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Biomedical subjects

E Ipp

Publications and source records attributed to E Ipp.

At least 37 records · Page 2Linked to original sources
PubMed1991

Sustained pulsatile insulin secretion from adenomatous human beta-cells. Synchronous cycling of insulin, C-peptide, and proinsulin.

The endocrine pancreas secretes insulin in a pulsatile fashion. This rhythm is generated at a site within the pancreas, although its precise location has not been determined. With an in vitro system, we tested the possibility that beta-cells might generate spontaneous pulsatile insulin secretion in the absence of any external influence. Human insulinoma tissue from five patients was perifused for 7-10 h with RPMI-1640 medium and constant concentrations of glucose (5.5 mM). Insulin, C-peptide, and proinsulin were measured in the effluent collected at 3.3-min intervals. All three peptides demonstrated pulsatility of secretion in a similar, synchronous fashion that was sustained throughout each study. The Clifton cycle detection program demonstrated cycling in all five tumors, with an average period for all tumors of 28, 29, and 26 min for insulin, C-peptide, and proinsulin, respectively. Spectral analysis confirmed the regularity and consistency of the hormonal secretory patterns. Mean hormone concentrations secreted by different tumors varied, but insulin and C-peptide were secreted in a nearly 1:1 ratio. This study demonstrates 1) that beta-cells are able to generate spontaneous pulsatile insulin secretory activity, which is independent of innervation or the presence of other islet cells, and 2) proinsulin secretion from the beta-cell also has an inherent pulsatility. The synchrony observed in the cycles of proinsulin and its peptide products confirms their common secretory pathway in the beta-cell. We conclude that the beta-cell may be the originator of insulin cycling.

Adenoma↗
PubMed1991

Catecholamine concentrations in the hepatic portal system: effect of surgical stress upon portal levels.

The biological effects of a hormone are dependent on the concentration delivered to the target tissue. This is generally best reflected in the arterial concentration. However, the liver is unique in that it receives substantial additional blood flow from the portal venous system. This may be important in the case of the catecholamines, where extraction or spillover from the splanchnic circulation may occur. In this study we examined portal venous catecholamine concentrations in anesthetized, laparotomized rabbits. We compared the values with simultaneously sampled arterial levels to evaluate the effects of the splanchnic tissues upon a wide range of catecholamine concentrations delivered to the liver during a state of stress. Spillover of norepinephrine and extraction of epinephrine were observed in all rabbits. Mean (+/- SEM) arterial norepinephrine concentrations were elevated, 716 +/- 167 pg/ml (n = 11); mean portal concentrations were 178 +/- 37% higher (p less than 0.01), at 1,425 +/- 301 pg/ml, representing net spillover from splanchnic tissues. In addition, significant extraction of epinephrine was observed; arterial concentrations were 2,144 +/- 580 pg/ml (n = 11). Portal levels were 1,205 +/- 382 pg/ml, 38 +/- 7.45% lower than corresponding arterial concentrations (p less than 0.02). Furthermore, there was a concentration-dependent effect upon norepinephrine spillover; the highest arterial norepinephrine concentrations were associated with the lowest splanchnic spillover. This resulted in a negative correlation between the arterial norepinephrine levels and the percent increase from spillover into the portal vein (r = -0.81, p less than 0.003). We conclude that portal venous catecholamine concentrations are significantly different from arterial levels in anesthetized, laparotomized rabbits over a wide range of concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Sulphonylurea effects on insulin secretion in islets desensitized to glucose.

