E. Karnieli - Academia.edu (original) (raw)

Papers by E. Karnieli

$Research paper thumbnail of Insulin-stimulated translocation of glucose transporters in the isolated rat adipose cells: Characterization of subcellular fractions$

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1983

A specific D-glucose-inhibitable [3H]cytochalasin Bbinding assay is used to examine the time cour... more A specific D-glucose-inhibitable [3H]cytochalasin Bbinding assay is used to examine the time course, reversibility, and hormone concentration dependency of an insulin-induced translocation of glucose transport systems from a large intracellular pool, associated with a low density subfraction of the microsomal membranes, to the plasma membrane in isolated rat adipose cells. The number of glucose transport systems in the plasma membrane and glucose transport activity in the intact cell are compared during the time course and reversal of insulin's action. Incubation of intact cells with 0.7 nm (100 microunits/ml) insulin at 37 'C rapidly increases the number of D-glucose-inhibitable cytochalasin B-binding sites in the plasma membrane fraction from 10 to 55 pmol and simultaneously decreases that in the low density microsomal membrane fraction from 95 to 34 pmol, each with a half-time of approximately 2.5 min. Furthermore, when maximally insulin-stimulated intact cells are exposed to a 300-fold excess of anti-insulin antibody, both effects of insulin are simultaneously reversed by 95% over a 30-min period with half-times of approximately 9 min. The concentrations of insulin producing half-maximal and maximal effects are approximately 0.11 nM (15 microunits/ml) and 0.35 nM (50 microunits/ml), respectively. The patterns of these reciprocal effects of insulin in time, during reversal, and with increasing hormone concentration are highly correlated (r = 0.93). At steady state, the magnitude of insulin's stimulatory effect on the number of D-glucose-inhibitable cytochalasin B-binding sites in the plasma membrane fraction closely correlates with the magnitude of insulin's stimulatory action on 3-0methylglucose transport in the intact cell. However, during the onset of insulin's action, the appearance of cytochalasin B-binding sites in the plasma membrane fraction precedes the rise in 3-0-methylglucose transport in the intact cell (half-time of 4.0 min) by approximately 1.5 min. No such lag is observed during the reversal of insulin's action. These results directly dem-* These investigations were supported in part by The Kroc Foundation. A preliminary report of this work was presented at the 1980 Annual Meeting of the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Personalized Medicine, 2015

The current article outlines the main issues presented during the 4th Up Close and Personalized (... more The current article outlines the main issues presented during the 4th Up Close and Personalized (UPCP), International Congress on Personalized Medicine, which took place in Tel Aviv (Israel) on 17-20 June 2015. The main topics presented included: phenotypic and 'omics' data in the personalized medicine of diabetes, obesity and oncology; updated reports on large-scale human genetics applied to drug discovery and precision medicine; new advances in disease targeted nano delivery systems, lessons derived from big clinical data and barriers for implementing personalized medicine in at the point of care.

Medical Clinics of North America, 2011

Hormone and Metabolic Research, 1985

Insulin resistance is well established in Cushing's syndrome, but its mechanisms are not ... more Insulin resistance is well established in Cushing's syndrome, but its mechanisms are not completely understood. We performed the euglycemic insulin clamp technique on four patients with Cushing's syndrome, five obese patients and five normal volunteers, in order to determine the role of impairments in insulin responsiveness and insulin clearance in hypercorticism and obesity. Insulin was infused at 0.3, 1, 3 and 10 mU/kg/min, and steady-state glucose-infusion rates required to maintain euglycemia were determined. Glucose disposal at maximal insulin levels was 11.9 +/- 0.4 mg/kg/min in normals, with a 29% decrease in obese and a 42% decrease in Cushing's syndrome patients. Half maximally effective insulin concentrations were increased in both abnormal groups compared to normals. Maximal insulin clearance rates were 1460 +/- 200 ml/min/m2 in normals, not significantly changed in obese and 40% decreased in Cushing's syndrome patients. These results indicate that the insulin resistance in Cushing's syndrome is distinct from that occurring in obesity and is characterized by both decreased insulin responsiveness and decreased insulin clearance. These impairments could be caused by a common defect which may be at or distal to the glucose transport level.

