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Biomedical subjects

J E Gerich

Publications and source records attributed to J E Gerich.

At least 145 records · Page 8Linked to original sources
PubMed1983

The adrenergic contribution to glucose counterregulation in type I diabetes mellitus. Dependency on A-cell function and mediation through beta 2-adrenergic receptors.

In order to assess the adrenergic contribution to hypoglycemic glucose counterregulation in type I diabetes mellitus and to determine whether the adrenergic contribution is mediated through beta 1- or beta 2-adrenergic receptors, hypoglycemia was induced by an i.v. insulin infusion (30 mU/m2 x min) for 60 min in 11 insulin-dependent diabetic patients (IDDM), 5 with normal plasma glucagon responses and 6 with blunted responses, and also in 7 age-weight-matched nondiabetic subjects. Rates of plasma glucose decrease and postnadir increase, as well as plasma concentrations of free insulin and of counterregulatory hormones, were measured when insulin was infused alone, and when insulin was infused along with propranolol (a beta 1- and beta 2-adrenergic receptor antagonist) or metoprolol (a selective beta 1-antagonist). Postnadir plasma glucose recovery was decreased in IDDM with blunted plasma glucagon responses (21 +/- 0.8 mumol x L-1 x min-1, P less than 0.001), but was normal in patients with normal plasma glucagon responses (30 +/- 0.4 versus 33 +/- 0.5 mumol x L-1 x min-1 in nondiabetic subjects, P = NS). Postnadir plasma glucose recovery was not affected by either propranolol or metoprolol in normal subjects and in IDDM with normal glucagon responses. However, in IDDM with blunted plasma glucagon responses, postnadir plasma glucose recovery was further decreased by propranolol (14 +/- 0.6 mumol x L-1 x min-1, P less than 0.01), but was unaffected by metoprolol (22 +/- 0.9 mumol x L-1 x min-1, P = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1983

Oral glucose tolerance test compared with a mixed meal in the diagnosis of reactive hypoglycemia. A caveat on stimulation.

Reactive hypoglycemia is being diagnosed with increasing frequency. We compared plasma glucose, insulin, glucagon, epinephrine, and norepinephrine responses to an oral glucose tolerance test and to a mixed meal containing equivalent carbohydrate in 33 patients who had been referred to our institution with a presumed diagnosis of reactive hypoglycemia and in 2 patients who had insulinomas. In addition, a control group of 36 normal volunteers underwent the meal study. During the meal studies, electroencephalograms were obtained. Despite provocation of hypoglycemia by the oral glucose tolerance test, no consistent relationship between hypoglycemia and symptoms was observed. Despite similar symptoms, hypoglycemia did not develop after the meal test in the 33 patients without insulinomas. Both patients with insulinoma became hypoglycemic after ingestion of the meal. When a physiologic stimulus such as a meal is used to duplicate the daily dietary experience of patients, reactive hypoglycemia in the absence of a pancreatic pathologic lesion is an uncommon occurrence.

Adolescent↗
PubMed1982

Effects of free fatty acids, insulin, glucagon and adrenaline on ketone body production in humans.

In normal human subjects, when plasma insulin, glucagon and growth hormone were 'clamped' at basal concentrations (by infusion of somatostatin plus replacement infusion of these hormones), infusion of Intralipid and heparin increased plasma free fatty acid (FFA) concentrations to approx. 1.3 mM, and ketone body production increased 4-5 fold to approx. 11 mumol . kg -1 . min-1. Hyperglucagonaemia did not further increase ketogenesis. In conditions of combined insulin and glucagon deficiency (by infusion of somatostatin without insulin and glucagon), administration of Intralipid and heparin increased plasma FFA concentrations to approx. 2.2 mM but a further increase in ketone body production did not accompany this increase. In these conditions hyperglucagonaemia increased ketogenesis by 2-3 fold the increment seen in control studies. Infusion of adrenaline (epinephrine) in conditions in which insulin secretion was not inhibited caused only a transient increase in plasma FFA concentrations and in ketone body production. These data indicate: (1) that in humans increased FFA availability can markedly augment ketogenesis in the absence of insulin deficiency and without hyperglucagonaemia; (2) that glucagon can increase ketone body production during insulin deficiency but not in its absence; and (3) that insulin deficiency may be accompanied by increased ketogenesis only because of a lack of its restraint on lipolysis and because of the action of glucagon. Glucagon may be important in determining the magnitude of ketone body production for a given degree of FFA availability and insulin deficiency, and may be necessary for attainment of maximal rates of ketogenesis. Adrenaline increases ketone body production in humans, but whether this is primarily due to a direct effect on the liver or is mediated through enhancement of lipolysis remains to be determined.

