Elsevier

The Lancet

Volume 359, Issue 9309, 9 March 2002, Pages 824-830
The Lancet

Articles
Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: a parallel-group study

https://doi.org/10.1016/S0140-6736(02)07952-7Get rights and content

Summary

Background

Glucagon-like peptide 1 (GLP-1) has been proposed as a treatment for type 2 diabetes. We have investigated the long-term effects of continuous administration of this peptide hormone in a 6-week pilot study.

Methods

20 patients with type 2 diabetes were alternately assigned continuous subcutaneous infusion of GLP-1 (n=10) or saline (n=10) for 6 weeks. Before (week 0) and at weeks 1 and 6, they underwent β-cell function tests (hyperglycaemic clamps), 8 h profiles of plasma glucose, insulin, C-peptide, glucagon, and free fatty acids, and appetite and side-effect ratings on 100 mm visual analogue scales; at weeks 0 and 6 they also underwent dexascanning, measurement of insulin sensitivity (hyperinsulinaemic euglycaemic clamps), haemoglobin A1c, and fructosamine. The primary endpoints were haemoglobin A1c concentration, 8-h profile of glucose concentration in plasma, and β-cell function (defined as the first-phase response to glucose and the maximum insulin secretory capacity of the cell). Analyses were per protocol.

Findings

One patient assigned saline was excluded because no veins were accessible. In the remaining nine patients in that group, no significant changes were observed except an increase in fructosamine concentration (p=0·0004). In the GLP-1 group, fasting and 8 h mean plasma glucose decreased by 4·3 mmol/L and 5·5 mmol/L (p<0·0001). Haemoglobin A1c decreased by 1·3% (p=0·003) and fructosamine fell to normal values (p=0·0002). Fasting and 8 h mean concentrations of free fatty acids decreased by 30% and 23% (p=0·0005 and 0·01, respectively). Gastric emptying was inhibited, bodyweight decreased by 1·9 kg, and appetite was reduced. Both insulin sensitivity and β-cell function improved (p=0·003 and p=0·003, respectively). No important side-effects were seen.

Interpretation

GLP-1 could be a new treatment for type 2 diabetes, though further investigation of the long-term effects of GLP-1 is needed.

Introduction

Type 2 diabetes is characterised by insulin resistance and β-cell dysfunction.1 It results in deterioration of glycaemic control over time, primarily through progressive β-cell dysfunction.1 Although strict glycaemic control reduces the risk of microvascular complications, the deterioration of β-cell function seems inevitable.1, 2

Glucagon-like peptide 1 (GLP-1) is an intestinally produced peptide hormone. Under physiological conditions, it is secreted in response to ingestion of food3 and has an important role in regulating postprandial blood glucose concentrations.4 GLP-1 secretion is lower than normal in patients with type 2 diabetes,5 which suggests that the hormone may contribute to the pathogenesis of the disease. Exogenous GLP-1 acutely stimulates insulin secretion, inhibits glucagon secretion, and lowers plasma glucose concentrations in people with type 2 diabetes.6 In addition, GLP-1 inhibits gastric emptying7 and reduces appetite in these patients.8 In rats, GLP-1 reverses age-dependent decline in β-cell function9 and stimulates β-cell proliferation and neogenesis.10 Thus, GLP-1 may be useful in the treatment of type 2 diabetes. This study was undertaken to investigate the long-term effects of GLP-1 on glycaemic control, bodyweight, insulin resistance, and β-cell function in patients with type 2 diabetes.

Section snippets

Patients

The patients were recruited from the Department of Endocrinology, Hvidovre Hospital, Denmark. Eligible patients had had type 2 diabetes diagnosed after the age of 40 years and normal concentrations of haemoglobin and creatinine and normal liver function. 20 patients were included in the study and assigned to either GLP-1 or saline. The first two consecutive eligible patients were assigned GLP-1 treatment, and the next two were assigned saline, and so on. Treatment allocation was concealed from

Results

Of the 20 patients enrolled, 10 were assigned to the GLP-1 group and 10 to the saline group (figure 1). One patient in the saline group was excluded at week 0 because no veins were accessible. Clinical characteristics of the assessable patients are shown in table 1.

For patients in the saline group, plasma concentrations of GLP-1 did not change (week 0, 10·8 pmol/L [SE 2·4]; week 1, 10·5 pmol/L [2·3]; week 6, 9·4 pmol/L [2·1]; p=0·8). By contrast, in the GLP-1 group, concentrations of GLP-1

Discussion

We found that GLP-1 significantly decreases concentrations of plasma glucose, haemoglobin A1c, fructosamine, and free fatty acids and improves insulin sensitivity and β-cell function in patients with type 2 diabetes. The study, however, has some methodological constraints. It was not randomised, nor was it carried out double blind, and such observational studies can overestimate intervention effects compared with randomised trials. However, the patients in our study were similar at entry, which

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