Management of type 2 diabetes: the GLP‐1 pathway

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Management of type 2 diabetes: the GLP-1 pathway Abd A Tahrani MMedSci, MD, MRCP, Milan K Piya MRCP, Anthony H Barnett MD, FRCP Centre for Endocrinology Diabetes and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham; Department of Diabetes and Endocrinology, Heart of England NHS Foundation Trust, Birmingham Heartlands Hospital Type 2 diabetes mellitus (T2DM) is a major challenge to healthcare systems around the world, with an estimated prevalence of 6% (246 million) in 2007 rising to 7.3% (380 million) in 2025 worldwide.1–5 In this article, the authors consider the significance of the GLP-1 pathway in the management of T2DM, and some of the advantages of incretin-based therapy.

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2DM is a complex disorder in which the interaction between environmental and genetic factors results in the development of insulin resistance (IR) and beta-cell dysfunction.6,7 The aim of treatment is to attain near-normal glucose and lipid levels and blood pressure. 8–10 Due to the multifactorial nature of T2DM and the complexity of achieving such targets, a variety of pharmacological and nonpharmacological inter ventions have been developed. Here we discuss the role of incretinbased therapies in the management of T2DM. 18

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BENEFIT OF STRATEGIES THAT IMPROVE BETA-CELL FUNCTION While IR is an important predisposing factor, beta-cell dysfunction is the critical step in developing T2DM.6,7 IR is defined as the lack of responsiveness of target cells to insulin, which initially leads to hyperinsulinaemia.11 The development of IR precedes the onset of T2DM by many years. 6,11 It is affected by many factors including puberty, ageing, pregnancy, physical activity and oral intake. 12–16 Obesity, however, is the single most important contributor.16 Obesity modulates insulin sensitivity via multiple factors including imbalance of hormones (leptin and adiponectin), cytokines (eg tumour necrosis factor-alpha, interleukin-6), suppressors of cytokine signalling, inflammatory signalling pathways (nuclear factor kappa-beta and inhibitor of kappa-beta kinase) and retinol binding protein-4.7,16–20 However, the crucial factor in developing IR in obesity is thought to be the release of non-esterified fatty acids (NEFAs) particularly from intraabdominal fat.16 Increased NEFAs result in increased intracellular diacylglycerol and fatty acyl-co A, which lead to phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2; this in turn diminishes downstream events of the insulin receptor signalling, resulting in IR.16,21 Despite the important role of obesity in driving IR, most obese insulin-resistant individuals do not develop T2DM.7,16,22 This is because their beta-cells can produce significantly more insulin to maintain

normoglycaemia.16,23–25 Hence, failure of beta-cells to secrete enough insulin to overcome IR (ie beta-cell dysfunction) is the crucial step in the development and progression of T2DM.16,26 The reason for the decline in beta-cell function is not entirely clear, but appears to involve hyperglycaemia per se, together with excessive production of NEFAs, amyloid formation and genetic factors.27–31 Based on our understanding of the pathophysiology of T2DM, multiple pharmacological and nonpharmacological interventions have been developed over the past five decades to improve glycaemia and (hopefully) slow disease progression. These have largely been disappointing in the sense that most of the observed initial improvements in glycaemia were not sustainable due to the progressive nature of beta-cell dysfunction.32,33 Hence, interventions that can slow/reverse beta-cell decline might be expected to have a significant sustained impact in patients with T2DM. THE GLP-1 PATHWAY AND THE ROLE OF INCRETIN HORMONES IN REGULATING GLUCOSE METABOLISM

The possibility that intestinal factors are secreted in response to nutrients that can lower blood glucose levels was described in the early 1900s.34,35 These factors were named ‘incretins’ in the 1930s.34 The incretin effect was first described by Elrick et al, following the observation that insulin responses to oral glucose exceed those measured after intravenous administration of equivalent amounts of glucose.36 w w w. f u t u r e p r e s c r i b e r. c o . u k

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carbohydrate and/or lipid intake vagal stimulation? L-cells in the distal ileum

DPP-4 inhibitors

Incretin mimetics GLP-1

DPP-4 inactivation

alpha-cells

glucose-dependent glucagon suppression

beta-cells

increased beta-cell mass?