Prolonged, continuous exposure of the islets of Langerhans to high glucose concentrations results in desensitization of the beta cell to glucose stimulation. This study tested the ability of a sulphonylurea to stimulate insulin secretion in this setting. Normal isolated rat islets were cultured for 18-20 h in RPMI-1640 with 300 mg/dl glucose to induce desensitization or with 100 mg/dl as a control. Islets were then placed into a perifusion system and perifused with 60 mg/dl glucose followed by a stimulus. After preincubation at 300 mg/dl, a significant 50% suppression of glucose-induced insulin secretion compared with secretion in the control group preincubated at 100 mg/dl glucose was observed (p less than 0.025-0.001). This confirmed the occurrence of desensitization to glucose in this in vitro model. In contrast, stimulation of insulin secretion by glyburide (500 ng/ml) was unaffected compared with control. We also tested whether glyburide corrects the defective response to glucose stimulation in glucose-desensitized islets. Control islets (preincubated at 100 mg/dl) were stimulated with 300 mg/dl glucose or with this glucose concentration plus glyburide. Peak incremental insulin responses were similar (0.81 +/- 0.07 and 0.77 +/- 0.12 microU/ml.islet). After preincubation at 300 mg/dl, perifusion with 300 mg/dl glucose alone or with glyburide was associated with smaller, but similar, peak insulin responses (0.53 +/- 0.13 and 0.62 +/- 0.06 microU/ml.islet). In conclusion, islets in which the insulin-secretory response is compromised by desensitization to glucose are nevertheless completely responsive to the direct stimulatory effects of a sulphonylurea. However, the sulphonylurea does not correct the defect in glucose-induced insulin secretion.

Animals↗
PubMed1990

Fetal catecholamine responses to maternal hypoglycemia.

The present studies were designed to determine the fetal catecholamine and metabolic responses to insulin-induced maternal hypoglycemia. Maternal hypoglycemia was induced by a primed constant infusion of insulin and glucose administered to pregnant ewes to maintain maternal glucose at 20-25 mg/dl. Maternal and fetal samples for measurement of catecholamine, glucose, and free fatty acid levels and arterial blood gas analysis were collected before insulin infusion and at intervals thereafter for 6 h. Maternal and fetal plasma catecholamine levels increased significantly in response to hypoglycemia (analysis of variance, P less than 0.01). Fetal insulin and glucagon levels did not change despite a 50% reduction in fetal whole blood glucose concentration. Fetal free fatty acid levels increased significantly during hypoglycemia (P less than 0.05). There were no significant changes in maternal or fetal heart rate, blood pressure, or arterial blood gases during hypoglycemia. These results suggest that the fetus is capable of responding to hypoglycemia with an increase in catecholamine and free fatty acid levels. These results are consistent with the interpretation that the fetus is able to mobilize alternative energy substrates in response to maternal insulin-induced hypoglycemia.

Animals↗
PubMed1990

A glucose reduction challenge in the differential diagnosis of fasting hypoglycemia: a two-center study.

Investigation of patients with suspected or proven hypoglycemia is often a time-consuming and expensive process. We describe a glucose reduction challenge test which may be useful as an out-patient screening procedure. Insulin is infused for 3 h at 40 mU/kg.h. Plasma glucose was monitored at the bedside during the test, and blood samples were collected for measurement of C-peptide. Responses were examined in 17 normal controls, and 6 patients with insulinomas. In normal subjects, mean plasma glucose fell to a plateau value of 3.2 +/- 0.2 mmol/L (57 +/- 2.6 mg/dL) and remained at that level with few symptoms. In contrast, five of six patients with insulinomas developed severe hypoglycemia, with plasma glucose levels between 1.9 (34 mg/dL) and 2.2 mmol/L (39 mg/dL). Plasma C-peptide concentrations were suppressed to 0.08 pmol/mL or less in normal subjects, but in insulinoma patients remained at 0.32-1.6 pmol/mL i.e. outside the normal range, and diagnostic of nonsuppressible insulin secretion. These data demonstrate that moderate reduction of serum glucose maintained for a prolonged period results in marked suppression of plasma C-peptide, permitting improved discrimination between normal subjects and patients with insulinomas. This glucose reduction challenge can, therefore, be used as a test of glucose-regulating ability, where failure (hypoglycemia) per se represents a measurable abnormality. C-Peptide measurements will determine whether the cause of hypoglycemia is due to hyperinsulinemia.

Adult↗
PubMed1990

Pulsatile insulin secretion in isolated rat islets.

