The Insulin:Glucagon Ratio and the Choice of Glucose-Lowering Drugs

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Abstract

The influence of alpha and beta cells, through glucagon and insulin, on energy metabolism is well known. The insulin:glucagon ratio (IGR) is a frequently discussed entity in the medical literature. However, in recent years, focus has shifted to other pathways and markers of health and disease. This communication revisits the insulin:glucagon bipolar axis and describes the significance of the IGR. It reviews the effects of various glucose-lowering drugs on this ratio, and hypothesizes that the ratio can be used to predict the appropriate choice of drugs for managing diabetes. Drugs which increase the IGR may be beneficial in insulinopenic conditions, while those which decrease IGR may be of help in the setting of hyperinsulinemia or insulin resistance.

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Regulation of insulin secretion in human pancreatic islets.

Patrik Rorsman, Matthias Braun (2013)

Pancreatic β cells secrete insulin, the body's only hormone capable of lowering plasma glucose levels. Impaired or insufficient insulin secretion results in diabetes mellitus. The β cell is electrically excitable; in response to an elevation of glucose, it depolarizes and starts generating action potentials. The electrophysiology of mouse β cells and the cell's role in insulin secretion have been extensively investigated. More recently, similar studies have been performed on human β cells. These studies have revealed numerous and important differences between human and rodent β cells. Here we discuss the properties of human pancreatic β cells: their glucose sensing, the ion channel complement underlying glucose-induced electrical activity that culminates in exocytotic release of insulin, the cellular control of exocytosis, and the modulation of insulin secretion by circulating hormones and locally released neurotransmitters. Finally, we consider the pathophysiology of insulin secretion and the interactions between genetics and environmental factors that may explain the current diabetes epidemic.

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Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus.

Michael Baron, James Ruggles, O Kolterman … (2005)

The pharmacology and tolerability of exenatide in patients with type 2 diabetes mellitus were studied. Two randomized, single-blind, placebo-controlled studies were conducted. Treatment with oral antidiabetic agents was stopped 14 days before study initiation. In the first study (study A), eight subjects received placebo, 0.1-, 0.2-, 0.3-, and either 0.4-microg/kg exenatide or placebo five minutes before a meal combined with liquid acetaminophen (to assess the rate of gastric emptying) on days 1, 3, 5, 7, and 9. In the second study (study B), subjects received a single s.c. dose of exenatide or placebo on consecutive days. Part 1 of study B used exenatide doses of 0.01 and 0.1 microg/ kg; 0.02-, 0.05-, and 0.1-microg/kg doses were given in part 2. After an overnight fast, the study drug was injected 15 minutes before a meal (part 1) and before a meal and acetaminophen (part 2). Parts 1 and 2 of study B enrolled six and eight patients, respectively. In both studies, plasma exenatide pharmacokinetic profiles appeared dose proportional. Exenatide doses of 0.02-0.2 microg/kg dose-dependently lowered postprandial glucose excursions. Exenatide suppressed postprandial plasma glucagon and slowed gastric emptying. There were no serious adverse events and no patient withdrawals related to treatment. Nausea and vomiting were the most common adverse events and were mild to moderate in severity at doses ranging from 0.02 to 0.2 microg/kg. Administration of preprandial exenatide by s.c. injection resulted in dose-proportional exenatide pharmacokinetics and antidiabetic pharmacodynamic activity. At doses ranging from 0.02 to 0.2 microg/kg, exenatide dose-dependently reduced postprandial plasma glucose excursion by insulinotropism, suppression of plasma glucagon, and slowing of gastric emptying.

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Pharmacodynamic characteristics of lixisenatide once daily versus liraglutide once daily in patients with type 2 diabetes insufficiently controlled on metformin

C Kapitza, T Forst, H-V Coester … (2013)

Aim Assess the pharmacodynamics of lixisenatide once daily (QD) versus liraglutide QD in type 2 diabetes insufficiently controlled on metformin. Methods In this 28-day, randomized, open-label, parallel-group, multicentre study (NCT01175473), patients (mean HbA1c 7.3%) received subcutaneous lixisenatide QD (10 µg weeks 1–2, then 20 µg; n = 77) or liraglutide QD (0.6 mg week 1, 1.2 mg week 2, then 1.8 mg; n = 71) 30 min before breakfast. Primary endpoint was change in postprandial plasma glucose (PPG) exposure from baseline to day 28 during a breakfast test meal. Results Lixisenatide reduced PPG significantly more than liraglutide [mean change in AUC0 :30–4:30h: −12.6 vs. −4.0 h·mmol/L, respectively; p < 0.0001 (0:30 h = start of meal)]. Change in maximum PPG excursion was −3.9 mmol/l vs. −1.4 mmol/l, respectively (p < 0.0001). More lixisenatide-treated patients achieved 2-h PPG <7.8 mmol/l (69% vs. 29%). Changes in fasting plasma glucose were greater with liraglutide (−0.3 vs. −1.3 mmol/l, p < 0.0001). Lixisenatide provided greater decreases in postprandial glucagon (p < 0.05), insulin (p < 0.0001) and C-peptide (p < 0.0001). Mean HbA1c decreased in both treatment groups (from 7.2% to 6.9% with lixisenatide vs. 7.4% to 6.9% with liraglutide) as did body weight (−1.6 kg vs. −2.4 kg, respectively). Overall incidence of adverse events was lower with lixisenatide (55%) versus liraglutide (65%), with no serious events or hypoglycaemia reported. Conclusions Once daily prebreakfast lixisenatide provided a significantly greater reduction in PPG (AUC) during a morning test meal versus prebreakfast liraglutide. Lixisenatide provided significant decreases in postprandial insulin, C-peptide (vs. an increase with liraglutide) and glucagon, and better gastrointestinal tolerability than liraglutide.

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Author and article information

Contributors

Sanjay Kalra: brideknl@gmail.com , brideknl-@gmail.com

Journal

Journal ID (nlm-ta): Diabetes Ther

Journal ID (iso-abbrev): Diabetes Ther

Title: Diabetes Therapy

Publisher: Springer Healthcare (Cheshire )

ISSN (Print): 1869-6953

ISSN (Electronic): 1869-6961

Publication date (Electronic): 10 March 2016

Publication date PMC-release: 10 March 2016

Publication date (Print): March 2016

Volume: 7

Issue: 1

Pages: 1-9

Affiliations

[ ]Department of Endocrinology, Bharti Hospital, Karnal, India

[ ]Department of Endocrinology, AIIMS, New Delhi, India

Article

Publisher ID: 160

DOI: 10.1007/s13300-016-0160-4

PMC ID: 4801814

PubMed ID: 26965024

SO-VID: c9bc5a9f-9e57-4df2-8f36-ca374675a2ab

History

Date received : 5 January 2016

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ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: antidiabetic drugs,glucagon,insulin,insulin:glucagon ratio,therapy choice

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ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: antidiabetic drugs, glucagon, insulin, insulin:glucagon ratio, therapy choice

The Insulin:Glucagon Ratio and the Choice of Glucose-Lowering Drugs

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GLUT4 biology

Most cited references 21

Regulation of insulin secretion in human pancreatic islets.

Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus.

Pharmacodynamic characteristics of lixisenatide once daily versus liraglutide once daily in patients with type 2 diabetes insufficiently controlled on metformin

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