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Biomedical subjects

N Barzilai

Publications and source records attributed to N Barzilai.

At least 73 records · Page 4Linked to original sources
PubMed1993

Role of glucokinase and glucose-6-phosphatase in the acute and chronic regulation of hepatic glucose fluxes by insulin.

Increased hepatic glucose production (HGP) is the major cause of fasting hyperglycemia in all forms of diabetes. Glucokinase (GK) and glucose-6-phosphatase (Glc-6-Pase) are the proximal and the distal enzymatic steps, respectively, in the regulation of HGP. We examined the impact of changes in GK and Glc-6-Pase activities on in vivo hepatic glucose fluxes in diabetic (D) and control (C) rats. In particular, the acute regulation by insulin was investigated using the euglycemic hyperinsulinemic clamp technique in conscious rats. In experimental diabetes (6 weeks): (a) GK mRNA was decreased by approximately 40%; (b) the Vmax of GK was markedly decreased (approximately 4 versus 9 mumol/g wet weight/min) and that of Glc-6-Pase was 2-fold increased (approximately 30 versus 15 mumol/g wet weight/min, D versus C), while (c) the Km of GK (approximately 10 mM) and Glc-6-Pase (approximately 1.5 mM) were unchanged. HGP was increased by 65% in diabetes and correlated highly with the ratio of Glc-6-Pase/GK (r = 0.81, p < 0.01). Following acute hyperinsulinemia (2 h): (a) GK mRNA increased by approximately 2-fold in both C and D; (b) GK Vmax did not change in C, but doubled to near-normal in D; (c) Glc-6-Pase Vmax decreased by 23% in C and by 34% in D; (d) the Km of GK decreased by approximately 40% (p < 0.01) in C. Acute hyperinsulinemia almost completely inhibited HGP in both C and D, and no correlation was demonstrated between HGP and the ratio of Glc-6-Pase/GK in these groups. Our data suggest that GK and Glc-6-Pase are important determinants of fasting HGP in diabetes. However, acute changes in Glc-6-Pase and GK activities can account for only a small portion of the in vivo inhibition of hepatic glucose flux by insulin, suggesting additional mechanisms for the short-term regulation of HGP.

Animals↗
PubMed1993

38-Amino acid form of pituitary adenylate cyclase activating peptide induces process outgrowth in human neuroblastoma cells.

Permanent cell lines from human neuroblastoma, a sympathoadrenal malignancy, are known to exhibit a more neuronal phenotype characterized by outgrowth of long processes in response to multiple second messenger analogs. In this report we demonstrate that the 38-amino acid form of a peptide homologous to vasoactive intestinal peptide (VIP), pituitary adenylate cyclase activating peptide (PACAP), as well as the 27-amino acid form of PACAP, induce NB-OK human neuroblastoma cells to extrude cellular processes within 5 hr of treatment with either peptide at 10(-8) M. Treatment of NB-OK cells with PACAP38 or PACAP27 at 10(-8) M for 1 hr also elevates cAMP content greater than 100-fold and inositol lipid turnover 11- to 12-fold. VIP acutely induces process outgrowth and elevates intracellular second messenger levels in NB-OK cells only at higher concentrations, 10(-6) M or greater. In contrast to the equipotency of PACAP27 and PACAP38 in stimulating the outgrowth of processes observed after 5 hr of treatment, PACAP38 is much more potent than PACAP27 when NB-OK cells are scored for process outgrowth after 72 hr of treatment. Correlating with the extended time course over which morphologic changes are seen with PACAP38, cAMP levels remain elevated for a more prolonged time span during treatment with PACAP38 than PACAP27. After 72 hr of treatment with PACAP38 versus treatment with PACAP27, cAMP levels are elevated 10-fold versus 3-fold, respectively. PACAP38 at 10(-8) M also induces process outgrowth in two additional human neuroblastoma lines tested, SMS-KAN and LA-N-1, whereas PACAP27 and VIP at the same concentration are less effective.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclic AMP↗
PubMed1993

Correlation between glucose disposal and amino acids levels in hyperthyroidism.

