María L. Villanueva

Elevated Plasma Glucagon Levels in Cirrhosis of the Liver

Abstract Plasma glucagon levels (in the basal state, after stimulation with arginine and after suppression by oral glucose) were determined in 36 patients with cirrhosis. The mean basal glucagon levels were 455 ± 63 (S.E.M.) pg per milliliter in eight patients with portacaval shunts, 217 ± 23 pg per milliliter in 28 patients without shunts, and 146 ± 10 pg per milliliter in 15 controls. After arginine stimulation, glucagon rose to 828 ± 122 pg per milliliter in 25 cirrhotic patients and to 409 ± 36 pg per milliliter in the controls. High fasting glucagon levels (490 to 560 pg per milliliter) and an exaggerated elevation after arginine were also found in a noncirrhotic subject with a mesocaval shunt. Since glucagon is degraded in the liver, the abnormal liver-cell function and hepatic blood flow of cirrhosis probably explain the hyperglucagonism found in this condition. The high plasma glucagon levels, however, do not necessarily explain the abnormalities of carbohydrate tolerance found in patients with ci...

Hyperglucagonism Induced by Glucocorticoid Treatment in Man

Abstract To elucidate further the nature of glucocorticoid-induced alteration of carbohydrate metabolism, plasma glucagon levels, both basal and after an arginine stimulus, were studied in normal volunteers before and after glucocorticoid treatment. In one group of 13, after oral administration of prednisolone (40 mg daily, for four days) an increase in fasting glucagon levels (+ 24 pg per milliliter) and a glucagon hyper-response to a high arginine load (+ 133 pg per milliliter at 10 minutes, + 80 pg per milliliter at 20 minutes and + 51 pg per milliliter at 30 minutes) were accompanied by an elevation of glucose, amino nitrogen and insulin concentrations. In another group of eight, after oral administration of prednisolone (60 mg daily for three days) a rise in fasting glucagon levels (+ 17 pg per milliliter) and a greater glucagon response to a low arginine load (+ 68 pg per milliliter at 10 minutes) were observed. In a third group of five, the intravenous injection of prednisolone (100 mg) failed to a...

Somatostatin, insulin and glucagon secretion by the perfused pancreas from the cysteamine-treated rat

In rats, administration of a single dose of cysteamine (300 mg/kg, intragastrically) induces a depletion of pancreatic somatostatin content (approximately 60%) without modifying pancreatic insulin or glucagon content. In perfused pancreases from cysteamine-treated rats, there was a lack of somatostatin response to glucose, arginine or tolbutamide. In the absence of stimulated somatostatin release, the secretory responses of insulin and glucagon to glucose, to arginine, and to tolbutamide were not significantly different from those observed in pancreases from control rats. Our data do not support the concept that pancreatic somatostatin plays a major role in the control of insulin and glucagon release.

Plasma glucagon immunoreactivity in a totally pancreatectomized patient.

SummaryAnalysis of the plasma from a totally pancreatectomized patient, with antiserum 30 K, has demonstrated basal glucagon immunoreactivity (GIR) levels in the normal range (80–110 pg/ml). Neither i. v. arginine nor oral glucose affected these GIR values, thus indicating the absence of functioning pancreatic or gastrointestinal A-cells. Furthermore, filtration of whole plasma on Bio Gel P-30 showed no GIR in the 3500 MW elution volume. GIR was found to be distributed in two peaks. One peak eluted in the protein region, similarly to “big plasma glucagon” (BPG), and the second peak appeared after the glucagon-I125 marker. The protein-sized moiety was not absorbable by charcoal, and on Sephadex G-100 it eluted within the globulin region. When subjected to trypsin treatment, it yielded smaller GIR fractions. According to these criteria, it can be assumed that this component is identical to BPG. Therefore, an extrapancreatic source for BPG is suggested. On the other hand, the presence of fasting hyperglycaemia in this patient indicates that insulin deficiency by itself suffices to raise blood sugar to diabetic levels.

Pancreastatin inhibits insulin secretion as induced by glucagon, vasoactive intestinal peptide, gastric inhibitory peptide, and 8-cholecystokinin in the perfused rat pancreas☆

Pancreastatin is a 49-amino acid straight chain molecule isolated from porcine pancreatic extracts. In the perfused rat pancreas, this peptide has been shown to inhibit unstimulated insulin release and the insulin responses to glucose, arginine, and tolbutamide. To further explore the influence of pancreastatin on islet cell secretion, the effect of synthetic porcine pancreastatin (a 2-micrograms priming dose, followed by constant infusion at a concentration of 15.7 nmol/L) was studied on the insulin, glucagon, and somatostatin responses to 1 nmol/L vasoactive intestinal peptide (VIP), 1 nmol/L gastric inhibitory peptide (GIP), and 1 nmol/L 26 to 33 octapeptide form of cholecystokinin (8-CCK). The effect of pancreastatin on the insulin and somatostatin secretion elicited by glucagon (20 nmol/L) was also examined. Pancreastatin infusion consistently reduced the insulin responses to VIP, GIP, and 8-CCK without modifying glucagon or somatostatin release. It also inhibited the insulin release but not the somatostatin output induced by glucagon. These observations broaden the spectrum of pancreastatin as an inhibitor of insulin release. The finding that pancreastatin does not alter glucagon or somatostatin secretion supports the concept that it influences the B cell directly, and not through an A cell or D cell paracrine effect.

