Altered regulation of pancreatic glucagon in male rats during aging.

Using x-ray diffraction, the interaction of calcium ions with dipalmitoyl phosphatidylcholine (DPPC) multilayers in excess solution has been studied as a function of temperature over a range of concentrations. We have discovered order-disorder-order transformations as a function of both increasing temperature and calcium concentration. For pure DPPC, the pretransition is characterized by a large increase in lattice disorder. For low calcium concentrations, a similar increase in lattice distortion occurs for all temperatures. The high temperature phase is marked by a significant reduction in this disorder. Likewise ordering of the multilayer is regained at high calcium concentrations.     

Insulin and glucagon response during hemorrhage induced hyperglycemia

Rapid hemorrhage to 50 mmHg (1 mmHg = 133.322 Pa) in the pentobarbital-anesthetized cat leads to severe hyperglycemia which declines only slightly by 90 min of hemorrhage. Insulin levels decline to less than one-half of control levels and remain low throughout, despite the hyperglycemia. Glucagon levels decline at 15 min but are significantly elevated by 90 min. These data confirm that the hepatic glycogenolysis is controlled almost entirely by hepatic sympathetic nerves and adrenal secretions with no role for elevated glucagon levels at the early stages in hemorrhage. Hepatic denervation leads to lesser insulin suppression and greater glucagon elevation at later times (45 and 90 min), suggesting that intact hepatic nerves are required for a normal pancreatic response. Hepatic sympathectomy did not produce these effects. Insulin responses remained normal, but glucagon levels were suppressed throughout the entire experiment in sympathectomized cats. The data suggest that hepatic nerves may modulate insulin and glucagon levels during hemorrhage in an unknown manner.     

Insulin and glucagon secretion in rats: effects of calcitonin gene-related peptide

Immunoreactive calcitonin gene-related peptide (CGRP) has been shown to occur in intrapancreatic nerves and islet somatostatin cells in the rat. Therefore, we investigated the effects of CGRP on insulin and glucagon secretion in the rat. CGRP was infused i.v. at one of 3 dose levels (4.3, 17 or 68 pmol/min). Infusion of CGRP alone was found to elevate basal plasma levels of both insulin and glucagon. In contrast, CGRP impaired the plasma insulin responses to both glucose (7 mg/min; P less than 0.001) and arginine (8.5 mg/min; P less than 0.001), and inhibited the arginine-induced increase in plasma glucagon concentrations (P less than 0.001). Since CGRP and somatostatin are colocalized within the D-cells, we also infused CGRP and somatostatin together at equimolar dose levels (17 pmol/min), with glucose (7 mg/min). By that, the increase in plasma insulin concentrations decreased more rapidly than during infusion of either peptide alone. Since alpha 2-adrenoceptor activation is known to inhibit glucose-stimulated insulin secretion, we also infused CGRP together with the specific alpha 2-adrenoceptor antagonist yohimbine (37 nmol/min). In that way, the plasma insulin-lowering effect of CGRP was prevented. We have shown in the rat: (1) that CGRP stimulates basal insulin and glucagon secretion; (2) that CGRP inhibits stimulated insulin and glucagon secretion; (3) that CGRP and somatostatin more rapidly induce a potent inhibitory action on glucose-stimulated insulin secretion when given together; and (4) that the alpha 2-adrenoceptor antagonist, yohimbine, counteracts the inhibitory action of CGRP on glucose-stimulated insulin secretion. We suggest that CGRP is of importance for the regulation of insulin and glucagon secretion in the rat. The mechanisms behind the islet effects of CGRP can not be established by the present results, though they apparently require intact alpha 2-adrenoceptors.     

Insulin and glucagon immunoreactivity during high-intensity exercise under opiate blockade

Eight fit men [maximum oxygen consumption (O_2max) 64.6 (1.9) ml · kg⁻¹ · min⁻¹, aged 28.3 (1.7) years (SE in parentheses) were studied during two treadmill exercise trials to determine the effect of endogenous opioids on insulin and glucagon immunoreactivity during intense exercise (80% O_2max). A double-blind experimental design was used with subjects undertaking the two exercise trials in counterbalanced order. Exercise trials were 20 min in duration and were conducted 7 days apart. One exercise trial was undertaken following administration of naloxone (N; 1.2 mg; 3 ml) and the other after receiving a placebo (P; 0.9% NaCl saline; 3 ml). Prior to each experimental trial a flexible catheter was placed into an antecubital vein and baseline blood samples were collected. Immediately after, each subject received either a N or P bolus injection. Blood samples were also collected after 20 min of continuous exercise (running). Glucagon was higher (P < 0.05), while insulin was lower (P < 0.05), during exercise compared with pre-exercise values in both trials. However, glucagon was higher (P < 0.05) in the P than in the N exercise trial [141.4 (8.3) ng · l⁻¹ vs 127.2 (7.6) ng · l⁻¹]. There were no differences in insulin during exercise between the P and N trials [50.2 (4.3) pmol · l⁻¹ vs 43.8 (5) pmol · l⁻¹]. These data suggest that endogenous opioids may augment the glucagon response during intense exercise. Accepted: 15 June 1996     