Insulin is known to decrease plasma levels of both glucose and amino acids. We have designed a study to examine whether in hyperthyroidism, where insulin sensitivity is changed, correlation between glucose disposal and amino acids levels is maintained. We studied 5 normal (N) and 5 hyperthyroid (HTD) subjects, and measured glucose disposal rate and serum levels of plasma amino acids before and during insulin infusion utilizing the euglycemic hyperinsulinemic clamp technique. Insulin was effective in decreasing the levels of all amino acids in the plasma of all subjects. The mean amino acid decrease in response to insulin infusion rate of 10 mu/kg/min was 35 +/- 3% in N and 50 +/- 3% in HTD. The half maximally effective dose of insulin on glucose disposal was 43 +/- 3 and 69 +/- 9 uU/ml in N and HTD respectively (p < 0.05). The half maximally effective dose of insulin on decreasing plasma amino acids was 37 +/- 7 and 75 +/- 5 uU/ml in N and HTD respectively (p < 0.01). The concentration of insulin giving a half maximal effect on serum amino acids correlated with the half-maximally effective dose on glucose disposal rate (r = 0.72, p < 0.01). The maximal effect on total amino acid levels correlated with maximal glucose disposal (r = 0.76, p < 0.001). Similar results were observed with branched chain amino acids. We conclude that in hyperthyroidism glucose disposal and decrease in amino acids levels are closely correlated as in healthy subjects. This also confirms the association between glucose disposal and amino acids levels in a variety of insulin sensitive and resistant states.

Adult↗
PubMed1993

Mechanism by which hyperglycemia inhibits hepatic glucose production in conscious rats. Implications for the pathophysiology of fasting hyperglycemia in diabetes.

To examine the relationship between the plasma glucose concentration (PG) and the pathways of hepatic glucose production (HGP), five groups of conscious rats were studied after a 6-h fast: (a) control rats (PG = 8.0 +/- 0.2 mM); (b) control rats (PG = 7.9 +/- 0.2 mM) with somatostatin and insulin replaced at the basal level; (c) control rats (PG = 18.1 +/- 0.2 mM) with somatostatin, insulin replaced at the basal level, and glucose infused to acutely raise plasma glucose by 10 mM; (d) control rats (PG = 18.0 +/- 0.2 mM) with somatostatin and glucose infusions to acutely reproduce the metabolic conditions of diabetic rats, i.e., hyperglycemia and moderate hypoinsulinemia; (e) diabetic rats (PG = 18.4 +/- 2.3 mM). All rats received an infusion of [3-3H]glucose and [U-14C]lactate. The ratio between hepatic [14C]UDP-glucose sp act (SA) and 2X [14C]-phosphoenolpyruvate (PEP) SA (the former reflecting glucose-6-phosphate SA) measured the portion of total glucose output derived from PEP-gluconeogenesis. In control rats, HGP was decreased by 58% in hyperglycemic compared to euglycemic conditions (4.5 +/- 0.3 vs. 10.6 +/- 0.2 mg/kg.min; P < 0.01). When evaluated under identical glycemic conditions, HGP was significantly increased in diabetic rats (18.9 +/- 1.4 vs. 6.2 +/- 0.4 mg/kg.min; P < 0.01). In control rats, hyperglycemia increased glucose cycling (by 2.5-fold) and the contribution of gluconeogenesis to HGP (91% vs. 45%), while decreasing that of glycogenolysis (9% vs. 55%). Under identical plasma glucose and insulin concentrations, glucose cycling in diabetic rats was decreased (by 21%) and the percent contribution of gluconeogenesis to HGP (73%) was similar to that of controls (84%). These data indicate that: (a) hyperglycemia causes a marked inhibition of HGP mainly through the suppression of glycogenolysis and the increase in glucokinase flux, with no apparent changes in the fluxes through gluconeogenesis and glucose-6-phosphatase; under similar hyperglycemic hypoinsulinemic conditions: (b) HGP is markedly increased in diabetic rats; however, (c) the contribution of glycogenolysis and gluconeogenesis to HGP is similar to control animals.