Blood Glucose↗
PubMed1982

Subcutaneous versus intraperitoneal administration of insulin on post-prandial hyperglycaemia and glucose turnover in alloxan diabetic dogs.

The effects of subcutaneous and intraperitoneal insulin delivery by a closed-loop insulin infusion device on post-prandial hyperglycaemia and rates of glucose appearance and disappearance were compared in alloxan diabetic dogs. No differences in basal or post-prandial values or patterns of response were observed between the two routes of insulin delivery. In addition, the amounts of insulin infused and the plasma insulin concentrations achieved were not different for the two routes of insulin administration. These studies demonstrate that in the dog there appears to be no difference in the pattern of disposal of glucose from a mixed meal when insulin was administered intraperitoneally or subcutaneously at the rates of insulin infusion used in these experiments.

Alloxan↗
PubMed1982

Theophylline potentiates glucagon-induced hepatic glucose production in man but does not prevent hepatic downregulation to glucagon.

Prolonged hyperglucagonemia causes only a transient increase in hepatic glucose production. To determine whether activation of hepatic phosphodiesterase by glucagon is responsible for the transient nature of this response, the effect of infusion of the phosphodiesterase inhibitor theophylline alone, glucagon alone, and glucagon plus theophylline on isotopically determined glucose production was examined in normal human subjects. Infusion of theophylline alone did not alter rates of glucose production or utilization. Infusion of glucagon alone increased glucose production transiently from a basal rate of 1.9 +/- 0.1 mg/kg/min to a maximum at min 30 of 2.8 +/- 0.3 mg/kg/min followed by a return to rates no different from basal by min 60; plasma glucose increased from 89 +/- 3 mg/dl to a maximum of 114 +/- 5 mg/dl. Infusion of glucagon in the presence of theophylline resulted in greater increases in both plasma glucose (maximum at min 60 of 134 +/- 9 mg/dl) and glucose production (maximum at min 30 of 3.5 +/- 0.3 mg/kg/min) than had occurred during infusion of glucagon alone; the increase in glucose production, however, was not sustained. Thus theophylline potentiated glucagon-induced stimulation of hepatic glucose production, but it did not prevent the evanescent hepatic response to sustained hyperglucagonemia. Therefore, the present studies indices that glucagon activation of hepatic phosphodiesterase does not appear to be responsible for the transient nature of the increase in hepatic glucose production observed during prolonged hyperglucagonemia.

Adult↗
PubMed1982

Adrenergic modulation of pancreatic somatostatin, insulin, and glucagon secretion: evidence for differential sensitivity of islet A, B, and D cells.

To characterize the adrenergic effects of epinephrine on somatostatin, insulin and glucagon release and to assess the potential interactions of islet A, B, and D cell function, isolated rat islets were incubated in vitro with epinephrine (0.05-20 microM) in the presence and absence of the alpha adrenergic antagonist, phentolamine (2 or 4 microM), and/or the beta adrenergic antagonist, propranolol (2 microM). At concentrations of epinephrine at or less than 1 microM, somatostatin and insulin release were inhibited while glucagon release was unaffected. At greater epinephrine concentrations, somatostatin and glucagon release were increased while insulin release was further suppressed. The threshold as well as the half-maximal effect of epinephrine occurred at lower concentrations for somatostatin release than for insulin and glucagon release. The inhibitory effect of 0.5 microM epinephrine on somatostatin and insulin release was completely reversed by phentolamine and was unaffected by propranolol. The stimulatory effect of 2 and 20 microM epinephrine on somatostatin and glucagon release was not observed when propranolol was included in the incubation medium along with epinephrine. These results demonstrate that rat islet A, B, and D cells differ in their sensitivity to alpha and beta adrenergic effects. At low concentrations of epinephrine, alpha adrenergic effects on D cells predominate over beta adrenergic effects whereas at greater concentrations of epinephrine alpha and beta effects appear to be equal; alpha adrenergic effects of epinephrine predominate over those of beta on the B cell at least up to 20 microM epinephrine: exclusively beta adrenergic effects of epinephrine are observed on the A cell at least up to 20 microM epinephrine.

