Glucagon-induced Insulin Release Research Articles

Risk Factors, Complications and Management of Diabetes Mellitus

Diabetes mellitus can be a complex disorder described by chronic progressive metabolic disorder and chronic hyperglycemia arising from dysregulation of carbohydrate, lipid and protein metabolism. Verapamil is a class of non-dihydropyridine calcium channel blockers, which prevents the second phase of glucose stimulated insulin release by inhibiting the intake of calcium into the cytosol of beta cells and also prevents sulfonylurea and glucagon-induced insulin release. The complications of diabetes mellitus are categorized as microvascular (nephropathy, neuropathy, and retinopathy) or macrovascular (cardiovascular and cerebrovascular disease). Diabetic nephropathy is a microvascular complication described by elevated urinary albumin excretion (proteinuria) or lowered kidney glomerular filtration rate in both types of diabetic mellitus. The objective of diabetes mellitus management is to inhibit the mortality and to delay the onset of disease complications and to hinder its progression by improving patients’ blood sugar level and controlling the risk of cardiovascular disease. Metformin enhances liver, muscle & adipose tissues sensitivity to the insulin and elevate peripheral glucose utilization and also prevents gluconeogenesis and obviates glucose absorption from gastrointestinal tract.

Highly efficient detection of insulinotropic action of glucagon via GLP-1 receptor in mice pancreatic beta-cell with a novel perfusion microchip

Abstract Glucagon exhibits insulinotropic ability by activating cAMP through glucagon or glucagon-like peptide-1 (GLP-1) receptors. To investigate the mechanism of endogenous and exogenous glucagon on insulin release, we studied the receptor selectivity on pancreatic islet beta-cells by switching the glucose concentration from 20 mmol/L to 0 mmol/L. To measure the exact temporal relationship between glucagon and insulin release, we developed a quick, small volume, multi-channel polydimethylsiloxane (PDMS) microchip. At 0 mmol/L glucose, we observed an insulinotropic effect in both INS-1 cells and islets. Meanwhile, we observed a 63 ± 6.27 s delay of endogenous glucagon-induced insulin release. After treatment with glucagon and GLP-1 receptor antagonists, we found that endogenous glucagon utilized the glucagon receptor, whereas exogenous glucagon primarily utilized the GLP-1 receptor to promote insulin secretion. The microchip can also be used to describe the “glucagonocentric” vision of diabetes pathophysiology. Taken together, the insulinotropic mechanism of different receptors should be taken into account in clinical treatments.

Pancreastatin and its 33–49 C-terminal fragment inhibit glucagon-stimulated insulin in vivo

1. 1. Pancreastatin, a 49 amino acid peptide derived from chromogranin A, has been shown to have an inhibitory effect on insulin secretion in the perfused pancreas and isolated islets. 2. 2. We have studied the effect of pancreastatin on glucagon-stimulated insulin release and the hyperglycemic of glucagon effect in vivo. 3. 3. When administered in the mesenteric vein, pancreastatin inhibited the increase in insulin levels induced by glucagon stimulation, thereby potentiating the hyperglycemic effect of glucagon. 4. 4. This study describes a regulatory role of pancreastatin on glucagon-induced insulin release in vivo.

Mechanisms of action of Cyclosporin A on islet α- and β-cells effects on cAMP- and calcium-dependent pathways

The involvement of cAMP- and calcium-dependent pathways on the inhibitory effect of CsA (0.5 μg/ml) on insulin and glucagon release was studied in collagenase-isolated islets. CsA suppressed by 50% the release of insulin in pertussis toxin treated islets stimulated by 20 mM D-glucose. CsA blocked glucagon and insulin release induced by 0.2 mM IBMX (80% and 50% respectively). Similarly it inhibited glucagon and insulin release induced by 1 μM A23187 (53% and 40% respectively). CsA also abolished 0.1 μM glucagon-induced insulin release and 10 ng/ml VIP-induced glucagon release (70% and 38% respectively). The glucagon response to 2 mM D-glucose and to 10 mM arginine was decreased 25% and 45% respectively by CsA. The inhibitory effect of 0.1 μM somatostatin on insulin release was significantly abolished by CsA (p< 0.001 vs control). On the other hand 1 μM forskolin induced insulin and glucagon release was not modified by CsA. Rats treated with CsA (10 mg/kg body wt) during 10 days showed hyperglycaemia, hypoglucagonemia and higher contents of pancreatic glucagon. It is concluded that CsA affects α- and β-cell function, in vivo and in vitro, acting through calcium and cAMP-dependent pathways. This latter pathways involves the Ca 2+-calmodulin dependent phosphodiesterase and the regulatory proteins G s and G i.