Animals↗
PubMed1992

[Dilutional hyponatremia and convulsions after strenuous exercise].

A 15-year-old girl who drank excessive amounts of water while walking in the desert on a warm day, is reported. Due to complaints of fatigue and headache she was treated with more fluids and had a generalized seizure. On admission her sodium level was 125 meq/l and serum muscle enzymes were increased. Hyponatremia due to exertion and dilution is well established and may be more common than thought. It can present as a generalized seizure and with rhabdomyolysis. This case illustrates the danger of overzealous water replacement, especially without adequate replacement of salts. When water discipline is in force this possibility should be considered in patients presenting after prolonged, strenuous exercise or marching.

Adolescent↗
PubMed1992

Regulation of gene expression in PC12 cells via an activator of dual second messengers: pituitary adenylate cyclase activating polypeptide.

In this study we demonstrate that the activator protein-1 (AP-1) DNA motif, initially considered to be unresponsive to cyclic AMP (cAMP), does function as a cAMP-response element in PC12 cells. A luciferase reporter gene driven by the collagenase promoter that contains the AP-1 motif is responsive to cAMP as well as phorbol esters when transfected in PC12 cells. We have recently shown that pituitary adenylate cyclase activating peptide (PACAP) has neurotrophic properties and activates both adenylylcyclase and the inositol lipid cascade in PC12 cells. Consistent with these actions, we demonstrate that PACAP is an effective activator of luciferase reporter genes whose promoters bear the AP-1 motif, as well as the related DNA element that binds the protein CREB. Both the cAMP and inositol lipid pathways appear to play a role in the activation of these motifs by PACAP. Mutation of the AP-1 motif and its juxtaposition to a heterologous promoter proves that the AP-1 motif is a locus for response to cAMP and PACAP. The luciferase reporter genes bearing the AP-1 motif are not cAMP responsive in HeLa tk- cells, indicating that the mode of second-messenger responsiveness is cell-type specific.

Adenylyl Cyclases↗
PubMed1991

In vivo insulin action in hepatocellular and cholestatic liver cirrhosis.

The in vivo dose response curve to insulin were studied, using an euglycemic insulin clamp technique, in 13 cirrhotic patients [8 with "hepatocellular" (HC) (nonalcoholics) and 5 with "cholestatic" (CHOL) cirrhosis] and 12 healthy controls (N). Subjects were studied in the basal state and during infusion of insulin at 3 different rates - 1, 3, 10 mU kg-1 min-1. Insulin responsiveness was similar in N and in HC, but it was 23% greater in CHOL (p less than 0.001). Insulin sensitivity was decreased in cirrhotics as compared with N but this difference was only significant (p less than 0.001) in HC. (ED50:62 + 5, 88 + 13 and 136 + 16 muu ml-1 in N, CHOL and HC respectively). Insulin clearance rate (ICR) was significantly (p less than 0.005) decreased in HC (1060 +/- 80, 996 +/- 95 and 776 +/- 128 ml sq m-1 ml-1 in N, CHOL and HC respectively. Basal hepatic glucose production (BHGP) was 39% lower in HC (p less than 0.005) and 24% lower in CHOL (p less than 0.05) than in N. Erythrocyte cholesterol phospholipid ratio was significantly elevated (p less than 0.001) in both groups of cirrhotic patients but was not correlated to specific metabolic changes described. In summary: i) intervariations in insulin dependent glucose metabolism were described in different cirrhotic groups; ii) basal hepatic glucose production and insulin clearance rate impaired in the different groups of cirrhotics; iii) the role of decreased cholesterol/phospholipid ratio on tissues glucose metabolism in cirrhotic patients should be further studied.

