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Biomedical subjects

Itamar Raz

Publications and source records attributed to Itamar Raz.

At least 19 recordsLinked to original sources
PubMed2007

Metabolic and genomic dissection of diabetes in the Cohen rat.

We investigated the metabolic and genetic basis of diabetes in the Cohen Diabetic rat, a model of diet-induced diabetes, as a means to identify the molecular mechanisms involved. By altering individual components in the diabetogenic diet, we established that the dietary susceptibility that leads to the development of diabetes in this model is directly related to the high casein and low copper content in chow. The development of diabetes is accompanied by depletion of the acini from the exocrine pancreas and replacement with fat cells, while the appearance of the islets of Langerhans remains intact. With reversion back from diabetogenic to regular diet, the diabetic phenotype disappears but the histological changes in the exocrine pancreas prevail. Using positional cloning, we detected a major quantitative trait locus (QTL) on rat chromosome 4 with a chromosomal span of 4.9 cM, and two additional loci on chromosomes 7 and X. A screen for genes within that QTL in the rat and in the syntenic regions in mouse and man revealed only 23 candidate genes. Notable among these genes is Ica1, which has been causally associated with diabetes and bovine casein. We conclude that the development of diabetes in our model is dependent upon high casein and low copper in diet, that it is accompanied by histomorphological changes in the exocrine but not endocrine pancreas, that it is reversible, and that it is associated with a major QTL on chromosome 4 in which we detected Ica1, a high priority candidate gene.

Analysis of Variance↗
PubMed2006

Possible association between diabetes and bisphosphonate-related jaw osteonecrosis.

CONTEXT: Bisphosphonate-related osteonecrosis (BON) of the jaws is a newly identified condition for which the exact mechanism involved in its pathogenesis remains obscure. OBJECTIVE: The objective of the study was to evaluate whether diabetes mellitus (DM) may be a contributing factor in the development of BON. DESIGN: From 2004 to 2006, 31 patients were diagnosed with BON. The diagnosis of BON was based on the medical and dental history of each patient as well as the observation of clinical signs and symptoms of this pathological process. DM was based on two consecutive fasting blood glucose levels above 7 mmol/liter. SETTING: The study was completed in the Hebrew University-Hadassah Hospital referral center. RESULTS: Of the 31 patients with BON, 18 (58%) were found to have DM or impaired fasting glucose. The proportion of diabetic patients was much higher than expected relative to the incidence of DM in the general population (14%) and compared with the proportion of diabetic patients in a control group of oncological patients treated with bisphosphonates and without BON (12%) (P = 0.00003). CONCLUSIONS: This finding indicates that DM may be a risk factor for BON and that DM patients treated with bisphosphonates should be carefully monitored. We discuss here the bone metabolic pathways characteristic of DM patients and the way in which these pathways can augment the effects of bisphosphonates.

Aged↗
PubMed2006

Noninjectable methods of insulin administration.

Optimal glycemic control is essential for the prevention of diabetes-related complications, and the intensive insulin regimens that best resemble physiological insulin secretion are most likely to attain it. However, there are many limitations that preclude the early use of insulin by patients with type 2 diabetes or wider implementation of the intensive regimens in type 1 diabetes. More acceptable alternative routes of insulin administration and effective, noninvasive, patient-friendly delivery systems that alleviate the burden of insulin injections have been researched over the years. To date, only pulmonary inhalation of insulin has become a feasible alternative; it has proved to be as effective and well tolerated as the subcutaneously injected regular insulin and it has a pharmacodynamic profile well suited for mealtime insulin therapy. Several pulmonary insulin delivery systems are in different stages of development, and one (Exubera, Nektar Therapeutics/Pfizer Inc.-Sanofi-Aventis Group) has already become clinically available in the United States and Europe for patients with diabetes. Other noninjectable methods of insulin administration are reviewed.

Administration, Inhalation↗
PubMed2006

DiaPep277 preserves endogenous insulin production by immunomodulation in type 1 diabetes.

