Tongue necrosis and pericarditis.
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Adult↗
Biomedical subjects
Itamar Raz
Publications and source records attributed to Itamar Raz.
Increased expression of endothelin-converting enzyme-1c isoform in response to high glucose levels in endothelial cells.
Endothelin-1 (ET-1) is both a potent vasoconstrictor and mitogenic factor that has been implicated as a cause of the micro- and macrovascular complications of diabetes mellitus. The pathway by which the high-glucose environment of diabetes mediates increased levels of endothelins has not been completely elucidated but appears to involve endothelin-converting enzyme (ECE-1), which converts inactive big ET-1 to active ET-1 peptide. To determine the effect of high glucose concentrations on the expression of ECE-1, hybrid endothelial cells (EA.hy926) and human umbilical vein endothelial cells (HUVEC) were both grown in various glucose concentrations. There was a 2-fold increase in ECE-1 immunoreactivity in the EA.hy926 cell line growing in medium containing 22.2 versus 5.5 mmol/l glucose after 24 h, which rose to greater than 20-fold after 5 days. Similar results were seen with HUVEC. Bradykinin or NG-nitro-L-arginine methyl ester did not change the effect of high glucose on ECE-1 protein expression. High glucose induced a 72 and 41% increase in total protein kinase C (PKC) activity in both EA.hy926 cells and HUVEC, respectively, and a 39, 49 and 109% elevation in PKC beta1, beta2 and delta expression, respectively, in EA.hy926 cells. The increase in ECE-1 expression was inhibited in both cell cultures by GF109203X (5 micromol/l), a general PKC inhibitor, while addition of 10 nmol/l phorbol myristic acid to EA.hy926 cells or HUVEC growing on medium containing 5.5 mmol/l glucose increased ECE-1 expression to a level similar to that of cells conditioned in high glucose. Human ECE-1 protein exists in four different isoforms, termed 1a, 1b, 1c and 1d. Northern blot analysis revealed that only ECE-1c isoform mRNA levels increased. Immunohistochemical staining of EA.hy926 cells grown in high glucose concentrations demonstrated an increase in the ECE-1c isoform, which occurred mainly in the plasma membrane. These results showed that the PKC pathway may play an important role in the glucose-mediated induction of ECE-1 expression. The main isoform to increase in response to high glucose was ECE-1c. This enzyme may be one of the factors contributing to the elevated ET-1 peptide levels observed in diabetes.
Aspartic Acid Endopeptidases↗
Predictors of cardiovascular events in patients with type 2 diabetic nephropathy and hypertension: a case for albuminuria.
Individuals with type 2 diabetes and nephropathy represent a particularly high-risk group for both adverse cardiac as well as renal events. Using the Irbesartan in Diabetic Nephropathy Trial (IDNT) cohort, our objective was to determine baseline characteristics of individuals with type 2 diabetic nephropathy and hypertension predictive for cardiac events. IDNT identified 1715 individuals with type 2 diabetic nephropathy and hypertension having serum creatinine of 1.0 to 3.0 mg/dL and urinary albumin excretion rates > or = 900 mg/day. A cardiovascular (CV) composite was used consisting of CV death, nonfatal MI, hospitalization for heart failure, stroke, amputation, and coronary and peripheral revascularization. Using multivariable Cox regression analysis, 41 baseline characteristics determined a priori were analyzed for their potential relationship to risk of experiencing a CV event. Of the 1715 individuals, 518 (30.2%) had at least one of the CV composite end points. Older age, male gender, longer duration of diabetes, history of cardiovascular disease, history of CHF, high urinary albumin:creatinine ratio, and low serum albumin were strong predictors for CV events; of these, prior history of CVD (RR 2.00, 95% CI 1.63-2.45; P < 0.0001) and high urinary albumin:creatinine ratio (RR 1.29 per natural log unit, 95% CI 1.13-1.48; P = 0.0002) at baseline were highly predictive for cardiovascular events. In conclusion, among individuals with hypertension and diabetic nephropathy, both the degree of albuminuria and lower serum albumin levels provide additional prognostic information concerning cardiovascular risk, in addition to traditional coronary risk factors.
Albuminuria↗
Primary prevention of type 2 diabetes: how do we do it?
