Inhibition of In Vivo Insulin Secretion by Prostaglandin E1

Self Cite

154

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

Section: Introductionmentioning

confidence: 99%

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

Robertson¹,

Chen²

1977

Self Cite

154

“…Thus, glucose, in addition to dominant positive signals for insulin release, also provides endogenous negative modulators (e.g., PGE 2 ). Indeed, in ␤ cells, inhibition of PGE 2 synthesis potentiates glucose-induced insulin release (50,51,70,71).…”

mentioning

confidence: 99%

Glucose activates the carboxyl methylation of gamma subunits of trimeric GTP-binding proteins in pancreatic beta cells. Modulation in vivo by calcium, GTP, and pertussis toxin.

Kowluru¹,

Li²,

Metz³

1997

The ␥ subunits of trimeric G-proteins ( ␥ 1 , ␥ 2 , ␥ 5 , and ␥ 7 isoforms) were found to be methylated at their carboxyl termini in normal rat islets, human islets and pure ␤ [HIT-T15] cells. Of these, GTP ␥ S significantly stimulated the carboxyl methylation selectively of ␥ 2 and ␥ 5 isoforms. Exposure of intact HIT cells to either of two receptor-independent agonists-a stimulatory concentration of glucose or a depolarizing concentration of K ϩ -resulted in a rapid (within 30 s) and sustained (at least up to 60 min) stimulation of ␥ subunit carboxyl methylation. Mastoparan, which directly activates G-proteins (and insulin secretion from ␤ cells), also stimulated the carboxyl methylation of ␥ subunits in intact HIT cells. Stimulatory effects of glucose or K ϩ were not demonstrable after removal of extracellular Ca 2 ϩ or depletion of intracellular GTP, implying regulatory roles for calcium fluxes and GTP; however, the methyl transferase itself was not directly activated by either. The stimulatory effects of mastoparan were resistant to removal of extracellular Ca 2 ϩ , implying a mechanism of action that is different from glucose or K ϩ but also suggesting that dissociation of the ␣␤␥ trimer is conducive to ␥ subunit carboxyl methylation. Indeed, pertussis toxin also markedly attenuated the stimulatory effects of glucose, K ϩ or mastoparan without altering the rise in intracellular calcium induced by glucose or K ϩ . Glucose-induced carboxyl methylation of ␥ 2 and ␥

“…Prostaglandin E (PGE)l is synthesized by pancreatic islets of Langerhans (1) and inhibits insulin secretion in vivo (2,3). This effect appears to be independent of the alpha adrenergic nervous system because it persists during blockade of alpha adrenergic receptors (2)(3)(4).…”

Section: Introductionmentioning

confidence: 99%

“…This effect appears to be independent of the alpha adrenergic nervous system because it persists during blockade of alpha adrenergic receptors (2)(3)(4). Serotonin has also been identified within the islet (5,6) and has also been shown to inhibit insulin secretion (7)(8)(9), but it is unclear whether or not this effect of serotonin is related to alpha adrenergic activ-ity.…”

Section: Introductionmentioning

confidence: 99%

Reversal by methysergide of inhibition of insulin secretion by prostaglandin E in the dog.

Robertson¹,

Guest²

1978

A B S T R A C T These studies were designed to examine whether interrelationships exist between serotonin and prostaglandin E (PGE) during regulation of insulin secretion in dogs in vivo. In our studies serotonin was found to inhibit insulin responses to intravenous glucose. This inhibition was not reversed by complete adrenergic blockade provided through combined phentolamine and propranolol pretreatment. This property of serotonin is similar to that of PGE which also inhibits glucose-induced insulin secretion in vivo independently of adrenergic activity. To investigate whether these effects of serotonin and PGE are related, studies with methysergide (a serotonin antagonist) and indomethacin (a PGE synthesis inhibitor) were performed. Methysergide reversed the effects of both PGE and serotonin. In contrast, indomethacin did not diminish the inhibitory effect of serotonin upon insulin secretion. It is hypothesized that endogenous serotonin may play a role in the inhibitory effect of PGE upon insulin secretion in dogs in vivo.