AGE, 1989

Hepatic glucose production was measured by tracer method in 9 elderly and 9 young subjects after ... more Hepatic glucose production was measured by tracer method in 9 elderly and 9 young subjects after an overnight fast. Blood samples were analyzed for glucoregulatory hormone levels. Hepatic glucose production was similar in elderly and young subjects. Significant hormone changes in the elderly in. cluded higher glucose and insulin levels and decreased glucagon. Nonsignificant decreases were seen in cortisol and urinary catecholamines, as well as a nonsignificant increase in growth hormone values. However, growth hormone was sig-nificantl~ correlated with hepatic glucose production in elderly (r = 0.79; p < 0.005), but not in young subjects. We conclude that elderly subjects are able to maintain~nor~al hepatic glucose production despite changes in glucoregulatory hormones. The rate of hepatic glucose production maybe related to growth hormone leveF In elderly, but not in young subjects.

Trends in Endocrinology & Metabolism, 2007

Israel journal of medical sciences, 1985

The euglycemic insulin clamp technique was used to evaluate in vivo insulin action in thyrotoxico... more The euglycemic insulin clamp technique was used to evaluate in vivo insulin action in thyrotoxicosis (TTX). Insulin was infused at 0.5, 3 and 10 mu/kg per min, and the steady-state glucose infusion rate was determined in five TTX patients with fasting hyperinsulinemia and five healthy subjects. TTX is accompanied by a significant increase in insulin responsiveness, clearance and basal insulin delivery rate. Therefore, insulin resistance in TTX does not reside at the postreceptor peripheral tissue level, but may be the consequence of increased hepatic glucose production.

Metabolism, 1986

Insulin clearance and secretion determine the plasma insulin concentration. To elucidate the sign... more 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/m' 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 f 80 mL/min/m* 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 f 0.3 mU/min/m', 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 < 0.001). but poorly with insulin sensitivity (r = .36). We have shown obesity to be characterized by unchanged clearance and responsiveness, decreased sensitivity to insulin, and increased insulin secretion rate; we have shown hyperthyroidism to be associated with increased responsiveness but decreased sensitivity, increased clearance, and increased insulin secretion, and we have shown Cushing's syndrome to include decreased insulin clearance, decreased sensitivity and responsiveness to insulin, and unchanged insulin secretion. Thus, insulin clearance is linked to insulin action in vivo. @ 1988 by Grune & Stratton, inc.

Diabetic Medicine, 2009

Aim To compare the effects of combining liraglutide (0.6, 1.2 or 1.8 mg/day) or rosiglitazone 4 m... more Aim To compare the effects of combining liraglutide (0.6, 1.2 or 1.8 mg/day) or rosiglitazone 4 mg/day (all n ≥ 228) or placebo (n = 114) with glimepiride (2-4 mg/day) on glycaemic control, body weight and safety in Type 2 diabetes. Methods In total, 1041 adults (mean ± SD), age 56 ± 10 years, weight 82 ± 17 kg and glycated haemoglobin (HbA 1c) 8.4 ± 1.0% at 116 sites in 21 countries were stratified based on previous oral glucose-lowering mono : combination therapies (30 : 70%) to participate in a five-arm, 26-week, double-dummy, randomized study. Results Liraglutide (1.2 or 1.8 mg) produced greater reductions in HbA 1c from baseline, (− 1.1%, baseline 8.5%) compared with placebo (+0.2%, P < 0.0001, baseline 8.4%) or rosiglitazone (− 0.4%, P < 0.0001, baseline 8.4%) when added to glimepiride. Liraglutide 0.6 mg was less effective (− 0.6%, baseline 8.4%). Fasting plasma glucose decreased by week 2, with a 1.6 mmol/l decrease from baseline at week 26 with liraglutide 1.2 mg (baseline 9.8 mmol/l) or 1.8 mg (baseline 9.7 mmol/l) compared with a 0.9 mmol/l increase (placebo, P < 0.0001, baseline 9.5 mmol/l) or 1.0 mmol/l decrease (rosiglitazone, P < 0.006, baseline 9.9 mmol/l). Decreases in postprandial plasma glucose from baseline were greater with liraglutide 1.2 or 1.8 mg [ − 2.5 to − 2.7 mmol/l (baseline 12.9 mmol/l for both)] compared with placebo (−0 .4 mmol/l, P < 0.0001, baseline 12.7 mmol/l) or rosiglitazone (− 1.8 mmol/l, P < 0.05, baseline 13.0 mmol/l). Changes in body weight with liraglutide 1.8 mg (− 0.2 kg, baseline 83.0 kg), 1.2 mg (+0.3 kg, baseline 80.0 kg) or placebo (− 0.1 kg, baseline 81.9 kg) were less than with rosiglitazone (+2.1 kg, P < 0.0001, baseline 80.6 kg). Main adverse events for all treatments were minor hypoglycaemia (< 10%), nausea (< 11%), vomiting (< 5%) and diarrhoea (< 8%). Conclusions Liraglutide added to glimepiride was well tolerated and provided improved glycaemic control and favourable weight profile.