Effect of Lithium on Pancreatic Islet Insulin Release*

Lithium exerts an inhibitory effect on glucose and amino acid-induced insulin release. The inhibitory effect of Li+ persists even in subsequent Li+-free conditions, indicating an only slowly reversible effect. Lithium fails to inhibit glucagon-induced insulin release. The exact mechanism of the lithium effect is as yet undetermined, but interference with calcium flux and/or microtubular function is an attractive hypothesis. The inhibitory effect of lithium on insulin release cannot be reversed by alteration in ionic (Ca++, Mg++, K+) concentrations in the incubation media. Studies involving the effect of low sodium on insulin release in which lithium had been used as an osmotic replacement for sodium must be carefully reassessed because of these findings.

Kinetics of Early Insulin Response by the Isolated and Perfused Rat Pancreas. Suggestion for Two Different Actions of Glucose on the Insulin Releasing Process

The permissive action of glucose (or glyceraldelhyde) is necessary to the glucagon induced insulin release. By collecting every 15 seconds the venous effluent of the perfused and isolated rat pancreas it was observed that the insulin response to glucagon (2 microgram/ml) was immediate if the pancreas was preperfused with low concentration of glucose (5 mM) or glyceraldelhyde (2,5 mM). On the other hand glucagon alone elicited no response, and the insulin discharge occurred 60 to 90 seconds after the addition of glucose (5 mM) or glyceraldelhyde (2,5 mM) this time being probably allowed to the metabolism of the sugar. The pancreatic response to 15 mM glucose occurred also 60 to 90 seconds after the stimulus. On the other hand when the medium contained a low concentration of glucose (or glyceraldelhyde) increasing the glucose concentration by 10 mM provoked an immediate insulin release. This suggests that glucose has two actions differing by their lag phase. One, "permissive", apparent after some delay, mimicked by glyceraldelhyde, necessary for glucagon induced insulin release, is mediated probably by the metabolic products of the sugar. The second, "triggering", initiates instantaneously the insulin release but appears dependent on the first action.

The comparison of glucose- and glucagon-induced insulin release in obese and nonobese subjects.

The comparison of glucose- and glucagon-induced insulin release in obese and nonobese subjects.

5′-Guanylylimidodiphosphate: A modulator of glucagon-induced insulin release from isolated rat pancreatic islets

GMP-PNP (0.1 or 0.01 mM) enhanced the glucagon-induced (5 μg/ml) IRI release from isolated rat pancreatic islets. Glucose-induced (8 or 16.6 mM) and theophylline-induced (0.5 mM) IRI release were unaffected. The modulatory effect of GMP-PNP on glucagon-induced IRI release might be explained by an alteration of the adenylate cyclase system in B-cells. Phosphotransferase reactions do not seem to be involved in this process.

Regulation of in Vitro Insulin Release from a Transplantable Syrian Hamster Insulinoma1

An insulin-producing islet cell tumor of the Syrian hamster has been studied in vitro for its capacity to respond to known stimuli of insulin release. Insulin secretion during short term incubation and perifusion of fragments of tumor was detected by radioimmunoassay. Insulin release was increased 2-4 fold by 40 mM potassium in the presence of calcium, glucose (22 mM), glucagon (0.3-3.0 muM), N6,02'-dibutyryl adenosine 3',5'-monophosphate (cAMP; 6mM), and theophylline (10 mM). Concentrations of glucagon that induced insulin release were also effective in activating adenylate cyclase in the membranes of tumor cells. Thus, this tumor appears to possess a cAMP-mediated mechanism for insulin release. Somatostatin (0.8-25 mum) inhibited glucagon-induced insulin release without altering basal or glucagon stimulated adenylate cyclase activity. It would appear that inhibition of glucagon induced insulin release by somatostatin is not mediated by adenylate cyclase. We propose that insulin release by this tumor is sufficiently similar to that found in normal islets so as to make it a suitable model for biochemical studies that require large quantities of homogeneous tissue.

Effect of tolbutamide on aminophylline-, 3,5-AMP-dibutyrate-or glucagon-induced insulin release from pancreatic islets after impairment of pyridine nucleotide metabolism caused by 6-aminonicotinamide (6-AN)