The pancreas secretes insulin in an oscillatory fashion, but the precise site of the pacemaker for pulsatile insulin secretion has not been identified. These studies were designed to determine whether islets also secrete insulin in a pulsatile fashion if they are isolated from their pancreatic milieu. Isolated rat islets (80-100) were perifused 8 h in culture medium after overnight incubation, and samples were collected at 3.3-min intervals. Insulin secretion was evaluated for pulsatility with the Clifton Cycle Detection Program. Perifusion of islets was associated with a spontaneous, persistent, and regular pulsatility of insulin secretion, which was observed in all conditions tested. Perifusion with medium containing 5.5 mM glucose (n = 11) demonstrated oscillations with a mean periodicity of 17.6 +/- 1.1 min and a mean amplitude of 4.8 +/- 0.4 microU/ml when overall mean insulin concentration was 16.7 +/- 2.4 microU/ml. When the glucose concentration was 16.7 mM (n = 9), overall mean insulin concentration was 54.4 +/- 2.6 microU/ml, with increases in periodicity (22.0 +/- 1.3 min) and amplitude (10.7 +/- 0.5 microU/ml). All measurements were significantly different from those observed during perifusion with 5.5 mM glucose (P less than 0.02-0.001). Theophylline (1 mM) also enhanced the overall mean insulin concentration and amplitude (69.4 +/- 10.4 and 14.2 +/- 1.2 microU/ml, respectively) compared with control studies without theophylline (16.7 +/- 5.3 and 4.3 +/- 0.5 microU/ml) (P less than 0.01). The period of the cycle was also increased from 17.5 +/- 1.1 to 26.4 +/- 6.3 min, but this was not significantly different from the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Pentamidine-induced beta cell toxicity is not preventable by high glucose.

The incidence of beta cell damage attributable to pentamidine treatment of pneumocystis pneumonia is increasing in frequency because of the AIDS epidemic. We carried out in vitro studies in perfused rat islets using insulin secretion as an index of beta cell damage to study the effects of pentamidine and to test whether glucose can prevent toxicity in this physiologic model. Isolated islets were cultured for 16-18 hours of static incubation, in a culture medium containing 100 mg/dl glucose, with or without pentamidine (10(-6) M, a therapeutic concentration). Islets were then perfused with media containing 60 mg/dl followed by 300 mg/dl glucose concentrations to study the insulin secretory response. Incubation of islets with pentamidine was associated with subsequent basal hypersecretion of insulin (0.40 +/- 0.05 microU/islet .5 minute vs. 0.18 +/- 0.04 microU/islet .5 minute, p less than .005), and an insulin secretory response to glucose which was completely abolished (0.05 +/- 0.04 microU/islet .5 minute versus 1.12 +/- 0.02 microU/islet .5 minute, p less than .005). To determine whether glucose may protect against the effects of pentamidine, islets were then exposed to high glucose concentrations during simultaneous incubation with pentamidine. Coincubation with high glucose did not prevent these insulin secretory defects. A more extended culture of pentamidine-treated islets in the absence of pentamidine and at a glucose concentration of 100 mg/dl did not result in any recovery of insulin secretion. We conclude that pentamidine-induced beta cell damage is irreversible, not preventable by incubation with high glucose concentrations, and may therefore result from a mechanism different to that of alloxan.

Amidines↗
PubMed1987

Sparing of cognitive function in mild hypoglycemia: dissociation from the neuroendocrine response.

