Donald L. Curry

Reversal of somatostatin inhibition of insulin secretion by calcium

Abstract Somatostatin infusion inhibits insulin secretion by perfused rat pancreases. This inhibition is reversed by elevating Ca++ from its control 4.6 meq/l to 8 meq/l or 11 meq/l.

Stimulation of insulin secretion by beta-endorphins (I-27 & I-31)

Synthetic human beta-endorphin potentiates insulin secretion by the isolated perfused rat pancreas when glucose is present in the perfusate at concentrations of either 125 or 200 mg/dl, whereas it fails to exert any effect on insulin secretion in the presence of a substimulatory concentration of 100 mg/dl. Similar potentiation of insulin secretion occurred in response to the 1-27 fragment (beta-endorphin1-27) of beta-endorphin. This transient potentiation lasts only 3 to 4 minutes, whereupon secretion returns toward control levels. Thus beta-endorphin produces only a transient spike-like secretory profile similar to the first phase of glucose-induced insulin secretion and it fails to produce any chronic insulin secretory response comparable to the second phase of insulin secretion. The insulinotropic effect of beta-endorphins occurred at concentrations varying from 0.1 to 5.0 ug/ml. These data suggest that beta-endorphin and beta-endorphin1-27 potentiate insulin secretion via a common beta cell opioid receptor, and that beta-endorphin may exert a paracrine control of insulin secretion. However, any such regulation appears to be via short-term alterations in the secretory process per se.

Redundant parasympathetic and sympathoadrenal mediation of increased glucagon secretion during insulin-induced hypoglycemia in conscious rats

Both the parasympathetic and sympathoadrenal inputs to the pancreas can stimulate glucagon release and are activated during hypoglycemia. However, blockade of only one branch of the autonomic nervous system may not reduce hypoglycemia-induced glucagon secretion, because the unblocked neural input is sufficient to mediate the glucagon response, ie, the neural inputs are redundant. Therefore, to determine if parasympathetic and sympathoadrenal activation redundantly mediate increased glucagon secretion during hypoglycemia, insulin was administered to conscious rats pretreated with a muscarinic antagonist (methylatropine, n = 7), combined alpha- and beta-adrenergic receptor blockade (tolazoline + propranolol, n = 5) or adrenergic blockade + methylatropine (n = 7). Insulin administration produced similar hypoglycemia in control and antagonist-treated rats (25 to 32 mg/dL). In control rats (n = 9), plasma immunoreactive glucagon (IRG) increased from a baseline level of 125 +/- 11 to 1,102 +/- 102 pg/mL during hypoglycemia (delta IRG = +977 +/- 98 pg/mL, P < .0005). The plasma IRG response was not significantly altered either by methylatropine (delta IRG = +677 +/- 141 pg/mL) or by adrenergic blockade (delta IRG = +1,374 +/- 314 pg/mL). However, the IRG response to hypoglycemia was reduced to 25% of the control value by the combination of adrenergic blockade + methylatropine (delta IRG = +250 +/- 83 pg/mL, P < .01 v control rats). These results suggest that the plasma glucagon response to hypoglycemia in conscious rats is predominantly the result of autonomic neural activation, and is redundantly mediated by the parasympathetic and sympathoadrenal divisions of the autonomic nervous system.

Ethanol-insulin interrelationships in the rat studied in vitro and in vivo: Evidence for direct ethanol inhibition of biphasic glucose-induced insulin secretion☆

The effect of ethanol (ETOH) on glucose-stimulated insulin secretion was studied using: (1) an in vitro isolated pancreas perfusion system, and (2) an in vivo preparation utilizing unrestrained, unanesthetized rats with indwelling jugular and aortic catheters. ETOH exposure in vitro resulted in a decrease in glucose-stimulated insulin secretion from the perfused rat pancreas. Second phase secretion (min 30-60) was inhibited at low ETOH exposure (100 mg/dl) and both first (min 2-8) and second phase secretion were inhibited at higher ETOH levels (1000 mg/dl). This indicates that second phase secretion of insulin from the pancreas is more sensitive to the acute effects of ETOH than is first phase secretion. ETOH preinfusion of 4 hr in vivo resulted in an approximate 20 mg/dl decrease in plasma glucose concentrations with little or no alteration in plasma insulin levels. One hour ETOH preinfusion produced a modest 8 mg/dl fall in plasma glucose. Intravenous glucose tolerance tests following low level ETOH infusion of 4 hr resulted in an enhancement in the insulin response with no change in glucose removal. This enhancement was not observed at higher ETOH levels or after high-level, short (1 hr) ETOH preinfusion. The data suggest that stimulus-induced insulin secretion may be enhanced by an ETOH metabolite if the ETOH exposure is prolonged and at a low level. Higher ETOH concentration appears to directly block this enhancement. Due to response similarities the rat model may be of considerable value to study the effects of ETOH on stimulus-induced insulin secretion in human subjects.

Dynamics of insulin hypersecretion by obese Zucker rats

The relationship between obesity and hypersecretion of insulin by the pancreas was studied. We found that pancreata from obese Zucker rats secrete significantly more insulin than do pancreata from lean Zucker rats. At a glucose stimulation of 300 mg/dL, the overall dynamic biphasic insulin secretory profiles from obese and lean rats were similar. Further studies to investigate the glucose-insulin dose response relationship in obese and lean rat pancreata demonstrated insulin hypersecretion by pancreata from obese rats which was particularly pronounced at normoglycemic and hypoglycemic levels (by factors as much as 14-fold). This hypersecretion is so striking as to suggest that in the intact state the obese animal may lack the ability to readily shut off its insulin secretion under normoglycemic conditions, whereas lean animals possess such an ability. Under hypoglycemic conditions (75 mg/dL), the hypersecretion is transient and insulin secretion returns to normal basal levels after 30 minutes of perfusion. Thus the degree to which this hypersecretory phenomenon may occur in vivo remains to be established.

