Insulin resistance is characteristic of the diabetic state. To define the role of hyperglycemia in generation of the insulin resistance, we examined the effect of phlorizin treatment on tissue sensitivity to insulin in partially pancreatectomized rats. Five groups were studied: group I, sham-operated controls; group II, partially pancreatectomized diabetic rats with moderate glucose intolerance; group III, diabetic rats treated with phlorizin to normalize glucose tolerance; group IV, phlorizin-treated controls; and group V, phlorizin-treated diabetic rats restudied after discontinuation of phlorizin. Insulin sensitivity was assessed with the euglyemic hyperinsulinemic clamp technique in awake, unstressed rats. Insulin-mediated glucose metabolism was reduced by approximately 30% (P < 0.001) in diabetic rats. Phlorizin treatment of diabetic rats completely normalized insulin sensitivity but had no effect on insulin action in controls. Discontinuation of phlorizin in phlorizin-treated diabetic rats resulted in the reemergence of insulin resistance. These data demonstrate that (a) a reduction of f-cell mass leads to the development of insulin resistance, and (b) correction of hyperglycemia with phlorizin, without change in insulin levels, normalizes insulin sensitivity. These results provide the first in vivo evidence that hyperglycemia per se can lead to the development of insulin resistance.

A B S T R A C T Tissue sensitivity to insulin was examined with the euglycemic insulin clamp technique in 17 chronically uremic and 36 control subjects. The plasma insulin concentration was raised by -100 ,uU/ ml and the plasma glucose concentration was maintained at the basal level with a variable glucose infusion. Under these steady-state conditions of euglycemia, the glucose infusion rate is a measure of the amount of glucose taken up by the entire body. In uremic subjects insulin-mediated glucose metabolism was reduced by 47% compared with controls (3.71 +0.20 vs. 7.38+0.26 mg/kg-min; P < 0.001). Basal hepatic glucose production (measured with [3H]-3-glucose) was normal in uremic subjects (2.17+0.04 mg/kg-min) and suppressed normally by 94±+2% following insulin administration. In six uremic and six control subjects, net splanchnic glucose balance was also measured directly by the hepatic venous catheterization technique. In the postabsorptive state splanchnic glucose production was similar in uremics (1.57+0.03 mg/kg.min) and controls (1.79+0.20 mg/ kg min). After 90 min of sustained hyperinsulinemia, splanchnic glucose balance reverted to a net uptake which was similar in uremics (0.42±0.11 mg/kg-min) and controls (0.53+0.12 mg/kg.min). In contrast, glucose uptake by the leg was reduced by 60% in the uremic group (21+1 vs. 52+8 ,umol/min kg of leg wt; P < 0.005) and this decrease closely paralleled the decrease in total glucose metabolism by the entire body. These results indicate that: (a) suppression of hepatic glucose production by physiologic hyperinsulinemia is not impaired by uremia, (b) insulinmediated glucose uptake by the liver is normal in uremic subjects, and (c) tissue insensitivity to insulin is the primary cause of insulin resistance in uremia.

We write supersymmetry preserving conditions for infinite M5-branes intersecting on a (3+1)-dimensional space. In contrast to previously known solutions, these intersections are completely localized. We solve the equations for a particular class of configurations which in the near-horizon decoupling limit are dual to N f = 2N c SeibergWitten superconformal field theories with gauge group SU(N ) and generalisations to SU(N ) n . We also discuss the relationship to D3-branes in the presence of an A k singularity.BRX TH-452 HUB-EP-99/11 hep-th/9902210 *

Pharmacological doses of GH are known to impair glucose tolerance. In the present study we have employed the euglycemic insulin and hyperglycemic clamp techniques to examine the effect of physiological elevations in plasma GH concentrations (27 ± 2 ng/ml) on the tissue responses to insulin and on glucose-stimulated insulin secretion. Three types of studies (low dose insulin clamp, high dose insulin clamp, and hyperglycemic clamp) were performed in young healthy volunteers before and after the infusion of GH (2 /ig/kg-h) for 2 and 12 h. In the low dose insulin clamp studies, the plasma insulin concentration was acutely raised and was maintained at 59 ± 4 juU/ml, while plasma glucose was maintained at basal levels. After 2 h of GH infusion, insulin-mediated glucose metabolism was slightly, although not significantly, decreased (4.48 ± 0.56 vs. 5.04 ± 0.39 mg/kg-min) in the control study. After 12 h of GH infusion, however, insulin-mediated glucose uptake decreased by 32 ± 9% (3.36 ± 0.40 mg/kg-min; P < 0.01). Basal endogenous glucose production (2.02 ± 0.07 mg/kg-min) was suppressed by 89 ± 4% in the control study. After short term GH infusion, the degree of suppression (90 ± 5%) was similar to the control value. After 12 h of GH infusion, however, suppression of endogenous glucose production (78 ± 5%) was slightly less than that in controls (P < 0.05). In the high dose insulin clamp studies, GH was infused for either 2 or 12 h, after which plasma insulin levels were increased to 2292 ± 96 /xU/ml while maintaining euglycemia (high dose insulin clamp study). Insulin-mediated glucose uptake was 11.22 ± 0.53 mg/kg-min in the control study, slightly lower during short term GH infusion (9.56 ± 1.00 mg/kg-min) and significantly diminished after long term GH infusion (7.16 ± 1.12 mg/kg-min; P < 0.02). In the hyperglycemic clamp studies, plasma glucose was raised and maintained at 125 mg/dl above the basal level. Glucose metabolism in controls (8.68 ± 0.53 mg/ kg-min) was decreased by 31 ± 7% after 2 h and by 44 ± 6% after 12 h of GH infusion. The mean increment in plasma insulin in response to hyperglycemia (control, 56 ± 10 juU/ml) was unaltered after 2 and 12 h of GH administration. Total binding of [ 125 I]insulin to monocytes was 7.0 ± 0.5% before GH infusion. After 2 h of GH administration, no change in total specific insulin binding (7.4 ± 0.4%) occurred. After 12 h of exposure to GH, however, total binding was decreased (5.9 ± 0.4%; P < 0.02) due to a decrease in receptor affinity.We conclude that physiological elevations in GH 1) induce a state of insulin resistance within 2-12 h, 2) only slightly impair insulin's suppressive effect on endogenous glucose production, indicating that the primary site of insulin resistance resides in peripheral tissues, 3) do not alter the plasma insulin response to hyperglycemia, and 4) cause a decrease in insulin binding that results from a decrease in receptor affinity. The inability to overcome the defect in glucose metabolism at high plasma insulin concentrations suggests that a...

We present an explicit relation between the Hanany-Witten and Geometric Engineering approaches of realising gauge theories in string theory. The last piece in the puzzle is a T-duality relating arbitrary Hanany-Witten setups and fractional branes.