Biochemical Journal, 1988

This study examines the relationship between insulin-stimulated glucose transport and insulin-ind... more This study examines the relationship between insulin-stimulated glucose transport and insulin-induced translocation of glucose transporters in isolated rat adipocytes. Adipose cells were incubated with or without cycloheximide, a potent inhibitor of protein synthesis, for 60 min and then for an additional 30 min with or without insulin. After the incubation we measured 3-O-methylglucose transport in the adipose cells, and subcellular membrane fractions were prepared. The numbers of glucose transporters in the various membrane fractions were determined by the cytochalasin B binding assay. Basal and insulin-stimulated 3-O-methylglucose uptakes were not affected by cycloheximide. Furthermore, cycloheximide affected neither Vmax. nor Km of insulin-stimulated 3-O-methylglucose transport. In contrast, the number of glucose transporters in plasma membranes derived from cells preincubated with cycloheximide and insulin was markedly decreased compared with those from cells incubated with ins...

The American Journal of the Medical Sciences, 1991

A 58-year-old man, with primary hemochromatosis, cirrhosis, and diabetes mellitus treated with in... more 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 IL/kg/ min. The insulin dose response curve was shifted to the left and at plasma insulin levels of 72 ILU/ mI, 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.

Lancet (London, England), Apr 23, 2017

Liraglutide 3·0 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-wee... more Liraglutide 3·0 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes. In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m(2), or at least 27 kg/m(2) with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3·0 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT0127221...

JOP: Journal of the pancreas

ABSTRACT

Skeletal growth, taking place in the cartilaginous growth plates of long bones, consumes high lev... more Skeletal growth, taking place in the cartilaginous growth plates of long bones, consumes high levels of glucose for both metabolic and anabolic purposes. We previously showed that Glut4 is present in growing bone and is decreased in diabetes. In the present study, we examined the hypothesis that in bone, GLUT4 gene expression and function are regulated via the IGF-I receptor (IGF-IR) and that Glut4 plays an important role in bone growth. Insulin and IGF-I actions on skeletal growth and glucose uptake were determined using mandibular condyle (MC) organ cultures and MC-derived primary cell cultures (MCDC). Chondrogenesis was determined by following proliferation and differentiation activities using immunohistochemical (IHC) analysis of proliferating cell nuclear antigen and type II collagen expression, respectively. Overall condylar growth was assessed morphometrically. GLUT4 mRNA and protein levels were determined using in situ hybridization and IHC, respectively. Glut4 translocation to the cell membrane was assessed using confocal microscopy analysis of GFP-Glut4 fusion-transfected cells and immunogold and electron microscopy on MC sections; glucose uptake was assayed by 2-deoxyglucose (2-DOG) uptake. Both IGF-I and insulinstimulated glucose uptake in MCDC, with IGF-I being tenfold more potent than insulin. Blockage of IGF-IR abrogated both IGF-I-and insulin-induced chondrogenesis and glucose metabolism. IGF-I, but not insulin, induced Glut4 translocation to the plasma membrane. Additionally, insulin induced both GLUT4 and IGF-IR gene expression and improved condylar growth in insulin receptor knockout micederived MC. Moreover, silencing of GLUT4 gene in MCDC culture abolished both IGF-I-induced glucose uptake and chondrocytic proliferation and differentiation. In growing bone, the IGF-IR pathway stimulates Glut4 translocation and enhances glucose uptake. Moreover, intact Glut4 cellular levels and translocation machinery are essential for early skeletal growth.

