Hyperglycemia contributes to impaired insulin response in GK rat islets.

Abstract

Insulin secretion and glucose metabolism were compared in pancreatic islets from type 2 diabetic GK rats treated with phlorizin or vehicle. Treatment of control and GK rats with phlorizin for 30 days did not affect body weight, islet glucose utilization, or islet glucose oxidation. In phlorizin-treated GK rats, glucose-induced insulin release was about twofold higher at 11.0 and 16.7 mmol/l glucose compared with vehicle-treated GK rats, whereas phlorizin had no effect on control Wistar rats. However, also in phlorizin-treated GK rats, the amount of insulin released by the islets was significantly less than that from control rats (5.29 ± 0.33 vs. 7.50 ± 1.31 pmol · min -1 · islet -1 at 16.7 mmol/l glucose; P < 0.001). Islet glucose-6-phosphatase activity was significantly higher in GK rats than in control rats; phlorizin treatment significantly decreased this activity. These findings demonstrate that hyperglycemia per se constitutes an important factor for impaired insulin release in GK rats. Correction of hyperglycemia normalizes islet glucose-6-phosphatase activity, which may be an underlying factor for the partial improvement of glucose-induced insulin release. Diabetes 50 (Suppl. 1):S108-S112, 2001

Programmed disorders of β-cell development and function as one cause for type 2 diabetes? The GK rat paradigm

“…These changes in islet function can be ascribed, at least in part, to a loss of differentiation of β-cells chronically exposed to even mild chronic hyperglycemia and elevated plasma nonesterified fatty acids, a process referred to as 'gluco-lipotoxicity'. Such a view is supported by the recent reports that chronic treatment of GK rats with phlorizin partially improved glucose-induced insulin release [35,36], while hyperlipidemia induced by high-fat feeding markedly impaired insulin secretion [37].…”

Mechanisms of β-cell dedifferentiation in diabetes: recent findings and future research directions

“…Indeed, G6pase overexpression in INS1 cells has been shown to increase GC and reduce GSIS (Trinh et al 1997). Upregulation of G6pase mRNA and enzymatic activity in the islets of Px and GK rats was reversed by phlorizin treatment thereby underscoring the role of hyperglycemia (Ling et al 2001, Laybutt et al 2002b.…”

“…Other metabolic genes presenting low expression under physiological conditions and upregulated in diabetes include the gluconeogenic genes G6pase (Ling et al 2001, Laybutt et al 2002b, Fbp1 (Laybutt et al 2002b) and Pck1 (Marselli et al 2010). The latter gene was also upregulated in isolated human islets cultured in the presence of high glucose levels (Shalev et al 2002) ( Table 3).…”

“…Px rat islets (Laybutt et al 2002b) GK rat islets (Ling et al 2001) mRNA and enzymatic activity Fbp1…”

Anaplerotic roles of pyruvate carboxylase in mammalian tissues

“…In pancreatic islets, however, it has been found that the level and activity of PC is as high as in the gluconeogenic tissues, liver and kidney [6,[26][27][28]. Yet b-cells have no detectable activity of PEPCK [29,30] to carry out gluconeogenesis, although they contain a significant level of G6Pase activity [31][32][33][34][35]. It appears that both PC and PDH are highly expressed in pancreatic islets, and their levels of expression and protein increase in response to high concentrations of glucose.…”