Disruption of circadian insulin secretion is associated with reduced glucose uptake in first-degree relatives of patients with type 2 diabetes

The objective of this study was to evaluate whether first-degree relatives (FDRs) of patients with type 2 diabetes had abnormal circadian insulin secr etion and, if so, whether this abnormality affected their glucose metabolis m. Six African-American FDRs with normal glucose tolerance and 12 matched n ormal control subjects (who had no family history of diabetes) were exposed to 48 h of hyperglycemic clamping (similar to 12 mmol/l). Insulin secretio n rates (ISRs) were determined by deconvolution of plasma C-peptide levels using individual C-peptide kinetic parameters, Detrending and smoothing of data (z-scores) and computation of autocorrelation functions mere used to i dentify ISR cycles. During the initial hours after start of glucose infusio ns, ISRs were similar to 60% higher in FDRs than in control subjects (585 v s. 366 nmol/16 h, P < 0.05), while rates of glucose uptake were the same (5 .6 mmol . kg(-1) . h(-1)), indicating that the FDRs were insulin resistant. Control subjects had well-defined circadian (24 h) cycles of ISR and plasm a insulin that; rose in the early morning, peaked in the afternoon, and dec lined during the night. In contrast, FDRs had several shorter ISR cycles of smaller amplitude that lacked true periodicity. This suggested that the la ck of a normal circadian ISR increase had made it impossible for the FDRs t o maintain their compensatory insulin hypersecretion beyond 18 h of hypergl ycemia. As a result, ISR decreased to the level found in control subjects, and glucose uptake fell below the level of control subjects (61 vs. 117 mu mol . kg(-1) . min(-1), P < 0.05). In summary, we found that FDRs with norm al glucose tolerance had defects in insulin action and secretion. The newly recognized insulin secretory defect consisted of disruption of the normal circadian ISR cycle, which resulted in reduced insulin secretion (and gluco se uptake) during the ascending part of the 24 h ISR cycle.