Correlation Between Pancreatic Islet Uncoupling Protein‐2 (UCP2) mRNA Concentration And Insulin Status in Rats

Abstract

Hypothesizing that UCP2 may influence insulin secretion by modifying the ATP/ADP ratio within pancreatic islets, we have investigated the expression of intraislet UCP2 gene in rats showing insulin oversecretion (non-diabetic Zucker fa/fa obese rats, glucose-infused Wistar rats) or insulin undersecretion (fasting and mildly diabetic rats). We found that in Zucker fa/fa obese rats, hyperinsulinemia (1222 4-98 pmol/1 vs. 128 4-22 pmol/1 in lean Zucker rats) was accompanied by a significant increase in UCP2 mRNA levels. In rat submitted to a 5 day infusion with glucose, hyperinsulinemia (1126 4-101 pmol/l vs. 215 4-25 pmol/1 in Wistar control rats), coincided with an enhanced intraislet UCP2 gene expression, whereas a 8h or a 2 day-infusion did not induce significant changes in UCP2 mRNA expression. In rats made hypoinsulinemic and mildly diabetic by the injection of a low dose of streptozotocin, and in 4-day-fasting rats (plasma insulin 28 4-5 pmol/1) UCP2 (Fig. 1). Plasma insulin was 10-fold higher in obese Zucker rats compared to lean Zucker rats (Fig. 1). Glucose-infused RatsSustained and steady hyperglycemia of about 20mmol/1 was produced in rats infused with glucose during 8h, or 2 days or 5 days. As a result, insulinemia was dramatically increased (Fig. 1). In both hyperglycemic-hyperinsulinemic groups, the glucose and insulin plateaus were reached after 4h of infusion with glucose (data not shown). STZ RatsTwo days after STZ injection, plasma glucose and insulin concentrations were, as compared to controls, significantly increased and decreased, respectively (Fig. 3).Fifteen days after STZ injection, STZ rats were hyperglycemic and hypoinsulinemic compared to control Wistar rats (Figs. 2 and 3). Moreover, glucose tolerance and glucose-induced insulin secretion were impaired as reflected in the AG and the AI/AG, respectively (Fig. 2) histochemistry (Fig. 4) (Fig. 1). Neither a 8h nor a 2-day infusion with glucose did not result in any significant change in UCP2 gene expression, whereas rats infused with glucose during 5 days showed higher UCP2 mRNA levels than controls (Fig. 1). In STZ rats studied 15 days after the injection of the drug, UCP2 mRNA levels were clearly decreased compared to Wistar non diabetic rats (Fig. 2). When the rats were studied 2 days after the injection no change in islet UCP2 gene expression could be observed. Islet UCP2 gene expression was also markedly lowered after a 4-day fast but a 3-day fast failed to alter this parameter (Fig. 2)

Uncoupling Protein 2 and Islet Function

“…UCP2 expression has been quantified in islets of several rodent models of type 2 diabetes. Ucp2 mRNA or protein is elevated in fa/fa rats (33) and ob/ob mice (19) but decreased in Zucker diabetic fatty rats (4,17). Induction of type 2 diabetes by high-fat feeding also upregulates UCP2 gene expression, which is associated in all cases with elevated plasma lipids (9,20,41).…”

“…Induction of type 2 diabetes by high-fat feeding also upregulates UCP2 gene expression, which is associated in all cases with elevated plasma lipids (9,20,41). Likewise, hyperglycemic models also display an increase in islet UCP2 transcripts, at least temporarily (32,33). These animal models differ in the degree of insulin insufficiency and thus hyperglycemia.…”

Genetic Regulation of Metabolic Pathways in β-Cells Disrupted by Hyperglycemia

“…In contrast with our results, it has been reported that glucose down-regulates UCP-2 expression in INS(832/13) cells (46) and that UCP-2 expression is reduced in diabetic ZDF rats (49). However, up-regulation of UCP-2 has been observed in islets after chronic glucose infusion in rats (50) and after culturing islets in high glucose (51). Fatty acids have been shown to lead to an increase in UCP-2 in islets (52).…”

A Systematic Review of in vitro Studies Conducted on Effect of Herbal Products on Secretion of Insulin from Langerhans Islets

“…Animal (114,115) and human (116,117) studies have shown that increased UCP2 expression in islets can lead to β-cell dysfunction and development of type 2 diabetes mellitus. Thus, UCP2 deficiency can prevent β-cell dysfunction.…”