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Biomedical subjects

J E Gerich

Publications and source records attributed to J E Gerich.

At least 91 records · Page 5Linked to original sources
PubMed1988

Lilly lecture 1988. Glucose counterregulation and its impact on diabetes mellitus.

Glucose counterregulation is the sum of processes that protect against development of hypoglycemia and that restore euglycemia if hypoglycemia should occur. In order of importance, the key counterregulatory factors are glucagon, epinephrine, growth hormone, cortisol, and hepatic autoregulation. These act primarily by increasing hepatic glucose output, initially via breakdown of glycogen and later by gluconeogenesis. In people without diabetes and in people with type II (non-insulin-dependent) diabetes, suppression of endogenous insulin secretion during hypoglycemia is also important in permitting full expression of the effects of counterregulation. People with diabetes are more prone to develop hypoglycemia for various reasons (e.g., insulin overdose, skipped meals, and intensive exercise); one that has recently been identified is impaired glucose counterregulation: patients with type I (insulin-dependent) diabetes (and to a lesser extent, patients with type II diabetes) lose the glucagon response to hypoglycemia; subsequent development of autonomic neuropathy with concomitant loss of the epinephrine response leads to almost complete paralysis of counterregulation and loss of recognition of hypoglycemia. To make matters worse, an episode of hypoglycemia that causes activation of counterregulation can lead to rebound hyperglycemia (Somogyi phenomenon); if this is improperly treated, brittle diabetes may follow. Thus, abnormalities in glucose counterregulation may predispose to severe hypoglycemia and prevent achievement of optimal glycemic control in patients with diabetes.

Diabetes Mellitus↗
PubMed1988

Regulation of whole-body leucine metabolism with insulin during mixed-meal absorption in normal and diabetic humans.

To determine the effects of insulin on dietary and endogenous leucine metabolism, five normal subjects, seven insulin-insufficient insulin-dependent (IDDM) diabetic patients, and five diabetic patients controlled with continuous subcutaneous insulin infusion (CSII) were studied before and for 8 h after ingestion of a chemically defined elemental test meal (10 cal/kg) containing crystalline amino acids. L-[1-14C]leucine was included in the meal to trace the entry and oxidation of the dietary leucine. Total (meal + endogenous) entry of leucine into the circulation was estimated with a constant infusion of [2H3]leucine. Postabsorptive and meal-related increases in the plasma leucine concentration were greater (P less than .05) in the insulin-insufficient IDDM than in the normal subjects but returned to near-normal values with CSII. Baseline leucine flux was approximately 40% greater in the insulin-insufficient IDDM than in normal subjects (2.17 +/- 0.17 vs. 1.55 +/- 0.15 mumol.kg-1.min-1, respectively; .05 less than P less than .01) but were near normal during CSII treatment (1.85 +/- 0.25 mumol.kg-1.min-1). Furthermore, total leucine entry during meal absorption was greater in the insulin-insufficient IDDM (1.41 +/- 0.10 mmol.kg-1.8 h-1) than in either normal (0.96 +/- 0.08 mmol.kg-1.8 h-1, P less than .01) or IDDM subjects during CSII treatment (1.09 +/- 0.11 mmol.kg-1.8 h-1, P less than .05). Fractional oxidation (approximately 40-50%) and entry of dietary leucine were similar in all three groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Subnormal pancreatic polypeptide and epinephrine responses to insulin-induced hypoglycemia identify patients with insulin-dependent diabetes mellitus predisposed to develop overt autonomic neuropathy.