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Acarbose↗
[Primary care for type 2 diabetes].
The prevalence of type 2 diabetes is dramatically increasing worldwide and expected to double over the next 25 years, reaching epidemic proportions and thus incurring a considerable financial burden on the health care system. In order to cure the epidemic and minimize expensive complications, a program aimed at optimizing metabolic control and improving surveillance and quality assessment needs to be developed and implemented nation-wide. Most diabetic patients should be treated within the primary care system. In order to meet treatment targets, improve metabolic control and avoid complications, the knowledge and skills needed to treat this chronic disease should be reinforced by dedicated multidisciplinary teams from centers specializing in diabetes care. The specialized diabetes clinics should be devoted to both the treatment of complicated cases of diabetes, that are not achieving treatment targets in the primary care setting, and to the education, updating and empowerment of all primary care teams involved in the treatment of patients with diabetes. A local framework for shared care should be developed through the combined efforts, of the staff of the diabetes center and the primary care physicians and nurses in order to secure the shared goals of optimal treatment and prevention of complications.
Diabetes Mellitus, Type 2↗
Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephropathy.
BACKGROUND: Patients with diabetes have increased risk for adverse cardiovascular events. Angiotensin-converting enzyme inhibitors are protective in type 1 diabetes. However, no definitive studies have examined the use of angiotensin-receptor blockers in patients with type 2 diabetes and overt nephropathy. The primary outcomes of the Irbesartan Diabetic Nephropathy Trial were doubling of serum creatinine levels, end-stage renal disease, and death from any cause. OBJECTIVE: To compare rates of cardiovascular events among patients with type 2 diabetic nephropathy who received conventional antihypertensive therapy with an angiotensin-receptor blocker (irbesartan) or a calcium-channel blocker (amlodipine), or placebo. DESIGN: Randomized double-blind, placebo-controlled trial with a median follow-up of 2.6 years. A time event analysis was used. SETTING: 209 centers in the Americas, Europe, Israel, and Australasia. PARTICIPANTS: 1715 adults with type 2 diabetic nephropathy and hypertension; serum creatinine levels of 89 micromol/L (1.0 mg/dL) to 266 micromol/L (3.0 mg/dL) in women and 106 micromol/L (1.2 mg/dL) to 266 micromol/L (3.0 mg/dL) in men; and urinary protein excretion rates of at least 900 mg/d. INTERVENTION: Treatment with irbesartan, amlodipine, or placebo. MEASUREMENTS: Time to cardiovascular death, myocardial infarction, congestive heart failure, strokes, and coronary revascularization. RESULTS: The three groups were not statistically different in the composite of cardiovascular events. Among the components of the composite, there was a trend toward a decrease in strokes in patients receiving amlodipine versus those receiving placebo (hazard ratio, 0.65 [95% CI, 0.35 to 1.22]; P = 0.18). Likewise, patients receiving amlodipine had a significantly lower rate of myocardial infarction when compared with placebo recipients (hazard ratio, 0.58 [CI, 0.37 to 0.92]; P = 0.02). In contrast, patients receiving irbesartan had a significantly lower incidence of congestive heart failure when compared with placebo recipients (hazard ratio, 0.72 [CI, 0.52 to 1.00]; P = 0.048) or amlodipine recipients (hazard ratio, 0.65 [CI, 0.48 to 0.87]; P = 0.004). CONCLUSION: The composite cardiovascular event rate did not differ in patients with type 2 diabetes and overt nephropathy treated with irbesartan, amlodipine, or placebo in addition to conventional antihypertensive therapy.
Amlodipine↗
Prevalence and risk factors for erectile dysfunction in men with diabetes, hypertension, or both diseases: a community survey among 1,412 Israeli men.
