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Biomedical subjects

Itamar Raz

Publications and source records attributed to Itamar Raz.

48 records · Page 3Linked to original sources
PubMed2003

Cardiovascular disease in type 2 diabetics: epidemiology, risk factors and therapeutic modalities.

Macrovascular complications associated with chronic hyperglycemia in type 2 diabetes mellitus is a major global health problem that is currently on the rise. Accelerated cardiovascular and cerebrovascular atherosclerosis is the major cause of mortality in patients with type 2 diabetes. Many of the risk factors for cardiovascular disease are operative or even exacerbated in diabetic patients, including hypercholesterolemia, hypertriglyceridemia, hypertension, central obesity, and smoking. Other diabetes-specific factors, such as increased levels of plasminogen activator 1 and fibrinogen, chronic inflammation, genetic susceptibility, and accelerated glycosylation end-products-mediated vascular damage, are thought to play a role in the development of CVD among patients with type 2 diabetes. Further studies will hopefully elucidate the clinical relevance of such factors. In addition, recent studies indicate that hyperglycemia is an important and independent risk factor for CVD. Increased risk of CVD is directly related to elevated 1 and 2 hour post-prandial blood glucose averages, as well as to fasting hyperglycemia. Thus, specific treatment regimens designed to reduce the development rate of cardiovascular complications in patients with type 2 diabetes must consider the impact of risk factors and their control, as well as the need for optimal metabolic and glycemic control.

Blood Glucose↗
PubMed2002

Pharmacokinetic-pharmacodynamic analysis of the glucose-lowering effect of metformin in diabetic rats reveals first-pass pharmacodynamic effect.

Metformin, a commonly used antidiabetic drug, exerts its glucose-lowering effect due to metabolic activities at several sites of action (biophases), including liver, intestine, muscle cells, and adipocytes. The relative contribution of the individual biophases to the overall glucose-lowering effect is not known. Thus, the aims of this investigation were to study the influence of mode of drug administration on the kinetics of glucose-lowering action of metformin in diabetic rats and identify the contribution of different sites of action to the overall response. Streptozotocin diabetic rats received metformin in crossover fashion via intraduodenal, intravenous, and intraportal routes as bolus dose or infusion regimens designed to yield similar pharmacokinetic profiles. Metformin plasma concentrations and blood glucose levels were measured following each mode of administration. Despite the similarity in the concentration-time profiles obtained for different routes of metformin administration, intraduodenal administration produced larger response than intraportal metformin infusion, and lowest response was observed following intravenous administration. This finding indicates that a significant "first-pass" pharmacodynamic effect, which occurs in the presystemic sites of action (liver and the gastrointestinal wall), contributes to the overall glucose-lowering response of metformin. We applied a combined pharmacokinetic-pharmacodynamic modeling approach to study the nature of the first-pass pharmacodynamic effect. The observed data were successfully described by a novel integrated indirect response pharmacokinetic-pharmacodynamic model that revealed a correlation between the temporal metformin concentrations that transit the portal vein and through the gut wall rather than with drug concentrations that accumulated in the liver and the intestinal wall.

Animals↗
PubMed2002

Reproducibility of glucose measurements using the glucose sensor.

OBJECTIVE: Recent studies have confirmed that improved glycemic control decreases the risk of diabetic complications in type 1 and type 2 diabetic patients. The Minimed glucose sensor allows continuous 72-h glucose monitoring and represents a potentially important tool to improve diabetes management. Its use is currently limited to the health care team. Our aim was to evaluate the reproducibility of data provided by the device by comparing data provided by two sensors worn simultaneously by the same subject. RESEARCH DESIGN AND METHODS: A total of 11 subjects (6 type 1 and 3 type 2 diabetic patients and 2 healthy subjects) agreed to wear two sensors and perform at least four daily finger-stick glucose determinations during 72 h. The simultaneous glucose values provided by the sensors were compared. To determine the clinical implications of the glucose data, each day was divided into eight periods, and for each period the glucose range was rated as satisfactory, too high, or too low by a blinded clinician experienced in interpreting glucose sensor data in the clinical setting. The evaluation of glycemic levels based on the recordings of the two sensors were compared for each paired time interval. RESULTS: We discarded 18% of the sensor data for technical reasons. Examined as a group, the remaining 3,370 paired data points in all 11 patients were highly correlated (r = 0.84). However, when individual pairs were evaluated, large differences in the glucose values were apparent, with differences of >10% in 70% of the measurements and >50% in 7% of the measurements. Moreover, clinical evaluation of the glucose range provided simultaneously by two sensors was concordant for only 65% of the evaluation periods. CONCLUSION: In a real-life setting, the accuracy of data provided by the Minimed glucose sensor may be less than expected. To avoid therapeutic errors, sensor findings should be confirmed by independent means before clinical decisions are made.

Blood Glucose↗
PubMed2001

Editor's Foreword.

Explore the source record for details and available documents.