Sixteen patients with insulin-dependent diabetes mellitus with no current evidence of autonomic dysfunction underwent an insulin tolerance test during which plasma pancreatic polypeptide and epinephrine responses were determined. Compared to 11 age- and weight-matched nondiabetic volunteers, 9 diabetic subjects had subnormal plasma pancreatic polypeptide responses (n = 6) or plasma epinephrine responses (n - 8). When autonomic function was reassessed 2 to 3 years later by standard cardiovascular reflex tests and clinical examination, 8 of 9 diabetic subjects with subnormal hormonal responses to hypoglycemia developed either abnormal cardiovascular reflexes (6 of 9) or overt symptoms consistent with diabetic autonomic neuropathy (6 of 9), whereas none of the subjects with previously normal plasma pancreatic polypeptide and epinephrine responses did (P less than 0.01). Diminished pancreatic polypeptide and epinephrine responses to hypoglycemia can predict the development of overt autonomic neuropathy in patients with insulin-dependent diabetes mellitus; identification of patients with a predilection to develop autonomic neuropathy may permit earlier treatment.

Adult↗
PubMed1988

Non-beta-cell islet abnormalities in noninsulin-dependent diabetes mellitus.

Although there are abnormalities in the function of pancreatic alpha, delta, and PP cells in NIDDM, only in the case of the glucagon-secreting alpha cells is there sufficient evidence to indicate that these abnormalities may be metabolically important. But the cause of abnormal glucagon secretion remains to be established. Studies of delta-cell secretion have been hampered by the inability to determine the source of circulating somatostatin-like immunoreactivity and the failure to distinguish between the potential molecular species being measured. Pancreatic polypeptide remains a hormone in search of a metabolic function; the main use of its measurement may be in the study of parasympathetic nervous system function in NIDDM.

Diabetes Mellitus, Type 2↗
PubMed1988

Effect of internalization and degradation of insulin on rat adipocyte insulin receptor binding kinetics.

We have assessed the influence of nondisplaceable (internalized) insulin and insulin degradation during binding reactions at 37 degrees C on the numbers and affinities of insulin binding sites on isolated rat adipocytes. Corrections for nondisplaceable insulin caused a 33% reduction in the number of the high affinity sites (p less than 0.01) and a 24% reduction (p less than 0.01) in the number of the low affinity sites which was associated with a 20% increase (p less than 0.01) in affinity when a two-site model was applied. With a one-site model, the number of insulin receptors decreased by approximately 33% (p less than 0.01), but the affinity did not change. These results indicate that the internalization and degradation of insulin that occurs during the binding reaction can significantly affect the estimation of insulin binding kinetics. Potential variations in internalization and degradation of insulin by cells obtained under various physiological or pathologic conditions should, therefore, be taken into consideration in the interpretation of insulin binding data.

Adipose Tissue↗
PubMed1987

A new alpha-glucosidase inhibitor (Bay-m-1099) reduces insulin requirements with meals in insulin-dependent diabetes mellitus.

Retardation of meal carbohydrate absorption by inhibition of starch degradation improves glucose tolerance in normal and diabetic humans. To determine the effects of Bay-m-1099, a new alpha-glucosidase inhibitor, on insulin requirements and prandial glucose tolerance in patients with insulin-dependent diabetes mellitus (IDDM), plasma glucose, triglyceride, and free insulin concentrations were measured after ingestion of a standard breakfast, lunch, and dinner in nine patients with IDDM in a single-blind, randomized, crossover design. A 20% reduction in insulin was given 30 minutes before the meals when the subjects received Bay-m-1099 (50 mg). This resulted in the AUC for plasma insulin to be significantly less with Bay-m-1099 (AUC, 8.2 +/- 1.3 vs. 12.8 +/- 1.6 microU/ml/min with placebo; P less than 0.01). Despite this reduction in plasma insulin levels, postprandial plasma glucose concentrations were reduced for the breakfast (73 +/- 15 vs. 112 +/- 14 mg/dl/min with placebo; P less than 0.01) and dinner (23 +/- 8 vs. 4 +/- 1 mg/dl/min with placebo; P less than 0.05) meal with Bay-m-1099. Bay-m-1099 did not affect postprandial plasma triglycerides and was well tolerated, the major side effect being flatulence (4/9) and mild diarrhea (4/9). We conclude that inhibition of intestinal alpha-glucosidases by Bay-m-1099 in IDDM reduces meal insulin requirements by at least 20% and that such an agent could be useful in the management of diabetes mellitus by reducing hyperinsulinemia.

