Fall In Plasma Insulin Research Articles

Liver autophagy contributes to the maintenance of blood glucose and amino acid levels

Both anabolism and catabolism of the amino acids released by starvation-induced autophagy are essential for cell survival, but their actual metabolic contributions in adult animals are poorly understood. Herein, we report that, in mice, liver autophagy makes a significant contribution to the maintenance of blood glucose by converting amino acids to glucose via gluconeogenesis. Under a synchronous fasting-initiation regimen, autophagy was induced concomitantly with a fall in plasma insulin in the presence of stable glucagon levels, resulting in a robust amino acid release. In liver-specific autophagy (Atg7)-deficient mice, no amino acid release occurred and blood glucose levels continued to decrease in contrast to those of wild-type mice. Administration of serine (30 mg/animal) exerted a comparable effect, raising the blood glucose levels in both control wild-type and mutant mice under starvation. Thus, the absence of the amino acids that were released by autophagic proteolysis is a major reason for a decrease in blood glucose. Autophagic amino acid release in control wild-type livers was significantly suppressed by the prior administration of glucose, which elicited a prompt increase in plasma insulin levels. This indicates that insulin plays a dominant role over glucagon in controlling liver autophagy. These results are the first to show that liver-specific autophagy plays a role in blood glucose regulation.

Islet Auto‐Transplantation into an Omental or Splenic Site Results in a Normal Beta Cell but Abnormal Alpha Cell Response to Mild Non‐Insulin‐Induced Hypoglycemia

The present studies were designed to determine if totally pancreatectomized dogs that underwent islet auto-transplantation retained a functional pancreatic counterregulatory response to mild non-insulin-induced hypoglycemia. Six dogs underwent total pancreatectomy followed by islet auto-transplantation to spleen or omentum. The animals recovered and fasting plasma glucose and insulin levels were normal. Each study consisted of a 40-min control and 2-h test period. At the onset of the test period, a glycogen phosphorylase inhibitor was administered to create mild hypoglycemia. Plasma glucose in the transplanted dogs fell from 120 +/- 4 to 80 +/- 3 mg/dL, similar to the minimum in control dogs without islet auto-transplantation (108 +/- 2 to 84 +/- 5 mg/dL). The fall in plasma insulin was similar in both groups. Glucagon, however, rose in response to hypoglycemia in the control dogs (Delta24 +/- 7 pg/mL; p < 0.05), but failed to rise significantly in the transplanted dogs (Delta9 +/- 6 pg/mL). In fact, only 1 of 7 control dogs failed to increase plasma glucagon by at least 25%, whereas 4 of 6 transplanted dogs failed to do so. In conclusion, in conscious dogs with successfully auto-transplanted islets, the beta cell response to mild non-insulin-induced hypoglycemia was normal, whereas the alpha cell response was not.

Effect of l-arginine–nitric oxide system on chemical-induced diabetes mellitus

Several in vitro studies have suggested that nitric oxide may be the mediator of cytokine-induced beta-cell destruction. On the other hand, in vivo studies have given conflicting results: some studies suggesting that nitric oxide synthase inhibitors do not suppress streptozotocin-induced diabetes in mice, while others revealed that nitric oxide synthase inhibitors can reduce the incidence of insulin-dependent diabetes mellitus in rats. The results of the present study indicate that alloxan-induced diabetes in the male Wistar rats can be abrogated to a large extent by prior and simultaneous administration of the precursor of nitric oxide, l-arginine, where as N G-monomethy- l-arginine ( l-NMMA), a specific inhibitor of nitric oxide synthase, can completely block the beneficial action of l-arginine. Sodium nitroprusside, a nitric oxide donor, also showed significant inhibitory effect on the severity of diabetes induced by alloxan. Alloxan treatment reduced nitric oxide generation, whereas l-arginine and sodium nitroprusside, when given along with alloxan, enhanced nitric oxide production to control values. Induction of diabetes by alloxan in the experimental animals was associated with a marked elevation in plasma lactate, ketone body, and lipid peroxide levels with a simultaneous fall in plasma insulin and nitric oxide levels. Alloxan-induced diabetes also induced a fall in the levels of anti-oxidant enzymes such as superoxide dismutase, glutathione reductase, and total glutathione, and antioxidants: vitamin E and ceruloplasmin, and an increase in glutathione peroxidase and glutathione- S-transferase. All these biochemical abnormalities and antioxidant levels have improved to near normal levels in animals treated with insulin, l-arginine, and sodium nitroprusside. From the results of the present study, it is apparent that l-arginine and nitric oxide can prevent alloxan-induced beta-cell damage, and the development of diabetes, and restore the antioxidant status to near normal levels.

