Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats.

Abstract

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.

Reduction of insulin resistance by combined kidney-pancreas transplantation in Type 1 (insulin-dependent) diabetic patients

“…The cause of insulin resistance is multifactorial and has been related to hormonal and metabolic abnormalities [13,[31][32][33][34][35][36][37][38][39][40][41][43][44][45][46][47][48][49][50][51]. In contrast with Type 1 diabetes, in chronic renal failure high polypeptide hormone levels, are not necessarily the result of hypersecretion, but can be due to clearance defects.…”

Role of insulin resistance in the pathogenesis of NIDDM

“…8). Exposure to hyperglycaemia decreased forearm glucose uptake significantly due to a decrease in glucose extraction (*p < 0.05 for hyper-vs normoglycaemia) rats [117,118]. In IDDM, simply increasing the glucose concentration for 24 h is sufficient to induce insulin resistance in skeletal muscle [115,116] (Figs.…”

“…8 and 9). In mildly diabetic rats, selective treatment of hyperglycaemia with phlorizin, which normalizes plasma glucose concentrations without changing plasma insulin concentrations, via inhibition of glucose reabsorption in the proximal tubuli, normalizes insulin sensitivity [117] and secretion [118]. The ability of hyperglycaemia itself to impair both insulin sensitivity and secretion has been referred to as 'glucose toxicity' [1,111,119].…”

Role of nutrient transporters in lifestyle-related diseases

“…A missense mutation of SGLT2 causes familial renal glucosuria 17) . An excellent idea has been proposed that inhibition of renal glucose reabsorption can decrease serum glucose levels in T2D patients 18) . Up to the present, several specific inhibitors of SGLT2 have been developed and are under Phase III clinical trials.…”