Central nervous system function during insulin-induced reductions in plasma glucose was studied by measuring plasma epinephrine concentrations and testing cognitive function. Mild glucose reduction [mean plasma glucose, 62 +/- 3 (+/- SEM) mg/dL (3.4 +/- 0.2 mmol/L)] was induced with an iv insulin infusion at the rate of 40 mU/kg.h for 180 min in 7 normal subjects. Despite a marked increase in mean plasma epinephrine concentrations, which peaked at 426 +/- 68 pm/mL (2325 +/- 371 pmol/mL; P less than 0.001), no significant differences in cognitive function occurred as determined by a series of trail-making tests compared with the results of serial tests in a group of 17 control subjects. In contrast, when hypoglycemia was induced (plasma glucose, less than 42 mg/dL; 2.3 mmol/L) by bolus injection of insulin in 4 normal subjects, cognitive function was impaired in every subject, as demonstrated by a delay in completion of the trail-making test. The mean completion time was prolonged to 107 +/- 16% of the baseline at the time of hypoglycemia vs. 74 +/- 4% in control subjects (P less than 0.01). These findings suggest that cognitive function may be spared during mild plasma glucose reductions and is dissociated from the neuroendocrine adrenergic response that is activated under these conditions. This dissociation may be part of a homeostatic process in which overall brain function is maintained during glucoprivation, although counterregulation has already been triggered to prevent a further decrease in plasma glucose.

Adult↗
PubMed1987

Somatostatin impairs clearance of exogenous insulin in humans.

Somatostatin has been widely used to suppress endogenous pancreatic hormone secretion in research studies. Many of these studies required the simultaneous infusion of a hormone together with somatostatin. A critical assumption for its use in metabolic investigation is that somatostatin has no effect on the action or clearance of a concomitantly infused hormone. To test whether clearance of an exogenously infused hormone is affected, we infused insulin with or without somatostatin in two sets of studies. Insulin (40 mU X kg-1 X h-1) was infused for 100 min (n = 6). Plasma glucose levels fell to 55 +/- 4.1 mg/dl with insulin alone and significantly lower, to 44 +/- 1.9 mg/dl, when somatostatin (250 micrograms/h) was also infused (P less than .01). Plasma immunoreactive insulin (IRI) rose to 57 +/- 12.5 microU/ml with insulin alone, which was significantly different from 88 +/- 15 microU/ml when insulin was infused together with somatostatin (P less than .01). When a smaller dose of insulin (30 mU X kg-1 X h-1) was infused for 100 min (n = 4), similar results were observed. When somatostatin was infused together with insulin, plasma glucose fell to lower levels (41 +/- 4.2 vs. 62 +/- 9.5 mg/dl; P less than .01) and plasma IRI rose higher (39 +/- 8.5 vs. 27 +/- 5.9 microU/ml; P less than .01) than when insulin was infused alone. C-peptide was equally suppressed by hypoglycemia regardless of whether somatostatin was administered, indicating suppression of endogenous insulin during these studies. We conclude that somatostatin infusion impairs the clearance of exogenous insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Glucose↗
PubMed1984

Naloxone decreases centrally induced hyperglycemia in dogs. Evidence for an opioid role in glucose homeostasis.

Intracerebroventricular (ICV) instillation of morphine and beta-endorphin causes centrally induced hyperglycemia. Locally active, endogenous opioids in the central nervous system may, therefore, also be involved in the elevation of blood sugar. This possibility was tested by examining the glucoregulatory response to central glucoprivation induced by ICV administration of 2-deoxy-D-glucose (2DG) in dogs. Administration of 2DG resulted in a rise in plasma glucose and immunoreactive glucagon (IRG) of 108 +/- 19 mg/dl and 70 +/- 20 pg/ml, respectively. These changes were attenuated by the simultaneous central infusion of the opiate antagonist naloxone: plasma glucose levels increased by 77 +/- 14 mg/dl and IRG by 43 +/- 3 pg/ml, both significantly different from the effect of 2DG alone (P less than 0.05-0.01). These findings suggest that opiate receptors participate in the counterregulatory response to central glucoprivation. They also provide a mechanism by which endogenous opioid peptides may play a role in the central regulation of glucose homeostasis.

Animals↗
PubMed1982

Circulating somatostatin acts on the islets of Langerhans by way of a somatostatin-poor compartment.

Somatostatin perfused in canine pancreases at 10 to 20 picograms per milliliter or 10 to 20 percent of the pancreatic vein somatostatin concentration inhibited insulin and glucagon secretion. This suggests that the high local concentration of endogenous somatostatin is not in contact with somatostatin receptors of the islets. The integrity of this separation may determine the sensitivity of islet cells to circulating somatostatin.