DiaPep277 is an immunomodulatory peptide that arrests beta cell destruction in mouse models of type 1 diabetes mellitus (T1DM). This article extends an original pilot observation to two studies of 61 patients (age > 16 years), diagnosed with T1DM within 6 months, and with measurable beta cell function. Patients were treated with placebo (n = 27) or 1.0 mg DiaPep277 (n = 34). After 13 months, 1.0 mg Dia Pep277 treatment significantly (P = 0.02) preserved beta cell function as compared to the control with a trend for reduced HbA1c. This was achieved without an increase in insulin dose in the DiaPep277 group and with excellent safety. DiaPep277-treated patients also had fewer Th1 DiaPep277-specific T cells.

Amino Acid Sequence↗
PubMed2006

Noninjectable methods of insulin administration.

Optimal glycemic control is essential for the prevention of diabetes-related complications, and the intensive insulin regimens that best resemble physiological insulin secretion are most likely to attain it. However, there are many limitations that preclude the early use of insulin by patients with type 2 diabetes or wider implementation of the intensive regimens in type 1 diabetes. More acceptable alternative routes of insulin administration and effective, noninvasive, patient-friendly delivery systems that alleviate the burden of insulin injections have been researched over the years. To date, only pulmonary inhalation of insulin has become a feasible alternative; it has proved to be as effective and well tolerated as the subcutaneously injected regular insulin and it has a pharmacodynamic profile well suited for mealtime insulin therapy. Several pulmonary insulin delivery systems are in different stages of development, and one (Exubera, Nektar Therapeutics/Pfizer Inc.-Sanofi-Aventis Group) has already become clinically available in the United States and Europe for patients with diabetes. Other noninjectable methods of insulin administration are reviewed.

Diabetes Mellitus↗
PubMed2006

Adiponectin and the development of diabetes in patients with coronary artery disease and impaired fasting glucose.

OBJECTIVES: Adiponectin has insulin-sensitizing properties, and high adiponectin levels have been shown to be associated with reduced risk of developing diabetes. Patients with coronary artery disease (CAD) have relatively low adiponectin levels and high prevalence of glucose intolerance. The role of adiponectin in predicting the development of diabetes in this high-risk group has not been determined. The study aimed to determine whether baseline adiponectin levels predict the development of diabetes in a group of patients with CAD and impaired fasting glucose (IFG). METHODS: A total of 588 patients who participated in the Bezafibrate Infarction Prevention (BIP) study and who had at baseline fasting glucose of 100-125 mg/dl were included and followed for 6.2+/-1.3 years. Adiponectin was determined in frozen plasma samples taken at baseline. RESULTS: Of the patients with IFG at baseline, 256 (44%) developed diabetes during follow-up. The patients who developed diabetes had at baseline higher body-mass index, fasting glucose, C-reactive protein, triglycerides, homeostatic assessment of insulin resistance (HOMA-IR) and diastolic blood pressure than patients who did not develop diabetes. Adiponectin levels at baseline were significantly lower in patients who developed diabetes than in patients who did not develop diabetes (P = 0.009, nonparametric Kruskall-Wallis test). An increase of 1 unit of natural logarithm of adiponectin level was associated with a hazard ratio of 0.77 (95% CI, 0.61-0.96) for diabetes development. CONCLUSION: Patients with CAD and IFG have a very high rate of conversion to type 2 diabetes. Even in this high-risk group, high adiponectin levels are associated with reduced risk of developing diabetes.

Adiponectin↗
PubMed2006

Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial.