Journal Article↗
PubMedDate not supplied

Diabetes: insulin resistance and derangements in lipid metabolism. Cure through intervention in fat transport and storage.

We present multiple findings on derangements in lipid metabolism in type 2 diabetes. The increase in the intracellular deposition of triglycerides (TG) in muscles, liver and pancreas in subjects prone to diabetes is well documented and demonstrated to attenuate glucose metabolism by interfering with insulin signaling and insulin secretion. The obesity often associated with type 2 diabetes is mainly central, resulting in the overload of abdominal adipocytes with TG and reducing fat depot capacity to protect other tissues from utilizing a large proportion of dietary fat. In contrast to subcutaneous adipocytes, the central adipocytes exhibit a high rate of basal lipolysis and are highly sensitive to fat mobilizing hormones, but respond poorly to lipolysis restraining insulin. The enlarged visceral adipocytes are flooding the portal circulation with free fatty acids (FFA) at metabolically inappropriate time, when FFA should be oxidized, thus exposing nonadipose tissues to fat excess. This leads to ectopic TG accumulation in muscles, liver and pancreatic beta-cells, resulting in insulin resistance and beta-cell dysfunction. This situation, based on a large number of observations in humans and experimental animals, confirms that peripheral adipose tissue is closely regulated, performing a vital role of buffering fluxes of FFA in the circulation. The central adipose tissues tend to upset this balance by releasing large amounts of FFA. To reduce the excessive fat outflow from the abdominal depots and prevent the ectopic fat deposition it is important to decrease the volume of central fat stores or increase the peripheral fat stores. One possibility is to downregulate the activity of lipoprotein lipase, which is overexpressed in abdominal relatively to subcutaneous fat stores. This can be achieved by gastrointestinal bypass or gastroplasty, which decrease dietary fat absorption, or by direct means that include surgical removal of mesenteric fat. Indirect treatment consists of the compliant application of drastic lifestyle change comprising both diet and exercise and pharmacotherapy that reduces mesenteric fat mass and activity. The first step should be an attempt to effectively induce a lifestyle change. Next comes pharmacotherapy including acarbose, metformin, PPARgamma, or PPARgammaalpha agonists, statins and orlistat, estrogens in postmenopausal women or testosterone in men. Among surgical procedures, gastric bypass has been proven to produce beneficial results in advance of other surgical techniques, the evidence basis of which still needs strengthening.

Animals↗
PubMedDate not supplied

Different contributions of insulin resistance and beta-cell dysfunction in overweight Israeli Arabs with IFG and IGT.

BACKGROUND: Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are both intermediate stages that exist between normal glucose tolerance and overt type 2 diabetes. Epidemiological studies demonstrated that the two categories define distinct populations. In this study, we examined the contributions of insulin resistance and beta-cell dysfunction to both states in overweight subjects of Arab origin. METHODS: Twelve subjects with isolated IFG, 10 with isolated IGT, and 20 with IFG and IGT (combined glucose in tolerance-CGT) were compared with 30 subjects with normal glucose tolerance (NGT) subjects; all were of Arab origin and were overweight or obese. Different indices for insulin resistance and beta-cell function were calculated from oral glucose tolerance (OGTT) values. RESULTS: Subjects with isolated IFG and CGT were more obese and had significantly higher values of insulin resistance than subjects with isolated IGT and NFG. There was no significant difference between the insulin resistance in subjects with isolated IGT and that in subjects with NGT. Indices of beta cell function were severely reduced among subjects with isolated IGT and CGT when compared with those with both isolated IFG and NGT, while subjects with isolated IFG had similar beta-cell indices to subjects with NGT. CONCLUSION: These data demonstrate that beta-cell dysfunction and insulin resistance contribute differently to the pathogenesis of IFG and IGT among overweight Arab subjects.

Adult↗
PubMedDate not supplied

Hyperglycemia and its effect after acute myocardial infarction on cardiovascular outcomes in patients with Type 2 diabetes mellitus (HEART2D) Study design.

OBJECTIVE: Cardiovascular (CV) disease is the major cause of death in patients with diabetes. Up to 40% of patients with Type 2 diabetes mellitus (T2DM) who survive an initial myocardial infarction (MI) suffer a recurrent event within 2 years, the majority of which are fatal. One independent risk factor for cardiovascular disease (CVD) may be postprandial blood glucose (PPBG) excursions. The HEART2D study seeks to determine the effect that PPBG control has on cardiovascular outcomes in patients who suffered an MI within the 21 days before study enrollment. RESEARCH DESIGN AND METHODS: Approximately 1355 patients with T2DM with recent MI will be entered in this multicenter study of about 3.0-year duration. Using infarct severity and peri-infarct treatment as randomization factors, patients will be assigned to one of two insulin treatment strategies: (1) postprandial strategy: premeal insulin lispro with basal insulin at bedtime if needed (NPH insulin), targeting 2-h PPBG < or = 7.5 mmol/l or (2) basal strategy: insulin (NPH insulin twice daily or insulin glargine once daily; or premixed human insulin (70% NPH/30% regular; 30/70) twice daily), targeting fasting and premeal blood glucose (BG; < or = 6.7 mmol/l). Both groups will aim for a target hemoglobin AlC (AlC) of < 7%. ANTICIPATED RESULTS: The anticipated difference in PPBG (approximately 2.0 to 2.5 mM) between strategies is expected to demonstrate a 15% to 18.5% relative risk reduction in CV events for the postprandial strategy. CONCLUSION: This study may provide practical insights into the clinical management of patients with diabetes who have an increased risk of recurrent CV events and death.

