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Biomedical subjects

G Grunberger

Publications and source records attributed to G Grunberger.

At least 37 records · Page 2Linked to original sources
PubMed1995

Insulin versus glipizide treatment in patients with non-insulin-dependent diabetes mellitus. Effects on blood pressure and glucose tolerance.

Insulin resistance that exists in patients with essential hypertension and in those with non-insulin-dependent diabetes mellitus (NIDDM) may be the common denominator for the impaired glucose homeostasis and elevated blood pressure (BP) levels in patients with NIDDM. Therefore, treatment that improves insulin action may also improve BP levels. Consequently, a four-phase (glipizide v insulin) cross-over design study was conducted to determine a better effect of glipizide treatment on insulin sensitivity and the effect this has on BP in 19 NIDDM patients. Patients were subjected to 1 month of diet only (phase I) followed by 3 months of glipizide treatment (phase II), then an additional 1 month of diet only (phase III), and finally 3 months of insulin treatment (phase IV). At the end of phases I, II, and IV oral glucose tolerance tests (OGTT) were performed and plasma glucose, insulin, and C-peptide levels were analyzed. Fasting plasma glucose, insulin, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and triglycerides, glycated hemoglobin, fructosamine, and 2-h postprandial plasma glucose were also analyzed at each phase. Supine and sitting BP levels and body weights were determined biweekly during the study. With the exception of higher plasma insulin and C-peptide levels during the OGTT (area under the curve) in phase IV (insulin) v phase II (glipizide) (both P < .05), and higher fasting plasma insulin levels (P < .06), there were no consistently significant metabolic differences between phases IV and II.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Diabetes and related metabolic risk factors among Arab Americans.

OBJECTIVE: To estimate the incidence of noninsulin-dependent diabetes mellitus (NIDDM) and associated metabolic abnormalities such as impaired glucose tolerance, increased blood pressure, hyperinsulinemia, and obesity in the Arab-American community in the Detroit metropolitan area. METHODS: Subjects were selected randomly from a computer-generated list provided by the Arab-American Center for Economic and Social Services. Laboratory studies included a 2-hour, 75-g oral glucose tolerance test with glucose, insulin, and C-peptide determinations. RESULTS: Of the 105 volunteers studied, 57 were women and 48 were men. Mean +/- SD age was 46.0 +/- 13.0 years. Body mass index was 30.4 +/- 6.8 kg/m2, with 68% of subjects having a body mass index of 27 kg/m2 or more. Of the study participants, 33% had NIDDM, 8.6% had impaired glucose tolerance, and 58% had normal glucose tolerance. Subjects with diabetes, compared with subjects who had normal glucose tolerance, exhibited increased fasting insulin (98 +/- 69 vs 55 +/- 31 pmol/L; p = 0.00056); higher cholesterol (6.03 +/- 1.03 vs 5.09 +/- 1.22 mmol/L; p = 0.00073); marginally lower high-density lipoprotein cholesterol (0.98 +/- 0.21 vs 1.14 +/- 0.31 mmol/L; p = 0.054); higher triglycerides (7.84 +/- 5.79 vs 3.83 +/- 2.15 mmol/L; p = 0.00002); and higher diastolic (83.7 +/- 8.9 vs 78.3 +/- 8.0 mm Hg; p = 0.014) as well as systolic (132.5 +/- 16.0 vs 119.0 +/- 10.6 mm Hg; p = 0.00001) blood pressures CONCLUSIONS: This pilot study demonstrates that diabetes may be a frequent medical problem in the Arab-American community. A well-designed epidemiologic study is warranted to validate these results and to elucidate the underlying mechanisms responsible for these findings.

Adult↗
PubMed1994

Inhibitors of the insulin receptor tyrosine kinase.

