Long-term effects of bariatric surgery on meal disposal and beta-cell function in diabetic and nondiabetic patients.

Gastric bypass surgery leads to marked improvements in glucose tolerance and insulin sensitivity in obese type 2 diabetes; the impact on glucose fluxes in response to a physiological stimulus - such as a mixed meal (MTT) - has not been determined. We administered an MTT to 12 obese type 2 diabetic patients (T2D) and 15 obese nondiabetic subjects (ND) before and one year after surgery (10 T2D and 11 ND) using the double-tracer technique and modeling of ß-cell function. In both groups postsurgery, tracer-derived appearance of oral glucose was biphasic, a rapid increase followed by a sharp drop, a pattern that was mirrored by postprandial glucose levels and insulin secretion. In diabetic patients, surgery lowered fasting and postprandial glucose levels; peripheral insulin sensitivity increased in proportion to weight loss (∼30%), ß-cell glucose sensitivity doubled but did not normalize (viz. 21 nonsurgical obese and lean controls). Endogenous glucose production, however, was less suppressed during the MMT as the combined result of a relative hyperglucagonemia and the rapid fall in plasma glucose and insulin levels.We conclude that, in type 2 diabetes bypass surgery changes the postprandial response to a dumping-like pattern, improves glucose tolerance, ß-cell function, and peripheral insulin sensitivity but worsens endogenous glucose output in response to a physiological stimulus

Impaired myocardial metabolic reserve and substrate selection flexibility during stress in patients with idiopathic dilated cardiomyopathy.

Under resting conditions, the failing heart shifts fuel use toward greater glucose and lower free fatty acid (FFA) oxidation. We hypothesized that chronic metabolic abnormalities in patients with dilated cardiomyopathy (DCM) are associated with the absence of the normal increase in myocardial glucose uptake and maintenance of cardiac mechanical efficiency in response to pacing stress. In 10 DCM patients and 6 control subjects, we measured coronary flow by intravascular ultrasonometry and sampled arterial and coronary sinus blood. Myocardial metabolism was determined at baseline, during atrial pacing at 130 beats/min, and at 15 min of recovery by infusion of [(3)H]oleate and [(13)C]lactate and measurement of transmyocardial arteriovenous differences of oxygen and metabolites. At baseline, DCM patients showed depressed coronary flow, reduced uptake and oxidation of FFA, and preferential utilization of carbohydrates. During pacing, glucose uptake increased by 106% in control subjects but did not change from baseline in DCM patients. Lactate release increased by 122% in DCM patients but not in control subjects. Cardiac mechanical efficiency in DCM patients was not different compared with control subjects at baseline but was 34% lower during stress. Fatty acid uptake and oxidation did not change with pacing in either group. Our results show that in DCM there is preferential utilization of carbohydrates, which is associated with reduced flow and oxygen consumption at rest and an impaired ability to increase glucose uptake during stress. These metabolic abnormalities might contribute to progressive cardiac deterioration and represent a target for therapeutic strategies aimed at modulating cardiac substrate utilization

The effect of rosiglitazone on the liver: Decreased gluconeogenesis in patients with type 2 diabetes

Aims/Hypothesis: Diabetic hyperglycemia results from insulin resistance of peripheral tissues and glucose overproduction due to increased gluconeogenesis (GNG). Thiazolidinediones have been shown to improve glycemic control and increase peripheral insulin sensitivity. Whether chronic thiazolidinedione treatment is associated with a decrease in GNG has not been determined. Materials and Methods: We studied 26 diet-treated type 2 diabetic patients randomly assigned to rosiglitazone (RSG; 8 mg/d; n=13) or placebo (n=13) for 12 wk. At baseline and 12 wk, we measured endogenous glucose production (by [(3)H] glucose infusion) and GNG( by the [(2)H](2)O technique) after a 15-h fast. Peripheral insulin sensitivity was evaluated by a two-step (240 and 960 pmol/min/m(-2)) euglycemic insulin clamp. Results: Compared with placebo, RSG reduced fasting plasma glucose (9.7 +/- 0.7 to 7.4 +/- 0.3 mmol/ liter; P<0.001), fasting fractional GNG (-15 +/- 4%; P=0.002), and fasting GNG flux (-3.9 +/- 1.2 mu mol/min/kg fat-free mass; P=0.004), with no effect on glycogenolytic flux. Changes in GNG flux and fasting glucose were tightly correlated (r=0.83; P<0.0001). During both clamp steps, RSG enhanced insulin-mediated glucose clearance (by 26% and 31%; P=0.01 and P<0.02, respectively). In a subgroup of patients studied with magnetic resonance imaging, the reduction in GNG flux was correlated (r=0.65; P<0.02) with the reduction in visceral fat area. Conclusion/Interpretation: RSG increases peripheral tissue insulin sensitivity and decreases endogenous glucose release via an inhibition of gluconeogenesis

Decreased whole body lipolysis as a mechanism of the lipid-lowering effect of pioglitazone in type 2 diabetic patients

Gastaldelli A, Casolaro A, Ciociaro D, Frascerra S, Nannipieri M, Buzzigoli E, Ferrannini E. Decreased whole body lipolysis as a mechanism of the lipid-lowering effect of pioglitazone in type 2 diabetic patients. Am J Physiol Endocrinol Metab 297: E225-E230, 2009. First published May 5, 2009; doi: 10.1152/ajpendo.90960.2008.-Pioglitazone has been shown to reduce fasting triglyceride levels. The mechanisms of this effect have not been fully elucidated, but decreased lipolysis may contribute to blunt the hypertriglyceridemic response to a meal. To test this hypothesis, we studied 27 type 2 diabetes mellitus (T2DM) patients and 7 sex-, age-, and body mass index-matched nondiabetic controls. Patients were randomized to pioglitazone (45 mg/day) or placebo for 16 wk. Whole body lipolysis was measured [as the [(2)H(5)] glycerol rate of appearance (R(a))] in the fasting state and for 6 h following a mixed meal. Compared with controls, T2DM had higher postprandial profiles of plasma triglycerides, free fatty acid (FFA), and beta-hydroxybutyrate, and a decreased suppression of glycerol R(a) (P < 0.04) despite higher insulin levels [268 (156) vs. 190 (123) pmol/l, median (interquartile range)]. Following pioglitazone, triglycerides and FFA were reduced (P = 0.05 and P < 0.04, respectively), and glycerol R(a) was more suppressed [-40 (137) vs. +7 (202) mu mol/min of placebo, P < 0.05] despite a greater fall in insulin [-85 (176) vs. -20 (58) pmol/l, P = 0.05]. We conclude that, in well-controlled T2DM patients, whole body lipolysis is insulin resistant, and pioglitazone improves the insulin sensitivity of lipolysis