OBJECTIVE: The aim of this trial was to evaluate the effects of alpha-lipoic acid (ALA) on positive sensory symptoms and neuropathic deficits in diabetic patients with distal symmetric polyneuropathy (DSP). RESEARCH DESIGN AND METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, 181 diabetic patients in Russia and Israel received once-daily oral doses of 600 mg (n = 45) (ALA600), 1,200 mg (n = 47) (ALA1200), and 1,800 mg (ALA1800) of ALA (n = 46) or placebo (n = 43) for 5 weeks after a 1-week placebo run-in period. The primary outcome measure was the change from baseline of the Total Symptom Score (TSS), including stabbing pain, burning pain, paresthesia, and asleep numbness of the feet. Secondary end points included individual symptoms of TSS, Neuropathy Symptoms and Change (NSC) score, Neuropathy Impairment Score (NIS), and patients' global assessment of efficacy. RESULTS: Mean TSS did not differ significantly at baseline among the treatment groups and on average decreased by 4.9 points (51%) in ALA600, 4.5 (48%) in ALA1200, and 4.7 (52%) in ALA1800 compared with 2.9 points (32%) in the placebo group (all P < 0.05 vs. placebo). The corresponding response rates (>/=50% reduction in TSS) were 62, 50, 56, and 26%, respectively. Significant improvements favoring all three ALA groups were also noted for stabbing and burning pain, the NSC score, and the patients' global assessment of efficacy. The NIS was numerically reduced. Safety analysis showed a dose-dependent increase in nausea, vomiting, and vertigo. CONCLUSIONS: Oral treatment with ALA for 5 weeks improved neuropathic symptoms and deficits in patients with DSP. An oral dose of 600 mg once daily appears to provide the optimum risk-to-benefit ratio.

Administration, Oral↗
PubMed2006

[The guidelines for the diagnosis prevention and treatment of type 2 diabetes mellitus--2005].

The incidence and prevalence of diabetes have reached epidemic proportions worldwide. The reasons for the pandemic are the sharp rise in obesity, decline in physical activity and the increase in life expectancy. There are some 400,000 people with diagnosed diabetes in Israel and they are at a markedly increased risk for cardiovascular disease, blindness, end-stage renal disease and lower limb amputation. To effectively lower this significantly increased burden of disease, a comprehensive multidisciplinary approach to chronic disease management is required. To facilitate such an approach, the Israel Diabetes Association published a guideline for the diagnosis, prevention and treatment of diabetes. The guideline, based on the ADA (American Diabetes Association) and IDF (International Diabetes Federation) guidelines, was approved by other national professional societies including hypertension, family practice, obesity, nephrology, atherosclerosis and internal medicine. The guidelines highlight the metabolic syndrome and prediabetic states, interventions for the prevention of diabetes, the new definitions of diabetes and impaired glucose metabolism and the newly defined targets for glucose, lipid, cholesterol and blood pressure control. In addition, the recommendations for periodic review and screening for complications are summarized. The need for patient education and empowerment are emphasized as is the need for the development and implementation of unique tools including computerized treatment flow-charts, prompts and quality measures, for the long term management of a complex metabolic disease.

Blood Glucose↗
PubMed2005

Role of renal nitric oxide synthase in diabetic kidney disease during the chronic phase of diabetes.

BACKGROUND: Several studies have suggested that an early increase in renal nitric oxide (NO) production or activity mediates pathophysiologic and morphologic changes in diabetic nephropathy. To evaluate the role of NO in developing diabetic kidney disease, we studied the NO system in streptozotocin (STZ)-induced diabetic rats for a period of 8 weeks. METHODS: Control rats, STZ-induced diabetic rats, and STZ-induced diabetic rats treated with insulin were monitored and sacrificed at 1, 2, and 8 weeks. Urinary cGMP was measured, and the levels and activity of NO synthase (NOS) isoforms in the kidney cortex were determined at specific times by immunoblotting and diaphorase staining. RESULTS: Diabetic rats had increased kidney weight, urinary volume, glucose, sodium and potassium excretion, which was precluded by insulin treatment. Creatinine clearance was increased in the diabetic group and reversed by insulin treatment. Urinary cGMP decreased by 71, 93, and 92% at 1, 2, and 8 weeks of diabetes, respectively, compared with the control animals. Insulin treatment curtailed the urinary cGMP reduction in diabetic animals. Total NOS activity in the renal cortex was reduced by 65, 52, and 44% after 1, 2, and 8 weeks of diabetes, respectively, and returned to normal levels upon insulin treatment. NADPH diaphorase staining of renal cortical slices showed a 77, 63, and 70% decrease in neuronal NOS isoform activity in the macula densa after 1, 2, and 8 weeks of diabetes, respectively, compared with control non-diabetic animals. This reduction was normalized by insulin treatment. Endothelial NOS protein expression in the kidney cortex tended to increase after 1 week of diabetes and its level was elevated significantly after 2 and 8 weeks of diabetes. However, neuronal NOS protein expression in the kidney cortex was reduced by 52% in 2-week diabetic animals, but this reduction was normalized by insulin treatment. CONCLUSIONS: The decreased renal NOS activity during the late phase of diabetes is partially associated with a decrease in neuronal NOS activity and protein expression in kidney macula densa.