glucosedependent insulin secretion

brain

stomach

reduced appetite

delayed gastric emptying

weight reduction

reduced hepatic glucose output, reduced fasting plasma glucose, reduced post-prandial plasma glucose

reduced postprandial plasma glucose

Figure 1. Functions of the GLP-1 pathway

The incretins are secreted from the gastrointestinal tract during food intake and bind to receptors on betacells, resulting in insulin secretion.37 Both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) bind to specific G protein-coupled receptors that are found in the pancreas, stomach, skeletal muscle, heart, lung and brain.38 The incretin effect in healthy individuals is responsible for 50–70% of the insulin response to a meal.39 GIP GIP was the first incretin to be described. It is a single 42-amino acid w w w. f u t u r e p r e s c r i b e r. c o . u k

peptide derived from a 153-amino acid precursor, whose gene is located on chromosome 17.40,41 It is secreted in a single bioactive form from the K-cells in the duodenum and jejunum in response to the ingestion of carbohydrates and/or lipids.34,40,41 GIP results in glucose-dependent insulin secretion in humans.34,41,42 In addition, GIP plays a role in fat metabolism in the adipocytes and has a proliferative effect on the beta-cells.41,43,44 Unlike GLP-1, GIP has no effect on the alpha-cells that secrete glucagon and has no impact on

food intake, satiety, gastric emptying or body weight.41,45 In T2DM, GIP levels are either normal or increased, while GLP-1 levels are usually reduced.46–48 GLP-1 This was the second incretin to be discovered. GLP-1 is cleaved from pro-glucagon (the gene is situated on chromosome 2) and secreted from the L-cells in the distal ileum and colon. 34,41 GLP-1 and GIP contribute and potentiate glucosedependent insulin secretion in an additive manner, but GLP-1 appears to be responsible for the majority FUTURE PRESCRIBER

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of the incretin effect on the betacell.34,37 Despite the distal location of the L-cells, GLP-1 is secreted within minutes following oral intake, which suggests that neural and endocrine factors rather than direct stimulation are involved.34,41 These factors are not well understood in humans, but animal models suggest a role for taste receptors and vagal stimulation.34,41,49,50 GLP-1 has a number of functions, including stimulation of glucose-dependent insulin secretion, glucose-dependent suppression of glucagon secretion, slowing of gastric emptying, reduction of food intake and possibly improved insulin sensitivity (Figure 1).37,39,51 In addition, GLP-1 increases insulin gene transcription and all steps of insulin biosynthesis. 46,47 Animal studies have shown that GLP-1 increases beta-cell mass, maintains beta-cell efficiency and reduces betacell apoptosis.51,52 Although GLP-1 levels are reduced in patients with T2DM, their response to exogenous GLP-1 remains intact. Inactivation of incretin hormones GIP and GLP-1 are rapidly degraded by the enzyme dipeptidyl peptidase4 (DPP-4).34 DPP-4 cleaves the active peptide at position 2 alanine (Nterminal) resulting in inactive petide.41 DPP-4 is widely expressed in human tissues including the brain, lungs, kidneys, adrenals, pancreas, intestine and lymphocytes, among others.41 Interestingly, it is found in the endothelial cells of the blood vessels that drain the intestinal mucosa, where the L-cells are situated.41,53 This suggests that the majority of GLP-1 is inactivated almost immediately following secretion. This rapid inactivation of GLP-1 and GIP contributes to a half-life of 80%) of subjects opted to enter the open-label extensions. In the exenatide-metformin extension trial, exenatide remained beneficial at 82 weeks.75 In addition to the 1% fall in HbA1c at 30 weeks, there was a further 0.2% fall by 82 weeks. Data from the two trials of exenatide added to a sulphonylurea or sulphonylurea plus metformin showed reductions in HbA1c by week 30 of 1% and this was sustained to week 82.76 It also showed that 44% of patients with HbA1c >7% achieved levels )7% at week 82. A pooled analysis of the open-label extensions from all subjects who achieved two years of exenatide exposure, showed w w w. f u t u r e p r e s c r i b e r. c o . u k

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DeFronzo et al 59

336 subjects

Metformin + exenatide (5µg twice daily versus 10µg twice daily) versus metformin + placebo

HbA1c: Dose-dependent reductions in the exenatide arm [-0.40 ± 0.11% (5µg), -0.78 ± 0.10% (10µg)] versus +0.08 ± 0.10% for placebo (p