Effects of neurotensin and substance P on plasma insulin, glucagon and glucose levels.

Neurotensin and substance P given iv 5, 10, 20 and 30 minutes prior to blood collection produce hypoinsulinemia, hyperglucagonemia and hyperglycemia in the rat. Glucagon similarly produces hyperglycemia in rats but results in hyperinsulinemia. On a molar basis neurotensin is ca. 10 and 30 times more active in inducing hyperglycemia than substance P and glucagon, respectively. The enhanced glucogenic effects of neurotensin and substance P over glucagon may well result from their inhibition of insulin release. Neurotensin and substance P may be important in glucose homeostasis.     

Circadian variations of blood sugar and plasma insulin levels in man

Summary Blood sugar, plasma insulin, non-esterified fatty acids (NEFA), plasma cortisol, and urinary catecholamines were measured for 24 h in seven normal subjects receiving a standard diet. During the night, blood sugar and plasma insulin remained low, NEFA decreased progressively, and the excretion of catecholamines diminished. During the day, the insulin response appeared particularly important after the morning meal. This last observation was also made when normal subjects were given three identical meals at intervals of four and a half hours. Under these conditions, the postprandial elevations of blood sugar were not statistically different, but the plasma insulin rose significantly higher after the morning meal. These observations may be explained by the existence of a periodicity which would regulate the insulin secretion. It is also possible that the insulin liberated postprandially conserves a certain activity at the moment of the next meal, and still intervenes in the maintaining of blood sugar homeostasis. Later in the day, however, blood sugar homeostasis would necessitate a new synthesis of insulin, which would explain the delayed plasma insulin response to the evening meal.Chargé de recherches du Fonds National de la Recherche Scientique.     

Effects of insulin and glucagon on plasma glucose levels and glycogen content in organs of the freshwater teleost Pimelodus maculatus

Mammalian insulin (350 IU/kg) and glucagon (2.5 mg/kg) were injected intraperitoneally into Pimelodus maculatus, a South American teleost. Extent of carbohydrate regulation was estimated through determination of plasma glucose levels, liver-somatic index, and liver and muscle glycogen contents. The effects of insulin administration, examined 6, 12, 24, 48, and 72 hr after injection, were manifested as a depletion of liver glycogen content after 12 hr and severe decrease in plasma glucose content after 24 hr; insulin had no effect on muscle glycogen or liver-somatic index. The effects of glucagon administration, examined 5, 15, 30, 90, and 360 min after injection, were a small increase in liver glycogen content after 15 min, and hyperglycemia, apparent after 30 min. Glucagon did not affect muscle glycogen or liver-somatic index. Control animals were injected intraperitoneally with saline solution. These results suggest that insulin and glucagon regulate the carbohydrate metabolism of P. maculatus by hormonal mechanisms similar to those operating in other teleost species and in mammals.     

Effect of propionate infusion on plasma glucagon, insulin and growth hormone concentrations in lactating dairy cows

Altered concentrations of metabolic hormones have been suggested as important mediators of energy partitioning during early lactation. This study was initiated to determine the effects of propionate (1.0 mmol/kg body weight) infusion on plasma concentrations of glucagon, insulin, growth hormone, propionate and glucose at 14 days ante-partum (AP) and days 5 and 30 postpartum (PP). No differences were seen in propionate concentrations between sampling days. Glucose concentrations were elevated following propionate infusion in pregnant cows but were not elevated in the PP cows. Insulin responses to propionate infusion did not differ between days while the glucagon response was blunted at day 5 PP. Basal glucagon concentrations were elevated between days 5 and 30 PP, insulin concentrations were unchanged between days, while the molar insulin/glucagon ratio was decreased during early lactation. Basal growth hormone (GH) concentrations were elevated between day 14 AP and day 30 PP. GH responsiveness to declining propionate concentrations was greatest at day 5 PP. These data further suggest a role for glucagon as well as GH in nutrient partitioning during early lactation.     