Adult↗
PubMed1991

Case report: increased insulin sensitivity in tumor hypoglycemia in a diabetic patient: glucose metabolism in tumor hypoglycemia.

A 58-year-old man, with primary hemochromatosis, cirrhosis, and diabetes mellitus treated with insulin developed hepatoma. As the tumor grew, he lost his dependence on insulin therapy and experienced episodes of hypoglycemia. His response to infuse insulin was studied using the euglycemic clamp technique. Insulin was infused at rates of 1 and 10 mu/kg/min. The insulin dose response curve was shifted to the left and at plasma insulin levels of 72 microU/ml, steady-state glucose consumption was 9.6 mg/kg/min, 50% more than in normals, and nearly three times greater than that in other cirrhotics. The insulin clearance rate was 4417 m1/m2/min, almost five and six times more than in normals and cirrhotics, respectively. Basal hepatic glucose production was 3.6 mg/kg/min, two and three times higher than in normal and in cirrhotic subjects, respectively. The decrease in amino acid during hyperinsulinemia was more than 30% higher than in normal and other cirrhotics. IFG-I and II levels were not elevated in this patient. Increased insulin sensitivity and increased insulin clearance and serum amino acid decrease in response to insulin in vivo, suggest that insulin responsive tissues are at last partially responsible for tumor hypoglycemia. The increased glucose disposal rate probably accounted for the disappearance of the diabetes.

Amino Acids↗
PubMed1991

Insulin effects on glucose and potassium metabolism in vivo: evidence for selective insulin resistance in humans.

UNLABELLED: The effects of insulin on in vivo glucose use and potassium uptake in healthy humans are well documented. However, the interrelationship between these two processes is not fully defined. In order to characterize it, we have used the euglycemic clamp technique on six normal volunteers, two patients with acanthosis nigricans and insulin resistance (AN), and one patient with idiopathic nonazotemic hyperkalemia (HK). In the basal state, all patients had normal fasting blood sugar, the AN patients had fasting hyperinsulinemia (600% of controls), and the HK patient had an elevated plasma potassium level of 5.1 mmol/L (n = 4.2 +/- 0.2 mmol/L). During low dose (1 mU/kg.min), and high dose (10 mU/kg.min) insulin infusions, normals used glucose at a rate of 220 +/- 10 and 470 +/- 20 mg/M2.min, respectively. The HK patient had a normal glucose use at both infusion rates, but the AN patients had a 20% decrease of glucose use compared to normals at the two infusion rates. In normal patients, plasma potassium fell by 0.7 and 1.4 mmol/L at the end of the two infusion periods, respectively. AN patients had a similar fall in potassium, but the HK patient displayed no change in plasma potassium levels during a low dose insulin infusion, and only a 0.6 mmol/L drop during the high dose insulin infusion. These results indicate that: 1) patients with AN are resistant to insulin action on glucose use, 2) AN patients have a normal response to insulin on potassium uptake, 3) HK is a patient with normal response to insulin on glucose use, and 4) this patient is resistant to insulin action on potassium uptake. IN CONCLUSION: 1) we have demonstrated the independence of insulin action on glucose and potassium uptake in vivo, 2) we documented the existence of selective insulin resistance in the above patients, 3) we speculate, that in patients with a normal response to insulin on one parameter of its actions, and subnormal response on another parameter, a postreceptor defect rather than a receptor abnormality must exist.

Acanthosis Nigricans↗
PubMed1991

Mechanism of metformin action in obese and lean noninsulin-dependent diabetic subjects.