Insulin is a polypeptide hormone consisting of 51 amino acids. Insulin promotes a variety of anabolic enzymatic pathways and inhibits many catabolic enzymatic pathways involved in energy storage, as well as in synthesis of structural tissue proteins. In addition, insulin serves as a growth factor, modulating mitogenesis, growth and differentiation. Insulin mediates all of its effects by initially binding and activating its specific cell-surface receptor. Conformational changes induced by insulin binding lead to activation of intrinsic receptor tyrosine kinase. Thus, the study of tyrosine kinase inhibitors, whether synthetically produced or purified from microorganisms or humans, has led to elucidation of molecular details of physiological insulin signaling.

Animals↗
PubMed1993

Insulin induces tyrosine phosphorylation of a 90-kDa protein during postischemic brain reperfusion.

Rat brain nuclear proteins were examined for tyrosine phosphorylation after resuscitation from a 10-min cardiac arrest. Insulin (1 unit/kg intravenously), given immediately after resuscitation, caused a marked increase in tyrosine phosphorylation of a 90-kDa brain protein. This effect occurred without hypoglycemia and was not observed after insulin administration in previously insulinopenic, diabetic, nonischemic animals. Insulin-responsive tyrosine phosphorylation of a specific 90-kDa protein during reperfusion may represent insulin stimulation of a neuroprotective brain response to an ischemic insult, consistent with recent observations that insulin administration during reperfusion protects selectively vulnerable neurons from postischemic death.

Analysis of Variance↗
PubMed1993

Insulin resistance in a case of coexisting insulinoma and type 2 diabetes.

Hyperinsulinaemia due to pancreatic beta-cell tumours has been reported to lead to insulin resistance. A possible contribution of dysregulated insulin receptors to the impaired insulin action of insulinoma has not been explored. Therefore, we studied insulin receptor function in a patient with insulin-producing adenoma. This patient was rather unusual in that she was found to have a very large tumour and strikingly high circulating levels of insulin. In addition, her previous history included type 2 (non-insulin-dependent) diabetes mellitus. We confirmed decreased glucose utilization and metabolic clearance rate for glucose in presence of marked endogenous hyperinsulinaemia (approximately 2000 pM). 125I-labelled insulin binding capacity and receptor affinity for insulin were normal in her intact blood monocytes and erythrocytes. Insulin receptors were purified from the patient's tumour as well as from the pancreas, omental fat, liver and erythrocytes. All parameters of insulin binding to these receptors were normal. Thus, no evidence of receptor downregulation due to the marked hyperinsulinaemia was found. As expected, addition of insulin in vitro stimulated receptor autophosphorylation and tyrosine kinase activity of the receptors isolated from the liver, fat and erythrocytes. However, the basal tyrosine kinase activities of the tumour and pancreatic receptors were very high when isolated and further addition of insulin in vitro increased the protein kinase activity only slightly.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1993

Serum alpha 2-HS-glycoprotein is an inhibitor of the human insulin receptor at the tyrosine kinase level.

The insulin-dependent tyrosine kinase activity (TKA) of the insulin receptor (IR) plays an essential role in insulin signaling. Thus, dysregulation of IR-TKA might be an important element in the states of insulin resistance. A phosphorylated rat hepatic glycoprotein (pp63) acting as an inhibitor of IR-TK has been described. In search of the human homolog of pp63, we isolated a cDNA clone from a human liver lambda gt11 cDNA library. DNA sequence analysis reveals identity with the mRNA product of a human gene AHSG encoding a serum protein, alpha 2-Heremans Scmid-glycoprotein (alpha 2HSG), with heretofore unknown physiological function. Northern blot analysis demonstrates a 1.8-kilobase mRNA in human liver and HepG2 hepatoma cells. alpha 2HSG, purified from human serum, specifically inhibits insulin-stimulated IR autophosphorylation in vitro and in vivo as well as exogenous substrate tyrosine phosphorylation. alpha 2HSG also inhibits both insulin-induced tyrosine phosphorylation of IRS-1 and the association of IRS-1 with the p85 subunit of phosphatidylinositol-3 kinase in H-35 hepatoma cells. alpha 2HSG inhibits insulin-dependent mitogenesis, but does not affect insulin-stimulated induction of the metabolic enzyme tyrosine aminotransferase. alpha 2HSG does not compete with insulin for binding to IR. Finally, the action of alpha 2HSG is specific toward the IR-TK; its effect does not extend to insulin-like growth factor-I-stimulated TKA. Our results allow us to assign a biochemical function for human alpha 2HSG, namely regulation of insulin action at the IR-TK level.