Hypercholesterolaemia type II: Changes in plasma insulin and glucagon levels after portacaval shunt

Insulinaemia and glucagonaemia were measured in two cases of hypercholesterolaemia type II, before and after portacaval shunt. The results show an increase of both hormones although these variations are not concomitant with the decrease in cholesterolaemia. The data still do not explain the mechanism of the decrease.     

Carbohydrate metabolism and plasma levels of insulin and glucagon in patients with atherosclerotic vascular disease

In non-obese, non-diabetic patients suffering acute myocardial infarction, angina pectoris, previous myocardial infarction and peripheral vascular disease, the plasma levels of glucose, insulin, C-peptide and glucagon were determined in basal condition and during an intravenous glucose tolerance test. In the four groups there was a high frequency of glucose intolerance. Basal hyperinsulinism was present in all groups; in groups; in those which maintained normal glucose tolerance there was a high B-cell response to the sugar. Basal hyperglucagonemia was found in the early stage of acute ischemic heart disease, in patients with previous myocardial infarction and in those with peripheral vascular disease. The elevated plasma glucagon levels may play a role in the complex disturbance of carbohydrate metabolism present in patients with atherosclerotic vascular disease.     

Plasma insulin and glucagon levels in protein-malnourished rats

The plasma concentrations of insulin and glucagon were measured in an experimental rat model for protein malnutrition. Plasma insulin levels were markedly reduced, while plasma glucagon levels were comparable to adequately fed age controls.     

Effect of bombesin on plasma insulin, pancreatic glucagon, and gut glucagon in man

The effect of bombesin on insulin, pancreatic glucagon, and gut glucagon was investigated in eight healthy volunteers and two pancreatectomized patients. Bombesin, infused iv at the constant rate of 5 ng kg-1 min-1, produced a sharp and statistically significant rise in the plasma insulin concentration. The peak was reached at 5 min (26 +/- 2.17 microU/ml; P less than 0.005 vs. basal values), followed by a prolonged and statistically significant (P less than 0.05) decrease in blood glucose. Pancreatic glucagon rapidly rose to a maximal value of 80.5 +/- 7.6 pmol/liter (P less than 0.005 vs. basal values). In contrast with the prompt increase in insulin and glucagon plasma levels, the peak in gut glucagon concentration (55.8 +/- 4.6 pmol/liter; P less than 0.005 vs. basal values) was reached 30 min after bombesin infusion was discontinued. In the two pancreatectomized patients, bombesin induced an increase in gut glucagon concentrations only. The results presented indicate that bombesin acts directly on the A and B cells of the pancreas, influencing glucose homeostasis; however, more complex mechanisms seem to be involved in gut glucagon secretion.     

Effect of changes in plasma levels of free fatty acids on plasma glucagon,insulin, and growth hormone in man

A regulatory role of acute changes in plasma concentration of free fatty acids on glucagon secretion has been suggested. We have studied the effect of such changes on plasma levels of glucagon, insulin, and growth hormone in man. Basal plasma levels of immunoreactive glucagon (IRG) were only slightly raised in 11 healthy subjects when the mean concentration of free fatty acids (FFA) was depressed to levels as low as 0.315 ± 0.043 (SEM) mM by infusion of nicotinic acid. Basal levels were increased modestly when the mean FFA level was elevated to 3.027 ± 0.184 mM by infusion of a triglyceride emulsion (Intralipid) with heparin. The plasma IRG response to intravenous arginine was unaffected by high or low levels of plasma FFA. These findings contrasted with the effects upon plasma levels of immunoreactive insulin (IRI) and growth hormone (IGH). During elevation of FFA levels, the mean basal level of plasma IRI increased by 100%, and the IRI response to arginine increased by 50%. Concomitantly, basal IGH levels and the plasma IGH response to arginine were suppressed markedly by elevation of FFA levels. The results of these studies do not offer support for a significant role of variation in plasma level of FFA as a regulator of acute changes in plasma IRG in man. An influence of changing levels of FFA on insulin secretion was found, and an effect on levels of growth hormone was confirmed.     

