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

Abstract

Godsland and colleagues [1], the investigators report a significant decline in beta cell function, which begins within the normal range of fasting plasma glucose (FPG) concentrations. Using the IVGTT in 553 non-diabetic men with an FPG<7.0 mmol/l, they observed a marked decline in first-phase insulin secretion, beginning at an FPG well within the normal range, without any change in insulin sensitivity. These results suggest that the decline in insulin secretion is the primary event and is unrelated to changes in insulin sensitivity. A similar observation has been reported in children [2], although most previous studies have demonstrated a decrease in insulin sensitivity in adults with an FPG >6.1 mmol/l (110 mg/dl) [3,4]. The defect in first-phase insulin secretion is reminiscent of the decline in insulin secretion observed in normal glucose-tolerant subjects with 2-h plasma glucose concentrations well within the normal range, reported by Gasteldelli and colleagues [5]. Both observations [1,5] suggest that the current cut-off values that define normal glucose tolerance do not correspond to plasma glucose levels that identify the presence of physiological alterations in insulin secretion in vivo. In their interpretation of the association between the decline in first-phase insulin secretion and the rise in FPG in response to intravenous glucose, Godsland et al. suggest that loss of pancreatic beta cell function in the first phase is, therefore, the critical factor in declining glucose homeostasis in the non-diabetic range of FPG [1]. Although we agree that impaired beta cell function occurs in individuals with FPG concentrations that are considered to be within the normal range [5], we are concerned about the authors' interpretation of their results. The decline in first-phase insulin secretion that accompanies the rise in FPG does not necessarily indicate a causal relationship. One could argue that the increase in FPG, secondary to excess hepatic glucose production or insulin resistance in peripheral tissues, is the primary event and that chronic, sustained modest hyperglycaemia leads to impaired insulin secretion, i.e. glucotoxicity. A 'glucotoxic' effect of hyperglycaemia has been demonstrated in vivo, both in humans and animals, and in vitro in cell culture systems [6][7][8]. 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]. Although a similar study in man is needed to establish that hyperglycaemia is the primary disturbance and leads to impaired insulin secretion, indirect evidence supports this scenario. First, correction of hyperglycaemia improves insulin ...