Animals↗
PubMed1982

Endocrine pancreatic response of children with onset of insulin-requiring diabetes before age 3 and after age 5.

The increased incidence of severe hypoglycemia reported in young children with diabetes is consistent with a defect in glucagon secretion or a generalized abnormality in islet hormone secretion. To assess pancreatic hormone and gastric inhibitory polypeptide secretion in children with early onset diabetes, 12 children with onset of diabetes prior to the age of 28 months were studied and the data compared to the hormone responses observed in 11 children with LOD, diagnosed after the age of 5 years. Plasma glucose, C-peptide, glucagon, pancreatic polypeptide, and gastric inhibitory peptide concentrations were measured during and following an arginine infusion (500 mg/kg over 60 minutes) and a mixed meal. During arginine infusion, plasma glucose and glucagon increased similarly in both groups and returned to basal concentrations following discontinuation of arginine infusion. In contrast, plasma C-peptide, hPP, and GIP concentrations did not change. Following the mixed meal plasma glucose, hPP, and GIP concentrations increased similarly in the two groups of children, but no change was observed in either plasma glucagon or C-peptide concentrations in either group. These data demonstrate that EOD and LOD are associated with insulin insufficiency alone and that abnormalities in secretion of other pancreatic islet hormone or GIP cannot be implicated in the high incidence of severe hypoglycemia observed in children with EOD.

Arginine↗
PubMed1982

Regulation of alpha-ketoisocaproate binding to albumin in vivo by free fatty acids.

The importance of alpha-keto acid binding to plasma proteins was investigated both in vitro and in vivo using alpha-ketoisocaproate (KIC), the alpha-keto acid of leucine. Gel chromatography indicated that 65% of the radioactivity comigrated with serum albumin. An ultrafiltration assay was developed to estimate the percentage of free and bound KIC. These percentages, along with total plasma KIC concentrations, were used to calculate the circulating concentrations of free and bound KIC. KIC or free fatty acids (FFA) displaced [14C]KIC bound to bovine albumin or whole plasma. KIC was totally displaced from plasma proteins by 10 mM oleate, stearate, and myristate; whereas the alpha-keto acids of isoleucine and value were 50 and 85%, respectively, as effective as KIC. To determine whether increased plasma FFA concentrations alter the binding of KIC to plasma proteins in vivo, five postabsorptive humans were infused with triglyceride and heparin during the simultaneous administration of somatostatin, glucagon, and insulin. During the FFA elevation, plasma leucine decreased by 9% (P less than 0.02). Total plasma KIC remained constant, whereas free KIC increased (P less than 0.02) and bound KIC decreased (P less than 0.001). These results indicate that KIC is bound to plasma albumin in vivo and suggests that FFA, by altering circulating free KIC concentrations, may influence protein metabolism in man.

Animals↗
PubMed1982

Cortisol-induced insulin resistance in man: impaired suppression of glucose production and stimulation of glucose utilization due to a postreceptor detect of insulin action.