Altered expression of type 2 CRH receptor mRNA in the VMH by glucocorticoids and starvation.

In the rat, high-dose corticosterone (Cort) administration, the hypercortisolism of starvation, and adrenalectomy are all associated with decreased food intake and weight loss. We report here a study of the effects of high-dose Cort administration, starvation, and adrenalectomy on two peripheral hormones known to influence food intake and energy use, insulin and leptin. We also studied the impact of these interventions on the levels of type 2 corticotropin-releasing hormone receptor (CRHR-2) mRNA in the hypothalamic paraventricular nucleus (PVN) and ventromedial hypothalamus (VMH). The VMH is classically referred to as the satiety center because electrical stimulation of the VMH leads to inhibition of food intake, whereas CRHR-2 are thought to transduce the profound anorexogenic effects of CRH or its related peptide urocortin. Starvation and adrenalectomy each lowered plasma insulin and leptin levels and were associated with decrements in CRHR-2 mRNA levels in the VMH. Cort administration increased plasma leptin levels profoundly, as well as plasma insulin levels and the levels of VMH CRHR-2 mRNA. Under all experimental conditions, a positive correlation was seen between plasma leptin levels and VMH CRHR-2 mRNA. These data suggest that decreased food intake and weight loss after high-dose Cort administration at least partially depend on the profound impact of Cort on plasma leptin secretion in the rat; they suggest, moreover, an additional mechanism for the satiety-inducing effects of leptin, namely increasing CRHR-2 in the VMH. The concordance of a fall in plasma insulin and leptin levels with the fall in VMH CRHR-2 mRNA levels further supports the idea that compensatory responses during starvation and adrenalectomy include not only the disinhibiting effects of reduced insulin and leptin levels on appetite through already-described mechanisms but also via an effect of leptin on VMH CRHR-2. Neither Cort administration, starvation, nor adrenalectomy influenced the levels of CRHR-2 mRNA in the PVN, suggesting that these receptors are differentially regulated in different hypothalamic regions.

Increased feeding in fatty Zucker rats by the thiazolidinedione BRL 49653 (rosiglitazone) and the possible involvement of leptin and hypothalamic neuropeptide Y.

1. The thiazolidinedione BRL 49653 (rosiglitazone) induces hyperphagia and weight gain in obese, insulin-resistant fatty Zucker rats but not in lean insulin-sensitive rats. We investigated whether these responses might involve neuropeptide Y (NPY), leptin and insulin. 2. BRL 49653 (1 mg kg(-1) day(-1), orally) was given for 7 or 20 days to fatty and lean Zucker and Wistar rats. 3. In lean rats of either strain, BRL 49653 had no effect on food intake, body weight, plasma insulin and corticosterone, NPY or NPY mRNA levels. 4. Fatty rats given BRL 49653 showed a 30% increase in food intake and accelerated body weight gain (both P<0.01) after 7 and 20 days, but without significant changes in regional hypothalamic NPY or NPY mRNA levels. 5. Plasma leptin levels were twice as high in untreated fatty Zucker rats as in lean rats (P<0.01), but were unaffected by BRL 49653 given for 20 days. However, BRL 49653 reduced insulin levels by 42% and increased corticosterone levels by 124% in fatty rats (both P<0.01). 6. Hyperphagia induced in fatty Zucker rats by BRL 49653 does not appear to be mediated by either a fall in circulating leptin levels or increased activity of hypothalamic NPYergic neurones. The fall in plasma insulin and/or rise in corticosterone levels during BRL 49653 treatment may be involved, consistent with the postulated role of these hormones in the control of food intake.

