Glucose-mediated glucose disposal in insulin-resistant normoglycemic relatives of type 2 diabetic patients.

Abstract

With the aim of investigating glucose-mediated glucose disposal (glucose effectiveness [GE]) in 15 (3 female and 12 male subjects) insulin-resistant normoglycemic relatives of patients with type 2 diabetes (DM2), and 15 age-, sex-, and BMI-matched control subjects without a family history of DM2, we performed 2 studies: 1) a 5-h euglycemic near-normoinsulinemic pancreatic clamp with somatostatin (360 µg/h), insulin (0.25 mU · kg -1 · min -1 ), glucagon (0.5 ng · kg -1 · min -1 ), growth hormone (6 ng · kg -1 · min -1 ), and tritiated glucose infusion and indirect calorimetry; and 2) on a separate day, an identical 5-h clamp but at hyperglycemia (~12 mmol/l) over the last 2 h. Fasting plasma insulin (PI) concentrations were elevated in the relatives compared with control subjects (49 ± 6 vs. 32 ± 5 pmol/l, P < 0.04), whereas plasma glucose (PG) was not (5.6 ± 0.1 vs. 5. (1), and several studies have demonstrated decreased insulin sensitivity (2-6), impaired activation of muscle glycogen synthase by insulin (5,6), and subtle defects of insulin secretion (2,4,7) in such subjects. Most recently, we demonstrated increased glucosemediated glucose disposal at basal insulin in insulin-resistant normoglycemic first-degree relatives of patients with DM2 (2), using the Bergman minimal model (8). From the latter study, we hypothesized that the increase in glucose sensitivity (S g ) might be a novel compensatory mechanism by which these relatives maintain normal glucose tolerance (2). This scenario was consistent with an earlier large-scale longitudinal follow-up study in normoglycemic relatives of 2 parents with DM2 in whom a decreased S g and decreased insulin sensitivity (S i ) both predicted an increased risk of future development of diabetes (9). In contrast, Doi et al. (10) noted a decreased S g with normal S i and decreased first-phase insulin secretion in normoglycemic relatives of Japanese DM2 patients. However, the estimation of S g may be influenced by the extent of the acute insulin secretory response, i.e., the lower the first-phase insulin response, the lower the S g (11-13). Concern has also been expressed as to whether the minimal model technique using unlabeled glucose accurately measures S g (14,15).Glucose-mediated glucose disposal is an important factor controlling glucose tolerance (16,17), but which metabolic pathways are involved is uncertain (18)(19)(20). Acute hyperglycemia itself is known to enhance peripheral glucose uptake (19-24) associated with enhanced glucose oxidation and gluFrom the Diabetes Research Centre

Effect of physical training on insulin secretion and action in skeletal muscle and adipose tissue of first-degree relatives of type 2 diabetic patients

“…Our hypothesis is that the training-induced increase in stimulated glucose uptake rates are due to a mixture of insulin-and glucose-mediated glucose uptake in CON, whereas in FDR the training effect is exclusively related to the glucose-mediated glucose uptake. This interpretation is compatible with an augmentation of glucose-mediated glucose uptake in FDR, as shown in some (19,20) but not all (39) previous studies.…”

Impaired Fat Oxidation After a Single High-Fat Meal in Insulin-Sensitive Nondiabetic Individuals With a Family History of Type 2 Diabetes

“…However, we did not measure insulin resistance by low-dose clamp, and the subjects with a family history of type diabetes did trend toward an increased insulin response after the high-carbohydrate meal, which may be indicative of insulin resistance. On the other hand, other studies have shown that hepatic insulin resistance is not present at this stage in human relatives of individuals with type 2 diabetes (27,28), and all other indicators of insulin resistance, such as fasting insulin, homeostasis model assessment, or metabolic flexibility to carbohydrate ingestion, were not different between groups. Furthermore, it is likely that the 20-h fast was sufficient to "stress the system," potentially allowing an early metabolic defect to become apparent after a highcarbohydrate meal when not apparent by the clamp.…”

Chronic consumption of a high-fat/high-fructose diet renders the liver incapable of net hepatic glucose uptake

“…For example, Commerford et al (6) demonstrated in rodents that consumption of a high-fat or high-sucrose diet resulted in a decrease in insulin's ability to suppress HGP and stimulate whole body glucose uptake during an HIEG clamp, but during an HIHG clamp, these parameters were restored to the rates observed in chow-fed controls. This was also demonstrated to be the case in insulin-resistant, normoglycemic relatives of type 2 diabetic patients, in which glucose disposal was increased during a hyperglycemic pancreatic clamp due in part to enhanced GE in the skeletal muscle (11). Thus, it is possible that increased non-HGU in the HFFD group during the HIHG clamps was reflective of enhanced GE in the skeletal muscle in the presence of hyperglycemia.…”