The present studies were undertaken to assess the mechanisms responsible for cortisol-induced insulin resistance in man. The insulin dose-response characteristics for suppression of glucose production and stimulation of glucose utilization and their relationship to monocyte and erythrocyte insulin receptor binding were determined in six normal volunteers after 24-h infusion of cortisol and 24-h infusion of saline. The infusion of cortisol (2 microgram kg-1 min-1) increased the plasma cortisol concentration approximately 4-fold (37 +/- 3 vs. 14 +/- 1 microgram/dl; P less than 0.01) to values observed during moderately severe stress in man. This hypercortisolemia increased postabsorptive plasma glucose (126 +/- 2 vs. 97 +/- 2 mg/dl; P less than 0.01) and plasma insulin (16 +/- 2 vs. 10 +/- 2 microU/ml; P less than 0.01) concentrations and rates of glucose production (2.4 +/- 0.1 vs. 2.1 +/- -0.1 mg kg-1 min-1; P less than 0.01) and utilization (2.5 +/- 0.1 vs. 2.1 +/- 0.1 mg kg-1 min -1; P less than 0.01). Insulin dose-response curves for both suppression of glucose production (half-maximal response at 81 +/- 19 vs. 31 +/ 5 microU/ml; P less than 0.05) and stimulation of glucose utilization (half-maximal response at 104 +/- 9 vs. 64 +/- 7 microU/ml; P less than 0.01) were shifted to the right, with preservation of normal maximal responses to insulin. Neither monocyte nor erythrocyte insulin binding was decreased. However, except at near-maximal insulin receptor occupancy, the action of insulin on glucose production and utilization per number of monocyte and erythrocyte insulin receptors occupied was decreased. These results indicate that the cortisol-induced insulin resistance in man is due to the decrease in both hepatic and extrahepatic sensitivity to insulin. Assuming that insulin binding to monocytes and erythrocytes reflects insulin binding in insulin-sensitive tissues, this decrease in insulin action can be explained on the basis of a postreceptor defect.

Adolescent↗
PubMed1982

Dopaminergic suppression of pancreatic somatostatin secretion.

To characterize dopaminergic influences on pancreatic islet D cell function and its potential interaction with islet A and B cell function, the effect of dopamine (0.5-100 micro M) on immunoreactive somatostatin (IRS), insulin (IRI), and glucagon (IRG) release from rat islets incubated in vitro was studied. Dopamine significantly suppressed the release of IRS (P less than 0.001) and IRI (P less than 0.001) and augmented IRG release (P less than 0.001). Maximum suppression of IRS and IRI release was evident at 20 micro M dopamine with half-maximal suppression occurring at 0.5-1 micro M. Maximal stimulation of IRG release was observed at 100 micro M dopamine with a half-maximal response occurring at 5-10 micro M. Suppression of IRS secretion by dopamine (20 micro M) was completely reversed by the dopaminergic antagonists haloperidol (5 micro M) and pimozide (5 micro M) but was only partially reversed by the alpha adrenergic antagonist phentolamine (2 micro M), and was further suppressed by the beta adrenergic antagonist phentolamine (2 micro M). Suppression of IRI release by dopamine was completely reversed by propranolol, but was unaffected by haloperidol, pimozide, and phentolamine. There results indicate that dopamine directly affects pancreatic islet D cell function, and that islet B and D cells appear to be more sensitive to dopamine than are A cells. Dopamine suppresses IRS secretion predominantly through activation of dopaminergic receptors, whereas it suppresses IRI release through an alpha adrenergic mechanism and stimulates IRG release through a beta adrenergic mechanism.

Adrenergic alpha-Antagonists↗
PubMed1982

Comparison of peripheral and portal venous insulin administration on postprandial metabolic responses in alloxan-diabetic dogs. Effects of identical preprogrammed complex insulin infusion waveforms.

