Home / Resources / Clinical Gems / International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #128: Beta-Cell Mass and Function in Human Type 2 Diabetes Part 4

International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #128: Beta-Cell Mass and Function in Human Type 2 Diabetes Part 4

Jun 5, 2018

Incretin defect

Oral glucose elicits a greater insulin response than does intravenous glucose. As first demonstrated by Nauck et al. [138], when tested at matched plasma glucose concentrations (iso- glycemic protocol) the oral route of glucose administration induces a robust increment in insulin secretion as compared with the intravenous route. In nondiabetic subjects, such potentiation — named incretin effect — averages 50 – 70% with a standard (75 g) oral glucose load, and increases with the size of the glucose load [134,139]. As depicted in Figure 24.10, the incretin effect is characteristically lost in patients with T2DM [138,140 – 146]. Recent work using mathematical modeling of β-cell function has made it possible to separate glucose-mediated from incretin-mediated potentiation by combined analysis of oral and intravenous isoglycemic protocols [135]. The results show that, while glucose potentiation is actually augmented in type 2 diabetic patients compared to nondiabetic subjects (due to the hyperglycemia), incretin potentiation is severely compromised (Figure 24.11). Relevant in this regard is collated evidence documenting that the secretory response of GLP-1 — the main incretin hormone — is quite variable in T2D, ranging from reduced to normal, and is poorly correlated with the extent of the incretin defect [133]. Thus, other factors, hormonal or neural, must contribute to the incretin defect of T2DM. Among the hormonal factors, glucose-dependent insulinotropic polypeptide (GIP) causes little potentiation of insulin release in T2DM despite raised GIP responses to oral stimuli [140]. Importantly, the incretin defect of T2DM, which can also be detected in youth [141] and in MODY-3 (HNF-1A) diabetes [142], is not reversed by treatment with a DPP-4 [143] or metformin [144]. These observations have led investigators to postulate that loss of incretin effect is an inherent, rather than secondary, characteristic of T2DM [145].


An important observation is that obesity per se is associated with an impaired incretin effect, that is, independently of glucose tolerance [146]. Because the insulin resistance of obesity involves adipose tissue as well as skeletal muscle, elevated circulating free fatty acids may be linked with the incretin defect, possibly via the reduction of Cx36 [137].

Additional aspects of ?-cell dysfunction

Detailed analysis of β-cell function in vivo has shown that the ability of β-cells to respond to the rate of increase in plasma glucose concentration (rate sensitivity) — a response modality first identified in the isolated rat pancreas [147] — is markedly impaired in patients with T2DM [80], and is improved by bariatric surgery [87]. Furthermore, the autocrine effect of insulin to stimulate its own release has been shown to be significantly reduced in insulin-resistant states [148]. With regard to the relationship between insulin resistance and β-cell function, separate measurement of insulin sensitivity (by the euglycemic hyperinsulinemic clamp technique) and β-cell function (as resolved by mathematical modeling of C-peptide responses to oral glucose or mixed meals) has demonstrated that these two key determinants of glucose levels are numerically independent of each other across a range of glucose tolerance [25,30] but are nevertheless co-present in diabetes and prediabetes, in adults [80] as well as children [141]. Recent studies in patients undergoing pancreatoduodenectomy [149] have shed some light on this issue. In fact, insulin-resistant subjects showed an increased islet size and an elevated number of β-cells as well as α cells, resulting in an reduced β-cell-to-α-cell area, as compared to insulin-sensitive subjects. Following surgical excision of comparable portions of pancreas, the insulin response to intravenous glucose and to a mixed meal was unchanged in the insulin-sensitive individuals whereas it was markedly impaired in the insulin-resistant group.

Finally, impaired β-cell glucose sensitivity is a powerful predictor of progression to dysglycemia and T2DM in subjects with normal glucose tolerance independently of insulin resistance and on top of the classical phenotypic indicators (age, adiposity, familial diabetes) [150]. In multivariate predictive models, absolute insulin secretion is a positive antecedent of deteriorating glucose tolerance, thereby emphasizing the contrasting value of absolute insulin release viz the dynamics of insulin response.

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