Glucagon-like peptide-1, glucose homeostasis and diabetes

doi:10.1016/j.molmed.2008.01.003

Trends in Molecular Medicine

Volume 14, Issue 4, April 2008, Pages 161-168

https://doi.org/10.1016/j.molmed.2008.01.003 Get rights and content

Incretins, enhancers of insulin secretion, are essential for glucose tolerance, and a reduction in their function might contribute to poor β-cell function in patients with type-2 diabetes mellitus. However, at supraphysiological doses, the incretin glucagon-like peptide-1 (GLP-1) protects pancreatic β cells, and inhibits glucagon secretion, gastric emptying and food intake, leading to weight loss. GLP-1 mimetics, which are stable-peptide-based activators of the GLP-1 receptor, and incretin enhancers, which inhibit the incretin-degrading enzyme dipeptidyl peptidase-4, have emerged as therapies for type-2 diabetes and have recently reached the market. The pathophysiological basis the clinical use of these therapeutics is reviewed here.

Introduction

During 2006–2007, an entirely novel therapeutic principle for the treatment of type-2 diabetes mellitus (2DM) was introduced onto the market in the US and Europe: the incretin-based therapies. These therapies fall into two groups: (i) incretin mimetics, which are injectable peptide preparations with actions similar to the natural incretin hormones, and (ii) the incretin enhancers, which are available in a form to be taken orally agents that inhibit the normal degradation of incretin hormones in the body and, thereby, increase their plasma concentrations and biological actions. Both types have been commercially successful, with millions of prescriptions already issued. In parallel with their launch, numerous studies – some of them forming the basis for drug approval – have been published. Here, we review the scientific basis for the development of incretin-based drugs and the clinical experience gathered to date.

Section snippets

The incretin effect

Incretins amplify insulin secretion, an effect that is observed when glucose is taken orally (as opposed to infused intravenously) in amounts that result in identical increases in plasma glucose concentrations (glucose excursions) [1] (Figure 1). The effect can, therefore, be presented as the ratio between the areas under the oral and intravenous (i.v.) insulin concentration curves and will, in healthy subjects given 75 g glucose orally, amount to an approximately threefold increase in insulin

Actions of GLP-1 in type-2 diabetes mellitus

To address whether supraphysiological doses of GLP-1 restore incretin action in 2DM patients, Zander et al.[14] studied the effects of a six-week continuous subcutaneous administration of GLP-1 (4.8 pmol⁻¹ kg⁻¹ min⁻¹) in 2DM patients. This dose of GLP-1 resulted in a dramatic reduction in fasting and postprandial glucose concentration levels, a 1.3% reduction in glycated hemoglobin levels (HbA_1c; a measure of average glucose concentrations over time), normalization of fructosamine levels, ∼2-kg

GLP-1-based therapies

Because of its rapid elimination, natural GLP-1 is unsuitable for clinical use (and continuous s.c. infusion is, for various reasons, not optimal). Two strategies have therefore been pursued to exploit the beneficial actions of the hormone: (i) development of stable activators of the GLP-1 receptor (so-called incretin or GLP-1 mimetics) and (ii) inhibitors of DPP-4 (i.e. incretin enhancers).

Concluding remarks

The most exciting aspect of incretin-based therapies (both GLP-1 mimetics and DPP-4 inhibitors) is the possibility that they, because of their protective and perhaps trophic effects on the pancreatic β cells, might halt the progression of disease that occurs despite intensified conventional treatment. So far, this has not been established in any clinical trials but animal studies with GLP-1 analogs and DPP-4 inhibitors have shown that β-cell proliferation and cytoprotection is seen with both.

Conflict-of-interest statement

J.J.H. is a consultant for Novo Nordisk (www.novonordisk.com) and Merck Sharp & Dohme (MSD, www.msd-uk.co.uk); is a member of advisory boards for Novo Nordisk, Roche (www.roche.com), Sanofi Aventis (www.sanofi-aventis.co.uk) and Amylin Corporation (www.amylin.com); and is a recipient of a research grant from Novartis (www.novartis.com). S.M. is a consultant Novo Nordisk, MSD, Pfizer (www.pfizer.com), Abbott Laboratories (www.abbott.com), Sanofi Aventis, Astra-Zeneca (www.astrazeneca.com),

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Cited by (151)