Effect of paraquat on plasma enzymes, insulin, glucose, and liver glycogen in the rat

Abstract Paraquat dichloride was administered (45 mg/kg i.p.) to male Sprague-Dawley rats. The rats were sacrificed at different times after treatment. Blood was collected and plasma was used for various biochemical measurements. A significant increase in creatine phosphokinase activity was obtained at 12, 24, and 48 hr after paraquat treatment. The activities of glutamic oxaloacetic transaminase (GOT) and sorbitol dehydrogenase were also consistently elevated in paraquat-treated animals but a statistically significant increase was obtained only at 48 hr for GOT. Paraquat had no effect on glutamic pyruvic transaminase activity. Paraquat caused a marked increase in blood glucose and a marked depletion of liver glycogen that lasted for at least a period of 48 hr. The plasma insulin level in paraquat-treated animals was markedly depressed as compared to saline control. Various possibilities have been discussed for the hyperglycemic and liver glycogen-depleting effects of paraquat in the rat.

Effects of intratracheal administration of bleomycin or saline in pair-fed and control-fed hamsters on daily food intake and on plasma levels of glucose, cortisol, and insulin, and lung levels of calmodulin, calcium, and collagen.

In the present study, the effects of intratracheal administration of bleomycin have been examined on daily food intake and on plasma levels of glucose, cortisol, and insulin, and on lung levels of calmodulin, calcium, and collagen in hamsters. Since bleomycin treatment caused nutritional deficiency leading to loss of body weight, we have included pair-fed and control-fed as control groups in order to rule out the nutritional deficiency-related effects on these measurements. Bleomycin-treated animals showed a dramatic decrease in daily food intake and body weight as compared to control-fed animals. Bleomycin-treated animals were hyperglycemic when compared to nutritionally comparable pair-fed animals and had plasma glucose levels similar to those of control-fed animals. Plasma cortisol levels in bleomycin-treated and pair-fed animals showed a time-dependent increasing trend, whereas plasma insulin levels in both groups tended to decrease. The lung levels of calmodulin and calcium in bleomycin-treated animals were significantly increased when compared with the pair-fed or control-fed group. Bleomycin-treated animals had significantly higher levels of lung collagen than pair-fed or control-fed at 7 and 13 days after treatment. The lung collagen content in pair-fed animals was significantly less than that of control-fed at 13 days. It was concluded that a disturbance in carbohydrate metabolism and increased lung levels of calmodulin and calcium might be somehow involved in fibroproliferative changes of the lung in bleomycin-treated animals.

Dynamics of insulin and glucagon secretion by the isolated perfused cat pancreas

1. The dynamics of insulin and glucagon secretion by the isolated perfused cat pancreas was studied in response to glucose and amino acid stimuli. 2. Insulin secretion is biphasic in response to either glucose or amino acid stimuli. 3. Glucose caused a much more pronounced first phase release than did a complete amino acid mixture; whereas glucose and the amino acid mixture stimulated late second phase insulin secretion equipotently. 4. The same amino acid mixture produced a biphasic secretion of glucagon characterized by a rapid and transient spike-release which was followed by a substantial, relatively steady-state, second secretory phase. 5. Various combinations of glucose and amino acids resulted in insulin secretion which suggests a simple additive stimuli phenomenon; whereas no such additive effect was observed with respect to amino acid stimulation of glucagon secretion. 6. Instead, various of the amino acids appear to stimulate maximal glucagon secretion independently. 7. Glucose failed to cause a suppression of amino acid induced glucagon release. 8. The quantitative aspects of this study suggest that the cat pancreas is very responsive to amino acid modulation of hormone release, a fact which may well reflect the high amino acid content of the cats diet.

Effects of paraquat on plasma glucose, cortisol, catecholamines, and insulin in the beagle.

Paraquat is known to produce hyperglycemia in rodents, although the mechanisms responsible for the hyperglycemic effect of paraquat are not clearly understood. In this study we report the effects of paraquat (25 mg/kg iv) on plasma glucose, cortisol, catecholamines, and insulin in dogs. Paraquat caused a significant increase in plasma glucose level at all times of measurement except at 0.5 hr following paraquat administration. The cortisol levels after paraquat treatment were increased to 133, 305, 279, 418, 517, 672, and 567% above zero time control at 0.5, 1.5, 3, 6, 12, and 24 hr, and at death time respectively. The catecholamines at these times were increased to 42, 17, 72, 118, 138, 226, and 435% above the control. In contrast to cortisol and catecholamines, the plasma insulin levels after paraquat treatment were significantly decreased at 3, 6, 12, and 24 hr. These hormonal observations can explain, at least in part, the observed hyperglycemia, since all promote hyperglycemic states. For example, cortisol is gluconeogenic, catecholamines are glycogenolytic, and lower insulin levels result in depressed peripheral glucose utilization.

In vitro enhancement of insulin secretion by growth hormone

Abstract Using the isolated perfused hamster pancreas bovine growth hormone at a concentration of 7.5 ug per ml was recycled for 1 hour prior to stimulation by glucose. Under these conditions the total insulin secreted was roughly doubled compared to the controls during 1 hour of glucose stimulation.