Inhibitory effect of somatostatin on human pancreatic polypeptide secretion

Abstract In this work we have investigated the effect of somatostatin on the secretion of human pancreatic polypeptide (HPP). In a group of five gastrectomized patients, somatostatin infusion induced a significant decline of fasting HPP plasma levels and completely abolished HPP response to oral glucose. Upon somatostatin withdrawal, HPP concentrations returned to pre-experimental values. These data add a new hormone to the list of those inhibited by somatostatin.

Fluctuations of Human Pancreatic Polypeptide in Plasma: Effect of Normal Food Ingestion and Fasting

Summary In this work we have examined the daily fluctuations of circulating hPP in normal individuals subjected to a conventional meal schedule (breakfast, lunch, and dinner) as well as during food deprivation for 84 hr. In addition, we have tested the effect of ingestion of a low-calorie, fiber-rich salad as well as 500 ml of tap water on hPP secretion. Ingestion of each meal was followed by a sustained hPP elevation. Between meals, circulating hPP did not return to basal values. Both the vegetable meal and the water load evoked hPP release, suggesting that the hPP response to food intake is partially a nonspecific effect. In the fasted group, plasma hPP rose significantly 24 hr after the last meal and persisted elevated for the remainder of the experimental period. Moreover, in this condition hPP showed circadian variations, with higher values in the late evening than in the preceding and subsequent morning. Since pancreatic polypeptide is suspected to possess gastrointestinal functions, its elevation in plasma throughout the daytime in conditions of normal feeding may be thought to exert a tonic influence on some digestive process. On this basis, the increase of hPP during prolonged fasting appears paradoxical and, indeed, the explanation of this phenomenon awaits a better knowledge of the biological activity of this peptide.

Enhanced Glucagon Secretion by Pancreatic Islets from Prednisolone-Treated Mice*

SummaryThis work was undertaken to study the effect of prednisolone on glucagon release in mouse pancreatic islets isolated by the collagenase technique. Pretreatment of the donors with prednisolone (0.2–0.3 mg daily) induced an increase in glucagon release both in the absence (1005±75, SEM, vs. 796±46 pg/10 islets/60 min, p = 0.019) and in the presence of 7.5 mM arginine (1500±119 vs. 1236±61 pg/10 islets/60 min, p = 0.05). The glucagon content of the islets was not modified by the treatment (28.6±1.1 vs. 28.0±1.1 ng/50 islets). The addition of prednisolone (5 · 10−5 M) into the medium, failed to affect significantly glucagon secretion. In agreement with previous human studies, our data indicate that chronic glucocorticoid administration augments the secretory activity of the A-cell. This does not seem to be a result of increased glucagon synthesis nor a direct effect of glucocorticoids on the glucagon-releasing mechanism. Rather, environmental changes induced by these hormones could be responsible for A-cell hyperfunction.

Inhibitory effect of galanin on pancreatic polypeptide release by the perfused rat pancreas

We have investigated the effect of galanin infusion on unstimulated pancreatic polypeptide (PP) release as well as on the PP response to arginine by the perfused rat pancreas. Galanin significantly reduced unstimulated PP output. Addition of arginine to the perfusate evoked a biphasic pattern of PP release; the second phase of this PP response was delayed when galanin was simultaneously infused. These findings point to a regulatory role of galanin in the control of PP secretion.

Human pancreatic polypeptide secretion in conditions of exogenous and endogenous hyperglycaemia.

SummaryThe effects of exogenous and endogenous hyperglycaemia on human pancreatic polypeptide secretion have been studied. In normal subjects elevation of plasma glucose concentration by glucose infusion both depressed the basal levels of circulating human pancreatic polypeptide (by 40–50%) and consistently reduced the human pancreatic polypeptide response to the ingestion of a protein-rich meal (areas above pre-meal value: 19.5±4.1 (mean ± SEM) vs. 9.6±2.1, p < 0.01) as well as to caerulein infusion (areas above pre-caerulein value: 8.8±2.2 vs. 4.6±1.4, p < 0.01). In diabetic subjects treated with sulphonylureas or diet (fasting plasma glucose: 166±11mg/dl, n = 24), human pancreatic polypeptide secretion evoked by food was similar to that of 24 healthy individuals (areas above basal value: 46.6±9.9 and 33.6±3.6, respectively). In insulin dependent diabetics (fasting plasma glucose: 231±19 mg/dl, n = 21) the human pancreatic polypeptide response to the meal (area above basal value: 78.2±13.7) was significantly greater than that of the controls as well as that of the noninsulin-dependent group (p < 0.05). Since the administration of pancreatic polypeptide to man has been shown to decrease pancreatic exocrine output, postprandial human pancreatic polypeptide hypersecretion may contribute to the decreased exocrine function of the pancreas often found in insulin-dependent diabetics.