BACKGROUND: Erectile dysfunction (ED) and cardiovascular disease share common risk factors and may be further aggravated by medical treatment for reducing them. HYPOTHESIS: The study was undertaken to assess the prevalence of ED in patients with diabetes (DM), hypertension (HTN), or both diseases, and to evaluate the effect of patient age, medical treatment, and disease duration and control on the prevalence of ED in this population. METHODS: A group of 150 primary practitioners who had patients with known DM and/or HTN conducted a survey, utilizing IIEF-15, a 15-item multidimensional, self-administered questionnaire used for the clinical assessment of ED. RESULTS: In all, 1,412 patients were included: 37% had DM, 38% had HTN, and 25% had both diseases. Their mean age was 55, 58, and 60 years, and 62, 46, and 67% had some degree of ED, respectively. The prevalence of ED increased with age and disease duration in each age group and was higher in subjects with DM than in those with HTN, especially in those aged < 65 years. Poor glycemic control was associated with a higher prevalence rate of ED early in the course of the disease. There was no significant difference in the prevalence of ED according to type and number of antihypertensive drugs. CONCLUSIONS: Erectile dysfunction is common among patients at high risk for cardiovascular disease because of diabetes and/or HTN. Diabetic men are affected earlier than those with HTN. Given the high frequency of ED in young patients with these risk factors, physicians should encourage an open discussion on the subject during routine visits to promote early detection and treatment.
Age Factors↗
Addition of biphasic insulin aspart 30 to rosiglitazone in type 2 diabetes mellitus that is poorly controlled with glibenclamide monotherapy.
BACKGROUND: The incidence of type 2 diabetes mellitus (DM) is rapidly increasing worldwide. Results from large-scale studies show that tight blood glucose (BG) control improves the outcome of patients with type 2 DM. OBJECTIVE: This trial assessed the short-term efficacy and tolerability of adding a thiazolidinedione (rosiglitazone [ROS]) to existing sulfonylurea (SU) therapy (glibenclamide) compared with switching to combination treatment with a premixed insulin (biphasic insulin aspart 30 [BIAsp 30], a rapid-acting insulin analog) and the thiazolidinedione in a select group of patients with type 2 DM whose metabolic control was inadequate with SU monotherapy. METHODS: In this 6-week, multicenter, open-label, parallel-group trial, patients with type 2 DM whose BG level was not adequately controlled with glibenclamide monotherapy (glycosylated hemoglobin [HbA1c] 8%-13%) were randomized either to replace glibenclamide with BIAsp 30 (individually titrated dosages starting with 6-8 U BID) plus rosiglitazone (4 mg once daily) (BIAsp 30 + ROS group) or to add rosiglitazone (4 mg once daily) to their pretrial doses of glibenclamide (GLIB + ROS group). Patients measured their BG levels immediately before each of the 3 main meals, 90 minutes after the start of each meal, and at bedtime, and mean BG levels were calculated at weeks 0 (baseline), 1, 2, 4, 6, and at 2-week follow-up (week 8). The primary end point was change in mean daily BG level during treatment. Secondary end points included preprandial, postprandial, and bedtime BG levels, serum fructosamine level HbA, and fasting BG level, which were measured at each study visit. Tolerability was assessed using hematologic and biochemical parameters, vital signs, and physical examination. RESULTS: Forty-nine patients (32 men, 17 women; mean [SD] age, 59.1 [8.9] years; mean [SD] body mass index, 27.7 [3.7] kg/m2) participated in the study. A significant difference was found between treatments in the change in mean daily BG level from baseline to week 6 (P=0.01). After the 6-week treatment period, change in mean serum fructosamine level was significantly greater for BIAsp 30 + ROS compared with GLIB + ROS (P=0.02). HbA1c decreased in both treatment groups from baseline to study end, but the difference between groups was nonsignificant. The changes in fasting BG from baseline to study end also were nonsignificant between groups. Both combinations were well tolerated. CONCLUSIONS: This short-term study in patients with type 2 DM whose BG level was poorly controlled with glibenclamide monotherapy suggests that switching to a combination of BIAsp 30 + ROS was efficacious and well tolerated and provided an alternative to adding rosiglitazone to existing glibenclamide treatment. The study also suggests that BIAsp 30 may be associated with greater improvements in short-term metabolic control.
Adult↗
Insulin-induced hypertension, L-arginine, and endothelial nitric oxide synthase in pregnant rats.