Animals↗
PubMed2005

Impact of achieved blood pressure on cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial.

Elevated arterial pressure enhances the risk for cardiovascular (CV) events in patients with diabetic nephropathy. The optimal BP and the component of the elevated BP that affect the risk have not been defined. A post hoc analysis was performed to assess the impact of achieved systolic, diastolic, and pulse pressures on CV outcomes in 1590 adults who had overt diabetic nephropathy and were enrolled in the Irbesartan Diabetic Nephropathy Trial (IDNT) and had a baseline serum creatinine above the normal range, up to 266 micromol/L (3.0 mg/dL), 24-h urine protein >900 mg/d, and at least 6 mo of follow-up. Patients were randomized to irbesartan, amlodipine, or placebo, with other antihypertensive agents to a BP goal of < or =135/85 mmHg. Progressively lower achieved systolic BP (SBP) to 120 mmHg predicted a decrease in CV mortality and congestive heart failure (CHF) but not myocardial infarctions (MI). A SBP below this threshold was associated with increased risk for CV deaths and CHF events. Achieved diastolic BP <85 mmHg was associated with a trend to increase in all-cause mortality, significant increase in MI, but decreased risk for strokes. Increased pulse pressure predicted increased all-cause mortality, CV mortality, MI, and CHF. It is concluded that achieved SBP approaching 120 mmHg and diastolic BP of 85 mmHg are associated with the best protection against CV events in these patients. BP < or =120/85 may be associated with an increase in CV events.

Antihypertensive Agents↗
PubMed2005

Early use of insulin in type 2 diabetes.

Type 2 diabetes is a disease characterised by peripheral insulin resistance, as well as by pancreatic beta cell dysfunction. This process is in part due to elevated blood glucose and free fatty acids--termed glucolipotoxicity. The traditional pathway of treating type 2 diabetes in a stepwise manner, beginning with life style modifications and continuing with oral hypoglycaemic agents leads to a protracted period of unnecessary hyperglycaemia. A new approach, targeted at alleviating the deleterious effects of hyperglycaemia and elevated free fatty acids by acutely lowering both with intensive insulin therapy, has yielded prolonged remissions in therapy in which only diet was necessary to maintain normoglycaemia. This new approach, its rationale, benefits and misgivings are discussed in this review.

Diabetes Mellitus, Type 2↗
PubMed2005

Efficacy and safety of biphasic insulin aspart 30 combined with pioglitazone in type 2 diabetes poorly controlled on glibenclamide (glyburide) monotherapy or combination therapy: an 18-week, randomized, open-label study.