Dietary impact on fasting and stimulated GLP-1 secretion in different metabolic conditions – a narrative review
2024, American Journal of Clinical Nutrition
Glucagon-like peptide 1 (GLP-1), a gastrointestinal peptide and central mediator of glucose metabolism, is secreted by L cells in the intestine in response to food intake. Postprandial secretion of GLP-1 is triggered by nutrient-sensing via transporters and G-protein-coupled receptors (GPCRs). GLP-1 secretion may be lower in adults with obesity/overweight (OW) or type 2 diabetes mellitus (T2DM) than in those with normal glucose tolerance (NGT), but these findings are inconsistent. Because of the actions of GLP-1 on stimulating insulin secretion and promoting weight loss, GLP-1 and its analogs are used in pharmacologic preparations for the treatment of T2DM. However, physiologically stimulated GLP-1 secretion through the diet might be a preventive or synergistic method for improving glucose metabolism in individuals who are OW, or have impaired glucose tolerance (IGT) or T2DM. This narrative review focuses on fasting and postprandial GLP-1 secretion in individuals with different metabolic conditions and degrees of glucose intolerance. Further, the influence of relevant diet-related factors (e.g., specific diets, meal composition, and size, phytochemical content, and gut microbiome) that could affect fasting and postprandial GLP-1 secretion are discussed. Some studies showed diminished glucose- or meal-stimulated GLP-1 response in participants with T2DM, IGT, or OW compared with those with NGT, whereas other studies have reported an elevated or unchanged GLP-1 response in T2DM or IGT. Meal composition, especially the relationship between macronutrients and interventions targeting the microbiome can impact postprandial GLP-1 secretion, although it is not clear which macronutrients are strong stimulants of GLP-1. Moreover, glucose tolerance, antidiabetic treatment, grade of overweight/obesity, and sex were important factors influencing GLP-1 secretion. The results presented in this review highlight the potential of nutritional and physiologic stimulation of GLP-1 secretion. Further research on fasting and postprandial GLP-1 concentrations and the resulting metabolic consequences under different metabolic conditions is needed.
GLP-1 receptor agonist, liraglutide, protects podocytes from apoptosis in diabetic nephropathy by promoting white fat browning
2023, Biochemical and Biophysical Research Communications
Glucagon like peptide-1 receptor agonists (GLP-1RAs) belong to the class of incretin drugs. Incretin is a hormone secreted into blood by intestinal cells after food stimulation that induces insulin secretion. Liraglutide is a long-acting GLP-1RA that can reduce blood pressure, blood lipids, and inflammation. Previous studies showed that liraglutide can promote white fat browning and improve renal outcomes in patients with type 2 diabetes mellitus. However, no studies have linked white fat browning to kidney damage. The objective of this study was to investigate the effects of liraglutide-induced white fat browning on podocyte apoptosis in diabetic nephropathy. We also aimed to determine whether podocytes express glucagon like peptide-1 receptor (GLP-1R) and if liraglutide directly affects podocytes via GLP-1R. We assessed fat and renal function in db/db and wild-type mice and the effects of adipocyte conditioned medium on cultured podocytes. Liraglutide (400 mg/kg/d) was subcutaneously injected for 8 weeks. Liraglutide promoted white fat browning in vivo. During adipogenic differentiation of 3T3-L1 cells in vitro, liraglutide also upregulated expression of peroxisome proliferator-activated receptor γ coactivator-1 alpha (PGC1α) and uncoupling protein 1 (UCP1), which can induce white fat browning in vitro. Furthermore, we found that supernatant from 3T3-L1 cells stimulated by liraglutide reduced podocyte apoptosis. The inhibitory effect of liraglutide on apoptosis was eliminated by exogenous TNF-α. Finally, podocytes express GLP-1R. In vivo and in vitro studies showed that the apoptosis of podocytes in diabetic nephropathy may be related to the effect of liraglutide on promoting white lipid browning. Similarly, liraglutide may directly affect podocytes via GLP-1R.
Is the steady-state concentration, duration of action, or molecular weight of GLP-1RA associated with cardiovascular and renal outcomes in type 2 diabetes?
2023, European Journal of Internal Medicine
Disparities were found in the cardiovascular and renal outcomes among different glucagon-like peptide 1 receptor agonist (GLP-1RA) subtypes. However, whether the characteristics of GLP-1RA itself are associated with these disparities remains unclear.
To assess the association between the steady-state concentration, duration of action, or molecular weight of GLP-1RA and the risks of cardiovascular and renal outcomes in patients with type 2 diabetes (T2D).
PubMed, MEDLINE, EMBASE, Cochrane and Clinicaltrial.gov from inception to April 2022.
Randomized controlled trials (RCTs) investigating GLP-1RAs in patients with T2D were included.
Literature screening and data extraction were performed independently by 2 researchers. The outcomes were computed as odds ratio (OR) and its 95% confidence interval (CI). Subgroup analyses were conducted according to steady-state concentration, duration of action and molecular weight of GLP-1RAs.
Primary outcomes were major adverse cardiovascular events (MACE), composite renal outcome and all-cause mortality.
In all, 61 RCTs were included. When compared with non-GLP-1RA agents, GLP-1RAs with high steady-state concentration were associated with greater risk reduction in MACE (p for subgroup difference = 0.01) and the composite renal outcome (p for subgroup difference = 0.008) in patients with T2D. Greater risk reductions in MACE between GLP-1RA users versus non-GLP-RA users were observed in long acting stratum when compared with short acting stratum (p for subgroup difference = 0.04) in patients with T2D. The molecular weight of GLP-1RAs was not associated with the risk of cardiovascular and renal outcomes.