The effect of metformin on glucose metabolism was examined in eight obese (percent ideal body weight, 151 +/- 9%) and six lean (percent ideal body weight, 104 +/- 4%) noninsulin-dependent diabetic (NIDD) subjects before and after 3 months of metformin treatment (2.5 g/day). Fasting plasma glucose (11.5-8.8 mmol/L), hemoglobin-A1c (9.8-7.7%), oral glucose tolerance test response (20.0-17.0 mmol/L; peak glucose), total cholesterol (5.67-4.71 mmol/L), and triglycerides (2.77-1.52 mmol/L) uniformly decreased (P less than 0.05-0.001) after metformin treatment; fasting plasma lactate increased slightly from baseline (1.4 to 1.7 mmol/L; P = NS). Body weight decreased by 5 kg in obese NIDD subjects, but remained constant in lean NIDD. Basal hepatic glucose production declined in all diabetics from 83 to 61 mg/m2.min (P less than 0.01), and the decrease correlated (r = 0.80; P less than 0.01) closely with the fall in fasting glucose concentration. Fasting insulin (115 to 79 pmol/L) declined (P less than 0.05) after metformin. During a 6.9 mmol/L hyperglycemic clamp, glucose uptake increased in every NIDD subject (113 +/- 15 to 141 +/- 12 mg/m2.min; P less than 0.001) without a change in the plasma insulin response. During a euglycemic insulin clamp, total glucose uptake rose in obese NIDD subjects (121 +/- 10 to 146 +/- 9 mmol/m2.min; P less than 0.05), but decreased slightly in lean NIDD (121 +/- 10 to 146 +/- 0.5; P = NS). Hepatic glucose production was suppressed by more than 80-90% in all insulin clamp studies before and after metformin treatment. In conclusion, metformin lowers the fasting plasma glucose and insulin concentrations, improves oral glucose tolerance, and decreases plasma lipid levels independent of changes in body weight. The improvement in fasting glucose results from a reduction in basal hepatic glucose production. Metformin per se does not enhance tissue sensitivity to insulin in NIDD subjects. The improvement in glucose metabolism under hyperglycemic, but not euglycemic, conditions suggests that metformin augments glucose-mediated glucose uptake. Metformin has no stimulatory effect on insulin secretion.

Blood Glucose↗
PubMed1991

Dose-dependent effects of glyburide on insulin secretion and glucose uptake in humans.

OBJECTIVE: To examine the relationship between plasma glyburide concentrations (0, 50, 100, 200, 400, and 800 nM) and the insulin response and glucose metabolism during euglycemic (4.6 +/- 0.1 mM) and hyperglycemic (11.6 +/- 0.2 mM) conditions. RESEARCH DESIGN AND METHODS: Nine healthy subjects participated in the study. Steady-state plasma glyburide concentrations were achieved by primed continuous intravenous infusion of glyburide. RESULTS: During both euglycemia and hyperglycemia, glyburide enhanced insulin secretion and glucose disposal only to drug levels of 100-200 nM corresponding to an oral dose less than or equal to 10 mg. CONCLUSIONS: The data suggest that glyburide (and probably other sulfonylureas), operates within a narrow range of plasma concentrations (50-200 nM), which can be achieved with very low doses of the drug. It remains to be shown whether the threshold of maximal effect also in clinical practice is achieved with lower sulfonylurea doses than that currently used.

Adult↗
PubMed1990

Insulin resistance and acanthosis nigricans: evidence for a postbinding defect in vivo.

Acanthosis nigricans (AN) with insulin resistance has been traditionally attributed to insulin receptor abnormalities. To further clarify the postbinding defects of in vivo insulin action in this state, we applied the euglycemic insulin clamp technique, combined with the glucose trace infusion method, to 26 subjects: 12 AN patients (eight normoglycemic and four hyperglycemic), eight obese, and eight lean control subjects. The normoglycemic AN group exhibited fasting hyperinsulinemia (666% of control), 160% elevated hepatic glucose production (HGP), 425% increased posthepatic insulin delivery rate, and only slightly reduced (19%) insulin clearance rates, compared with controls. Except for the latter, all these abnormalities were statistically significant (P less than .05), and could not be accounted for by body overweight. AN patients with diabetes mellitus (AN + DM) exhibited a further decreased insulin responsiveness (30%) and clearance (38%), together with a major increase in HGP (320%). All AN patients showed a significant right-shift in the insulin dose-response curve, indicating a decrease in insulin sensitivity. In conclusion, AN is characterized by increased basal rates of HGP, and peripheral insulin resistance, which can be partially attributed to postbinding defects. In AN + DM, a worsening of these abnormalities may be responsible for unmasking the existence of diabetes.