1-Deoxynojirimycin↗
PubMed1987

The effect of two new alpha-glucosidase inhibitors on metabolic responses to a mixed meal in normal volunteers.

1. alpha-Glucosidase inhibitors delay carbohydrate absorption and have been proposed as adjunctive therapy for diabetes mellitus. 2. To determine the effects of two new alpha-glucosidase inhibitors, Bay-m-1099 and Bay-o-1248, on meal carbohydrate and lipid tolerance, plasma glucose, insulin and triglyceride levels were measured at 15-60 min intervals over 12 h after ingestion of a standard breakfast, lunch and dinner of identical composition in 31 normal volunteers. 3. The volunteers were randomized to receive either Bay-m-1099 (50 or 25 mg) or placebo prior to each meal, or the single administration of Bay-o-1248 (20 or 10 mg) or placebo prior to breakfast. 4. Only Bay-m-1099 at the 50 mg dose reduced significantly the postprandial increase in plasma insulin levels after each meal when compared with placebo (25, 36, 54% at breakfast, lunch, and dinner, respectively; P less than 0.05). Both drugs were well tolerated, with side effects limited to complaints of flatulence. 5. Thus, with the dosage schedule employed, Bay-m-1099, but not Bay-o-1248, significantly reduced postprandial increments in plasma insulin.

1-Deoxynojirimycin↗
PubMed1987

The pancreatic-adrenocortical-pituitary clamp technique for study of counterregulation in humans.

The present experiments were undertaken to develop an approach to analyze the contribution of individual glucose counterregulatory hormones in humans. For this purpose, 24 normal subjects were studied twice: once (control experiments) hypoglycemia was induced by subcutaneous infusion of insulin; and once [pancreatic-adrenocortical-pituitary (PAP) clamp technique] the spontaneous responses of plasma glucagon, growth hormone, and cortisol to hypoglycemia were prevented by intravenous somatostatin and oral metyrapone, respectively, and each hormone was infused at variable rates, which reproduced spontaneous changes in their circulating concentrations in the control experiments. Plasma glucose rate of decrease (0.052 +/- 0.003 vs. 0.06 +/- 0.003 mg X dl-1 X min-1), plasma glucose nadir (49.8 +/- 1.2 vs. 50 +/- 1.0 mg/dl), initial suppression of glucose production (0.22 +/- 0.01 vs. 0.23 +/- 0.01 mg X kg-1 X min-1), subsequent compensatory increase in glucose production (0.54 +/- 0.05 vs. 0.48 +/- 0.04 mg X kg-1 X min-1), and the increase in glucose utilization (0.45 +/- 0.05 vs. 0.42 +/- 0.05 mg X kg-1 X min-1) in PAP clamp and control experiments, respectively, were not significantly different and were significantly correlated. Changes in plasma alanine, lactate, free fatty acids, 3-beta-hydroxybutyrate concentrations were also virtually identical in the PAP clamp experiments and in control experiments. We conclude that the PAP clamp technique can faithfully reproduce the spontaneous hormonal and substrate responses to hypoglycemia and should be useful to assess the contribution of individual hormones during counterregulation by creating an isolated (total or partial) deficiency of a particular hormone without confounding compensatory changes in secretion of other counterregulatory hormones.

3-Hydroxybutyric Acid↗
PubMed1987

Lipolysis during fasting. Decreased suppression by insulin and increased stimulation by epinephrine.

