Loss of beta cell function as fasting glucose increases in the non-diabetic range

Abstract

Aims/hypothesis. Our aim was to define the level of glycaemia at which pancreatic insulin secretion, particularly first-phase insulin release, begins to decline. Methods. Plasma glucose and insulin concentrations were measured during an IVGTT in 553 men with non-diabetic fasting plasma glucose concentrations. In 466 of the men C-peptide was also estimated. IVGTT insulin secretion in first and late phases was assessed by: (i) the circulating insulin response; (ii) population parameter deconvolution analysis of plasma C-peptide concentrations; and (iii) a combined model utilising both insulin and C-peptide concentrations. Measurements of insulin sensitivity and elimination were also derived by modelling analysis.Results. As fasting plasma glucose (FPG) increased, IVGTT first-phase insulin secretion declined by 73%, 71% and 68% for the three methods respectively. The FPG values at which this decline began, determined by change point regression, were 4.97, 5.16 and 5.42 mmol/l respectively. The sensitivity of late-phase insulin secretion to glucose declined at FPG concentrations above 6.0 mmol/l. Insulin elimination, but not insulin sensitivity, varied with FPG. IntroductionThe respective roles of insulin deficiency and insulin resistance in the development of Type 2 diabetes mellitus remain controversial [1,2]. In response to a glucose stimulus, two phases of insulin secretion may be distinguished [3]. The first occurs as an immediate response to a rise in blood glucose concentrations. Low first-phase insulin release is an early abnormality in deteriorating glucose homeostasis and predicts the subsequent development of Type 2 diabetes [4,5,6,7]. Late-phase insulin release is more prolonged, but of lesser amplitude. It includes the progressively increasing second phase of insulin secretion seen in response to sustained hyperglycaemia [3], and also the compensatory insulin secretion that is the feedback response to a continued increase in circulating glucose. This late-phase insulin secretion may seem to be preserved even when glucose metabolism is defective,In the course of this work, our colleague and co-author James Jeffs died unexpectedly after a short illness. His contribution will be greatly missed.

Beta cell dysfunction in patients with acute myocardial infarction but without previously known type 2 diabetes: a report from the GAMI study

“…Indeed, fasting hyperinsulinaemia, known to reflect decreased insulin sensitivity, and decreased insulin secretion together constitute the strongest independent predictor of type 2 diabetes [10]. Furthermore, decreased beta cell function may exist already at normal fasting plasma glucose levels [11]. Thus, detailed information on the pathogenesis of disturbed glucose regulation in AMI patients may pave the way for novel treatments aimed at improving cardiovascular outcome and delaying the onset of clinical diabetes and typical diabetes complications.…”

To: Godsland IF, Jeffs JA, Johnston DG (2004) Loss of beta cell function as fasting glucose increases in the non-diabetic range. Diabetologia 47:1157–1166

“…In normal rats, small (0.89 mmol/l or 16 mg/dl) increments in mean daylong FPG have been shown to completely abolish first-phase insulin secretion [7]. Such an effect in humans could explain the results observed by Godsland et al [1]. Moreover, in animal studies, correction of chronic hyperglycaemia with phlorizin restores first-phase insulin secretion, indicating that the reduction in first-phase insulin secretion is the result of chronic hyperglycaemia rather than the cause in this animal model [6].…”

Comment on: Godsland IF, Jeffs JAR, Johnston DG (2004) Loss of beta cell function as fasting glucose increases in the non-diabetic range. Diabetologia 47:1157–1166

“…Returning to the work of Godsland and co-workers [1], I believe that it may serve not only to challenge the definition of normal glycaemic values, but also to support the reassessment of the concept of prediabetes, i.e. that there is a non-hyperglycaemic stage of diabetes-just as diabetologists such as Rolf Luft and Stefan Fajans suggested almost 50 years ago.…”

“…The data of Godsland et al [1] provide convincing evidence in support of the ADA initiative and offer both evidence and logic for lowering the upper normal limits for fasting plasma glucose, which Schriger and Lorber [4] question aggressively in their paper on the Expert Committee's proposal. The anxiety of these two researchers derives from the calculation that, due to the changes proposed by the Expert Committee, the number of patients with impaired fasting glucose in the USA will rise from 10 to 35 million, thus affecting 22.5% of the adult population.…”

“…To the Editor For more than two decades I have awaited data such as those published by Godsland and co-workers [1] in the July issue of your journal. Although they focused primarily on the identification of the early disturbances that occur in the natural history of type 2 diabetes (the progressive loss of the first, and then of the second phase of insulin response), it seems of great importance to me that these changes occur at blood glucose levels between 5.0 and 5.4 mmol/l.…”