Acanthosis Nigricans↗
PubMed1989

[Ectopic spleen syndrome].

2 women with ectopic spleen are described. Because of the broad spectrum of clinical presentations, a high index of suspicion is needed to reach a correct diagnosis before the appearance of complications, which may be fatal. Diagnosis is usually possible by noninvasive means. Because of the high incidence of complications, splenectomy is recommended, even in asymptomatic cases.

Adult↗
PubMed1986

Correlation between insulin clearance and insulin responsiveness: studies in normal, obese, hyperthyroid, and Cushing's syndrome patients.

Insulin clearance and secretion determine the plasma insulin concentration. To elucidate the significance of these parameters in man, we employed the euglycemic insulin clamp technique to measure insulin sensitivity, insulin responsiveness, and insulin clearance, and we calculated the basal insulin delivery rate. In 27 patients (six normal, six obese, ten hyperthyroid, and five with Cushing's syndrome), insulin was infused at rates of 0.3, 1, 3, or 10 mU/Kg/min, and insulin concentration and glucose utilization were measured. C-peptide concentrations were measured before and during insulin infusion and decreased significantly, indicating a reduction of endogenous insulin secretion to 62% of basal in normals and a similar reduction in the other groups. Maximal responsiveness to insulin was a glucose utilization rate of 450 +/- 20 mg/min/m2 in normals, unchanged in obese, 42% increased in hyperthyroid, and 34% decreased in Cushing's syndrome patients. Sensitivity to insulin was decreased in all three abnormal groups. Insulin clearance rates were 1,050 +/- 80 mL/min/m2 for normals, not significantly changed in obese, 45% increased in hyperthyroid, and 33% decreased in Cushing's syndrome patients. All three abnormal groups showed hyperinsulinemia compared to normal. The basal insulin delivery rates were calculated as 7.0 +/- 0.3 mU/min/m2, with a threefold increase in obese and in hyperthyroid and no significant change in Cushing's syndrome patients. Insulin clearance correlated well with insulin responsiveness (r = .65, P less than 0.001), but poorly with insulin sensitivity (r = .36).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Lack of suppression of insulin secretion by hyperinsulinemia in a patient with an insulinoma.

The regulation of insulin secretion in patients with insulinoma is known to be abnormal. For example, physiological and pharmacological stimuli often fail to stimulate insulin in such patients. Recently, insulin has been found to inhibit its own secretion in normal subjects. To determine if insulin has this effect in patients with insulinoma, we infused insulin at rates of 1 and 10 mU/kg X min in such a patient and in eight normal subjects. Euglycemia was maintained by the euglycemic glucose clamp technique, and endogenous insulin secretion was estimated by measuring plasma C-peptide levels. In the normal subjects, plasma C-peptide declined from 1.60 +/- 0.22 (+/- SEM) to 1.16 +/- 0.17 and 0.82 +/- 0.11 ng/ml during the low and high dose insulin infusions, respectively, indicating 27% (P less than 0.01) and 48% (P less than 0.001) decreases in endogenous insulin secretion at moderately elevated and extremely elevated insulin levels, respectively. In the insulinoma patient, plasma C-peptide was 2.6 ng/ml basally, did not change during the low dose insulin infusion, and rose to 3.4 ng/ml during the high dose insulin infusion. We conclude that the feedback regulation of insulin secretion by insulin that occurs in normal subjects is absent in insulinoma patients. This finding could have pathophysiological and possibly diagnostic significance.

Adenoma, Islet Cell↗