These studies were designed to determine whether the insulin resistance of fasting extends to its antilipolytic effects and whether fasting enhances the lipolytic effects of adrenergic stimulation independent of changes in plasma hormone and substrate concentrations. Palmitate flux was determined isotopically ([1-14C]palmitate) before and during epinephrine infusion in normal volunteers after a 14-h (day 1) and an 84-h (day 4) fast. Using a pancreatic clamp, constant plasma hormone and glucose concentrations were achieved on both study days in seven subjects. Six subjects were infused with saline and served as controls. During the pancreatic clamp, palmitate flux was greater (P less than 0.01) on day 4 than day 1, despite similar plasma insulin, glucagon, growth hormone, cortisol, epinephrine, norepinephrine, and glucose concentrations. The lipolytic response to epinephrine was greater (P less than 0.05) on day 4 than day 1 in both groups of subjects. In conclusion, lipolysis during fasting is less completely suppressed by insulin and more readily stimulated by epinephrine.

Adult↗
PubMed1987

The significance of impaired pancreatic polypeptide and epinephrine responses to hypoglycemia in patients with insulin-dependent diabetes mellitus.

The impaired epinephrine and glucagon responses to hypoglycemia often found in patients with insulin-dependent diabetes mellitus (IDDM) may be due to autonomic neuropathy. Since the pancreatic polypeptide response to hypoglycemia is mediated by cholinergic mechanisms, we used this response as an indicator of autonomic neuropathy to determine whether deficient epinephrine and glucagon responses in IDDM could be ascribed to an autonomic defect. The relationships between pancreatic polypeptide, epinephrine, and glucagon responses during insulin-induced hypoglycemia were assessed in 18 patients with IDDM who had no overt evidence of autonomic neuropathy, including normal standard cardiovascular reflex tests, and 11 age-matched nondiabetic subjects. All of the diabetic patients had impaired glucagon responses [19 +/- 3 (SEM) vs. 96 +/- 11 pg/ml, peak increment, P less than 0.001]. Ten of the 18 diabetic patients had either impairment of plasma epinephrine or plasma pancreatic polypeptide responses or both to hypoglycemia. Moreover, pancreatic polypeptide responses were significantly correlated with epinephrine responses (r = 0.53, P less than 0.003). There was no association between the plasma glucagon response and the epinephrine (r = 0.02, NS), norepinephrine (r = 0.03, NS), or pancreatic polypeptide (r = 0.35, NS) response. Last, there was no correlation between the plasma hormone responses and the cardiovascular reflex test results. Therefore, the association of impaired plasma pancreatic polypeptide responses with impaired plasma epinephrine responses suggests that the impaired epinephrine responses are due to autonomic neuropathy, whereas the dissociation of plasma glucagon responses with both plasma pancreatic polypeptide and epinephrine responses suggests that the impaired pancreatic alpha-cell response to hypoglycemia is not due to autonomic neuropathy. In addition, the plasma pancreatic polypeptide and epinephrine responses to hypoglycemia appear to be an earlier indicator of underlying autonomic dysfunction than standard cardiovascular reflex tests. Thus, the responses of plasma pancreatic polypeptide and epinephrine to insulin-induced hypoglycemia may be a useful test for the identification of early autonomic neuropathy in IDDM.

Adolescent↗
PubMed1987

Adverse effects of insulin antibodies on postprandial plasma glucose and insulin profiles in diabetic patients without immune insulin resistance. Implications for intensive insulin regimens.