Insulin and aging

In invertebrates, signaling pathways homologous to mammalian insulin and insulin-like growth factor (IGF-1) signal transduction have a major role in the control of longevity. There are numerous indications that these pathways also influence aging in mammals, but separating the role of insulin from the effects of IGF-1 and growth hormone (GH) is difficult. In mice, selective disruption of the insulin receptor in the adipose tissue extends longevity. Increases in lifespan were also reported in mice with deletion of insulin receptor substrate 1 (IRS1) in whole body or IRS2 only in the brain. GH deficiency or resistance in mutant mice leads to hypoinsulinemia and enhanced insulin sensitivity along with remarkably extended longevity. These characteristics resemble animals subjected to calorie restriction. Studies of physiological characteristics and polymorphisms of insulin-related genes in exceptionally long-lived people suggest a role of insulin signaling in the control of human aging.     

Insulin and glucagon in rats with islet cell tumors induced by small doses of streptozotocin

Plasma insulin and glucagon responses to oral glucose loading were examined in rats with islet cell tumors induced by a single intravenous injection of streptozotocin (30 or 40 mg/kg body weight). Twenty-four macroscopic and six microscopic tumors occurred in 21 rats. In 15 of 21 tumor-bearing rats, there was exaggerated insulin release in response to oral glucose. Plasma glucose levels did not rise with the oral glucose load and were comparable to those seen in normal animals. Hence these rats are described as having "responsive tumors." In six rats with "nonresponsive tumors" there was no insulin response and the plasma glucose levels rose. No significant differences in plasma levels were observed between the two groups. Nonresponsive tumors as well as responsive tumors contained a significant amount of extractable insulin (17.68 +/- 8.60 and 35.07 +/- 10.05 mg/g wet weight, respectively) and detectable amounts of immunoreactive glucagon (1.47 +/- 0.61 and 2.24 +/- 0.67 micrograms/g wet weight, respectively). These results suggest that a small dose of streptozotocin produces two types of islet cell tumors. One is insulin producing and insulin secreting whereas the other is insulin producing but not insulin secreting.     

Insulin tolerance in rats.

Insulin tolerance was studied in young (8- to 10-week-old) Wistar rats: a) after the administration of mounting doses of long-acting insulin (10, 40, 160 and 320 units/kg bw.) to animals fed ad libitum on two different diets); b) after the administration of long-acting insulin (1 and 5 units/kg b.w.) to animals which had fasted for different lengths of time. In rats fed ad libitum on the two diets, graded doses of insulin induced (except for the smallest dose) hypoglycaemia of roughly the same intensity, but varying in duration in correlation to the dose. The administration of insulin to fasting rats showed differences in insulin tolerance which were correlated to the duration of the fast. A significant decrease in insulin tolerance was already found after 6 hours. During the given testing period (72 hours), the lowest insulin tolerance was found after a 12 hours' fast and the highest after 48 hours. Insulin tolerance after 24 and 72 hours' fasting was approximately the same; it was higher than after 12 hours, but lower than after 48 hours. The initial blood sugar level (before administering insulin) was not in any way correlated to insulin tolerance determined at various intervals during fasting.     

Insulin and glucagon share the same mechanism of neuroprotection in diabetic rats: role of glutamate

In patients with acute ischemic stroke, diabetes and hyperglycemia are associated with increased infarct size, more profound neurologic deficits and higher mortality. Notwithstanding extensive clinical and experimental data, treatment of stroke-associated hyperglycemia with insulin is controversial. In addition to hyperglycemia, diabetes and even early prediabetic insulin resistance are associated with increased levels of amino acids, including the neurotoxic glutamate, in the circulation. The pleiotropic metabolic effects of insulin include a reduction in the concentration of amino acids in the circulation. In this article, we show that in diabetic rats exposed to transient middle cerebral artery occlusion, a decrease of plasma glutamate by insulin or glucagon reduces CSF glutamate, improves brain histology, and preserves neurologic function. The neuroprotective effect of insulin and glucagon was similar, notwithstanding their opposite effects on blood glucose. The therapeutic window of both hormones overlapped with the short duration (~30 min) of elevated brain glutamate following brain trauma in rodents. Similar neuroprotective effects were found after administration of the glutamate scavenger oxaloacetate, which does not affect glucose metabolism. These data indicate that insulin and glucagon exert a neuroprotective effect within a very brief therapeutic window that correlates with their capacity to reduce glutamate, rather than by modifying glucose levels.     

