Glucose tolerance factor extracted from yeast: oral insulin-mimetic and insulin-potentiating agent: in vivo and in vitro studies

Abstract

In search for an effective oral treatment for diabetes, we examined the capacity of glucose tolerance factor (GTF) extracted from yeast and administered orally to reduce hyperglycaemia in rat models exhibiting insulin deficiency. The cellular effect of GTF on the insulin signalling pathway was investigated in vitro. GTF (oral bolus), insulin (intraperitoneal) or their combination was administered to streptozotocindiabetic (STZ) or hyperglycaemic Cohen diabetic-sensitive (hyp-CDs) rats. Blood glucose (BG) and insulin levels were measured in the postprandial (PP) state and during an oral glucose tolerance test. Deoxy-glucose transport and insulin signal transduction were assessed in 3T3-L1 adipocytes and myoblasts incubated with the GTF. Low dose of insulin produced a 34 and 12·5 % reduction in the PP-BG levels of hyp-CDs and STZ rats, respectively. GTF induced a 33 and 17 % reduction in the PP-BG levels of hyp-CDs and STZ rats, respectively. When combined with insulin, a respective decrease (58 and 42 %) in BG levels was observed, suggesting a partially additive (hyp-CDs) or synergistic (STZ rats) effect of the GTF and insulin. GTF did not induce insulin secretion in hyp-CDs rats, yet it lowered their BG levels, proposing an effect on glucose clearance by peripheral tissues. GTF induced a dose-dependent increase in deoxy-glucose transport into myoblasts and fat cells similar to insulin, while the combined treatment resulted in augmented transport rate. GTF induced a dose-and timedependent phosphorylation of insulin receptor substrate 1, Akt and mitogen-activated protein kinase independent of insulin receptor phosphorylation. GTF exerts remarkable insulin-mimetic and insulin-potentiating effects, both in vivo and in vitro. It produces an insulin-like effect by acting on cellular signals downstream of the insulin receptor. These results demonstrate a potential source for a novel oral medication for diabetes.Key words: Diabetes: Yeast: Glucose tolerance factor: Glucose-lowering effect: Insulin signalling Drug treatment options for diabetes mellitus are many and diverse. Despite the use of intensive regimens combining several anti-diabetic drugs and insulin, glycaemic control declines over time in most diabetic patients, reflecting ongoing deterioration of b-cell function. As a consequence, much research has focused on identifying new therapeutic targets and pharmacological compounds that might correct impaired glucose homeostasis via novel pathways.

Glucose Tolerance Factor – Insulin Mimetic and Potentiating Agent – A Source for a Novel Anti Diabetic Medication

“…They found a stimulation of glucose uptake (5.6 times greater than the basal level) in the absence of insulin. Our group also showed an increase in glucose transport both to yeast cells [63,64], and to animal cells [65].…”

“…In vitro studies done in our laboratory showed insulin mimetic and insulin potentiating activity for GTF [65].…”

“…Studies done in our laboratory on L6 myoblasts and 3T3-L1 adipocytes presented a marked increase in 2-deoxy-glucose [2-DG) uptake induced by GTF, in a rate similar to insulin, indicating a high positive effect on glucose uptake ( Figure 13) (From Weksler-Zangen et al, [65].…”

“…The decrease in BG-AUC depended on the dose of GTF administered. Insulin secretion in response to glucose stimulation did not change significantly in GTF treated hyp-CDs rats (From Wexler-Zangen et al, [65], indicating that the glucose lowering effect of GTF is not related to stimulation of insulin secretion. …”

“…We examined GTF effects in two rat models exhibiting insulin deficiency: the streptozotocin (STZ) diabetic rat, which is characterized by the damage induced to beta cells by the drug, and the hyperglycemic Cohen diabetic-sensitive ((hyp-CDs) rat, which is characterized by beta cell dysfunction and decreased glucose stimulated insulin secretion (from WexlerZangen et al, [65].…”