Impaired early- but not late-phase insulin secretion in subjects with impaired fasting glucose

Abstract

Subjects with impaired fasting glucose (IFG) are at increased risk for type 2 diabetes. We recently demonstrated that IFG subjects have increased hepatic insulin resistance with normal insulin sensitivity in skeletal muscle. In this study, we quantitated the insulin secretion rate from deconvolution analysis of the plasma C-peptide concentration during an oral glucose tolerance test (OGTT) and compared the results in IFG subjects with those in subjects with impaired glucose tolerance (IGT) and normal glucose tolerance (NGT). One hundred and one NGT subjects, 64 subjects with isolated IGT, 24 subjects with isolated IFG, and 48 subjects with combined (IFG + IGT) glucose intolerance (CGI) received an OGTT. Plasma glucose, insulin, and C-peptide concentrations were measured before and every 15 min after glucose ingestion. Insulin secretion rate (ISR) was determined by deconvolution of plasma C-peptide concentration. Inverse of the Matsuda index of whole body insulin sensitivity was used as a measure of insulin resistance; 56 subjects also received a euglycemic hyperinsulinemic clamp. The insulin secretion/insulin resistance (disposition) index was calculated as the ratio between incremental area under the ISR curve (∆ISR[AUC]) to incremental area under the glucose curve (∆G[AUC]) factored by the severity of insulin resistance (measured by Matsuda index during OGTT or glucose disposal during insulin clamp). Compared to NGT, the insulin secretion/insulin resistance index during first 30 min of OGTT was reduced by 47, 49, and 74% in IFG, IGT, and CGI, respectively (all < 0.0001). The insulin secretion/insulin resistance index during the second hour (60-120 min) of the OGTT in subjects with IFG was similar to that in NGT (0.79 ± 0.6 vs. 0.72 ± 0.5, respectively, P = NS), but was profoundly reduced in subjects with IGT and CGI (0.31 ± 0.2 and 0.19 ± 0.11, respectively; P < 0.0001 vs. both NGT and IFG). Early-phase insulin secretion is impaired in both IFG and IGT, while the late-phase insulin secretion is impaired only in subjects with IGT.

Normal Fasting Plasma Glucose and Risk of Prediabetes and Type 2 Diabetes: The Isfahan Diabetes Prevention Study

“…Putative mechanisms include increased hepatic insulin resistance [26,27], impaired early insulin response [28], and decrease non-insulin-dependent glucose clearance [29]. Progressive beta-cell failure is the principal factor responsible for the development of prediabetes and diabetes [30].…”

Pancreatic β-cell dysfunction in polycystic ovary syndrome: role of hyperglycemia-induced nuclear factor-κB activation and systemic inflammation

“…Nevertheless, our data indicate that the regulation of early and late-phase blood glucose control in response to glucose ingestion appears to be synergistically hampered by inflammation unique to PCOS in conjunction with the inflammatory load of excess body fat. Our findings are of clinical relevance because they highlight the unique pancre- atic endocrine phenotypes in lean and obese women with PCOS that may differentially elevate risk of developing fasting vs. postprandial glucose intolerance (30).…”

“…Although the link between insulin resistance and inflammation in the pathogenesis of T2D is well established, inflammation may also play an important role in disrupting pancreatic insulin secretion (13,50). Within the ␤-cell, there is a readily available pool of insulin released upon initial glucose ingestion (1st phase) that is followed by synthesis of new insulin to manage postprandial glucose fluctuations (2nd phase) (30). Recent studies demonstrate that macrophages derived from circulating MNC infiltrate pancreatic islets in primates (39) and humans with T2D (15) and disrupt pancreatic insulin secretion.…”

Enhanced leptin synthesis and secretion in vitro by human adipocytes from type 2 diabetic donors occurs only under hyperinsulinaemic conditions

“…23 Should the delayed effect of insulin treatment on leptin secretion in adipocytes from type 2 diabetic donors be proven in subsequent studies, the phenomenon may be analogous to the biphasic response of insulin secretion to glucose 37 where impairment of early and late phase insulin secretion leads to different clinical outcomes. 38 A final point is that the contrasting findings regarding the effect of insulin on leptin secretion may reflect the different situations in which data has been collected. For example, the ob/ob mouse is perhaps the most commonly used model for investigating the metabolic effects of obesity including diabetes.…”