Effect of clofibrate on arginine-induced insulin and glucagon secretion

The influence of clofibrate therapy on insulin and glucagon secretion was examined in the rat. Following arginine stimulation, serum insulin and glucagon levels rose significantly, resulting an an $\text{I}\text{G}$ molar ratio of 1.0 ± 0.3. In contrast, clofibrate therapy completely suppressed the arginine-stimulated insulin secretion, but potentiated the simultaneous glucagon response. The resulting $\text{I}\text{G}$ molar ratio fell to 0.45 ± 0.06, consistent with a change in the bihormonal status in the direction of increased catabolism. These effects on hormonal balance may mediate in part the hypolipemic action of clofibrate that simultaneously occurs.     

Effect of fasting on alanine-stimulated insulin and glucagon secretion

The effect of a 5-day fast on glucose- and alanine-stimulated insulin and glucagon secretion was examined in the dog. As predicted from investigation of other species, prolonged fasting markedly inhibited glucogenic insulin secretion. In contrast, insulin and glucagon secretion after alanine challenge were unaltered by the prolonged fast. These data support the hypothesis that the physiologic response to this amino acid with fasting may be partially responsible for the regulation of insulin secretion in this state.     

Glucose homeostasis during prolonged suppression of glucagon and insulin secretion by somatostatin.

Somatostatin was infused for 5-8 hr into five normal men and eleven normal, conscious dogs. This infusion resulted in a persistent decline in plasma glucagon (40-60%) and insulin (30-45%). Plasma gluccose fell 15-25% during the initial 1-2 hr, but subsequently rose to hyperglycemic levels (130-155 mg/100ml) by 3-6 hr, despite persistent hypoglucagonemia. Glucose production initially declined by 40-50%, but later rose to levels 15-20% above basal rates while peripheral glucose utilization fell to levels 20-30% below basal, thereby accounting for hyperglycemia. Infusion of exogenous insulin so as to restore plasma insulin to preinfusion values or cessation of the somatostatin infusion with restoration of endogenous insulin secretion resulted in a prompt reduction of plasma glucose to baseline values. Prevention of the initial somatostatin-induced hypoglycemic response by intravenous infusion of glucose failed to prevent the delayed hyperglycemia. We conclude that somatostatin caused only transient hypoglycemia in normal subjects and that hyperglycemia eventually developes as a consequence of insulin deficiency. These data indicate that basal glucagon secretion is not essential for the development of fasting hyperglycemia and support the conclusion that insulin deficiency rather than glucagon excess is the primary factor responsible for abnormal glucose homeostasis in the diabetic.     

Kisspeptin-13 inhibits insulin secretion without affecting glucagon or somatostatin release: study in the perfused rat pancreas

Kisspeptins are a family of peptides encoded by the KISS1 gene, which binds to G-protein-coupled receptor (GPR54), an orphan GPR54 related to galanin receptors. Endogenous forms composed of 54, 14, and 13 amino acids have been identified. Kisspeptin and GPR54 mRNAs have been detected in pancreatic B and A cells. Furthermore, kisspeptin-54 has been shown to slightly stimulate the last phase of glucose-induced insulin secretion in mouse and human islets and to inhibit insulin release in MIN6 cells. We have investigated the effect of kisspeptin-13 on insulin, glucagon, and somatostatin secretion. The study was performed in the perfused rat pancreas. Glucose, arginine, carbachol, and exendin-4 were used as secretagogues. Hormones were measured by RIA. Kisspeptin-13 reduced glucose-induced insulin secretion in a dose-dependent manner (IC(50)=1.2 nM) and inhibited the insulin responses to both carbachol and exendin-4. Kisspeptin-13 blocked arginine-induced insulin secretion without affecting the glucagon or somatostatin responses to this amino acid, thus indicating that kisspeptin-13 influences B cells directly, rather than through an A- or D-cell paracrine effect. The reduction of the insulin response to exendin-4 induced by kisspeptin-13 was also observed in pertussis toxin-treated rats, thus suggesting an inhibition independent of G(i) proteins. In view of the potent insulinostatic effect of kisspeptin-13, it is tempting to speculate that kisspeptins may be implicated in the regulation of B-cell secretion.     