BACKGROUND: Few large randomized controlled trials have assessed the value of adding insulin to an oral antidiabetic drug regimen. OBJECTIVE: This trial compared the efficacy and safety of biphasic insulin aspart 30/70 (BIAsp 30) plus pioglitazone (n = 93), glibenclamide (glyburide) plus pioglitazone (n = 91), or BIAsp 30 monotherapy (n = 97). METHODS: This 18-week, multinational, multicenter, randomized, open-label, parallel-group trial involved 281 patients with type 2 diabetes (60% male; mean age, 56 years; mean body mass index, 29.5 kg/m2) with inadequate glycemic control (mean glycosylated hemoglobin [HbA(1c)], 9.5%; range, 7.4%-14.7%) on glibenclamide monotherapy or combination therapy. The primary objective was to compare end-of-trial HbA(1c) among the 3 treatment groups. Fasting and mean 7- and 8-point blood glucose profiles, blood lipid levels, plasminogen activator inhibitor levels, adverse events, and hypoglycemia frequency were also compared. Patients using BIAsp 30 (alone or with pioglitazone) were injected twice daily (immediately before breakfast and dinner). Pioglitazone (30 mg/d) and glibenclamide (5-15 mg/d) were taken orally once daily with or immediately after breakfast. RESULTS: At the end of the trial, HbA(1c) was significantly lower for the BIAsp 30 plus pioglitazone group than for the glibenclamide plus pioglitazone group (mean [SD], -0.64% [0.23%]; P = 0.005) and the BIAsp 30 monotherapy group (-0.60% [0.22%]; P = 0.008). Mean (SD) fasting blood glucose (before breakfast) was significantly lower for BIAsp 30 plus pioglitazone than for glibenclamide plus pioglitazone (153 [45] mg/dL vs 169 [65] mg/dL, respectively; P = 0.012). Each time point on the 8-point blood glucose profile was lower for BIAsp 30 plus pioglitazone than for glibenclamide plus pioglitazone (P < 0.001 to P < 0.05). No major hypoglycemic episodes were reported, and the absolute rate of hypoglycemic events was low (<1 event/patient-week) in the BIAsp-only group. Edema was reported in < or =9% of patients in each treatment group, but no occurrence was classified as serious. Weight gain (mean, 4.0 kg) was more common in the BIAsp plus pioglitazone group (8%); however, this was consistent with improved glycemic control and is similar to that reported in other pioglitazone trials. CONCLUSIONS: BIAsp 30 plus pioglitazone provided an efficacious and well-tolerated treatment alternative to glibenclamide plus pioglitazone or BIAsp 30 alone in this population of patients who previously were not well controlled on glibenclamide monotherapy or combination therapy.

Blood Glucose↗
PubMed2005

Dose-response relationship of an oral insulin spray in six patients with type 1 diabetes: a single-center, randomized, single-blind, 5-way crossover study.