Annals of Plastic Surgery, 1994

Fat injection is being used for the correction of various soft-tissue defects. In this study, the... more Fat injection is being used for the correction of various soft-tissue defects. In this study, the manner of fat injection yielding the greatest transplant viability was examined. Autologous fat was obtained from the inguinal area of rats and subsequently reinjected to the nuchal region, an area naturally poor in subcutaneous fat. Before injection, the fat was processed by one or more of the following methods: suture of the recipient area, repeated washing to remove residual blood, and addition of insulin. Transplant status was evaluated by both macroscopic and microscopic examination of the recipient sites 2 weeks and 12 weeks after the injection. The results demonstrated that the injected fat remained in part as viable new fatty tissue in the nuchal area. No statistically significant improvement in the viability of the injection fat was noticed at 2 weeks and 12 weeks after its processing by the different methods just described. Significant positive correlation was demonstrated bet...

Journal of Biological Chemistry, May 25, 1981

The Endocrine Society's 92nd Annual Meeting, June 19–22, 2010 - San Diego

Type 2 diabetes mellitus (DM2) is the most commonly diagnosed metabolic disease and its prevalenc... more Type 2 diabetes mellitus (DM2) is the most commonly diagnosed metabolic disease and its prevalence is expected to increase. Epidemiological studies clearly show excess mortality associated with DM2, as well as an increased risk of DM2-related complications. Advances in personalized medicine would greatly improve patient care in the field of diabetes and other metabolic diseases. Prediction of the disease in asymptomatic patients as well as its harsh complications in patients already diagnosed is becoming a necessity, with the considerable increase in the cost of the treatment. In the current article, we review the known clinical, molecular metabolic and genetic biomarkers that should be integrated in a future bioinformatic platform to be used at the point-of-care, and discuss the challenges we face in applying this vision of personalized medicine for diabetes into reality.

Journal of Biological …, 1999

We report that the vanadium ligand l-Glu (γ) HXM potentiates the capacity of free vanadium ions t... more We report that the vanadium ligand l-Glu (γ) HXM potentiates the capacity of free vanadium ions to activate glucose uptake and glucose metabolism in rat adipocytes in vitro (by 45-fold) and to lower blood glucose levels in hyperglycemic rats in vivo (by 57-fold). ...

International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity, 1995

OBJECTIVE To investigate the effect of weight reduction induced by gastric bypass operation (GBO)... more OBJECTIVE To investigate the effect of weight reduction induced by gastric bypass operation (GBO), on the peripheral resistance to insulin in extremely obese subjects. DESIGN A three-stage euglycemic clamp was applied to assess the metabolic clearance rate of glucose (g-MCR) in lean controls and in obese subjects, prior to and 6-12 months post operation. SUBJECTS Six obese subjects (four obese normoglycemics-ON and two obese non-insulin dependent diabetics-OD) before and after GBO and six healthy, lean controls (LC) were compared. MAIN OUTCOME MEASURES Body mass index after GBO, metabolic clearance rate of glucose under increasing insulin concentrations. RESULTS GBO resulted in a significant change in body mass index from a pre-operation value (mean +/- s.d.) of 45.0 +/- 8.5 to 30.4 +/- 5.9 kg m-2 and remained significantly greater than controls (23.3 +/- 2.3 kg m-2). Glucose MCR increased from a mean baseline value of 3.0 +/- 1.6 to 6.7 +/- 3.9 ml kg-1 min-1 at post GBO (P) (P <...