Amino Acid Sequence↗
PubMed1993

Continuous versus intermittent sulphonylurea therapy in non-insulin-dependent diabetes mellitus.

Although it is 50 years since the discovery of the hypoglycaemic effects of sulphonylureas, the molecular basis of their effects are still not fully understood. It has been suggested that long term sulphonylurea therapy may desensitise the pancreatic beta-cells to further drug effects, and that intermittent sulphonylurea therapy may be the best approach to maintain their effectiveness. A randomised, double-blind study has been carried out to attempt to answer the question of whether intermittent sulphonylurea therapy is more effective then continuous administration. Responders to oral glibenclamide (glyburide) went on to receive continuous or intermittent treatment (glibenclamide for 2 weeks then placebo for 2 weeks) for 16 weeks. Glycaemic control was maintained in the continuous treatment group. However, glucose levels deteriorated in the intermittent treatment group, suggesting that there is no merit to intermittent sulphonylurea treatment. Other strategies to investigate include administration on an alternate-day basis or a shorter period off the drug (e.g. 1 week). The underlying question of optimal glycaemic control with sulphonylureas warrants a definitive answer.

Diabetes Mellitus, Type 2↗
PubMed1993

Regulation of hepatic insulin receptor tyrosine kinase in rat models of mild insulin resistance.

Hepatic insulin receptor tyrosine kinase activity (IR-TKA) correlates with plasma insulin levels in severely hyperinsulinemic Zucker rats (Diabetes 1990; 39: 619-625). We tested such a correlation in rat models of insulin resistance with plasma insulin concentrations in the physiologic range. Female Sprague Dawley rats drank either 10% glucose (G; n = 7) or 10% fructose (F; n = 5) in their water for two months and were compared to a control group (C; n = 6). The rats in both experimental groups developed hyperglycemia (G = 8.4 +/- 0.3, F = 8.5 +/- 1.1, C = 4.9 +/- 0.3 mM) but plasma insulin levels did not differ significantly (G = 144 +/- 30, F = 162 +/- 12, C = 108 +/- 6 pmol/L). There were no differences observed in any function of the hepatic insulin receptors between the rat groups. 125I-insulin binding to purified liver receptors was normal. However, for all groups, there was a significant correlation between in vivo plasma insulin levels and IR-TKA measured both in the absence (r = 0.47, p < 0.05) and presence (r = 0.57, p < 0.02) of added insulin in in vitro experiments. The same correlation was seen for the insulin/glucose ratio (as a measure of in vivo insulin resistance) vs. IR-TKA (r = 0.62, p < 0.01; r = 0.49, p < 0.05, in the basal and insulin-stimulated states, respectively). Thus, insulin in the physiologic range regulates TKA of rat liver IR. The TKA of hepatic IR isolated from such rats maintains the ability to be further stimulated by exogenous insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Insulin and IGF1 receptor function among type II diabetic responders and nonresponders to glyburide.