OBJECTIVE: This study evaluated the pharmacokinetic and pharmacodynamic properties and dose-response effects of an oral insulin spray formulation compared with those of subcutaneously injected regular insulin and placebo in patients with type 1 diabetes mellitus. METHODS: This was a single-center, randomized, single-blind, open-label, 5-way crossover study in which patients with type 1 diabetes received 5, 10, and 20 puffs of the oral insulin spray; regular insulin 0.1 U/kg SC; and placebo spray. The pharmacokinetic parameters of interest were the maximum serum insulin concentration (Ins-C(max)); the incremental insulin AUC from 0 to 120 minutes (Ins-AUC(0-120)), from 0 to 240 minutes, and from 0 to 360 minutes; and the time to maximum serum insulin concentration (Ins-T(max)). The pharmacodynamic parameters of interest were the maximum glucose infusion rate (GIR(max)); the incremental glucose AUC from 0 to 120 minutes (GIR-AUC(0-120)), from 0 to 240 minutes, and from 0 to 360 minutes; the time to maximum GIR (GIR-T(max)); the time to early half-maximal GIR (early T50%); and the time to late half-maximal GIR (late T50%). Pharmacokinetic and pharmacodynamic parameters were assessed using the euglycemic clamp technique. RESULTS: The study enrolled 6 white men with type 1 diabetes (mean [SD] age, 37.5 [16.2] years, mean weight, 82.7 [17.0] kg). Ins-T(max) was shorter for 5, 10, and 20 puffs of oral insulin spray than for SC insulin (26.7 [13.7], 29.2 [7.4], 23.3 [5.2], and 142.5 [73.2] min, respectively; P < 0.05). There was no effect of dose on Ins-T(max). The Ins-AUC(0-120) for 5, 10, and 20 puffs of oral insulin spray (304.8 [277.9], 689.2 [353.0], and 1808.8 [1252.6] microU/mL per min, respectively; P < 0.05) and the corresponding Ins-Ca(max) (12.9 [8.7], 26.7 [14.5], and 47.6 [40.1] microU/mL; P < 0.05) suggested a dose-response relationship. Five, 10, and 20 puffs of oral insulin spray had an earlier onset of action than SC insulin (early T50%: 23.3 [15.1], 28.3 [12.3], 31.2 [111.8], and 87.0 [39.6] min, respectively; P < 0.05), an earlier maximal effect (GIR-T(max): 40.0 [23.7], 45.8 [22.7], 44.2 [5.8], and 145.0 [43.7] min; P < 0.05), and a shorter duration of action (late T50%: 56.5 [31.0], 70.2 [12.9], 75.5 [6.0], and 290.8 [84.0] min; P < 0.05). Dose-dependent increases in maximal metabolic effect were observed with 5, 10, and 20 puffs: the GIR(max) was 0.9 (0.5), 2.0 (1.3), and 3.9 (2.5) mg/kg per minute, respectively (P < 0.05), and the GIR-AUC(0-120) was 39.6 (34.9), 76.8 (67.4), and 189.1 (163.0) mg/kg per minute (P < 0.05). CONCLUSIONS: In this study in patients with type 1 diabetes, oral insulin spray had a faster onset and shorter duration of action than subcutaneously injected regular insulin. A dose-response relationship was noted in the metabolic effect and absorption of oral insulin spray.

Administration, Oral↗
PubMed2005

Immune modulation for prevention of type 1 diabetes mellitus.

Prevention of type 1 diabetes mellitus requires early intervention in the autoimmune process directed against beta cells of the pancreatic islets of Langerhans. This autoimmune inflammatory process is thought to be caused by the effect of Th1 cells and their secreted cytokines (e.g. interferon) and to be suppressed by Th2-secreted anti-inflammatory cytokines (e.g. IL-4, IL-10). Various methods aimed specifically at halting or modulating this response have been attempted. An alternative method is the re-induction of tolerance towards the putative self antigen that causes the disease. Proposed antigens such as insulin, glutamic acid decarboxilase (GAD) and the heat shock protein 60 (Hsp60)-derived peptide 277 have been used successfully in murine diabetes models and in initial clinical trials in early diabetes patients. Here, we review the results of these trials.

Animals↗
PubMed2005

Nonproteinuric diabetes-associated nephropathy in the Cohen rat model of type 2 diabetes.

The Cohen diabetic rat is an experimental model reminiscent of human type 2 diabetes. The aim of this study was to characterize the development of end-organ damage in this model. Cohen diabetic sensitive (CDs) and Cohen diabetic resistant (CDr) rats were fed regular diet or a diabetogenic diet. Glucose tolerance, renal function, and renal and retinal histology were studied at set intervals. CDs fed diabetogenic diet were the only strain that expressed the diabetic metabolic phenotype. In this strain, urinary protein excretion did not increase with the development of diabetes, but plasma urea and creatinine levels increased and creatinine clearance decreased. Light microscopy revealed in CDs enlarged glomeruli with increased mesangial matrix and thickening of the glomerular capillary wall; electron microscopy demonstrated thickened basement membrane and mesangial abundance. There was increased staining for type IV collagen in glomeruli and interstitium of CDs. The retinas of diabetic CDs demonstrated pathology consistent with nonproliferative diabetic retinopathy. The histological findings in the kidneys, the absence of proteinuria, the impairment in glomerular filtration, and the development of retinopathy in CDs are consistent with diabetes-associated nephropathy that is similar to a nonalbuminuric type of nephropathy associated with type 2 diabetes in humans.

Animals↗