Role of endogenous nitric oxide in the control of exocrine and endocrine pancreatic secretion in humans.

Nitric oxide (NO) is an unstable vasodilator formed by NO synthetase (NOS) from L-arginine (L-Arg) in various cells but its role in the control of pancreatic secretion in humans has not been examined. This study was designed to determine the role of endogenous NO in the control of exocrine and endocrine pancreas using NOS inhibitor, NG-monomethyl-L-Arg (L-NMMA). Pancreatic secretion was stimulated by intravenous infusion of secretin (80 pmol/kg/h) plus caerulein (50 pmol/kg/h) and duodenal content was aspirated by gastroduodenal tube. Two series of tests with secretagogue infusion were performed, one, with addition of graded doses of L-NMMA and, another, with addition of a constant dose of L-Arg alone followed by L-NMMA alone and finally by a combination of L-Arg and L-NMMA. Addition of L-NMMA in graded doses (2-8 mumol/kg/h) reduced dose dependently the secretin-caerulein stimulated pancreatic enzyme secretion without alterations in the volume flow and bicarbonate outputs. The addition of L-Arg to L-NMMA reversed the inhibitory action of L-NMMA on protein enzyme response to secretin-caerulein in these subjects. Secretin-caerulein infusion caused significant increase in plasma insulin and pancreatic polypeptide levels but without changes in plasma glucagon or somatostatin levels. L-NMMA alone resulted in a significant fall in plasma insulin and pancreatic polypeptide levels, while L-Arg added to pancreatic secretagogue infusion caused a significant increase of plasma insulin and pancreatic polypeptide levels above those attained with secretagogues alone. After the addition of L-Arg to L-NMMA, both plasma insulin and pancreatic polypeptide levels rose significantly above the levels observed with L-NMMA plus secretin-CCK stimulation. This study provides evidence that the suppression of NOS reduces pancreatic enzyme secretion and the plasma insulin and pancreatic polypeptide levels suggesting that endogenous NO affects both exocrine and endocrine pancreatic secretion in humans.

Impaired metabolic response to recombinant insulin-like growth factor-1 in dialysis patients

The acute metabolic effects of recombinant human insulin-like growth factor-1 (rhIGF-1) were studied after an overnight fast in six maintenance hemodialysis (MHD) patients, six chronic peritoneal dialysis (PD) patients and six normal subjects. Each subject received a subcutaneous injection of rhIGF-1, 50 or 100 micrograms/kg body wt, given in random order on two occasions separated by 7 to 21 days. After the rhIGF-1 injection, plasma insulin, C-peptide, cortisol, amino acids and glucose decreased. The magnitude of the decrease was greater with the larger rhIGF-1 dose. The fall in plasma insulin, C-peptide and many amino acid concentrations was less and the decrease in glucose was similar in the MHD and CAPD patients as compared to normals. With 50 micrograms rhIGF-1/kg, plasma insulin and C-peptide decreased more quickly and often to a greater magnitude in normal individuals. With 100 micrograms rhIGF-1/kg, the decrease in plasma insulin, C-peptide and amino acids in the MHD and CAPD patients was almost as frequent as in the normal subjects, but the magnitude of the fall was often significantly less. This impaired response occurred in both MHD and CAPD patients even though, with the 100 micrograms rhIGF-1/kg dose, their plasma IGF-1 was significantly higher than in normals during most of the first four hours after injection. These results provide the first in vivo evidence for resistance to the metabolic effects of rhIGF-1 in patients with advanced renal failure.