To assess the possible influence of moderate titer insulin antibodies on diabetic glycemic control, we examined insulin-antibody equilibrium binding characteristics, postprandial glucose tolerance, and plasma free-insulin profiles after subcutaneous injection of both porcine and human insulin (0.15 U/kg) in 12 patients with insulin-dependent diabetes mellitus under conditions stimulating intensive insulin therapy. The patients' antibodies bound porcine and human insulin indistinguishably, and their plasma glucose and free-insulin profiles after ingestion of a standard meal were similar with both insulins. Initial increases in plasma free-insulin levels after injection of both insulins were negatively correlated with both insulin-antibody binding (r = -.55, P less than .006) and postprandial hyperglycemia (peak level r = -.56, P less than .006); the latter was positively correlated with insulin-antibody binding (r = .48, P less than .02). The effects of insulin antibodies on postprandial plasma free-insulin and glucose levels could be accounted for substantially by the association constant of the high-affinity insulin-antibody binding sites (K1); patients in the highest quartile for K1 had significantly slower initial increments in plasma free insulin (0.31 +/- 0.04 vs. 0.46 +/- 0.06 microU/min, P less than .05) and greater postprandial hyperglycemia (peak value 237 +/- 10 vs. 166 +/- 12 mg/dl, P less than .001) than patients in the lowest quartile. We conclude that moderate insulin-antibody titers commonly found in insulin-treated patients can slow the early increase in plasma free insulin after subcutaneous injection and that this impairs postprandial glucose tolerance; such an effect may limit the effectiveness of intensive insulin therapy.

Adult↗
PubMed1986

Effect of insulin antibodies and their kinetic characteristics on plasma free insulin dynamics in patients with diabetes mellitus.

To determine the influence of insulin antibodies (and their equilibrium kinetic properties) on the pharmacokinetics of insulin, we examined the relationship between insulin antibody binding and the initial rate of increase, time to peak, and return to baseline of therapeutic doses of insulin injected subcutaneously (0.15 U/kg) and the half-life, distribution space, and metabolic clearance rate of intravenously infused insulin (2 mU/kg/min) in insulin-treated patients with diabetes mellitus. Compared to age-weight-matched nondiabetic subjects, the diabetic subjects had reduced initial rates of increase (0.33 +/- 0.2 v 0.44 +/- 0.03 microU/mL/min, P less than 0.05), delayed time to peak (130 +/- 12 v 86 +/- 8 min, p less than 0.02), and prolonged return to baseline (485 +/- 37 v 313 +/- 13 min, P less than 0.01) of plasma free insulin levels after subcutaneous injection of insulin, and a prolonged half-life (19.8 +/- 5.8 v 4.3 +/- 0.3 min, P less than 0.02), increased distribution space (904 +/- 284 v 109 +/- 10 mL/kg, P less than 0.001), and augmented metabolic clearance rate (28.5 +/- 1.8 v 17.3 +/- 0.7 mL/kg/min, P less than 0.001) after intravenously infused insulin. All of these abnormal parameters were significantly correlated with binding of insulin to insulin antibodies at tracer insulin concentrations (Bo) and with the high affinity of insulin antibody binding sites as determined by Scatchard analysis. However, patients with 125I insulin antibody binding (Bo) less than 10 percent had normal or near normal plasma free insulin pharmacokinetics.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Insulin-dependent diabetes mellitus: pathophysiology.

Diabetes mellitus is a heterogeneous disorder. About 80% of the patients with this disease are categorized as having non-insulin-dependent diabetes mellitus, a disorder resulting from varied degrees of insulin resistance and impaired insulin secretion; the causes for these abnormalities are unknown. The remaining 15 to 20% of patients have insulin-dependent diabetes mellitus, a disorder caused by the destruction of insulin-producing endocrine cells within the pancreas and currently considered to be the result of an autoimmune process. During the course of both types of diabetes mellitus, the so-called long-term complications of diabetes invariably occur to some extent in all patients. These complications include retinopathy, nephropathy, neuropathy, and premature atherosclerosis. The molecular basis for these complications is not completely understood, but recent evidence obtained from both experiments in animals and prospective clinical studies indicates that metabolic derangements associated with poor glycemic control are a major determinant of the frequency and severity of these complications. Such evidence is the rationale for current attempts to maintain near-normal glycemia in patients with diabetes mellitus.

Autoimmune Diseases↗
PubMed1986

Familial insulin resistance and acanthosis nigricans. Presence of a postbinding defect.

