Acute elevations in free fatty acids (FFAs) stimulate insulin secretion, but prolonged lipid exposure impairs ␤-cell function in both in vitro studies and in vivo animal studies. In humans data are limited to short-term (<48 h) lipid infusion studies and have led to conflicting results. We examined insulin secretion and action during a 4-day lipid infusion in healthy normal glucose tolerant subjects with (FH؉ group, n ‫؍‬ 13) and without (control subjects, n ‫؍‬ 8) a family history of type 2 diabetes. Volunteers were admitted twice to the clinical research center and received, in random order, a lipid or saline infusion. On days 1 and 2, insulin and C-peptide concentration were measured as part of a metabolic profile after standardized mixed meals. Insulin secretion in response to glucose was assessed with a ؉125 mg/dl hyperglycemic clamp on day 3. On day 4, glucose turnover was measured with a euglycemic insulin clamp with [3-3 H]glucose. Day-long plasma FFA concentrations with lipid infusion were increased within the physiological range, to levels seen in type 2 diabetes (ϳ500 -800 mol/l). Lipid infusion had strikingly opposite effects on insulin secretion in the two groups. After mixed meals, day-long plasma C-peptide levels increased with lipid infusion in control subjects but decreased in the FH؉ group (؉28 vs. ؊30%, respectively, P < 0.01). During the hyperglycemic clamp, lipid infusion enhanced the insulin secretion rate (ISR) in control subjects but decreased it in the FH؉ group (first phase: ؉75 vs. ؊60%, P < 0.001; second phase: ؉25 vs. ؊35%, P < 0.04). When the ISR was adjusted for insulin resistance (ISR Rd ‫؍‬ ISR ، [1/R d ], where R d is the rate of insulin-stimulated glucose disposal), the inadequate ␤-cell response in the FH؉ group was even more evident. Although ISR Rd was not different between the two groups before lipid infusion, in the FH؉ group, lipid infusion reduced first-and second-phase ISR Rd to 25 and 42% of that in control subjects, respectively (both P < 0.001 vs. control subjects). Lipid infusion in the FH؉ group (but not in control subjects) also caused severe hepatic insulin resistance with an increase in basal endogenous glucose production (EGP), despite an elevation in fasting insulin levels, and impaired suppression of EGP to insulin. In summary, in individuals who are genetically predisposed to type 2 diabetes, a sustained physiological increase in plasma FFA impairs insulin secretion in response to mixed meals and to intravenous glucose, suggesting that in subjects at high risk of developing type 2 diabetes, ␤-cell lipotoxicity may play an important role in the progression from normal glucose tolerance to overt hyperglycemia.

The effect of pioglitazone on splanchnic glucose uptake (SGU), endogenous glucose production (EGP), and hepatic fat content was studied in 14 type 2 diabetic patients (age 50 ؎ 2 years, BMI 29.4 ؎ 1.1 kg/m 2 , HbA 1c 7.8 ؎ 0.4%). Hepatic fat content (magnetic resonance spectroscopy) and SGU (oral glucose load-insulin clamp technique) were quantitated before and after pioglitazone (45 mg/day) therapy for 16 weeks. Subjects received a 7-h euglycemic insulin (100 mU ⅐ m ؊2 ⅐ min ؊1 ) clamp, and a 75-g oral glucose load was ingested 3 h after starting the insulin clamp. Following glucose ingestion, the steady-state glucose infusion rate during the insulin clamp was decreased appropriately to maintain euglycemia. SGU was calculated by subtracting the integrated decrease in glucose infusion rate during the 4 h after glucose ingestion from the ingested glucose load. 3-[ 3 H]glucose was infused during the initial 3 h of the insulin clamp to determine rates of EGP and glucose disappearance (R d ). Pioglitazone reduced fasting plasma glucose (10.0 ؎ 0.7 to 7.5 ؎ 0.6 mmol/l, P < 0.001) and HbA 1c (7.8 ؎ 0.4 to 6.7 ؎ 0.3%, P < 0.001) despite increased body weight (83 ؎ 3 to 86 ؎ 3 kg, P < 0.001). During the 3-h insulin clamp period before glucose ingestion, pioglitazone improved R d (6.9 ؎ 0.5 vs. 5.2 ؎ 0.5 mg ⅐ kg ؊1 ⅐ min ؊1 , P < 0.001) and insulinmediated suppression of EGP (0.21 ؎ 0.04 to 0.06 ؎ 0.02 mg ⅐ kg ؊1 ⅐ min ؊1 , P < 0.01). Following pioglitazone treatment, hepatic fat content decreased from 19.6 ؎ 3.6 to 10.4 ؎ 2.1%, (P < 0.005), and SGU increased from 33.0 ؎ 2.8 to 46.2 ؎ 5.1% (P < 0.005). Pioglitazone treatment in type 2 diabetes 1) decreases hepatic fat content and improves insulin-mediated suppression of EGP and 2) augments splanchnic and peripheral tissue glucose uptake. Improved splanchnic/peripheral glucose uptake and enhanced suppression of EGP contribute to the improvement in glycemic control in patients with type 2 diabetes. Diabetes 52:1364 -1370, 2003 T he splanchnic tissues play a pivotal role in the maintenance of normal glucose homeostasis (1). Hyperglycemia, plasma free fatty acid (FFA) concentration, and route of glucose administration all exert independent effects on splanchnic glucose uptake (SGU). When glucose is administered intravenously, the resultant hyperglycemia enhances SGU in proportion to the increase in plasma glucose concentration such that the splanchnic glucose clearance remains unchanged (2,3). This mass-action effect of hyperglycemia to augment SGU is dependent upon maintained portal insulin levels (2-5,8). Insulin per se does not increase SGU (2,5). Studies by DeFronzo and colleagues (3,5) in humans and by Cherrington and colleagues (6,7) in dogs have shown that the gastrointestinal/portal route of glucose administration has a specific enhancing effect on SGU. Thus, following glucose ingestion, the fractional, as well as absolute rate of glucose uptake by the splanchnic tissues is significantly greater than the combined effects of hyperinsulinemia plus hyperglycemia created...