The regulation of insulin‐like growth factor binding protein (IGFBP)‐1 during prolonged fasting

Insulin-like growth factor binding protein (IGFBP)-1 levels increase overnight, being inversely related to changes in insulin. With prolonged fasting IGFBP-1 levels increase further. In animal studies high IGFBP-1 levels increase plasma glucose levels possibly by regulating the insulin-like actions of 'bio-available' plasma IGF. Following prolonged fasting, there is an increase in insulin requirement. A proportion of this reversible insulin resistance may be due to inhibitory effects of high IGFBP-1 levels on IGF action. This study examined the regulation of IGFBP-1 in the presence of reversible insulin resistance. Nine normal adult volunteers, seven female and two male (mean age 27.6 +/- SD 2.6 years, range 21.7-46.0 years) of normal body mass index were studied. Subjects fasted from 2200 h day 0 to 0900 h day 3 (59 hours), the fast being completed with a 75-g glucose meal. At least one week later, an 11-hour overnight fast was performed, followed by a repeat glucose meal. Blood samples were taken at regular intervals from 0900 h day 1 and for 5 hours during both glucose meal studies via an indwelling cannula. Serum levels of IGFBP-1, insulin, GH, glucose, IGF-I and cortisol were measured at varying intervals during the fast and both glucose meal studies. Following the initial 11-hour overnight fast IGFBP-1 levels rose from (mean +/- SEM) 32 +/- 5 micrograms/l to reach a maximum of 144 +/- 24 micrograms/l after 32 hours of fasting. IGFBP-1 levels then fluctuated, falling in the morning (93 +/- 8 micrograms/l) and then rising overnight (126 +/- 9 micrograms/l), but not regaining the initial peak levels. The increase of IGFBP-1 from overnight fasting levels was associated with a fall in plasma insulin from 5.7 +/- 0.7 to 2.2 +/- 0.2 mU/l. In comparison, 30 minutes after termination of the fast with the glucose meal, IGFBP-1 levels fell from 120 +/- 11 to 24 +/- 2 micrograms/l within 4 hours. After an overnight fast IGFBP-1 levels fell from 35 +/- 5 to 13 +/- 2 micrograms/l within 3 hours. There was glucose intolerance and increased insulin levels following the glucose meal preceded by the 59-hour fast when compared with the overnight fast. The fall of IGFBP-1 levels after the glucose meal was best expressed, taking into account subject variation, by the following regression equations: Glucose meal preceded by 11-hour fast: log [IGFBP-1] = 1.64-0.255 log [1 h previous insulin] (R2 0.51); Glucose meal preceded by 59-hour fast: log [IGFBP-1] = 1.41-0.265 log [1 h previous insulin] + 0.557 log [current glucose] (R2 0.82). In man, insulin appears to regulate circulating IGFBP-1 levels in all circumstances, this regulation being unaffected by the resistance to insulin action induced by prolonged fasting. The high IGFBP-1 levels were statistically related to the higher glucose levels and may have directly contributed to the increased insulin requirement observed after prolonged fasting.

Dominant role of glucagon in the initial induction of phosphoenolpyruvate carboxykinase mRNA in cultured hepatocytes from fetal rats.

The injection of streptozotocin to 18-day-old rat fetuses induced, 2 days later, a 50% fall in plasma insulin and a twofold increase in plasma glucagon concentrations and liver cAMP levels. Phosphoenolpyruvate carboxykinase mRNA that were undetectable in the fetal rat liver, accumulated 48 h after streptozotocin injection, their concentration being 30% of that found in the liver of 1-day-old newborn rats in whom liver phosphoenolpyruvate carboxykinase gene expression is maximal. Physiological concentrations of glucagon (0.7 +/- 0.2 nM) induced, within 2 h, phosphoenolpyruvate carboxykinase mRNA accumulation in cultured hepatocytes from 20-day-old fetuses. The addition of insulin (0.01-100 nM) inhibits, by no more than 30%, the glucagon-induced phosphoenolpyruvate carboxykinase mRNA accumulation. Exposure of fetal hepatocytes to insulin for 24 h did not change the glucagon dose/response curve and did not lead to a more efficient inhibition of the glucagon-induced phosphoenolpyruvate carboxykinase mRNA accumulation, despite a clear stimulatory effect on the rate of lipogenesis. In contrast, when hepatocytes were cultured in the presence of dexamethasone, the glucagon-induced phosphoenolpyruvate carboxykinase mRNA accumulation can be totally inhibited by pharmacological concentrations of insulin (10 nM). From these in-vivo and in-vitro studies, it is concluded that, under physiological conditions, the postnatal rise in plasma glucagon concentration is more important than the fall in the plasma insulin concentration for the primary induction of liver phosphoenolpyruvate carboxykinase gene expression.

