Predominant role of reduced beta-cell sensitivity to glucose over insulin resistance in impaired glucose tolerance

Abstract

Aims/hypothesis. Impaired glucose tolerance (IGT) is an insulin-resistant state and a risk factor for Type 2 diabetes. The relative roles of insulin resistance and insulin deficiency in IGT have been disputed. Methods. In 40 IGT subjects and 63 sex-, age-, and weight-matched controls with normal glucose tolerance (NGT), we measured (i) indices of insulin sensitivity of fasting glucose production (by tracer glucose) and glucose disposal (M value on a 240 pmol·min -1 ·m -2 insulin clamp) and (ii) indices of beta-cell function (glucose sensitivity, rate sensitivity, and potentiation) derived from model analysis (Am J Physiol 283:E1159-E1166, 2002) of the insulin secretory response (by C-peptide deconvolution) to oral glucose. Results. In comparison with NGT, IGT were modestly insulin resistant (M=29±2 vs 35±2 µmol·min −1 ·kg FFM −1 , p=0.01); insulin sensitivity of glucose production also was reduced, in approximate proportion to M. Despite higher baseline insulin secretion rates, IGT was characterized by a 50% reduction in glucose sensitivity [53 (36) concept has evolved that in IGT, a mixture of insulin resistance and insulin deficiency is responsible for the abnormal rise in postglucose plasma glucose concentrations [12,13]. However, many previous studies of IGT have based conclusions on the measurement of plasma insulin concentrations rather than true insulin secretion rates. More importantly, to what extent insulin response to intravenous glucose reflects the insulin secretory response to oral glucose or mixed meals remains uncertain. In studies using graded glucose infusions and the C-peptide deconvolution technique to reconstruct insulin secretory rates, one study [14] documented a slower rise in insulin secretion as a function of rising plasma glucose concentrations in IGT subjects in comparison with subjects with normal gluImpaired glucose tolerance (IGT) is a condition of high risk for the development of Type 2 diabetes. Early physiological studies consistently showed that IGT is an insulin-resistant state [1,2,3,4,5] and documented the presence of impaired insulin response to intravenous glucose [6,7,8,9,10,11]. The general

Different contributions of insulin resistance and beta‐cell dysfunction in overweight Israeli Arabs with IFG and IGT

“…Our results are consistent with other studies performed in other populations, which found that an increase in insulin resistance is the principal defect observed in subjects with IFG, while impairment in beta-cell function is the major pathology that leads to the development of IGT [8][9][10][11]. However, some other studies found opposite results [12][13][14].…”

“…Studies that aimed to clarify this question had conflicting results. Some studies reported an increase in insulin resistance as the main contributor to the development of IFG, while IGT was associated with impairment of betacell function [8][9][10][11]. Other studies demonstrated that subjects with IFG had mainly a reduction in insulin secretion, while IGT subjects had a reduction in insulin sensitivity [12][13][14].…”

Restoration of normal glucose tolerance in severely obese patients after bilio-pancreatic diversion: role of insulin sensitivity and beta cell function

“…Our results show that those obese subjects who are IGT or have type 2 diabetes prior to surgery are characterised by impairment of beta cell glucose sensitivity. This result confirms previous findings that impaired beta cell glucose sensitivity is the main determinant of IGT and type 2 diabetes, rate sensitivity and potentiation being relatively minor factors [17][18][19]. The impairment in beta cell glucose sensitivity was seen together with a variable degree of insulin resistance and the attendant upregulation of insulin secretion (Fig.…”

“…As expected from previous work [17][18][19], we found a strong inverse relationship between beta cell glucose sensitivity and glucose tolerance (as the 2-h plasma glucose concentration). This relationship was maintained after surgery, but became significantly steeper (Fig.…”

Plasma glucose levels as predictors of diabetes: the Mexico City diabetes study

“…Impaired glucose tolerance (IGT), defined by the 2 h glucose concentration, carries heightened risk of diabetes [3][4][5] and, possibly, cardiovascular disease [6][7]. The pathophysiology of IGT is a combination of insulin resistance, hepatic as well as peripheral, and beta cell dysfunction [8] that is similar to that of diabetes, only of a milder degree. As an obvious antecedent of type 2 diabetes, IGT is identified by a screening OGTT, which costs time, facilities and money.…”