The effect of tolbutamide on pyridine nucleotides and insulin secretion stimulated by aminophylline, 3,5-AMP-dibutyrate or glucagon was studied in pancreatic islets of rats previously treated with 6-aminonicotinamide (6-AN), an inhibitor of pyridine nucleotide synthesis. After being incubated for 60 min in a Krebs-Ringer-Bicarbonate-Buffer in the absence of glucose, pancreatic islets of rats i.p. injected with 35 mg/kg of 6-AN 6 hrs before pancreas removal contained about 30% less NADP and NADPH than did islets of control rats. No changes of NDA or NADH were observed in islets of 6-AN-treated animals. Addition of 16.5 mM glucose led to an increase of NADH, NADPH and a decrease of NADP in islets of both groups of animals; NAD levels remained unchanged. In vitro addition of tolbutamide to islets of control rats did not affect the levels of NADPH or NADP in the presence of 5.5 mM glucose. When 16.5 mM glucose were present, a decrease of NADPH and an increase of NADP was obvious. No effect of tolbutamide on insular NADPH or NADP was observed in islets of rats previously treated with 6-AN be it in the presence of 5.5 or 16.5 mM glucose. In islets of 6-AN-treated rats insulin release in response to aminophylline or 3,5-AMP-dibutyrate in the presence of 5.5 mM glucose was significantly depressed, when compared to islets of untreated controls. Addition of tolbutamide increased insulin release due to aminophylline, 3,5-AMP-dibutyrate or glucagon islets of controls. Tolbutamide alone was without effect. In islets of 6-AN-treated rats aminophylline, 3,5-AMP-dibutyrate or glucagon stimulated insulin release only when tolbutamide was present. Our data suggest that there is no direct interference of tolbutamide with pyridine nucleotides of pancreatic islets, and that tolbutamide increases the secretory response of the beta-cell to aminophylline, 3,5-AMP-dibutyrate or glucagon when insulin release due to these agents is inhibited during decrease of insular NADP and NADPH, caused by 6-AN.

Alcohol inhibition of cyclic AMP-induced insulin release.

In order to define the role of alcohol in cAMP-induced insulin release, the two agents were infused into the pancreas or liver of normal dogs separately or in combination. Blood levels of insulin and glucose were measured in the portal vein. CAMP infusion in the pancreatic artery provoked a greater early insulin response than did a similar infusion into the portal vein when glycemic levels were comparable. The addition of alcohol suppressed insulin response to intrapancreatic cAMP. Alcohol in the absence of the stimulus failed to suppress insulin below basal levels. It is concluded that pancreatic alcohol directly inhibits cAMP-related insulin release and that this is the mechanism by which glucagon-induced insulin release is blunted by alcohol. Glucose-induced release, which is potentiated by intravenous alcohol, apparently involves another mechanism.

Glucagon stimulation of insulin release in man: inhibition during hypoglycemia.

ABSTRACT The plasma insulin response to iv administered glucagon was studied in five healthy subjects both in the basal state and during insulin induced hypoglycemia. Insulin response to glucagon was blunted when the blood glucose level was decreased. This inhibition was not entirely mediated by catecholamines liberated during hypoglycemia, since the alpha adrenergic blocking agent phentolamine could not restore the effect of glucagon. Phentolamine itself, in the absence of hypoglycemia, had no significant effect on glucagon induced insulin release. It is concluded that, in man, the insulin releasing action of glucagon is dependent on the presence of a normal blood glucose concentration.

Differential plasma insulin response to glucose and glucagon stimulation following ethanol priming.

The early phase of the insulin secretory response to glucose may not be derived from the total pool of stored insulin, but possibly from a specific and relatively small fraction in a state or locus necessary for its immediate release. In an attempt to deplete this hypothetical fraction, and thereby to support the concept of its existence and obtain an estimate of its size under different circumstances, normal and mildly diabetic subjects were given a series of three large glucose loads followed by glucagon, with and without alcohol “priming”. Results indicate that repetitive glucose or glucagon challenges over a two-hour period failed to exhaust the supply of immediately releasable insulin in either group of subjects as judged by the increments in plasma insulin during the first few minutes after each challenge. Alcohol pretreatment resulted in a larger early insulin secretory response to the first of three glucose loads, but a decreasing response to the subsequent two, possibly indicating that the initially augmented secretory response had resulted in depletion of a finite supply of immediately available insulin. An unexpected finding was the inhibitory effect of alcohol on glucagon-induced insulin release, in direct contrast to its effect when glucose is the insulinogogue, suggesting that glucose and glucagon exert their effects throughdifferent mechanisms or on different fractions of the insulin pool.

Insulin release after ACTH, glucagon and adenosine-3'-5'-phosphate (cyclic AMP) in the perfused isolated rat pancreas.

An isolated rat pancreas preparation has been employed for the study of insulin Secretion. The preparation consists of the pancreas and the duodenum in which the thoracic aorta is cannulated for arterial inflow and the portal vein cannulated to collect the venous effluent. The administration of ACTH, glucagon and cyclic AMP will increase the secretion of insulin from the isolated perfused pancreas. Theophylline was infused into the pancreas with glucagon and compared with glucagon alone. Theophylline did not have any effect on altering insulin secretion from the pancreas nor did it potentiate the glucagon-induced insulin release. While glucagon, ACTH, and cyclic AMP all stimulate insulin secretion, there is no definitive evidence that the effect of glucagon or ACTH on the beta cell is due to intracellular generation of cyclic AMP.