Itamar Raz

Pre‐clinical Cushing's syndrome: an unexpected frequent cause of poor glycaemic control in obese diabetic patients

OBJECTIVE Autonomous cortisol secretion without clinical stigmata of Cushings syndrome (CS) has been recently recognized and termed pre‐clinical or sub‐clinical CS. The common assumption is that CS is an extremely rare cause of uncontrolled diabetes; however, the prevalence of this entity has not been studied. We assessed the prevalence of pre‐clinical CS among obese patients with uncontrolled diabetes.

Predicting the 20-year diabetes incidence rate

The long‐range prediction from clinical variables of the onset of diabetes is important to patients and clinicians. Our objective was to evaluate the efficacy of various glucose‐related clinical measurements in predicting the 20‐year risk of developing type 2 diabetes (T2DM) in an elderly population.

Pharmacokinetics of valpromide after oral administration of a solution and a tablet to healthy volunteers

SummaryThe pharmacokinetics of valpromide, a primary amide of valproic acid, was investigated in 6 healthy, adult male volunteers, each of whom was given 900 mg as a marketed, enteric-coated tablet and a solution. Valpromide was biotransformed to valproic acid after the administration of the tablet and the solution with a bioavailability of 0.79±0.24 and 0.77±0.12, respectively, relative to a marketed tablet of valproic acid. The absorption of valpromide was not rate-limited by dissolution. As a solid, non-hygroscopic, neutral prodrug of valproic acid, valpromide may be a good alternative to valproic acid and sodium valproate.

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

Abstract:  DiaPep277 is an immunomodulatory peptide that arrests β 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 β 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 β 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.

Assessment of insulin resistance by a 13C glucose breath test: a new tool for early diagnosis and follow-up of high-risk patients.

Background/AimsInsulin resistance (IR) plays an important role in the pathogenesis of diabetes and non-alcoholic fatty liver disease (NAFLD). Current methods for insulin resistance detection are cumbersome, or not sensitive enough for early detection and follow-up. The BreathID® system can continuously analyse breath samples in real-time at the point-of-care. Here we determined the efficacy of the BreathID® using the 13C-Glucose breath test (GBT) for evaluation of insulin resistance.MethodsTwenty healthy volunteers were orally administered 75 mg of 13C-glucose 1-13C. An oral glucose tolerance test (OGTT) was performed immediately; followed by serum glucose and insulin level determinations using GBT. GBT and OGTT were repeated following exercise, which alters insulin resistance levels.ResultsWithin-subject correlations of GBT parameters with serum glucose and serum insulin levels were high. Before and after exercise, between-subjects correlations were high between the relative insulin levels and the % dose recoveries at 90 min (PDR 90), and the cumulative PDRs at 60 min (CPDR 60). Pairwise correlations were identified between pre-exercise Homeostasis Model Assessment (HOMA) IR at 90 min and PDR 90; HOMA B (for beta cell function) 120 and CPDR 30; HOMA IR 60 and peak time post-exercise; and HOMA B 150 with PDR 150.ConclusionsThe non-invasive real-time BreathID® GBT reliably assesses changes in liver glucose metabolism, and the degree of insulin resistance. It may serve as a non-invasive tool for early diagnosis and follow up of patients in high-risk groups.

A comparative pharmacokinetic study of valpromide and valproic acid after intravenous administration in humans

The pharmacokinetics of valpromide and valproic acid were investigated comparatively in 6 healthy subjects after intravenous administration of the two drugs. Valpromide was very rapidly and almost completely biotransformed to valproic acid (fm = 81.2 ± 10.5%; mean ± S.D.; n = 6). Relative to valproic acid valpromide has a very short half-life (0.84 ± 0.33 h) a high-clearance value (70 ± 30.5 l/h) and a large volume of distribution (Vβ = 75.3 ± 12.7 l). The results of this study showed that there was no significant difference between the biotransformation of valpromide to valproic acid after intravenous administration and that obtained after oral administration of valpromide. Therefore, in humans, valpromide appears to be a prodrug of valproic acid after intravenous as well as oral administration.

Characterization of the regulatory region of the human testis-specific form of the pyruvate dehydrogenase α-subunit (PDHA-2) gene

The alpha-subunit of human pyruvate dehydrogenase (E(1)) is encoded by two separate genes. The gene located on chromosome X (PDHA-1) is expressed in somatic tissues, whereas the second gene (PDHA-2), located on chromosome 4, is expressed only in post-meiotic spermatogenic cells. A genomic fragment harboring the human gene encoding PDHA-2 has been isolated and approximately 800 nucleotides of the promoter region have been characterized. Functional studies of the promoter indicate the presence of both enhancer and repressor elements that are common to other genes that are only expressed in mature sperm.

Basal state hyperinsulinemia in healthy normoglycemic adults heralds dysglycemia after more than two decades of follow up

In a preliminary report, we found an association between hyperinsulinemia in the basal (fasting) state and the development of diabetes.

Comparative pharmacokinetic evaluation of sustained-release theophylline formulations in dogs and humans

Abstract Several new sustained-release formulations of theophylline were developed and their sustained-release performance was evaluated in a comparative pharmacokinetic analysis. These new formulations, Theo-Dur, Theotrim and aminophylline were administered to 5 dogs and 6 healthy volunteers. Plasma levels of theophylline were determined by an HPLC assay. The absorption profiles of the various formulations were analyzed pharmacokinetically, using the Wagner-Nelson procedure. Two new formulations, Theotrim and Theo-Dur demonstrated very good sustained-release performance in humans and dogs. One formulation (T-2-A) showed incomplete absorption in both species, and its bioavailability relative to aminophylline was about 65% in humans and 78% in dogs. These results were also confirmed by the Wagner-Nelson Procedure. In this study the dog was found to be a good animal model as far as the rate and extent of absorption of the various tested theophylline formulations were concerned; the dog may be useful in primary screening of new formulations from this series.

Serum adiponectin is associated with homocysteine in elderly men and women, and with 5,10-methylenetetrahydrofolate reductase (MTHFR) in a sex-dependent manner.

Plasma homocysteine associates positively with cardiovascular disease. C-to-T substitution at base 677 of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene associates with increased plasma homocysteine. The association of adiponectin with cardiovascular disease is unclear. This study of survivors of a 30-year cohort of the Jewish Israeli population, 310 men and 273 women (mean age, 70.5 ± 7.0 years for both), investigated the relationship between adiponectin and homocysteine, and between adiponectin and the MTHFR C677T genotype. Serum adiponectin associated positively with total homocysteine in both men (r = 0.27, P < .001) and women (r = 0.22, P < .001). In women, the TT MTHFR genotype associated with lower median adiponectin levels, 8.98 mg/L, compared with 9.88 and 10.57 mg/L for TC and CC, respectively (P = .05; CC vs TT, P = .01). In men, the trend was opposite, but not statistically significant: 7.90, 7.03, and 6.88 mg/L for TT, TC, and CC genotypes, respectively (P = .5). This study demonstrated a positive association between homocysteine and adiponectin in both elderly men and women and a statistically significant association between adiponectin and MTHFR C677T genotypes in women only.