GLP-1RAs with high steady-state concentrations might be associated with greater risk reductions in cardiovascular and renal outcomes in patients with T2D. Long acting GLP-1RAs might outperform short acting ones in reducing the risk of cardiovascular outcomes. These findings provided new insights for guiding the clinical applications of GLP-1RAs in patients with T2D.
Glucagon-like peptide-1 analog liraglutide leads to multiple metabolic alterations in diet-induced obese mice
2022, Journal of Biological Chemistry
Liraglutide, a glucagon-like peptide-1 analog, has beneficial metabolic effects in patients with type 2 diabetes and obesity. Although the high efficacy of liraglutide as an anti-diabetic and anti-obesity drug is well known, liraglutide-induced metabolic alterations in diverse tissues remain largely unexplored. Here, we report the changes in metabolic profiles induced by a 2-week subcutaneous injection of liraglutide in diet-induced obese mice fed a high-fat diet for 8 weeks. Our comprehensive metabolomic analyses of the hypothalamus, plasma, liver, and skeletal muscle showed that liraglutide intervention led to various metabolic alterations in comparison with diet-induced obese or nonobese mice. We found that liraglutide remarkably coordinated not only fatty acid metabolism in the hypothalamus and skeletal muscle but also amino acid and carbohydrate metabolism in plasma and liver. Comparative analyses of metabolite dynamics revealed that liraglutide rewired intertissue metabolic correlations. Our study points to a previously unappreciated metabolic alteration by liraglutide in several tissues, which may underlie its therapeutic effects within and across the tissues.
Emerging roles of Glucagon like peptide-1 in the management of autoimmune diseases and diabetes-associated comorbidities
2022, Pharmacology and Therapeutics
Citation Excerpt :
It is speculated that the clinical effects of GLP-1-RA may be related to the plasma concentrations of active GLP-1. Holst et al. summarized a dose-response relationship between GLP-1 and its biological effects, indicating that higher concentration of GLP-1 is required to slow gastric emptying and thereby reduce food intake (Holst, Deacon, Vilsboll, Krarup, & Madsbad, 2008). Thus, plasma GLP-1 concentration theoretically may also influence the cardiovascular outcome.
Currently, gastrointestinal hormone glucagon like peptide-1 (GLP-1) has received significant attention in maintaining glucose homeostasis through mechanisms involving augmentation of insulin, inhibition of glucagon secretion and regulation of gut motility. Therefore, GLP-1 receptor agonist (GLP-1RA) turns to be one of the most promising hypoglycemic agents for the treatment of type 2 diabetes mellitus (T2DM) and obesity. However, the benefits of GLP-1 and GLP-1RAs are not limited to glucose control and weight loss. Here, we provide a concise overview of the roles of GLP-1 and GLP-1RAs in autoimmune disease, cardiovascular disease (CVD), diabetic kidney disease (DKD), diabetic foot ulcer (DFU), polycystic ovary syndrome (PCOS), and Alzheimer's disease (AD) as well as future challenges in this regard.
Effect of stevia aqueous extract on the antidiabetic activity of saxagliptin in diabetic rats
2021, Journal of Ethnopharmacology
Stevia rebaudiana Bertoni is a perennial herb that belongs to the Asteraceae family. It is a natural sweetener plant known as “Sweet Leaf”, “Sweet Herbs” and “Honey Leaf”, which is estimated to be 300 times more sweetening than sugar cane. Stevia has been used as a traditional treatment for diabetes in many countries for hundreds of years. Several animal studies referred to the antihyperglycemic activity of stevia. However, the combined use of stevia with saxagliptin has not been studied so far, so this study has been done. The aim of the present study was to evaluate the antihyperglycemic effect of stevia alone and in combination with saxagliptin.
Diabetes was induced in rats by i.p. injection of streptozotocin and nicotinamide. Animals were divided into five groups, each contains eight rats. Group I: included negative controland group II: included diabetic control that received saline. Group III: included diabetic rats that received 400 mg/kg/day stevia aqueous extract. Group IV: included diabetic rats that received saxagliptin 10 mg/kg/day. Group V: included diabetic rats that received stevia 400 mg/kg + saxagliptin 10 mg/kg. Food and water intake were measured daily while body weight was measured weekly. After 3 weeks animals were sacrificed and blood and tissue samples were collected. Fasting blood glucose (FBG), serum insulin, serum dipeptidylepeptidase-4 (DPP-4), TC, TGs, LDL, HDL, GSH and MDA were measured in treated and control rats by colorimetric and ELISA methods.
Both stevia and saxagliptin significantly reduced food, water intake, body weight and FBG. Stevia with saxagliptin produced more significant decrease in FBG. While serum insulin increased significantly in stevia, saxagliptin treated groups and their combination. Serum DPP-4 decreased significantly in all treated groups, concerning lipid profile, stevia and saxagliptin notably lowered TC, TGs, and LDL and increased HDL. Both stevia and saxagliptin remarkably decreased MDA and increased GSH compared to diabetic rats. In addition, stevia significantly improved the antidiabetic effects of saxagliptin.
Stevia has an antihyperglycemic effect and could enhance the antidiabetic activity of saxagliptin. DPP-4 attenuation, antihyperlipidemic and antioxidant activity as well as improvement of insulin sensitivity may be involved in the antidiabetic action of stevia.