This study evaluated the insulin and insulin-like growth factor-1 (IGF-1) receptor function among patients with type II diabetes who did or did not respond to 1 month of treatment with the oral sulfonylurea agent glyburide. Patients with type II diabetes were initially placed on dietary treatment alone. Patients whose fasting plasma glucose level exceeded 9 mmol/L were enrolled in a prospective 1-month trial of oral glyburide. Clinical, laboratory, and receptor characteristics were assessed before and after glyburide therapy and were compared between the responders and non-responders as well as with matched nondiabetic control subjects. Of the 34 patients who participated in the study, 17 (50%) responded (fasting plasma glucose decreased to 7.8 mmol/L or by 30% from basal level) to the drug. There were no clinical parameters that could distinguish between patients responding and not responding to glyburide. Iodine 125-labeled insulin binding to intact erythrocytes tended to be higher among responders both before and after glyburide. However, the studies of specific insulin binding and insulin receptor tyrosine kinase activities of purified erythrocyte receptors could not distinguish between the two groups of patients with diabetes either before or after glyburide treatment. Compared with weight-matched nondiabetic controls, the erythrocyte insulin receptor tyrosine kinase activity in the patients with diabetes was significantly (by about 45%) decreased. Studies of the IGF-1 receptor likewise did not reveal differences between the two diabetic groups. In conclusion, one half of ambulatory patients with type II diabetes showed a satisfactory hypoglycemic response to a short-term glyburide treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Maintenance of sulfonylurea responsiveness in NIDDM. Randomized double-blind study of intermittent glyburide therapy.

OBJECTIVE: To assess the effectiveness of intermittent administration of sulfonylurea (glyburide) to patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: A randomized, double-blind, prospective trial compared daily administration with intermittent administration of glyburide to patients who initially responded to the drug. Twenty-eight of 60 patients with NIDDM achieved the predetermined improvement in plasma glucose concentration on glyburide therapy. These 28 responders were enrolled into a 16-wk trial of daily versus intermittent (2 wk on, 2 wk off) glyburide treatment. Laboratory assessment of glycemic control and insulin secretion in fasting and 2-h postprandial states was done every 2 wk. RESULTS: Patients on continuous glyburide therapy maintained their glycemic control throughout the study. In contrast, patients on the intermittent schedule lost their glycemic control immediately after being placed on placebo. Despite a significant response to each sulfonylurea pulse, these subjects never regained their baseline glycemic levels. Their fructosamine and HbA1c concentrations deteriorated and remained significantly higher than those of the continuously treated subjects. CONCLUSIONS: Results suggest that administration of glyburide on an intermittent basis after a 2-wk drug-free period to patients initially rendered responsive to sulfonylurea therapy is without clinical merit.

Biomarkers↗
PubMed1992

Functional characterization of insulin and IGF-I receptors in chicken lens epithelial and fiber cells.

Insulin and insulin-like growth factor I (IGF-I) play a role in lens cell growth and development. The binding of these hormones to their respective receptors with its concomitant signal transduction is an important step in these cellular processes. Hormone binding to adult chicken lens insulin and IGF-I receptors, partially purified from epithelial and fiber cells, was studied to examine this activity in lens. The associated stimulation of receptor-mediated tyrosine kinase by the hormones was also studied. At an insulin concentration of 0.02 nM, specific binding was similar for epithelial and fiber receptor preparations (Epi = 0.23 +/- 0.03 fmol, Fib = 0.19 +/- 0.02 fmol). Displacement studies revealed that there was also no difference between epithelial and fiber receptor preparations in the concentration of insulin necessary for half maximal displacement of specific [125I]-insulin binding (IC50: Epi = 0.32 nM +/- 0.07 nM, Fib = 0.31 nM +/- 0.05 nM). Comparison of IGF-I (0.02 nM) binding to receptor preparations from epithelial and fiber cells demonstrated that specific binding was similar in the two preparations (Epi = 0.50 +/- 0.05 fmol, Fib = 0.42 +/- 0.05 fmol). Also, there was no difference in the concentration of IGF-I necessary for half maximal displacement of specific [125I]-IGF-I binding (IC50 = Epi: 0.27 +/- 0.05 nM, Fib: 0.28 +/- 0.04 nM). The ability of IGF-I to displace bound [125I]-insulin was also examined. The IC50 for IGF-I binding to the insulin receptors isolated from epithelial and fiber cells was 37.4 +/- 2.4 nM, and 35.4 +/- 2.8 nM, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Impaired translocation of protein kinase C activity in human non-insulin-dependent diabetes mellitus.