Type A insulin resistance, associated with acanthosis nigricans and menstrual irregularity, has been ascribed to a decreased concentration of insulin receptors. We now report four affected females from one family, a mother and three daughters (including identical twins) who appear to have the type A syndrome. Two of the kindred had no apparent ovarian dysfunction, while the other two had hyperprolactinemia without other findings of polycystic ovary disease, suggesting a genetic disease with variable penetrance. All had normal erythrocyte and monocyte insulin binding. Insulin dose-response studies to assess glucose metabolism and insulin sensitivity were performed in the affected twins. The dose response to insulin was shifted to the right with a decrease in maximal response. These results are consistent with a postbinding defect in insulin action in these patients.

Acanthosis Nigricans↗
PubMed1986

Insulin dose-response characteristics for suppression of glycerol release and conversion to glucose in humans.

To compare the dose-response characteristics for suppression of lipolysis and suppression of glucose production by insulin, 13 normal nonobese individuals were infused with insulin at rates of 0.1, 0.2, 0.4, 0.8, and 1.6 mU X kg-1 X min-1 while normoglycemia was maintained with the glucose clamp technique. Glucose appearance and glycerol appearance (taken as index of lipolysis) were measured isotopically with simultaneous infusions of 3-[3H]glucose and U-[14C]glycerol. Baseline glucose and glycerol rates of appearance were 14 +/- 0.5 and 1.7 +/- 0.2 mumol X kg-1 X min-1, respectively. Approximately 3% of plasma glucose originated from glycerol, and this accounted for approximately 50% of glycerol disposal. During the insulin infusions, arterial insulin (basal, 9.8 +/- 0.6 microU/ml) increased to 14 +/- 0.5, 20 +/- 0.5, 31 +/- 1, 58 +/- 2, and 104 +/- 6 microU/ml; calculated portal venous insulin (basal, 24 +/- 2 microU/ml) increased to 26 +/- 1, 32 +/- 3, 70 +/- 4, and 115 +/- 6 microU/ml. The rate of glucose appearance was suppressed 100%, whereas the rate of appearance of glycerol was maximally suppressed only 85%. Nevertheless, the insulin concentration that produced half-maximal suppression of glucose appearance was twice as great as that required for half-maximal suppression of glycerol appearance (26 +/- 2 vs. 13 +/- 2 microU/ml, P less than .001). Insulin decreased both the absolute rate of glycerol conversion to plasma glucose and the percent of glycerol disposal appearing in plasma glucose (both P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Occurrence of dawn phenomenon without change in insulin clearance in patients with insulin-dependent diabetes mellitus.

To assess the possible role of increased insulin clearance in the pathogenesis of the dawn phenomenon, we compared plasma free-insulin concentrations, free-insulin clearance rates, and plasma glucose concentrations in eight subjects with insulin-dependent diabetes mellitus (IDDM) during infusion of insulin from midnight to 0800 h (0.15 mU . kg-1 . min-1) with a Biostator and a Harvard pump. During infusion of insulin with the Biostator, plasma free insulin decreased 40% (from 14 +/- 1 to 9 +/- 1 microU/ml, P less than .01), insulin clearance increased 54% (from 11 +/- 1 to 17 +/- 2 ml/min, P less than .05), and plasma glucose increased from 101 +/- 4 to 217 +/- 27 mg/dl, P less than .01. During infusion of insulin with the Harvard pump, neither plasma free insulin (14 +/- vs. 13 +/- 1 microU/ml) nor free-insulin clearance (12 +/- 2 vs. 13 +/- 2 ml/min) changed significantly, but plasma glucose increased from 100 +/- 3 to 167 +/- 21 mg/dl, P less than .01. The increases in plasma glucose during infusion of insulin with the Biostator and the Harvard pump were not significantly different (t = 1.44, P = .19). When insulin was delivered directly into test tubes with the Biostator and the Harvard pump, insulin concentrations in the test tubes decreased 46% over 8 h (P less than .05) with the Biostator, whereas no decrease was observed with the Harvard pump.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