Abbas E. Kitabchi

Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: Four-year results of the look AHEAD trial

BACKGROUND Lifestyle interventions produce short-term improvements in glycemia and cardiovascular disease (CVD) risk factors in individuals with type 2 diabetes mellitus, but no long-term data are available. We examined the effects of lifestyle intervention on changes in weight, fitness, and CVD risk factors during a 4-year study. METHODS The Look AHEAD (Action for Health in Diabetes) trial is a multicenter randomized clinical trial comparing the effects of an intensive lifestyle intervention (ILI) and diabetes support and education (DSE; the control group) on the incidence of major CVD events in 5145 overweight or obese individuals (59.5% female; mean age, 58.7 years) with type 2 diabetes mellitus. More than 93% of participants provided outcomes data at each annual assessment. RESULTS Averaged across 4 years, ILI participants had a greater percentage of weight loss than DSE participants (-6.15% vs -0.88%; P < .001) and greater improvements in treadmill fitness (12.74% vs 1.96%; P < .001), hemoglobin A(1c) level (-0.36% vs -0.09%; P < .001), systolic (-5.33 vs -2.97 mm Hg; P < .001) and diastolic (-2.92 vs -2.48 mm Hg; P = .01) blood pressure, and levels of high-density lipoprotein cholesterol (3.67 vs 1.97 mg/dL; P < .001) and triglycerides (-25.56 vs -19.75 mg/dL; P < .001). Reductions in low-density lipoprotein cholesterol levels were greater in DSE than ILI participants (-11.27 vs -12.84 mg/dL; P = .009) owing to greater use of medications to lower lipid levels in the DSE group. At 4 years, ILI participants maintained greater improvements than DSE participants in weight, fitness, hemoglobin A(1c) levels, systolic blood pressure, and high-density lipoprotein cholesterol levels. CONCLUSIONS Intensive lifestyle intervention can produce sustained weight loss and improvements in fitness, glycemic control, and CVD risk factors in individuals with type 2 diabetes. Whether these differences in risk factors translate to reduction in CVD events will ultimately be addressed by the Look AHEAD trial. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00017953.

Dipivalyl Epinephrine: A New Pro-Drug in the Treatment of Glaucoma

The dansyl chloride technique in conjunction with thin layer chromatography and autoradiography has shown that dipivalyl epinephrine is a pro-drug in the human eye. Dipivalyl epinephrine appears to be a more effective epinephrine compound, in that it penetrates the cornea approximately 17 times greater than epinephrine.

Actos Now for the prevention of diabetes (ACT NOW) study

BackgroundImpaired glucose tolerance (IGT) is a prediabetic state. If IGT can be prevented from progressing to overt diabetes, hyperglycemia-related complications can be avoided. The purpose of the present study was to examine whether pioglitazone (ACTOS®) can prevent progression of IGT to type 2 diabetes mellitus (T2DM) in a prospective randomized, double blind, placebo controlled trial.Methods/Design602 IGT subjects were identified with OGTT (2-hour plasma glucose = 140–199 mg/dl). In addition, IGT subjects were required to have FPG = 95–125 mg/dl and at least one other high risk characteristic. Prior to randomization all subjects had measurement of ankle-arm blood pressure, systolic/diastolic blood pressure, HbA1C, lipid profile and a subset had frequently sampled intravenous glucose tolerance test (FSIVGTT), DEXA, and ultrasound determination of carotid intima-media thickness (IMT). Following this, subjects were randomized to receive pioglitazone (45 mg/day) or placebo, and returned every 2–3 months for FPG determination and annually for OGTT. Repeat carotid IMT measurement was performed at 18 months and study end. Recruitment took place over 24 months, and subjects were followed for an additional 24 months. At study end (48 months) or at time of diagnosis of diabetes the OGTT, FSIVGTT, DEXA, carotid IMT, and all other measurements were repeated.Primary endpoint is conversion of IGT to T2DM based upon FPG ≥ 126 or 2-hour PG ≥ 200 mg/dl. Secondary endpoints include whether pioglitazone can: (i) improve glycemic control (ii) enhance insulin sensitivity, (iii) augment beta cell function, (iv) improve risk factors for cardiovascular disease, (v) cause regression/slow progression of carotid IMT, (vi) revert newly diagnosed diabetes to normal glucose tolerance.ConclusionACT NOW is designed to determine if pioglitazone can prevent/delay progression to diabetes in high risk IGT subjects, and to define the mechanisms (improved insulin sensitivity and/or enhanced beta cell function) via which pioglitazone exerts its beneficial effect on glucose metabolism to prevent/delay onset of T2DM.Trial Registrationclinical trials.gov identifier: NCT00220961

Patterns of weight change associated with long-term weight change and cardiovascular disease risk factors in the Look AHEAD Study.

This article provides an assessment of the associations that weight‐loss patterns during the first year of an intensive lifestyle intervention have with 4‐year maintenance and health outcomes. Two components described patterns of weight change during the first year of intervention: one reflected the typical pattern of weight loss over the 12 months, but distinguished those who lost larger amounts across the monthly intervals from those who lost less. The second component reflected the weight change trajectory, and distinguished a pattern of initial weight loss followed by regain vs. a more sustained pattern of weight loss. Two thousand four hundred and thirty eight individuals aged 45–76 years with type 2 diabetes mellitus, who enrolled in the weight‐loss intervention of a randomized clinical trial, were assigned scores according to how their weight losses reflected these patterns. Relationships these scores had with weight losses and health outcomes (glycosolated hemoglobin—hemoglobin A1c (HbA1c); systolic blood pressure, high‐density lipoprotein (HDL)‐cholesterol, and triglycerides) over 4 years were described. When compared to those with lower scores on the two components, both individuals who had larger month‐to‐month weight losses in year 1 and whose weight loss was more sustained during the first year had better maintenance of weight loss over 4 years, independent of characteristics traditionally linked to weight loss success (P < 0.001). While relationships with year 4 weight loss were stronger, the pattern of larger monthly weight loss during year 1 was also independently predictive of year 4 levels of HbA1c, HDL‐cholesterol, and systolic blood pressure.

