Exenatide's Effect on Beta-cell Function in New Onset T2DM
Exenatide's Effect on Beta-cell Function in New Onset T2DM
Objective To determine the effect of chronic daily exenatide treatment on β-cell function in type 2 diabetes (T2DM).
Background Glucagon-like peptide receptor agonists, such as exenatide, are commonly used to treat patients with T2DM. Drugs in this class are insulinotropic but lower blood glucose by multiple mechanisms such that effects on β-cell function can be difficult to discern by conventional measures.
Design Seventy-nine subjects with previously untreated T2DM were studied before and after 24 weeks of treatment with one of the two doses of exenatide, 5- or 10-μg twice daily, or placebo. All subjects had oral glucose tolerance tests (OGTT) before and after randomization with measurement of plasma glucose, insulin and C-peptide concentrations. Insulin secretion rates (ISR), peripheral insulin sensitivity (OGIS) and hepatic insulin resistance index (Hep-IR) were calculated.
Results During the trial, all three groups lost similar, small but significant, amounts of weight. Compared to placebo, 24 weeks of daily high- or low-dose exenatide treatment reduced HbA1c and improved fasting and postprandial hyperglycaemia. Exenatide was associated with improved OGIS and Hep-IR independent of changes in weight. Plasma insulin levels and ISR during the OGTT did not differ before or after treatment with exenatide or placebo. However, when considered as a function of plasma glucose and insulin sensitivity, both doses of exenatide improved ISR proportionately to the improvement in plasma glucose. The higher dose of exenatide was associated with a significant improvement in β-cell sensitivity to glucose.
Conclusions These findings demonstrate that in persons with early T2DM, chronic treatment with exenatide enhanced ISR and increased β-cell sensitivity to glucose. These improvements in β-cell function were not clearly reflected in plasma insulin and C-peptide levels, but became apparent when glycemia and insulin sensitivity were accounted for.
Signalling by the gastrointestinal hormone glucagon-like peptide 1 (GLP-1) is essential for normal glucose tolerance and helps to regulate a range of physiologic systems that control blood glucose, including islet function, gastric emptying, glucose production and food intake. Enhancement of glucose-stimulated insulin secretion is central to the effects of GLP-1 on glycemic regulation. Uniquely among the insulinotropic gastrointestinal hormones, the effects of GLP-1 to stimulate β-cell function are retained in subjects with type 2 diabetes mellitus (T2DM). GLP-1 restores some of the first-phase insulin secretion in subjects with T2DM and normalizes pulsatile insulin secretion in individuals with impaired glucose tolerance. For this reason, the GLP-1 system has been targeted in the development of drugs to treat T2DM through strategies that include long-acting agonists of the GLP-1 receptor (GLP-1r) and small molecules that inhibit the primary metabolism of GLP-1.
Exenatide is a synthetic replica of the reptilian peptide exendin-4 that shares approximately 50% of sequence identity to GLP-1 and is a potent GLP-1r agonist. Subcutaneous administration of exenatide leads to plasma concentrations that far exceed those of native GLP-1 released after meals. Intravenous (IV) exenatide given to T2DM subjects increases insulin release and improves the defects in β-cell function that are thought to be central to the disease such as early insulin release in response to oral and IV glucose. In clinical practice, the original formulation of exenatide is delivered as a subcutaneous injection twice daily and has been shown to reduce HbA1c by approximately 1% when used as monotherapy or combined with other medications to treat T2DM.
The effect of the short-acting formulation of exenatide on the postprandial glucose profile is acute and probably results from a combination of enhanced insulin secretion, delayed gastric emptying and suppressed glucagon release. However, it appears that exenatide may also have actions on hepatic metabolism, and this may contribute to the known effect to reduce fasting glucose. Distinguishing among the various glucose-lowering actions of exenatide in diabetic subjects can be difficult. Trials of daily exenatide treatment in T2DM patients have demonstrated plasma insulin levels to be similar in treated and control subjects despite effective reduction of HbA1c. Although maintenance of similar insulin concentrations at a lower chronic glycemic state is consistent with improved insulin secretion, the β-cell response to exenatide treatment could be understated in studies where plasma insulin or C-peptide is the only measure of β-cell function. Mari and colleagues addressed this problem using mathematical modelling to determine the effects of 30 weeks of twice daily exenatide treatment on insulin secretion in diabetic patients also taking metformin alone or with sulfonylurea. Using before-and-after comparisons, they showed a significant effect of exenatide, used with oral agents, to improve β-cell function. However, changes in insulin sensitivity that are important determinants of the β-cell response were not considered in this study. In the analysis presented here, we evaluated the effects of chronic exenatide treatment on insulin secretion after oral glucose tolerance tests (OGTT) in T2DM subjects not taking other medications, taking into account the effects of insulin sensitivity as well as glycemia on the β-cell response.
