Impaired hepatic glucose uptake (HGU) has been implicated in the development of hyperglycemia in type 2 diabetes; the relative impact of plasma glucose and insulin levels on this process remains controversial. We compared the effects of euglycemic hyperinsulinemia on HGU, skeletal muscle glucose uptake, and hepatic influx rate-constant (H-Ki) in 38 diettreated diabetic patients and 22 nondiabetic controls, using positron emission tomography with 18F-fluorodeoxyglucose and the insulin clamp technique. Control subjects were divided into two subgroups: one including older, heavier, insulin- resistant controls (whole-body glucose uptake, M ! 21.4 " 5.4 #mol!min$1!kg$1) to match characteristics of diabetic patients (M ! 20.4 " 9.9); the other including younger, leaner, insulin-sensitive controls (M ! 48.2 " 9.9, P < 0.01). Skeletal muscle glucose uptake showed a similar group distribution as the M value. Insulin clearance rates were lower, whereas glycosylated hemoglobin and clamp plasma insulin levels were higher in diabetic patients than in controls.HGUandH-Kiwere similar in the two nondiabetic subgroups and lower in diabetic patients than in controls (1.9 " 0.5 vs. 2.3 " 0.7 #mol!min$1!100 ml$1, and 0.37 " 0.09 vs. 0.44 " 0.14 ml!min$1!100 ml$1, P < 0.01). In the whole dataset, H-Ki was inversely related to fasting plasma glucose (correlation coefficient! $0.40, P ! 0.0018). In diabetic subjects, H-Ki was reciprocally related to glycosylated hemoglobin (correlation coefficient! $0.36, P ! 0.029). We conclude that insulin-mediated HGU is impaired, in type 2 diabetes, in some proportion to the degree of glycemic control. (J Clin Endocrinol Metab 88: 2055–2060, 2003) IMPAIRED INSULIN-MEDIATED GLUCOSE uptake plays an important role the pathogenesis of type 2 diabetes (1, 2). Sites of impairment and their relative contribution to the overall defect remain a field of active investigation. The liver plays an important role in the maintenance of glucose homeostasis, and insulin resistance at the level of hepatic glucose output is a mechanism of fasting hyperglycemia in type 2 diabetes (1–5). Vice versa, at plasma insulin levels similar to those encountered in the postprandial phase, hepatic glucose output is normally suppressed in diabetic subjects (6, 7). Growing evidence supports the concept that reduced hepatic glucose uptake (HGU) might significantly contribute to fasting (2) and postprandial hyperglycemia in patients with type 2 diabetes (8, 9). Insulin and glucose are both involved in the regulation of HGU. In particular, the former promotes short-term hepatic glucokinase transcription (10 –13) and HGU (10, 14, 15) and plays a permissive and synergistic role in glucose-mediated HGU (16). In a recent dose-response study, Basu et al. (2) confirmed that insulin promotes splanchnic glucose uptake in humans, and provided indirect evidence of a defect in the early steps of HGU in type 2 diabetic patients under conditions of mild hyperglycemia and hyperinsulinemia simulating the typical postabsorptive situation associated with the disease. This finding was subsequently extended to a condition of higher (but still modest) hyperinsulinemia (!50 !U!ml"1) (8). Studies conducted at postprandial plasma insulin levels in humans have been fewer and less conclusive. DeFronzo et al. (6) were unable to show a difference in splanchnic glucose uptake, between diabetic and healthy subjects, using the euglycemic clamp and iv glucose administration, whereas Ludvik et al. (9) reported a significant impairment in diabetic patients after combined iv and oral glucose administration. Differences in study design, experimental techniques, and data extrapolation (from the splanchnic vascular bed to the liver itself) contribute to the controversy. Furthermore, given that HGUis influenced both by plasma insulin and glucose levels, experiments combining hyperglycemia and hyperinsulinemia cannot discriminate which response is lost and to what extent in patients with type 2 diabetes. The present study was undertaken to selectively and noninvasively evaluate whether insulin-stimulated HGU is impaired in type 2 diabetic subjects. To this purpose, liver glucose influx rates were estimated in 38 patients with newly diagnosed, diet-treated type 2 diabetes and 22 nondiabetic controls, using positron emission tomography (PET) in combination with 18F-fluorodeoxyglucose (18F-FDG) under conditions of euglycemic physiological hyperinsulinemia. Abbreviations: BMI, Body mass index; 18F-FDG, 18F-fluorodeoxyglucose; FFA, free fatty acids; H-Ki, hepatic glucose influx rate constant; HbA1c, glycosylated hemoglobin; HGU, hepatic glucose uptake; ICR, insulin clearance rate; IR controls, insulin-resistant controls; IS controls, insulin-sensitive controls; Ki, influx rate constant; M, whole-body glucose uptake; MLBM, M expressed per kg of lean body mass; n.s., not significant; PET, positron emission tomography; r, correlation coefficient; SGU, skeletal muscle glucose uptake; WHR, waist to hip ratio.
Xanya Sofra Weiss
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