Animals↗
PubMed1982

Effect of somatostatin on determinants of bile flow in unanesthetized dogs.

Seven dogs each underwent cholecystectomy, ligation of the accessory pancreatic duct, and insertion of a Thomas duodenal cannula opposite the ampulla of Vater. After full recovery, bile secretions were studied in the unanesthetized dogs by opening the cannula and placing a ureteric catheter through the papilla into the common bile duct. All animals received, throughout study, constant infusions of taurocholic acid to replace losses caused by interruption of the enterohepatic circulation and 14 C-erythritol for measurement of erythritol clearance. After bile flow stabilized somatostatin 800 ng/kg/minute was infused for 100 minutes and bile flow declined from 3.0 +/- 0.7 ml/10 minutes (SD) to 1.19 +/- 0.47 ml/10 minutes (p less than 0.001) and 14C-erythritol clearance fell from 3.6 +/- 1.14 to 1.77 +/- 0.43 ml/10 minutes (p less than 0.001). Bile salt output was unchanged, indicating that somatostatin inhibited bile salt-independent canalicular flow (BSICF). In other experiments animals underwent intraduodenal acidification which resulted in a marked increase in bile flow. Somatostatin infusion again causes a sharp fall in bile flow (p less than 0.05) suggesting that somatostatin also inhibited ductular flow. Infusion of somatostatin did not inhibit choleresis produced by exogenous secretin administration. Thus, somatostatin inhibits 1) ductular flow by inhibiting secretin release and 2) BSICF by a direct effect or by decreasing the release of hormones which induce canalicular flow.

Animals↗
PubMed1982

Central control of peripheral circulating somatostatin in dogs: effect of 2-deoxyglucose.

Circulating plasma somatostatin concentrations are known to fluctuate in response to nutrients and hormones. However, little is known about neural or central nervous system (CNS) control of somatostatin secretion. To test whether peripheral circulating somatostatin is influenced by a central stimulus, 2-deoxyglucose (37.5 mg/kg) was infused into a lateral cerebral ventricle of six conscious dogs over a period of 15 min. Plasma somatostatin levels rose from a base line of 105 +/- 6 pg/ml (mean +/- SE) to a peak of 154 +/- 10 pg/ml (P less than 0.005) at 30 min after the onset of the infusion. Somatostatin levels were still significantly elevated (P less than 0.025) at 60 min (119 +/- 6 pg/ml) and thereafter gradually returned toward base line. Plasma glucose and glucagon levels increased in response to intraventricular 2-deoxyglucose. Glucose concentrations rose from 105 +/- 5 mg/dl to peak at 203 +/- 16 mg/dl (P less than 0.005) at 80 min and remained elevated to 120 min. The concentration of plasma glucagon increased from 41 +/- 6 to 92 +/- 18 pg/ml at 60 min (P less than 0.05) and then declined. In marked contrast to intraventricular 2-deoxyglucose, similar concentrations of 2-deoxyglucose administered intravenously (n = 4) resulted in a slight fall in plasma somatostatin. Intraventricular saline did not result in a change in plasma somatostatin. It is concluded that peripheral circulating somatostatin may be susceptible to central nervous system control.

Animals↗
PubMed1980

Morphine-induced hyperglycemia: role of insulin and glucagon.

An iv bolus injection of 0.5 mg/kg morphine, about twice the therapeutic dose, caused plasma glucose to rise more than 120 mg/dl in alloxan-diabetic conscious dogs but had little effect on conscious normal dogs. Plasma glucagon rose in the diabetic and nondiabetic groups by 30 +/- 10 and 100 +/- 29 pg/ml, respectively, but insulin levels increased significantly only in the nondiabetics. The hyperglycemic action on morphine may, at least in part, be the result of an increase in glucagon secretion without a sufficient accompanying release of insulin.

Animals↗