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Trends in Molecular Medicine

ReviewGlucagon-like peptide-1, glucose homeostasis and diabetes

Introduction

Section snippets

The incretin effect

Actions of GLP-1 in type-2 diabetes mellitus

GLP-1-based therapies

Concluding remarks

Conflict-of-interest statement

J. Biol. Chem.

Regul. Pept.

Cell Metab.

Metabolism

Lancet

Biochem. Biophys. Res. Commun.

Int. J. Biochem. Cell Biol.

Bioorg. Med. Chem. Lett.

Endocr. Pract.

Incretins, insulin secretion and type 2 diabetes mellitus

Diabetologia

Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses

J. Clin. Endocrinol. Metab.

Incretin hormones – an update

Scand. J. Clin. Lab. Invest.

The physiology of glucagon-like peptide 1

Physiol. Rev.

On the physiology of GIP and GLP-1

Horm. Metab. Res.

Cell and molecular biology of the incretin hormones glucagon-like peptide-I and glucose-dependent insulin releasing polypeptide

Endocr. Rev.

International Union of Pharmacology. XXXV. The glucagon receptor family

Pharmacol. Rev.

Glucagon-like peptide-1 prevents β cell glucolipotoxicity

Diabetologia

Glucagon-like peptide 1(GLP-1): an intestinal hormone signalling nutritional abundance, with an unusual therapeutic potential

Trends Endocrinol. Metab.

Glucagon-like peptide containing pathways in the regulation of feeding behaviour

Int. J. Obes. Relat. Metab. Disord.

GLP-1 analogs: satiety without malaise?

Am. J. Physiol. Regul. Integr. Comp. Physiol.

Inhibition of gastric inhibitory polypeptide signaling prevents obesity

Nat. Med.

Reduced incretin effect in type 2 diabetes: cause or consequence of the diabetic state?

Diabetes

Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients

J. Clin. Endocrinol. Metab.

Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus

J. Clin. Invest.

The Influence of GLP-1 on glucose-stimulated insulin secretion: effects on β-cell sensitivity in type 2 and nondiabetic subjects

Diabetes

Defective amplification of the late phase insulin response to glucose by GIP in obese type II diabetic patients

Diabetologia

Four weeks of near-normalizatioin of blood glucose restores the insulin response to GIP and improves the insulin response to GLP-1 in patients with type 2 diabetes

Diabetes

Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms

Diabetologia

Review
Glucagon-like peptide-1, glucose homeostasis and diabetes