Effect of bombesin infused intrapancreatically on glucagon and insulin secretion

Synthetic bombesin was infused at a dose of 20 pmoles/kg/min for 10 min into the cranial pancreaticoduodenal artery of anesthetized dogs. Plasma immunoreactive glucagon concentrations in the cranial pancreaticoduodenal vein as well as in the femoral artery were concurrently and slowly elevated. However, the net release of glucagon from the pancreas did not increase significantly during infusion of bombesin. Plasma immunoreactive insulin concentrations in the pancreatic vein were transiently raised, and a delayed rise was noted in arterial plasma IRI. Net release of insulin was significantly augmented during infusion of the tetradecapeptide. Plasma glucose levels did not change after bombesin. These results indicate that the gastrointestinal tetradecapeptide may stimulate secretion of both insulin and gut glucagonlike immunoreactivity in the dog.     

Sulphonylurea effects on insulin secretion in islets desensitized to glucose

Prolonged, continuous exposure of the islets of Langerhans to high glucose concentrations results in desensitization of the beta cell to glucose stimulation. This study tested the ability of a sulphonylurea to stimulate insulin secretion in this setting. Normal isolated rat islets were cultured for 18-20 h in RPMI-1640 with 300 mg/dl glucose to induce desensitization or with 100 mg/dl as a control. Islets were then placed into a perifusion system and perifused with 60 mg/dl glucose followed by a stimulus. After preincubation at 300 mg/dl, a significant 50% suppression of glucose-induced insulin secretion compared with secretion in the control group preincubated at 100 mg/dl glucose was observed (p less than 0.025-0.001). This confirmed the occurrence of desensitization to glucose in this in vitro model. In contrast, stimulation of insulin secretion by glyburide (500 ng/ml) was unaffected compared with control. We also tested whether glyburide corrects the defective response to glucose stimulation in glucose-desensitized islets. Control islets (preincubated at 100 mg/dl) were stimulated with 300 mg/dl glucose or with this glucose concentration plus glyburide. Peak incremental insulin responses were similar (0.81 +/- 0.07 and 0.77 +/- 0.12 microU/ml.islet). After preincubation at 300 mg/dl, perifusion with 300 mg/dl glucose alone or with glyburide was associated with smaller, but similar, peak insulin responses (0.53 +/- 0.13 and 0.62 +/- 0.06 microU/ml.islet). In conclusion, islets in which the insulin-secretory response is compromised by desensitization to glucose are nevertheless completely responsive to the direct stimulatory effects of a sulphonylurea. However, the sulphonylurea does not correct the defect in glucose-induced insulin secretion.     

Effect of ventromedial hypothalamic lesions on the secretion of somatostatin,insulin, and glucagon by the perfused rat pancreas

Somatostatin, insulin, and glucagon secretion by the perfused pancreas were studied in adult female rats 10 days after ventromedial hypothalamic (VMH) lesions and in sham operated controls to assess the role of their hypothalamic control. Insulin secretion was significantly greater in VMH-lesioned rats both under basal conditions and after stimulation by theophylline and arginine plus theophylline. Basal glucagon secretion was greater in VMH-lesioned rats as was the glucagon response to theophylline alone and in combination with arginine. Basal somatostatin secretion was similar in VMH and control rats but somatostatin secretion induced by theophylline and by arginine plus theophylline was significantly increased in VMH-lesioned rats. Both the pancreatic content and concentration of somatostatin were increased in VMH-lesioned rats. These results indicate the presence of hyperresponsiveness of A, B, and D cells following VMH destruction and provide new evidence for a role of the hypothalamus in the regulation of pancreatic somatostatin secretion.     

Effect of clofibrate on arginine-stimulated glucagon and insulin secretion in man