Impaired regulation of corticosterone levels during fasting in aging rats.

The concentration of corticosterone in aortal blood of 3-day fasted rats decreases approximately 75% between 2- and 24-months of age. The reduced level of hormone in aging rats is not attributable to an enhanced rate of corticosterone utilization from the blood or to a diminished steroidogenic capacity of the adrenal cortex, but apparently reflects a deficiency in extraadrenal regulatory mechanisms.     

Insulin receptor kinase activity in rat adipocytes is decreased during aging

The tyrosine kinase activity of the insulin receptor derived from rat adipocyte plasma membranes was examined during aging. In the absence of insulin, autophosphorylation and histone H2B phosphorylation activities, measured with equal numbers of insulin receptors, were comparable among 3- and 24-month-old rats. In contrast, insulin-stimulated kinase activity was significantly reduced in the old animals. We have also found that the insulin dependent phosphorylation of a putative endogenous substrate of 60 kDa was drastically reduced in old animals. These results suggest that the decrease in kinase activity in old rats could be related with the insulin resistance of aging.     

Insulin,glucagon and catecholamine interactions in avian liver explants

• 1.1. A mechanical tissue chopper was used to obtain liver explants (35–75 mg) from 2- to 3-week-old chickens to determine both tissue sensitivity and metabolic effects of isoproterenol, avian insulin and glucagon.
• 2.2. Avian insulin had no effect on lipogenesis; however, lipogenesis was decreased by dibutyryl cyclic AMP. Insulin did not overcome a decrease in lipogenesis caused by catecholamines. Therefore, this control mechanisms is not modulated by insulin.
• 3.3. Preincubation in the presence of glucagon decreased in vitro lipogenesis. Preincubation in the presence of a 19–29 amino acid construct that approximated the radioimmune site for glucagon did not result in a similar effect. Therefore, this site does not relate to the biopotency of the hormone.
• 4.4. A previously noted catecholamine induced decrease in in vitro lipogenesis was verified, showing that points of in vitro regulation are under phosphorylation-dephosphorylation control.
• 5.5. Preincubation of slices (1 hr) with propranolol blocked the inhibition of lipogenesis caused by α and β adrenergic agonists (arterenol or isoproterenol) during a subsequent 2-hr incubation.
• 6.6. Preincubation of slices with either of these agonists decreased lipogenesis even following an extensive washout.
• 7.7. Inhibition could be overcome with propranolol, a β adrenergic antagonist.

     

Insulin stimulates somatostatin and inhibits glucagon secretion from the perfused chicken pancreas-duodenum.

The isolated perfused chicken pancreas-duodenum was used to study the secretion of somatostatin and glucagon. With perfusate glucose at 50 mg/dl, bovine insulin was infused at a concentration of 20, 000 μU/ml, resulting in a rapid increase of somatostatin secretion, with peak concentrations seen at 5 minutes. This was accompanied by suppression of glucagon secretion. These data suggest that there may be a paracrine negative feedback loop between B and D cells.     

Insulin and glucagon secretion and the insulin sensitivity of peripheric organs of colony-bred sand rats fed with pellet diet after weaning.

Colony-bred sand rats were fed with rat pellet chow in restricted quantities or ad libitum for 8--10 or 28--31 weeks after weaning. The changes of glucose metabolism were characterized by an intraperitoneal glucose tolerance test. The daily food intake and the average weight gain differed only in the first 5--7 weeks of pellet nutrition. In the impaired glucose tolerance tests of all sand rats the high basal plasma IRI levels were not significantly increased by the grossly enhanced blood glucose concentrations. The insulin secretion of either acutely incubated or for 8 days cultivated isolated pancreatic islets, however, was stimulated already by low (1.7 and 5 mM) glucose concentrations in all diet groups. Otherwise the glucagon secretion of isolated islets was not suppressed by high glucose concentrations. No changes of insulin or glucagon contents of islets were found in the different diet groups. The adipocytes of all animals revealed a complete ineffectiveness of insulin on the glucose utilization to CO2 and triglycerides. The basal glucose conversion to CO2 and glycogen in skeletal muscle and the stimulatory potency of insulin was low and not distinctly different in all groups. In liver glycogen and triglyceride contents as well as gluconeogenic enzyme activities were not influenced by feeding of different quantities of pellet diet at the investigated time points. The time course of the metabolic and clinical alterations demonstrates that the peripheral organs become insensitive to insulin in the first weeks after weaning.