Short time effects of growth hormone on glucose metabolism and insulin and glucagon secretion in normal man

The present study was undertaken in order to evaluate the acute metabolic and hormonal effects of human growth hormone in healthy subjects. Glucose turnover, plasma glucose, FFA, insulin, C-peptide, glucagon, and somatostatin concentrations were determined in the fasting state after a bolus injection of placebo or growth hormone in quantities producing increases in plasma growth hormone levels within the normal physiological range. We found that growth hormone administration resulted in negligible changes in plasma glucose, no significant changes in appearance or disappearance rates of glucose, a moderate increase in FFA and a moderate fall in plasma insulin, C-peptide and glucagon concentrations, while plasma somatostatin levels were unchanged. These findings suggest that rapid changes in plasma growth hormone concentrations, corresponding to the fluctuations seen during normal daily life, may play a role in the short time regulation of blood glucose concentration through an inhibition of insulin and glucagon secretion.

Glycemic response to stress stimulation by ether exposure in adrenalectomized rats

Stress was induced by short-term ether exposure (2 min) and tail vein puncture in normal (SO), adrenodemedullated (ADM), and adrenalectomized (ADR) rats. In ADM and SO rats stress provoked a significant hyperglycemic response with no change in plasma insulin levels. In ADR rats, on the other hand, the hyperglycemic response was not present. Actually, a significant rapid decrease in blood glucose, plasma insulin and hepatic glycogen content was observed. When the hypoglycemic effect of stress was prevented by glucose injection into ADR rats the decrease in plasma insulin and hepatic glycogen was not observed. The data suggest that the fall in plasma insulin and hepatic glycogen content observed in ADR animals result from an activation of the sympathetic nervous system induced by the decrease in blood glucose.

Traditional plant treatments for diabetes. Studies in normal and streptozotocin diabetic mice

The effects on glucose homeostasis of eleven plants used as traditional treatments for diabetes mellitus were evaluated in normal and streptozotocin diabetic mice. Dried leaves of agrimony (Agrimonia eupatoria), alfalfa (Medicago sativa), blackberry (Rubus fructicosus), celandine (Chelidonium majus), eucalyptus (Eucalyptus globulus), lady's mantle (Alchemilla vulgaris), and lily of the valley (Convallaria majalis); seeds of coriander (Coriandrum sativum); dried berries of juniper (Juniperus communis); bulbs of garlic (Allium sativum) and roots of liquorice (Glycyrhizza glabra) were studied. Each plant material was supplied in the diet (6.25% by weight) and some plants were additionally supplied as decoctions or infusions (1 g/400 ml) in place of drinking water to coincide with the traditional method of preparation. Food and fluid intake, body weight gain, plasma glucose and insulin concentrations in normal mice were not altered by 12 days of treatment with any of the plants. After administration of streptozotocin (200 mg/kg i.p.) on day 12 the development of hyperphagia, polydipsia, body weight loss, hyperglycaemia and hypoinsulinaemia were not affected by blackberry, celandine, lady's mantle or lily of the valley. Garlic and liquorice reduced the hyperphagia and polydipsia but did not significantly alter the hyperglycaemia or hypoinsulinaemia. Treatment with agrimony, alfalfa, coriander, eucalyptus and juniper reduced the level of hyperglycaemia during the development of streptozotocin diabetes. This was associated with reduced polydipsia (except coriander) and a reduced rate of body weight loss (except agrimony). Alfalfa initially countered the hypoinsulinaemic effect of streptozotocin, but the other treatments did not affect the fall in plasma insulin. The results suggest that certain traditional plant treatments for diabetes, namely agrimony, alfalfa, coriander, eucalyptus and juniper, can retard the development of streptozotocin diabetes in mice.