The mechanism of the effect of oxytocin on plasma concentrations of glucose, insulin and glucagon in conscious dogs

Injections and infusions of oxytocin into conscious dogs caused an increase in plasma concentrations of glucose, insulin and glucagon. When blood glucose was clamped at a raised level the injection of oxytocin still increased insulin and glucagon concentrations in plasma. Infusion of somatostatin suppressed plasma concentrations of glucagon and insulin but did not prevent oxytocin-induced increments in blood glucose. Injection of oxytocin still caused a marked release of glucagon, whereas the insulin response was greatly diminished. When endogenous insulin and glucagon secretion was suppressed by infusion of somatostatin and glucose levels were stabilized by concomitant infusions of glucagon and insulin, injections of oxytocin did not alter blood glucose concentrations. It is concluded that the increase in blood glucose following the administration of oxytocin is secondary to the release of glucagon and that oxytocin exerts a direct stimulatory effect on glucagon and possibly insulin secretion.     

Effects of glimepiride on insulin and glucagon release from isolated rat pancreas at different glucose concentrations

The effects of glimepiride, the newest sulphonylureic compound, on pancreatic insulin and glucagon secretion were studied using the classical, isolated, perfused rat pancreas model. The influence of four different environmental glucose conditions (during a glycaemic stimulus with glucose increasing from 5 to 8.33 mM and at stable 0, 5 and 2.22 mM glucose levels) on the effects of glimepiride was also assessed. At a pharmacological concentration glimepiride strongly stimulated beta-cell activity, producing a characteristic biphasic insulin release with a sharp first-phase secretory peak, followed by a prolonged and sustained second phase. Environmental glucose concentrations markedly influenced the extent, but not the pattern of glimepiride-induced insulin secretion, as hormone release dropped significantly when the glucose level was reduced. Glimepiride failed to influence alpha-cell activity at any of the environmental glycaemic levels.     

Elevated plasma adiponectin concentrations in patients with liver cirrhosis correlate with plasma insulin levels

Abstract: Background: Adiponectin is a hormone secreted by adipocytes and has anti‐diabetic and anti‐atherogenic properties. Hypoadiponectinemia is associated with insulin‐resistant diabetes and liver dysfunction. The aim of this study was to determine plasma adiponectin and insulin levels in patients with liver cirrhosis. Methods: Adiponectin and insulin levels were determined in 38 patients with cirrhosis and 30 healthy controls, and were correlated with various clinical and biochemical parameters. Patients included 21 with Child A, eight Child B, and nine with Child C liver cirrhosis. Results: Log adiponectin and insulin levels were significantly elevated in patients with cirrhosis compared with the control. In liver cirrhosis, the level of adiponectin increased proportionately with the Child's classification score. In control subjects, plasma adiponectin correlated inversely with insulin levels. In contrast, plasma adiponectin correlated positively with insulin levels in patients with liver cirrhosis. Plasma adiponectin levels did not correlate with age, sex, body mass index, total bilirubin, aspartate aminotransferase, and fasting blood sugar levels in both groups, while alanine aminotransferase correlated negatively with adiponectin in control subjects as reported previously. Conclusion: Our results of high plasma adiponectin in patients with liver cirrhosis could reflect an imbalance between its production by adipocytes and metabolism in the liver.     

Hyperglucagonism and glucagon resistance in cirrhosis. Paradoxical effect of propranolol on plasma glucagon levels