Abstract and Introduction
Abstract
Objective To determine the effect of chronic daily exenatide treatment on β-cell function in type 2 diabetes (T2DM).
Background Glucagon-like peptide receptor agonists, such as exenatide, are commonly used to treat patients with T2DM. Drugs in this class are insulinotropic but lower blood glucose by multiple mechanisms such that effects on β-cell function can be difficult to discern by conventional measures.
Design Seventy-nine subjects with previously untreated T2DM were studied before and after 24 weeks of treatment with one of the two doses of exenatide, 5- or 10-μg twice daily, or placebo. All subjects had oral glucose tolerance tests (OGTT) before and after randomization with measurement of plasma glucose, insulin and C-peptide concentrations. Insulin secretion rates (ISR), peripheral insulin sensitivity (OGIS) and hepatic insulin resistance index (Hep-IR) were calculated.
Results During the trial, all three groups lost similar, small but significant, amounts of weight. Compared to placebo, 24 weeks of daily high- or low-dose exenatide treatment reduced HbA1c and improved fasting and postprandial hyperglycaemia. Exenatide was associated with improved OGIS and Hep-IR independent of changes in weight. Plasma insulin levels and ISR during the OGTT did not differ before or after treatment with exenatide or placebo. However, when considered as a function of plasma glucose and insulin sensitivity, both doses of exenatide improved ISR proportionately to the improvement in plasma glucose. The higher dose of exenatide was associated with a significant improvement in β-cell sensitivity to glucose.
Conclusions These findings demonstrate that in persons with early T2DM, chronic treatment with exenatide enhanced ISR and increased β-cell sensitivity to glucose. These improvements in β-cell function were not clearly reflected in plasma insulin and C-peptide levels, but became apparent when glycemia and insulin sensitivity were accounted for.
Introduction
Signalling by the gastrointestinal hormone glucagon-like peptide 1 (GLP-1) is essential for normal glucose tolerance and helps to regulate a range of physiologic systems that control blood glucose, including islet function, gastric emptying, glucose production and food intake. Enhancement of glucose-stimulated insulin secretion is central to the effects of GLP-1 on glycemic regulation. Uniquely among the insulinotropic gastrointestinal hormones, the effects of GLP-1 to stimulate β-cell function are retained in subjects with type 2 diabetes mellitus (T2DM). GLP-1 restores some of the first-phase insulin secretion in subjects with T2DM and normalizes pulsatile insulin secretion in individuals with impaired glucose tolerance. For this reason, the GLP-1 system has been targeted in the development of drugs to treat T2DM through strategies that include long-acting agonists of the GLP-1 receptor (GLP-1r) and small molecules that inhibit the primary metabolism of GLP-1.
Exenatide is a synthetic replica of the reptilian peptide exendin-4 that shares approximately 50% of sequence identity to GLP-1 and is a potent GLP-1r agonist. Subcutaneous administration of exenatide leads to plasma concentrations that far exceed those of native GLP-1 released after meals. Intravenous (IV) exenatide given to T2DM subjects increases insulin release and improves the defects in β-cell function that are thought to be central to the disease such as early insulin release in response to oral and IV glucose. In clinical practice, the original formulation of exenatide is delivered as a subcutaneous injection twice daily and has been shown to reduce HbA1c by approximately 1% when used as monotherapy or combined with other medications to treat T2DM.
The effect of the short-acting formulation of exenatide on the postprandial glucose profile is acute and probably results from a combination of enhanced insulin secretion, delayed gastric emptying and suppressed glucagon release. However, it appears that exenatide may also have actions on hepatic metabolism, and this may contribute to the known effect to reduce fasting glucose. Distinguishing among the various glucose-lowering actions of exenatide in diabetic subjects can be difficult. Trials of daily exenatide treatment in T2DM patients have demonstrated plasma insulin levels to be similar in treated and control subjects despite effective reduction of HbA1c. Although maintenance of similar insulin concentrations at a lower chronic glycemic state is consistent with improved insulin secretion, the β-cell response to exenatide treatment could be understated in studies where plasma insulin or C-peptide is the only measure of β-cell function. Mari and colleagues addressed this problem using mathematical modelling to determine the effects of 30 weeks of twice daily exenatide treatment on insulin secretion in diabetic patients also taking metformin alone or with sulfonylurea. Using before-and-after comparisons, they showed a significant effect of exenatide, used with oral agents, to improve β-cell function. However, changes in insulin sensitivity that are important determinants of the β-cell response were not considered in this study. In the analysis presented here, we evaluated the effects of chronic exenatide treatment on insulin secretion after oral glucose tolerance tests (OGTT) in T2DM subjects not taking other medications, taking into account the effects of insulin sensitivity as well as glycemia on the β-cell response.