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Normoglycemic subjects with a strong family history of type 2 diabetes are insulin resistant, but the mechanism of insulin resistance in skeletal muscle of such individuals is unknown. The present study was undertaken to determine whether abnormalities in insulin-signaling events are present in normoglycemic, nonobese subjects with a strong family history of type 2 diabetes. Hyperinsulinemic-euglycemic clamps with percutaneous muscle biopsies were performed in eight normoglycemic relatives of type 2 diabetic patients (FH ؉ ) and eight control subjects who had no family history of diabetes (FH ؊ ), with each group matched for age, sex, body composition, and ethnicity. The FH ؉ group had decreased insulin-stimulated glucose disposal (6.64 ؎ 0.52 vs. 8.45 ؎ 0.54 mg ⅐ kg ؊1 fat-free mass ⅐ min ؊1 ; P < 0.05 vs. FH ؊ ). In skeletal muscle, the FH ؉ and FH ؊ groups had equivalent insulin stimulation of insulin receptor tyrosine phosphorylation. In contrast, the FH ؉ group had decreased insulin stimulation of insulin receptor substrate (IRS)-1 tyrosine phosphorylation (0.522 ؎ 0.077 vs. 1.328 ؎ 0.115 density units; P < 0.01) and association of PI 3-kinase activity with IRS-1 (0.299 ؎ 0.053 vs. 0.466 ؎ 0.098 activity units; P < 0.05). PI 3-kinase activity was correlated with the glucose disposal rate (r ‫؍‬ 0.567, P ‫؍‬ 0.02). In five subjects with sufficient biopsy material for further study, phosphorylation of Akt was 0.266 ؎ 0.061 vs. 0.404 ؎ 0.078 density units (P < 0.10) and glycogen synthase activity was 0.31 ؎ 0.06 vs. 0.50 ؎ 0.12 ng ⅐ min ؊1 ⅐ mg ؊1 (P < 0.10) for FH ؉ and FH ؊ subjects, respectively. Therefore, despite normal insulin receptor phosphorylation, postreceptor signaling was reduced and was correlated with glucose disposal in muscle of individuals with a strong genetic background for type 2 diabetes. Diabetes 50: 2572-2578, 2001

The purpose of this study was to determine the factors contributing to the ability of exercise to enhance insulin-stimulated glucose disposal. Sixteen insulin-resistant nondiabetic and seven Type 2 diabetic subjects underwent two hyperinsulinemic (40 mU x m-2 x min-1) clamps, once without and once with concomitant exercise at 70% peak O2 consumption. Exercise was begun at the start of insulin infusion and was performed for 30 min. Biopsies of the vastus lateralis were performed before and after 30 min of insulin infusion (immediately after cessation of exercise). Exercise synergistically increased insulin-stimulated glucose disposal in nondiabetic [from 4.6 +/- 0.4 to 9.5 +/- 0.8 mg x kg fat-free mass (FFM)-1x min-1] and diabetic subjects (from 4.3 +/- 1.0 to 7.9 +/- 0.7 mg. kg FFM-1x min-1) subjects. The rate of glucose disposal also was significantly greater in each group after cessation of exercise. Exercise enhanced insulin-stimulated increases in glycogen synthase fractional velocity in control (from 0.07 +/- 0.02 to 0.22 +/- 0.05, P < 0.05) and diabetic (from 0.08 +/- 0.03 to 0.15 +/- 0.03, P < 0.01) subjects. Exercise also enhanced insulin-stimulated glucose storage (glycogen synthesis) in nondiabetic (2.9 +/- 0.9 vs. 4.9 +/- 1.1 mg x kg FFM-1x min-1) and diabetic (1.7 +/- 0.5 vs. 4.2 +/- 0.8 mg x kg FFM-1. min-1) subjects. Increased glucose storage accounted for the increase in whole body glucose disposal when exercise was performed during insulin stimulation in both groups; effects of exercise were correlated with enhancement of glucose disposal and glucose storage (r = 0.93, P < 0.001). Exercise synergistically enhanced insulin-stimulated insulin receptor substrate 1-associated phosphatidylinositol 3-kinase activity (P < 0.05) and Akt Ser473 phosphorylation (P < 0.05) in nondiabetic subjects but had little effect in diabetic subjects. The data indicate that exercise, performed in conjunction with insulin infusion, synergistically increases insulin-stimulated glucose disposal compared with insulin alone. In nondiabetic and diabetic subjects, increased glycogen synthase activation is likely to be involved, in part, in this effect. In nondiabetic, but not diabetic, subjects, exercise-induced enhancement of insulin stimulation of the phosphatidylinositol 3-kinase pathway is also likely to be involved in the exercise-induced synergistic enhancement of glucose disposal.