The optimal route for insulin administration by insulin infusion devices has not been established. To assess the differences between the peripheral venous and portal venous routes of insulin administration on postprandial metabolic responses, six alloxan-diabetic dogs were studied on four occasions. On the first, the insulin infusion rates given by the Biostator for disposal of a mixed meal were recorded electronically. On two subsequent occasions, these insulin infusion profiles were administered by a peripheral vein. On an additional occasion, the identical insulin infusion profile was given via the portal vein. No differences were observed in basal or peak plasma glucose, insulin, glucagon, branched chain amino acids, and lactate concentrations between portal and peripheral venous insulin administration. Furthermore, no differences in isotopically ( [2-3H]glucose) determined rates of systemic glucose appearance and disappearance were observed between the two routes. Although preprandial plasma alanine concentrations were greater when insulin was infused via the portal vein, the postprandial increments did not differ from those observed during infusion of insulin by a peripheral vein. These studies suggest that under the current experimental conditions, there appears to be no difference in the disposition of a mixed meal, measured as net whole body glucose appearance and disappearance rates, when insulin is administered in an open-loop fashion via either a peripheral or the portal vein.

Alanine↗
PubMed1982

Effects of growth hormone on insulin action in man. Mechanisms of insulin resistance, impaired suppression of glucose production, and impaired stimulation of glucose utilization.

The present studies were undertaken to assess the mechanisms responsible for growth hormone-induced insulin resistance in man. The insulin dose-response characteristics for suppression of glucose production and stimulation of glucose utilization and their relationship to monocyte insulin binding were determined in six normal volunteers after 12-h infusion of growth hormone and 12-h infusion of saline. The infusion of growth hormone (2 micrograms . kg-1 . h-1) increased plasma growth hormone nearly threefold (to congruent to 9 ng/ml) within the range observed during sleep and exercise. This increased plasma insulin (14 +/- 1 versus 8 +/- 1 microunits/ml, P less than 0.005) concentrations without significantly altering plasma glucose concentrations or basal rates of glucose production and utilization. Insulin dose-response curves for both suppression of glucose production (half-maximal response at 37 +/- 3 versus 20 +/- 3 microunits/ml, P less than 0.01) and stimulation of glucose utilization (half-maximal response at 98 +/- 8 versus 52 +/- 8 microunits/ml, P less than 0.01) were shifted to the right with preservation of normal maximal responses to insulin. Monocyte insulin binding was unaffected. Thus, except at near maximal insulin receptor occupancy, the action of insulin on glucose production and utilization per number of monocyte insulin receptors occupied was decreased. These results indicate that increases in plasma growth hormone within the physiologic range can cause insulin resistance in man, which is due to decreases in both hepatic and extrahepatic effects of insulin. Assuming that insulin binding to monocytes reflects insulin binding in insulin sensitive tissues, this decrease in insulin action can be explained on the basis of a postreceptor defect.

Adolescent↗
PubMed1981

Mechanisms of insulin resistance in man. Assessment using the insulin dose-response curve in conjunction with insulin-receptor binding.

During the past few years it has become increasingly apparent that insulin resistance may be a more frequent cause of carbohydrate intolerance or contributing factor in carbohydrate intolerance than was hitherto appreciated. Abnormal insulin action may result from prereceptor, receptor or postreceptor defects. These may be manifested by an increase in the concentration of insulin necessary for a half-maximal effect (decreased sensitivity) or a decrease in the maximal response to insulin (decreased responsiveness), or both. Alterations in sensitivity and responsiveness to insulin can be distinguished only by evaluating insulin dose-response curves. When used in conjunction with measurements of insulin binding to its receptor, the characteristics of these curves can provide insight into the mechanism or mechanisms responsible for insulin resistance.

Diabetes Mellitus↗
PubMed1981

Somatostatin and diabetes.

Somatostatin, a tetradecapeptide originally isolated from the hypothalamus on the basis of its ability to inhibit the secretion of growth hormone, is now known to be widely distributed in various endocrine and gastrointestinal tissues and to have diverse actions, including inhibition of insulin and glucagon secretion. The location of somatostatin in pancreatic islet D cells suggests that it may act as a local regulator of insulin and glucagon secretion. Changes in islet D-cell function in experimentally-induced and spontaneous diabetes in animals suggest that the peptide may be involved in the pathogenesis of diabetes. Clinical studies with the peptide have provided insight into the physiologic roles of glucagon and growth hormone, and have indicated a potential therapeutic use for somatostatin in diabetes in man.

Diabetes Mellitus↗