Calcium- and phospholipid-dependent protein kinase (protein kinase C; PKC) may be an important mediator in transduction of some of the cellular actions of insulin. We studied PKC activity in freshly isolated circulating mononuclear cells obtained from healthy subjects and patients with non-insulin-dependent (type II) diabetes mellitus (NIDDM). The kinase activity was measured using a specific nonapeptide substrate, Ala-Ala-Ala-Ser-Phe-Lys-Ala-Lys-Lys-amide. There was negligible calcium- and phospholipid-independent kinase activity in cytosolic and particulate fractions of cells from both control and diabetic subjects. Total (cytosolic and particulate) PKC activity of mononuclear cells from poorly controlled diabetic patients was significantly reduced compared with controls; this reduction was mainly due to a decrease in the cytosolic kinase activity. Tumor-promoting phorbol ester (TPA, 0.1 mumol/L) induced translocation of PKC activity in control cells; in contrast, this subcellular redistribution was not observed in cells from a majority of poorly controlled diabetic subjects. Increased calcium influx into the cells caused by the calcium ionophore A23187-triggered translocation of PKC activity in control cells, while it was ineffective in cells from poorly controlled diabetic patients. Cells from well-controlled diabetic patients demonstrated TPA-induced translocation of the PKC activity approaching that of control cells. The total PKC activity in cells from patients with good glycemic control was normal. Impaired activation of PKC is thus associated with the insulin resistance found in patients with poorly controlled NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Glucose↗
PubMed1991

Diacylglycerols modulate insulin action in rat adipocytes.

Effect of 1,2-diacylglycerols on the insulin receptor function and insulin action in rat adipocytes was studied. 1,2-dioctanoylglycerol (100 micrograms/ml) did not alter insulin binding but it did stimulate phosphorylation of the beta-subunit of the insulin receptor as well as its tyrosine kinase activity. However, dioctanoylglycerol inhibited insulin-stimulated receptor autophosphorylation. This concentration of dioctanoylglycerol inhibited insulin-stimulated CO2 metabolism, lipogenesis and 3-O-methyl-glucose transport in a dose-dependent manner but did not alter any of these bioeffects in absence of insulin. While there was no direct link between diacylglycerol effect on tyrosine kinase activity of the insulin receptor and insulin action in rat adipocytes, the parallel inhibition of insulin-stimulated receptor autophosphorylation and insulin bioeffects by dioctanoylglycerol suggests its direct or indirect role in insulin signalling in rat fat cells.

3-O-Methylglucose↗
PubMed1990

Diacylglycerols modulate phosphorylation of the insulin receptor from human mononuclear cells.

It has been found that 1,2- but not 1,3-diacylglycerols stimulated phosphorylation of the insulin receptor of cultured human monocyte-like (U-937) and lymphoblastoid (IM-9) cells both in the intact- and broken-cell systems. The stimulation of the receptor's beta-subunit phosphorylation was dose-dependent, with optimal effect at 100 micrograms/ml of diacylglycerol. The effects of insulin and 1,2-diacylglycerols on the phosphorylation of partially purified insulin receptors were additive. Phosphoamino acid analysis showed a major effect of diacylglycerols on phosphorylation of tyrosine residues. The diacylglycerols also stimulated tyrosine kinase activity of the partially purified U-937 and IM-9 insulin receptors 2.5-3.5-fold when measured by phosphorylation of an exogenous substrate, poly(Glu80Tyr20) in the absence of any added insulin, calcium or phospholipid. Since this diacylglycerol effect could not be reproduced under conditions optimal for protein kinase C activation and the purified protein kinase C did not stimulate phosphorylation of the beta-subunit of the insulin receptor in this system, it is unlikely that the diacylglycerol effect was mediated by protein kinase C. Since these exogenous 1,2-diacylglycerols at the same high concentration also inhibited 125I-insulin binding to the insulin receptor of the intact U-937 and IM-9 cells, diacylglycerols could modulate the function of the insulin receptor and insulin action in human mononuclear cells.

Cell Line↗