Effect of prolonged overnight fasting on energy metabolism in non-insulin-dependent diabetic and non-diabetic subjects

The effect on energy metabolism of a 6-h prolongation of the conventional 12-h overnight fast was examined in 9 healthy subjects and in 7 patients with non-insulin-dependent diabetes mellitus. Plasma glucose concentration decreased by 7 and 23%, in control and diabetic subjects, respectively. In control subjects, the fall in plasma glucose was associated with a slight but significant fall in plasma insulin and a rise in plasma free fatty acid concentrations. During this same period, the rates of plasma free fatty acid oxidation, measured by infusion of [14C]palmitate, and net lipid oxidation, measured by indirect calorimetry, increased in normal subjects by 55 and 76%, respectively; the rate of glucose oxidation measured by indirect calorimetry decreased by 37%. In the diabetic patients, the free fatty acid oxidation rate was enhanced already after 12 h of fasting compared with controls (2.06 vs 1.30 mumol.kg-1.min-1; p less than 0.05) and did not change significantly during the 6-h observation period. After 18 h of fasting, the rate of plasma free fatty acid oxidation was similar in control and diabetic subjects. The data thus emphasize the need for strict standardization of the overnight fasting period for metabolic studies, and demonstrate the difficulties in comparing basal rates of substrate oxidation between healthy and diabetic subjects.

Metabolic Adaptations to Change of Nutrition at Birth

Birth represents a dramatic change of nutrition from a fetal diet rich in carbohydrates and poor in fat to a neonatal diet rich in fat and poor in carbohydrates. Gluconeogenesis and ketogenesis are absent or very low in the fetal liver when the mother is correctly fed, and these metabolic pathways emerge after birth to reach adult values after 24 h. Gluconeogenesis increases rapidly in the liver of the newborn in parallel with the appearance of phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme of this metabolic pathway. The rise in plasma glucagon, the fall in plasma insulin and the resulting increase in liver cAMP which occur immediately after birth are the factors which induce the activation of liver PEPCK gene transcription. The appearance of ketogenesis is also controlled by the changes of plasma insulin and glucagon that increase the capacity for liver fatty acid oxidation by decreasing lipogenesis and malonyl-CoA concentration, by reducing the sensitivity of carnitine palmitoyl-CoA I to the inhibitory influence of malonyl-CoA, and by activating hydroxymethylglutaryl-CoA synthase by desuccinylation. Once liver PEPCK has reached adult value, i.e. 12 h after birth, other factors are involved in the regulation of hepatic gluconeogenesis. Indeed, the supply of gluconeogenic substrates and of free fatty acid is of crucial importance to support a high rate of gluconeogenesis and to maintain normoglycemia in the newborn. In the liver, fatty acid oxidation provides essential co-factors (acetyl-CoA, NADH and ATP) to support gluconeogenesis, and in peripheral tissue fatty acid oxidation inhibits glucose oxidation and stimulates the production of gluconeogenic precursors (lactate, pyruvate and alanine). Similar mechanisms are operative in human newborn. A defective hepatic fatty acid oxidation is likely to explain the frequent hypoglycemia observed in small-for-date neonates. Administration of oral triglycerides is an efficient mean to prevent hypoglycemia in these newborns.