Diabetes Mellitus, Type 2↗
PubMedDate not supplied

Innovative immune-based therapeutic approaches for the treatment of type 1 diabetes mellitus.

Type 1 diabetes mellitus is an autoimmune disease caused by a culmination of noxious processes of autoimmunity composed of various components of the innate and adaptive immune systems. Current treatment of type 1 diabetes focuses on restraining the endocrine disease without affecting the autoimmune process that underlies it. Prevention of this disease requires immune modulation and early intervention. New therapeutic approaches can be classified on the basis of the immunological arm targeted, that is, T-cell immune modulation (using cytokines, anti-CD3 monoclonal antibodies, and peptide MHC class II dimers), innate immune system modulation (using alpha-galactosylceramide or peptide 277), or specific antigen vaccination (glutamic acid decarboxylase and insulin). Here we review the most promising therapies developed based on these targets and emphasize those that have reached human phase clinical investigation.

Animals↗
PubMedDate not supplied

Effect of mild hypoinsulinemia on renal hypertrophy: growth hormone/insulin-like growth factor I system in mild streptozotocin diabetes.

The metabolic aberrations associated with diabetes mellitus profoundly alter the growth hormone/insulin-like growth factor I (GH/IGF-I) system. In severe experimental diabetes, serum IGF-I level is reduced, reflecting altered hepatic expression. On the other hand, increased levels of kidney IGF-I have been implicated in the development of diabetic kidney disease. This study aimed to examine the effect of mild experimental diabetes with hypoinsulinemia on both the systemic and renal GH/IGF-I systems in a low-dose streptozotocin (STZ)-induced diabetic rat. Diabetic animals with mild hypoinsulinemia developed renal hyperfiltration within 3 days of diabetes, whereas the renal size increased significantly only between 30 and 48 days of diabetes. Plasma GH levels were unchanged during the entire course of the study, but a decrease in serum IGF-I, IGF-binding protein 3 (IGFBP-3), and IGF-binding protein 4 (IGFBP-4) occurred after 10, 30, and 48 days. Kidney IGF-I and IGF-binding protein 1 (IGFBP-1) mRNA expression increased after 10 and 30 days of diabetes. A significant increase in kidney IGFBP-1/2, IGFBP-3, and IGFBP-4 proteins was seen after 48 days of diabetes. A positive correlations was found between renal growth and insulin/glucose ratio (r=.57), kidney IGF-I (r=.57), IGFBP-1 mRNA (r=.43), IGFBP-1/2 (r=.41), and IGFBP-4 levels (r=.40). These results demonstrate hyperfiltration within 3 days of diabetes and a similar response in the IGF-I system in mildly and severely hypoinsulinemic rats; however, renomegaly develops slower in mildly diabetic rats at least partly due to delayed changes in the renal IGF and IGF BPs.

Animals↗
PubMedDate not supplied

Effects of tamoxifen on insulin-like growth factors, IGF binding proteins and IGFBP-3 proteolysis in breast cancer patients.

BACKGROUND: Recently an association between increased serum insulin-like growth factor I (IGF-I) levels and the development of breast cancer was demonstrated. Tamoxifen used in the postoperative treatment of breast cancer patients may exert significant effects on the IGF-I system. MATERIALS AND METHODS: To examine the effect of Tamoxifen treatment (20 mg/day) on changes in the IGF-I axis in 11 breast cancer patients before and after 4 months of Tamoxifen treatment and compared to 8 healthy subjects. IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3 and IGFBP-6 were examined by specific assays. IGFBPs were examined by Western ligand blotting and IGFBP-3 proteolytic activity by specific protease assay. RESULTS: Serum IGF-I was decreased before (63%) and increased during Tamoxifen treatment (60%). Total IGFBP-3 levels measured by IRMA were unchanged, however, intact IGFBP-3 measured by WLB was decreased (58%) before and increased (67%) during Tamoxifen treatment. IGFBP-3 proteolysis was increased before and reduced during treatment. IGFBP-4 and IGFBP-6 were decreased before and increased during Tamoxifen treatment. CONCLUSION: Significant changes in the IGF system were demonstrated before and during Tamoxifen treatment and may in part be involved in the effects of Tamoxifen treatment in breast cancer patients.

Breast Neoplasms↗