Pregnancy-induced hypertension in rats with chronic exogenous hyperinsulinemia is associated with reduced urinary excretion of nitric oxide metabolites. We tested the hypothesis that there are perturbations of endothelial nitric oxide synthase in their kidneys. We studied three groups of rats: control pregnant rats (n = 6); pregnant rats with hyperinsulinemia by subcutaneous sustained-release insulin pellet (n = 5); and hyperinsulinemic pregnant rats treated with l-arginine 2 gL in drinking water (n = 5). By the end of pregnancy blood pressure was 78 +/- 12 mm Hg in controls, 119 +/- 15 mm Hg in hyperinsulinemic rats, and 77 +/- 8 mm Hg in l-arginine-treated hyperinsulinemic rats, p < 0.007. Serum creatinine was 0.4 mg/dl in controls, 0.6 mg/dl in hyperinsulinemic rats, and 0.5 mg/dl in l-arginine-treated rats, p < 0.05. Corresponding urinary excretion of nitric oxide metabolites was 2.1 +/- 0.5, 1.2 +/- 0.2, and 1.5 +/- 0.2 micromols/mg creatinine, p < 0.01. Expression of endothelial nitric oxide synthase protein in kidneys by Western blot was not different between controls and hyperinsulinemic rats, 5.6 +/- 2.4 and 5.8 +/- 3.4 OD x mm2, but was nearly doubled in l-arginine-treated rats, 10.8 +/- 2.3, p < 0.03. Thus, the salutary effect of l-arginine on hyperinsulinemic pregnancy-induced hypertension (PIH) may be mediated, in part, by endothelial nitric oxide synthase in their kidneys.
Amino Acids, Essential↗
Role of insulin and the IGF system in renal hypertrophy in diabetic Psammomys obesus (sand rat).
BACKGROUND: Diabetic nephropathy is caused by multiple factors related to the altered metabolic environment in diabetes mellitus (DM). Experimental diabetic kidney disease is characterized by renal hypertrophy associated with increased tissue concentrations of insulin-like growth factor I (IGF-I). To assess the specific roles of serum insulin and glucose in mediating the development of diabetic nephropathy, the effects of both hyperinsulinaemic and hypoinsulinaemic DM were studied in Psammomys obesus (sand rat), a model of type 2 DM. METHODS: The IGF-I system was studied in normal Psammomys obesus gerbils and at 5, 15 and 70 days after the induction of either hyper- or hypoinsulinaemic DM. To induce hyperinsulinaemic DM, Psammomys were raised on a high-energy diet. Hypoinsulinaemic DM was induced by either administration of streptozotocin or a specially designed diet. RESULTS: Hyperinsulinaemic hyperglycaemic Psammomys did not exhibit renal hypertrophy (unchanged kidney/body-weight ratio) and renal IGF-I levels were in the normal range on days 5, 15 and 70. In contrast, Psammomys with hypoinsulinaemic hyperglycaemia induced either by streptozotocin injection or by pancreas exhaustion brought on by a long-term caloric excess diet, had significant increases in kidney/body-weight ratio which were associated with elevated renal IGF-I and mRNA and protein levels of kidney IGF binding protein I. CONCLUSIONS: This study shows that serum insulin levels in the presence of hyperglycaemia have an important role in the development of experimental diabetic nephropathy in the Psammomys model. The implication of this finding is that the pathophysiological mechanisms for diabetic kidney disease in experimental models may be different for type 1 and type 2 DM.
Animals↗
The emerging role of VEGF in diabetic kidney disease.
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Animals↗
Association of hyperglycemia and insulin with diabetic cardiovascular complications.
Patients with diabetes and/or insulin resistance syndrome are at increased risk for developing cardiovascular disease. The UKPDS raised a great debate about the relative importance of hyperglycemia in the development of cardiovascular disease. Recently, several epidemiologic studies have suggested that high postprandial blood glucose levels are associated with a significant risk for the development of cardiovascular disease well as a grave prognosis for these patients during acute coronary events. In addition, a number of reports reinforce the thesis that postprandial hyperglycemia is a risk factor for mortality. Our review summarizes the current knowledge on the relation between blood glucose, insulin levels, and cardiovascular morbidity and mortality, relating these data to the new World Health Organization and American Diabetes Association classification of disturbed glucose metabolism.
Blood Glucose↗
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↗
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↗
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↗
Diabetes epidemic and the thrifty gene.
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Diabetes Mellitus↗
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↗