Effect of exogenous insulin on plasma free carnitine levels during exercise in normal man

Preliminary data from our laboratory have shown that the decrease in plasma free carnitine levels normally found during prolonged exercise is blunted in type 1 diabetic man. This study was designed to test the hypothesis that this might be due to the sustained peripheral hyperinsulinemia seen during exercise in diabetics treated by subcutaneous insulin. Ten male subjects underwent 90 min of cycle ergometry at 60% of their maximal oxygen uptake capacity on two occasions, one with and the other without a constant 0.13 mU.kg-1.min-1 i.v. insulin infusion. Blood samples were taken at rest, during exercise, and after exercise for measurement of plasma glucose, insulin, C-peptide, free fatty acids, and carnitine. Plasma glucose dropped significantly (p less than 0.01) from basal during both infusions, but values at 30, 45, and 60 min of exercise were lower (p less than 0.05) during insulin infusion compared with the saline infusion. Exercise produced a significant (p less than 0.01) fall in plasma insulin in both infusions. However, from 30 to 90 min of exercise, the plateau insulin level was higher during the insulin infusion compared with the saline infusion (91.4 +/- 3.0 vs. 32.9 +/- 3.0 pmol/L; p less than 0.001). Plasma C-peptide decreased significantly (p less than 0.01) during exercise and recovery in both infusions, but values between infusions were not significantly different. Plasma free fatty acids increased significantly (p less than 0.01) at 90 min of exercise during the saline infusion, while during the insulin infusion this was noted during recovery only.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of transplantation and resection of a radiation-induced rat insulinoma on glucose homeostasis and the endocrine pancreas.

Twenty-one days after s.c. subscapular transplantation of a radiation-induced insulinoma, male NEDH rats exhibited hyperinsulinaemia and hypoglycaemia. These features were associated with islet atrophy, degenerative changes in pancreatic A and B cells, and decreases in the pancreatic contents of insulin, glucagon and somatostatin. The immunoreactive glucagon and somatostatin contents of extrapancreatic tissues of insulinoma-bearing rats were unchanged. Surgical resection of the tumour resulted in an immediate fall of plasma insulin, attaining concentrations similar to those of anaesthetised control rats by 10 min. The estimated half-life of insulin was 3.5 min. Hypoglycaemia persisted until 60 min after resection, followed by hyperglycaemia of 1-2 days duration. Glucose tolerance was impaired 1 day after tumour resection despite the coexistence of raised insulin concentrations. Evidence for abnormal pancreatic B cell function was gained by injection of arginine which failed to evoke a plasma insulin response in the resected rats. Two days after resection, plasma glucose and insulin concentrations were similar to those of control rats. Plasma glucose and insulin responses to glucose and arginine were suggestive of tumour recurrence by 12 days. A single large encapsulated tumour was eventually observed in each rat, with resection giving a 17-56 day prolongation of life.

Reduced glomerular angiotensin II receptor density in diabetes mellitus in the rat: time course and mechanism.

