EVIDENCE FOR A CIRCADIAN-RHYTHM OF INSULIN SENSITIVITY IN PATIENTS WITH NIDDM CAUSED BY CYCLIC CHANGES IN HEPATIC GLUCOSE-PRODUCTION

Diurnal variation in insulin sensitivity in patients with NIDDM has lo ng been suspected but has been difficult to document mainly because of the interdependence of changes in glucose and insulin, Stable serum i nsulin levels during hyperglycemic clamping in patients with NIDDM in the present study provided the opportunity to examine changes in insul in sensitivity unaffected by changes in blood glucose and insulin conc entrations, Six patients with NIDDM (four men and two women, BMI 33.9 +/- 2.5) underwent hyperglycemic (11.1 mmol/l, similar to 200 mg/dl) c lamping for 72 h, Measured were serum insulin, free fatty acid (FFA), cortisol, and growth hormone concentrations and rates of insulin secre tion, insulin clearance, and glucose infusion rate (GIR) needed to mai ntain hyperglycemia, In addition, five patients (three men and two wom en, BMI 32.6 +/- 0.6) underwent hyperglycemic clamping for 24 h with h ourly determinations of hepatic glucose production (HGP) and glucose d isappearance rates (G(Rd)). GIR, reflecting insulin sensitivity, chang ed rhythmically with a cycle duration of 22.9 +/- 1.4 h and an amplitu de of 47.8 +/- 11.2%, GIR was lowest at 8:31 a.m. (+/-52 min) and high est at 7:04 p.m. (+/-58 min). Circadian changes in GIR were completely accounted for by changes in HGP, while G(Rd) remained unchanged. Plas ma levels of FFAs and cortisol also exhibited circadian fluctuations, and their blood levels correlated negatively with GIR (r = -0.72 and - 0.64, respectively). We concluded that insulin sensitivity in patients with NIDDM changed with circadian (similar to 24 h) rhythmicity (decr easing during the night and increasing during the day), These changes were unrelated to blood levels of glucose and insulin, insulin clearan ce, exercise, food intake, and sleep, They were caused by circadian ch anges in HGP, which in turn were closely correlated with circadian cha nges in blood FFA and cortisol levels. We believe that recognition of these circadian changes has implications for the diagnosis and the tre atment of patients with NIDDM.