Specific binding sites for d-α-tocopherol on human erythrocytes

Abstract Since vitamin E deficiency is associated with increased susceptibility of erythrocytes to hemolysis, we investigated the presence of tocopherol binding sites in human red blood cells. Erythrocytes were found to have specific binding sites for d -α-[ 3 H]tocopherol with properties of receptors. Kinetic studies of binding demonstrated two binding sites: one with high affinity (equilibrium association constant K a = 2.6·10 7 M −1 ), low capacity (7600 sites/cell) and the second with low affinity ( K a = 1.24·10 6 M −1 ), high capacity (150000 sites/cell). These sites are at least partly protein in nature.

Proteolytic degradation of insulin and glucagon

The degradation of insulin and glucagon by a highly purified enzyme isolated from rat skeletal muscle was investigated. A sensitive assay for proteolytic degradation of insulin and glucagon using fluorescamine to detect an increase in primary amine groups was established. As measured by an increase in fluorescamine reactive materials, insulin was rapidly degraded by this highly purified enzyme without requiring initial disulfide cleavage. Associated with the increase in fluorescamine reactive materials was a decrease in immunoassayable insulinmglucagon wal also proteolytically degraded by this enzyme but a number of other peptides and proteins including proinsulin, and A and B chains of insulin were not degraded. Thus, we have demonstrated that insulin (and glucagon) can be proteolytically degraded by an enzyme isolated from an insulin sensitive tissue, skeletal muscle. Proteolytic degradation by this enzyme requires the intact insulin molecule rather than separate A and B chains.

Steroidogenesis in isolated adrenal cells of rat: II. Effect of caffeine on ACTH and cyclic nucleotide-induced steroidogenesis and its relation to cyclic nucleotide phosphodiesterase (PDE)

Abstract Corticosterone production in isolated adrenal cells (IAC) of rat has been measured in response to ACTH or ribonucleoside 3′,5′-cyclic phosphate of adenosine (c-AMP), guanosine (c-GMP), inosine (c-IMP) and N 6 -2′-0 dibutyryl adenosine monophosphate (dc-AMP) in the presence and absence of caffeine. Caffeine inhibited ACTH-induced steroidogenesis in a manner independent of its effect on PDE. Study of PDE in whole adrenal homogenate showed hydrolysis of c-AMP, c-GMP and c-IMP but not of dc-AMP and other cyclic nucleotides. No PDE activity was demonstrable in IAC. High sensitivity of IAC to minute quantities of ACTH and various cyclic nucleotides may be due in part to lack of PDE activity in these preparations.

Decreased Insulin Binding of Human Erythrocytes After Dexamethasone or Prednisone Ingestion

We have investigated changes in insulin binding in erythrocytes in response to overnight ingestion of 1 mg dexamethasone or 10 mg of prednisone in two groups of eight lean, healthy subjects. Dexamethasone administration reduced insulin binding from 9.6 to 6.8% (P <0.001) with concomitant increase in basal plasma insulin from 10.5 to 14.1 μU/ml (P <0.05). Prednisone ingestion reduced insulin binding from 9.9 to 7.9% (P <0.01), but the increase in basal insulin from 16.9 to 20.6 μU/ml was not significantly different. The decrease in insulin binding with both dexamethasone and prednisone was associated with decreased affinity of erythrocyte for insulin at low occupancy and the increase in the dose of unlabeled insulin resulted in 50% inhibition of specific binding without changes in the number of receptors. The earliest decrease in insulin binding was noted within 2 h after ingestion of 1 mg of dexamethasone. These data suggest that acute alteration of insulin receptor function could occur in erythrocytes by small amounts of dexamethasone or prednisone through a mechanism consistent with a decrease in receptor affinity rather than a decrease in the number of receptors.

Dual role of calcium in steroidogenesis in the isolated adrenal cell of rat

Summary Corticosterone synthesis in isolated rat adrenal cells in response to ACTH and dibutyryl cyclic-AMP (dcAMP) and formation of cyclic-AMP (cAMP) from prelabeled 8- 14 C-adenine have been studied in the presence of varying Ca ++ concentrations. At physiologic concentrations of ACTH steroidogenesis is proportional to Ca ++ . In the absence of Ca ++ , 10 4 higher concentrations of ACTH is necessary. cAMP formation is detectable only at supraphysiologic concentrations of ACTH. Maximum corticosterone formation in response to dcAMP is dependent upon Ca ++ concentration. Action of Ca ++ may be both prior to and following elaboration of the second messenger; other compounds besides cAMP may be the mediators of ACTH action at physiologic concentrations.

A simplified fluorometric method for determination of blood cortisol using phase-separating filter paper

Abstract The fluorometric method of Silber et al. for determination of plasma cortisol has been modified by the use of phase-separating filter paper. This effects a faster and more efficient method for this assay. Greater than 97% recovery of added cortisol was obtained in measurements on plasma. Repeated freezing and thawing of blood samples did not significantly change measurable cortisol levels. This method agrees favorably with other, more complicated, fluorometric methods as well as the classical colorimetric method of Porter-Silber. It appears to be suitable for the determination of blood cortisol in clinical studies and in studies in which accurate and rapid determination of cortisol levels in large numbers of samples is desirable.