Glomerular angiotensin II receptors are reduced in number in early diabetes mellitus, which may contribute to hyperfiltration and glomerular injury. The time course and role of the renin-angiotensin-aldosterone system in the pathogenesis of the receptor abnormality were studied in male Sprague-Dawley rats made diabetic with streptozotocin (65 mg, iv). Glomerular angiotensin II receptors were measured by Scatchard analysis; insulin, renin activity, angiotensin II, and aldosterone were measured by RIA. Diabetes mellitus was documented at 24 h by a rise in plasma glucose (vehicle-injected control, 133 +/- 4; diabetic, 482 +/- 22 mg/dl; P less than 0.001) and a fall in plasma insulin (control, 53.1 +/- 5.7; diabetic, 35.6 +/- 4.0 microIU/ml; P less than 0.05). At 24 h glomerular angiotensin II receptor density was decreased by 26.5% in diabetic rats (control, 75.5 +/- 9.6 X 10(6); diabetic, 55.5 +/- 8.3 X 10(6) receptors/glomerulus; P less than 0.01). Receptor occupancy could not explain the defect, because there was reduced binding in diabetic glomeruli after pretreatment with 3 M MgCl2, a maneuver that caused dissociation of previously bound hormone. There was a progressive return of the receptor density toward normal over the 60 days following induction of diabetes, with diabetic glomeruli measuring 22.7%, 14.8%, and 3.7% fewer receptors than age-matched controls at 11 days, 1 month, and 2 months, respectively (r = 0.99; n = 4; P less than 0.01). Three lines of evidence suggested that reduced angiotensin II receptor density at 24 h was not due to down-regulation by angiotensin II: PRA and angiotensin II were identical in control and diabetic rats; angiotensin II infusion (50 ng/min) caused down-regulation in both control and diabetic rats, but the change in receptor density persisted (control, 33.6 +/- 6.9 X 10(6); diabetic, 18.5 +/- 1.3 X 10(6) receptors/glomerulus; P less than 0.05); and angiotensin-converting enzyme inhibition with enalapril caused receptor up-regulation, but the differences persisted (control, 105.5 +/- 21.2 X 10(6); diabetic, 67.1 +/- 3.0 X 10(6) receptors/glomerulus; P less than 0.05). Rats with chronic diabetes (7-60 days) had normal PRA and angiotensin II, but plasma aldosterone was elevated (control, 29.8 +/- 3.3; diabetic, 68.6 +/- 12.4 ng/dl; P less than 0.005). The return of angiotensin II receptor density to normal levels in chronic diabetes may be the result of receptor up-regulation by increased plasma aldosterone rather than recovery of the underlying defect.

Galanin-Induced Hyperglycemia: Effect on Insulin and Glucagon

Synthetic galanin, infused at a rate of 4 micrograms/kg body weight/h for 30 min, elicited a mild but significant hyperglycemia in conscious dogs and a fall in plasma insulin. Pancreatic glucagon, epinephrine, norepinephrine, cortisol and growth hormone levels were not affected significantly. The mild hyperglycemic action of galanin seems to be due to an inhibition of insulin production. Thus galanin appears to be involved in glucose homeostasis.

Gluconeogenesis in late fetal and early neonatal life.

Birth in most mammalian species represents an abrupt change from a high-carbohydrate and low-fat diet to a high-fat and low-carbohydrate diet. Gluconeogenesis is absent from the liver of the fetus of well fed mothers, but can be induced prematurely by prolonged fasting of the mother. Gluconeogenesis increases rapidly in the liver of newborn mammals in parallel with the appearance of phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme of this pathway. The rise in plasma glucagon and the fall in plasma insulin which occur immediately after birth are the main determinants of liver PEPCK induction. When liver PEPCK has reached its adult value, i.e. 24 h after birth, other factors are involved in the regulation of hepatic gluconeogensis. In order to maintain a high gluconeogenic rate, the newborn liver must be supplied with sufficient amount of gluconeogenic substrates and free fatty acids. An active hepatic fatty acid oxidation is necessary to support hepatic gluconeogenesis by providing essential cofactors such as acetyl CoA and NADH. The relevance of animal studies for the understanding of neonatal glucose homeostasis in man is discussed.

Insulinotropic Effect of Ovarian Steroid Hormones in Streptozotocin Diabetic Female Mice

To investigate the protective effect of ovarian sex steroids against streptozotocin diabetes, groups of ovariectomized streptozotocin diabetic female mice were treated orally with estradiol-17 beta (5 and 500 ug/kg/day) or progesterone (1 mg/kg/day) for 10 weeks. Streptozotocin produced a more severe hyperglycaemia and a greater fall in plasma insulin concentrations in ovariectomized mice than intact female mice. The estradiol-17 beta and progesterone treatments reduced both the severity of the hyperglycaemia and the fall in plasma insulin. Loss of pancreatic insulin after streptozotocin administration was reduced in intact mice and in mice treated with estradiol-17 beta. These observations suggest that ovarian sex steroids reduce the severity of streptozotocin diabetes at least partly by countering the cytotoxic effect of the drug on the islet B-cells, thereby reducing the fall in pancreatic and plasma insulin.