. Read More

Medicine (Baltimore) 2020 Apr;99(14):e19685

Shandong University School of Medicine, Jinan.

The effect of intensive insulin therapy on hyperglucagonemia in newly diagnosed type 2 diabetes (T2DM), and its associations with β-cell function, has not been elucidated. This study assessed the effect of 12 weeks of intensive insulin therapy on hyperglucagonemia in newly diagnosed T2DM and its associations with β-cell function, with reference to the effects of 12 weeks of oral hypoglycemic agents (OHAs).One hundred eight patients with newly diagnosed T2DM were enrolled from January 2015 to December 2015. Read More

BMJ Open Diabetes Res Care 2020 03;8(1)

Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

Introduction: Hyperglucagonemia is a key pathophysiological driver of type 2 diabetes. Although Roux-en-Y gastric bypass (RYGB) is a highly effective treatment for diabetes, it is presently unclear how surgery alters glucagon physiology. The aim of this study was to characterize the behavior of proglucagon-derived peptide (glucagon, glucagon-like peptide-1 (GLP-1), oxyntomodulin, glicentin) secretion after RYGB surgery. Read More

Am J Physiol Endocrinol Metab 2020 05 24;318(5):E779-E790. Epub 2020 Mar 24.

Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee.

Glucagon's effect on hepatic glucose production (HGP), under hyperglycemic conditions, is time dependent such that after an initial burst of HGP, it slowly wanes. It is not known whether this is also the case under hypoglycemic conditions, where an increase in HGP is essential. This question was addressed using adrenalectomized dogs to avoid the confounding effects of other counterregulatory hormones. Read More

Diabetes 2020 05 6;69(5):915-926. Epub 2020 Feb 6.

Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany

Genes of the Notch signaling pathway are expressed in different cell types and organs at different time points during embryonic development and adulthood. The Notch ligand Delta-like 1 (DLL1) controls the decision between endocrine and exocrine fates of multipotent progenitors in the developing pancreas, and loss of leads to premature endocrine differentiation. However, the role of Delta-Notch signaling in adult tissue homeostasis is not well understood. Read More

Diabetes 2020 06 23;69(6):1090-1099. Epub 2020 Jan 23.

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

Glucagon secretion is regulated by circulating glucose, but it has turned out that amino acids also play an important role and that hepatic amino acid metabolism and glucagon are linked in a mutual feedback cycle, the liver-α-cell axis. On the basis of this knowledge, we hypothesized that hepatic steatosis might impair glucagon's action on hepatic amino acid metabolism and lead to hyperaminoacidemia and hyperglucagonemia. We subjected 15 healthy lean and 15 obese steatotic male participants to a pancreatic clamp with somatostatin and evaluated hepatic glucose and amino acid metabolism when glucagon was at basal levels and at high physiological levels. Read More