Propranolol, a non-selective beta-blocker, is known to decrease glucagon release in normal subjects. The present study was aimed at investigating the effects of propranolol on the hyperglucagonism commonly observed in patients with cirrhosis. Eight cirrhotic patients and 6 matched healthy controls were studied. The plasma concentrations of glucagon, insulin, c-peptide and glucose were measured in basal conditions and after stimulating glucagon secretion by an i.v. infusion of arginine (0.4 g/kg/30 min). The study was repeated 24 h later after inducing beta-blockade by the i.v. infusion of propranolol (10 mg). In baseline conditions, patients with cirrhosis, despite normal levels of insulin and glucose, had a marked hyperglucagonism (654 +/- 303 pg/ml vs. 269 +/- 90 in controls, P less than 0.01). Prior to propranolol, arginine infusion caused greater glucagon release in cirrhotics (71 +/- 31 ng.h.ml-1) than in controls (33 +/- 17 ng.h.ml-1, P less than 0.02), but despite a similar insulin secretion (assessed from c-peptide), blood glucose did not increase. After propranolol, glucagon secretion decreased as expected in controls (29 +/- 12 ng.h.ml-1, P less than 0.05) but experienced a paradoxical increase in cirrhotics (113 +/- 64 ng.h.ml-1, P less than 0.05). Again, despite the marked increase in glucagon release, there was no increase in glucose production, providing further evidence of the glucagon resistance that accompanies hyperglucagonism in cirrhosis. Our results suggest that hyperglucagonism with glucagon resistance might be the initial disturbance in carbohydrate metabolism in patients with cirrhosis. Contrary to what could be expected, propranolol does not correct but further accentuates this disturbance.     

Association of fasting glucagon and proinsulin concentrations with insulin resistance

Aims/hypothesis Hyperproinsulinaemia and relative hyperglucagonaemia are features of type 2 diabetes. We hypothesised that raised fasting glucagon and proinsulin concentrations may be associated with insulin resistance (IR) in non-diabetic individuals. Methods We measured IR [by a euglycaemic–hyperinsulinaemic (240 pmol min⁻¹ m⁻²) clamp technique] in 1,296 non-diabetic (on a 75 g OGTT) individuals [716 women and 579 men, mean age 44 years, BMI 26 kg/m² (range 18–44 kg/m²)] recruited at 19 centres in 14 European countries. IR was related to fasting proinsulin or pancreatic glucagon concentrations in univariate and multivariate analyses. Given its known relationship to IR, serum adiponectin was used as a positive control. Results In either sex, both glucagon and proinsulin were directly related to IR, while adiponectin was negatively associated with it (all p < 0.0001). In multivariate models, controlling for known determinants of insulin sensitivity (i.e. sex, age, BMI and glucose tolerance) as well as factors potentially affecting glucagon and proinsulin (i.e. fasting plasma glucose and C-peptide concentrations), glucagon and proinsulin were still positively associated, and adiponectin was negatively associated, with IR. Finally, when these associations were tested as the probability that individuals in the top IR quartile would have hormone levels in the top quartile of their distribution independently of covariates, the odds ratio was ∼2 for both glucagon (p = 0.05) and proinsulin (p = 0.02) and 0.36 for adiponectin (p < 0.0001). Conclusions/interpretation Whole-body IR is independently associated with raised fasting plasma glucagon and proinsulin concentrations, possibly as a result of IR at the level of alpha cells and beta cells in pancreatic islets. Electronic supplementary material The online version of this article (doi:) contains a list of the European Group for the Study of Insulin Resistance RISC investigators, which is available to authorised users.     

Effect of a long acting glucagon selective somatostatin analogue on plasma glucose,insulin and glucagon levels in the anaesthetized rat during arginine infusion

Summary The effects of somatostatin and a long acting, glucagon selective somatostatin analog (des-Ala¹Gly²[His^4,5-D-Trp⁸]-somatostatin), were studied during arginine tolerance tests in normal anaesthetized rats. Arginine infusion in control animals resulted in a rapid increase in plasma insulin and glucagon, and an increase of 15±5 mg/dl in plasma glucose. Somatostatin infusion (1 mg/kg/h) resulted in suppression of basal insulin secretion and a decrease in arginine-induced insulin and glucagon release. Glucose levels increased rapidly during the combined arginine-somatostatin infusion reaching a peak of 72±10 mg/dl above basal levels. Similar results were obtained when somatostatin was injected SC (1 mg/kg) at times 0, 15, 30, and 45 minutes (arginine infused from 30–60 minutes). A single injection (1 mg/kg) of the long-acting somatostatin analogue resulted in significant inhibition of basal insulin and glucagon release; during arginine infusion glucagon levels rose only slightly, the insulin response was, however, nearly normal, and only a small arginine-induced increase in glucose levels was observed. Carbohydrate absorption was not influenced by either somatostatin or the analogue.