Insulin and glucagon have been reported to have opposing effects upon the mechanisms regulating serum triglyceride concentration. Glucagon in excess of insulin will lower serum lipids in man. In the present studies, we have examined the possibility that a change in glucagon and insulin regulation might contribute to the hypolipemic action of the drug clofibrate. Control insulin and glucagon secretion were evaluated in 24 normal subjects by intravenous arginine infusion, which resulted in a prompt rise in both serum immunoreactive insulin and glucagon concentration. During the maximum rise in concentration of these hormones, plasma triglyceride concentration was acutely reduced from basal levels of $\text{104 ± 6}\text{mg}\text{100}\text{ml}$ to $\text{75 ± 5}\text{mg}\text{100}\text{ml}$ (p ≤ 0.001). Following 7 days of clofibrate therapy, basal plasma triglyceride concentration attained a new mean level of $\text{78 ± 5}\text{mg}\text{100}\text{ml}$, while basal insulin and glucagon concentrations remained unchanged. However, arginine infusion now resulted in a reduction of the insulin secretory response to 56% of the preclofibrate studies with an associated normal glucagon secretory response. Serum triglyceride concentration was further reduced during arginine infusion to $\text{46 ± 3}\text{mg}\text{100}\text{ml}$, demonstrating this minimum level as maximum plasma glucagon levels were attained, representing an excess of this hormone relative to the reduced insulin concentration. These observations are consistent with an effect of clofibrate on the hormonal regulation of triglyceride physiology in man. Glucose tolerance was unimpaired by clofibrate therapy in these normal subjects, in spite of an apparent reduction in glucose-stimulated insulin secretion.     

Effect of calcitonin on insulin and glucagon secretion by the pancreas

A study was made of the effect of pig calcitonin (CT) on the levels of insulin and glucagon, glucose stimulated insulin secretion and glucagon secretion in insulin hypoglycemia in rats. Disorder of glucose tolerance after administration of CT at a dose of 1 U per 100 g of body mass was established. CT administration did not influence the level of insulin and inhibited its secretion in GTT. CT resulted in a considerable decrease in the basal level of glucagon and an increase in its secretion in insulin hypoglycemia. CT could be involved in neuroendocrine regulation of carbohydrate metabolism.     

The inhibitory effect of somatostatin on growth hormone, insulin and glucagon secretion in diabetes mellitus.

The inhibitory effect of somatostatin on insulin, glucagon and growth hormone secretion was studied in 5 patients with diabetes mellitus. In three maturity onset diabetics, somatostatin infusion abolished the insulin rise induced by breakfast and oral glucose, and in 2 of them, inhibited the basal insulin secretion by 50% seen during control studies. Concomitantly, there was a marked and prompt reduction of glucagon levels (50%) with a sustained effect. The plasma glucose levels were either unchanged or slightly increased. Following the somatostatin infusion, there was a prompt rebound increase in both insulin and glucagon levels with a relatively stable plasma glucose concentration. In contrast, a drastic reduction of plasma glucose in face of a relatively small fall in plasma glucagon in response to somatostatin infusion was observed in 2 insulin-dependent diabetics. In all patients, the episodic release of growth hormone seen during the control day was abolished during somatostatin infusion.     

静脉输注胰淀素对大鼠胰岛激素分泌及血糖的影响

目的 观察外源性胰淀素对高脂饲养的SD大鼠胰岛素分泌第一时相胰高血糖素和胰岛素分泌的影响.方法 32只8周龄雄性SD大鼠随机分为常规饲养组(CC组)、高脂饲养组(CF组)、高脂饲养低剂量胰淀素组(AmyL组)、高脂饲养高剂量胰淀素组(AmyH组).饲养28周后进行静脉葡萄糖耐量试验(IVGTT),分别于静脉注射葡萄糖后0、3、5、10 min留取动脉血检测胰岛素及胰高血糖素水平,并同时测定血糖.AmyL组和AmyH组大鼠IVGTT前50 min开始以410 pmol·kg-1·min-1及610 pmol·kg-1·min-1的速度泵入胰淀素溶液.结果 AmyH组胰高血糖素水平显著低于CF组(P＜0.01);AmyL组及AmyH组大鼠胰岛素水平均显著低于CF组(P＜0.05, P＜0.01);AmyL组及AmyH组血糖均高于CF组(P＜0.05).结论 胰淀素在一定浓度范围可抑制胰高血糖素的异常分泌,但同时降低胰岛素分泌,且此作用强于抑制胰高血糖素的作用,造成血糖升高,提示胰淀素对血糖的影响可能与其对胰岛素及胰高血糖素分泌抑制之间的平衡有关.     

