A Role for Prostaglandin E in Defective Insulin Secretion and Carbohydrate Intolerance in Diabetes Mellitus

Abstract

A B S T R A C T Prostaglandin E2 (PGE2) infusion in normal humans inhibited acute insulin responses to a glucose (5 g i.v.) pulse (response before PGE2 = 593 + 104%; during PGE2 = 312+55%, mean+SE, mean change 3-5 min insulin, % basal, P < 0.005). This effect was associated with a decrease in glucose disappearance rates (KG before PGE2= 0.73+0.07; during PGE2= 0.49+0.06 %/min, P < 0.025). Acute insulin responses to arginine (2 g i.v.) were not affected by PGE2 (response before PGE2 = 592+164%; during PGE2 = 590+118%; P = NS). Infusion of sodium salicylate (SS), an inhibitor ofendogenous prostaglandin synthesis, augmented acute insulin responses to glucose in normals (response before SS = 313+62%; during SS = 660+86%; P < 0.001). In adult-onset diabetes with fasting hyperglycemia, SS restored absent acute insulin responses to glucose (20 g i.v.) pulses (response before SS = 5+6%; during SS = 97+24%; P < 0.005). This was accompanied by a fourfold augmentation in second phase insulin secretion (second phase before SS = 1,696+430%; during SS = 5,176±682%; change 10-60 min insulin, A min, % basal, P < 0.001) and by acceleration ml of glucose disappearance rates (KG before SS = 0.56 ±0.06; during SS = 1.02+0.17 %/min, P < 0.005). These findings uniquely demonstrate that (a) PGE2 inhibits glucose-induced acute insulin responses and decreases glucose disposal in nondiabetic humans and (b) SS restores acute insulin responses, augments second phase insulin secretion, and accelerates glucose disposal in hyperglycemic, adultonset diabetics. It is hypothesized that endogenous

Inhibition of Interleukin-1β-Induced COX-2 and EP3 Gene Expression by Sodium Salicylate Enhances Pancreatic Islet β-Cell Function

“…These events lead to increased synthesis of PGE 2 and EP3 receptor protein. Binding of PGE 2 to EP3 has been shown by us to decrease islet cAMP levels (27), thereby decreasing glucose-induced insulin secretion. Interference with these events by sodium salicylate occurs at the site of IL-1␤ activation of NF-B and of COX-2 enzymatic activity.…”

“…Sodium salicylate has been known for Ͼ30 years to be an inhibitor of COX activity (44,45) and has been demonstrated to improve defective insulin secretion in patients with diabetes (2,46,47). This drug has been reported to inhibit dissociation of NF-B from NF-B/IB complexes (17,18), thereby preventing transport of NF-B from the cytoplasm to the nucleus of cells, where it stimulates COX-2 and EP receptor transcription (19,20).…”

“…These findings indicate that the sites of action through which sodium salicylate inhibits these negative effects of IL-1␤ on ␤-cell function include activation of NF-B as well as generation of PGE 2 by COX-2. Diabetes 51: 1772-1778, 2002 I nterleukin-1␤ (IL-1␤) and prostaglandin E 2 (PGE 2 ) both inhibit glucose-induced insulin secretion from the pancreatic islet (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). The similarity of their actions and that both are mediators of inflammation have led to a consideration of whether PGE 2 might mediate the effects of IL-1␤ to inhibit insulin secretion (7,12).…”

The -765G>C Cyclooxygenase-2 Promoter Polymorphism is associated with Type 2 Diabetes Mellitus, Low High-density Lipoprotein and Manifest Angina

“…Conversely, both prostaglandin E2 and prostacyclin synthesis are thought to have an adaptive role in the reduction of high blood pressure in patients with diabetes through increased COX-2 expression resulting in vasodilation [10], as well as playing a cardio protective role [11]. COX-2 also contributes to insulin signalling, as prostaglandin E2 in pancreatic β-cells has a negative effect on insulin secretion [12,13]. It is clear that COX-2 regulates a number of key pathways producing paracrine hormones with a range of physiological functions and has the potential to be a therapeutic to prevent cardiovascular disease [14].…”

Failure of indomethacin to affect arginine-induced C-peptide and glucagon release in insulin-treated diabetics

“…The influence of indomethacin on residual insulin secretion was also assessed by measuring C-peptide plasma levels during the arginine infusions. Indeed, Robertson and his group [2,22,26] have reported that blocking the synthesis of prostaglandins by sodium salicylate intravenous infusion improved the insulin response to glucose in Type 2 (insulin independent) diabetics. In addition we attempted to correlate the magnitude of the blood glucose rise induced by arginine infusion with the insulin-secretory reserve and the amplitude of the glucagon rise.…”