Multiple effects of leucine on glucagon, insulin, and somatostatin secretion from the perfused rat pancreas

The effects of increasing concentrations of leucine (0.2, 2.0, and 15.0 mmol/liter) on glucagon secretion from the perfused rat pancreas were examined at various glucose levels (0, 3.3, or 8.3 mmol/liter) and in the absence or presence of either arginine (5.0 mmol/liter) or glutamine (10.0 mmol/liter). At a low glucose concentration (3.3 mmol/liter), leucine caused a dose-related biphasic increase in glucagon output in the absence of arginine, but only a transient increase in the presence of the latter amino acid. These positive responses were markedly reduced and, on occasion, abolished at a high glucose concentration (8.3 mmol/liter). Moreover, at a low glucose concentration (3.3 mmol/liter) and in the presence of arginine, the highest concentration of leucine (15.0 mmol/liter) provoked a sustained and reversible inhibition of glucagon release. Likewise, leucine (15.0 mmol/liter) reversibly inhibited glucagon secretion evoked by glutamine in the absence of glucose. Thus, leucine exerted a dual effect on the secretion of glucagon, the inhibitory effect of leucine prevailing at a high concentration of the branched chain amino acid and when glucagon secretion was already stimulated by arginine or glutamine. At a physiological concentration (0.2 mmol/liter), however, leucine was a positive stimulus for glucagon release, especially in the absence of another amino acid. Concomitantly, leucine was always a positive stimulus for both insulin and somatostatin secretion. The intimate mechanisms involved in the dual effect of leucine on glucagon secretion remain to be elucidated.     

Relation between blood somatostatin concentration and somatotropin, insulin and glucagon secretion in endocrine diseases

Somatostatin content in the blood of healthy persons, of patients with cerebral nanism, diabetes mellitus, Icenko-Cushing's disease, and obesity, was studied by radioimmuno--assay. Comparative analysis of somatostatin, somatotropin, glucagon and immunoreactive insulin content in the blood of patients with different endocrine disturbances was carried out. Significant elevation of somatostatin level was revealed in cerebral nanism. An increase in the blood somatostatin concentration of patients with diabetes mellitus, Icenko-Cushing's disease and obesity was accompanied by a fall in somatotropin and glucagon secretion and a rise in the blood insulin level.     

Effect of vasoactive intestinal polypeptide infused intrapancreatically on glucagon and insulin secretion

Synthetic vasoactive intestinal polypeptide (VIP) was infused at a dose of 50 ng/kg/min for 10 min into the cranial pancreaticoduodenal artery in anesthetized dogs. Both mean blood flow and plasma glucagon concentration in the cranial pancreaticoduodenal vein were significantly enhanced during the infusion, indicating a great augmentation in glucagon output. The pancreatic venous plasma concentration of insulin was not significantly raised, but its output increased during the infusion, again due to the increase in plasma flow. Plasma concentration of glucagon in the femoral artery was not significantly augmented, whereas that of insulin was enhanced during VIP infusion. Mean arterial plasma glucose levels rose gradually during the infusion. Intrapancreatic pretreatment with propranolol failed to exert any significant inhibiting effect upon the VIP-induced enhancement in plasma glucose, pancreatic venous blood flow, or bihormonal output. These results suggest that the vasoactive polypeptide of intestinal origin may regulate the function of the endocrine pancreas and that this effect may not be mediated mainly via the β-adrenergic receptor system.     

Effect of alloxan on insulin and glucagon secretion in perifused isolated islets

Summary The effect of alloxan on insulin and glucagon secretion was investigated in perifused isolated rat islets. Five minutes of exposure to 1.4 mmol/l alloxan in a low-glucose medium (5.6 mmol/l) abolished subsequent leucine stimulated insulin and glucagon secretion. In a medium containing 19 mmol/l arginine and 3.3 mmol/l glucose, insulin secretion was only slightly diminished by alloxan pretreatment, whereas glucagon secretion was reduced to about 60% of controls. Exposure to alloxan in a high glucose medium (27.8 mmol/l) did not effect insulin or glucagon secretion.     

Inhibition of glucagon and insulin secretion from the perfused rat pancreas by a B-cell-selective somatostatin analog

The isolated perfused rat pancreas was used to study the effects of somatostatin and the analog des-Asn⁵-[D-Trp⁸, D-Ser¹³]-somatostatin on arginine-stimulated insulin and glucagon secretion. Even though the analog was found to inhibit glucagon secretion at concentrations of 10 and 100 ng/ml, it had a relatively more inhibitory effect on the B cell than on the A cell than did somatostatin itself. These data suggest that the A- and B-cell receptors for these two peptides differ.