Angelo Avogaro

Effect of Metformin on Insulin-Stimulated Glucose Turnover and Insulin Binding to Receptors in Type II Diabetes

Euglycemic insulin glucose-clamp and insulin-binding studies on erythrocytes and monocytes were performed in seven type II (non-insulin-dependent) diabetic subjects before and after 4 wk of metformin treatment (850 mg 3 times/day) and in five obese subjects with normal glucose tolerance. Glucose turnover was also measured at basal insulin concentrations and during hyperinsulinemic euglycemic clamps. During euglycemic insulin-glucose clamps, diabetic subjects showed glucose disposal rates of 3.44 ± 0.42 and 7.34 ± 0.34 mg · kg−1 · min−1 (means ± SD) before metformin at insulin infusion rates of 0.80 and 15.37 mU · kg−1 · min−1, respectively. With the same insulin infusion rates, glucose disposal was 4.94 ± 0.55 (P < .01) and 8.99 ± 0.66 (P < .01), respectively, after metformin treatment. Glucose disposal rates in normal obese subjects were 5.76 ± 0.63 (P < .01) and 10.92 ± 1.11 (P < .01) at 0.80 and 15.37 mU · kg−1 · min−1, respectively. Insulin maximum binding to erythrocytes in diabetics was 9.6 ± 4.2 and 5.8 ± 2.6 × 109 cells (means ± SD) before and after metformin treatment, respectively (NS). Insulin maximum binding to monocytes in diabetics was 6.2 ± 2.3 × 107 cells before and 5.0 ± 1.6% after metformin. Hepatic glucose production was higher in the diabetic patients at basal insulin levels, but not at higher insulin concentrations, and was not significantly changed by drug treatment. Basal glucose and insulin concentrations decreased with metformin. Thus, metformin treatment improved glucose disposal rate without significant effect on insulin-binding capacity on circulating cells. Basal hepatic glucose output was slightly lower after metformin treatment in view of lower (9 vs. 15 μU/ml) insulin levels, potentially indicating increased sensitivity of the liver to insulin.

Intracellular lactate- and pyruvate-interconversion rates are increased in muscle tissue of non-insulin-dependent diabetic individuals.

The contribution of muscle tissues of non-insulin-dependent diabetes mellitus (NIDDM) patients to blood lactate appearance remains undefined. To gain insight on intracellular pyruvate/lactate metabolism, the postabsorptive forearm metabolism of glucose, lactate, FFA, and ketone bodies (KB) was assessed in seven obese non-insulin-dependent diabetic patients (BMI = 28.0 +/- 0.5 kg/m2) and seven control individuals (BMI = 24.8 +/- 0.5 kg/m2) by using arteriovenous balance across forearm tissues along with continuous infusion of [3-13C1]-lactate and indirect calorimetry. Fasting plasma concentrations of glucose (10.0 +/- 0.3 vs. 4.7 +/- 0.2 mmol/liter), insulin (68 +/- 5 vs. 43 +/- 6 pmol/liter), FFA (0.57 +/- 0.02 vs. 0.51 +/- 0.02 mmol/liter), and blood levels of lactate (1.05 +/- 0.04 vs. 0.60 +/- 0.06 mmol/liter), and KB (0.48 +/- 0.04 vs. 0.29 +/- 0.02 mmol/liter) were higher in NIDDM patients (P < 0.01). Forearm glucose uptake was similar in the two groups (10.3 +/- 1.4 vs. 9.6 +/ 1.1 micromol/min/liter of forearm tissue), while KB uptake was twice as much in NIDDM patients as compared to control subjects. Lactate balance was only slightly increased in NIDDM patients (5.6 +/- 1.4 vs. 3.3 +/- 1.0 micromol/min/liter; P = NS). A two-compartment model of lactate and pyruvate kinetics in the forearm tissue was used to dissect out the rates of lactate to pyruvate and pyruvate to lactate interconversions. In spite of minor differences in the lactate balance, a fourfold increase in both lactate- (44.8 +/- 9.0 vs. 12.6 +/- 4.6 micromol/min/liter) and pyruvate-(50.4 +/- 9.8 vs. 16.0 +/- 5.0 micromol/min/liter) interconversion rates (both P < 0.01) were found. Whole body lactate turnover, assessed by using the classic isotope dilution principle, was higher in NIDDM individuals (46 +/- 9 vs. 21 +/- 3 micromol/min/kg; P < 0.01). Insights into the physiological meaning of this parameter were obtained by using a whole body noncompartmental model of lactate/pyruvate kinetics which provides a lower and upper bound for total lactate and pyruvate turnover (NIDDM = 46 +/- 9 vs. 108 +/- 31; controls = 21 +/- 3 - 50 +/-13 micromol/min/kg). In conclusion, in the postabsorptive state, despite a trivial lactate release by muscle, lactate- and pyruvate-interconversion rates are greatly enhanced in NIDDM patients, possibly due to concomitant impairment in the oxidative pathway of glucose metabolism. This finding strongly suggest a major disturbance in intracellular lactate/pyruvate metabolism in NIDDM.

Ketone bodies increase glomerular filtration rate in normal man and in patients with Type 1 (insulin-dependent) diabetes mellitus

SummaryThe purpose of this study was to investigate whether the administration of acetoacetic and hydrochloric acids in a group of control and Type 1 (insulin-dependent) diabetic patients influenced renal haemodynamics. Renal plasma flow increased from 657±88 to 762±81 ml·min−1. 1.73 m−2 in diabetic patients (p<0.01) and from 590±71 to 691±135 in control subjects (p<0.01). Glomerular filtration rate increased from 135±9 to 180±8 ml·min−1·1.73 m−2 in diabetic patients (p< 0.001) and from 117±8 to 145±7 in control subjects (p<0.01). Similar effects on renal haemodynamics, even if less pronounced, were observed with low dose acetoacetic but not with hydrochloric acid infusion. Total protein, β2-microglobulin but not albumin excretion rates were increased by acetoacetic acid. We conclude that an acute increase in blood concentration of ketone bodies within the range found in diabetic patients with poor metabolic control (1) increases renal plasma flow and glomerular filtration rate both in control subjects and diabetic patients and (2) causes a tubular proteinuria.

Ketone body metabolism in NIDDM. Effect of sulfonylurea treatment.

We assessed the metabolism of the two KBs, AcAc and 3-BOH; the relationships between ketogenesis and FFA inflow rate; and the effect of chronic sulfonylurea treatment in mild NIDDM patients (plasma glucose < 10 mM). We studied 10 nonobese NIDDM patients in a crossover, randomized, double-blind, placebo-controlled fashion. Each patient was studied 4 times: after a run-in period with placebo, after 3 mo of placebo treatment, after 3 mo of glibenclamide treatments, respectively, and after 3 mo of sulfonylurea treatment during an acute exogenous Intralipid infusion. Ten normal, nondiabetic subjects served as the control group. Glibenclamide treatment decreased plasma FFAs. When these substrates were exogenously increased, plasma FFAs were comparable with placebo and baseline concentrations. In NIDDM patients, baseline and placebo blood total KB concentration was significantly higher than in control subjects (216 ± 22 and 244 ± 25, respectively vs. 127 ± 18 μM; P < 0.01). Glibenclamide treatment significantly decreased total KBs to 177 ± 19 μM (P < 0.05). When FFAs were exogenously increased, total KBs were similar to the placebo and baseline period. In the baseline study, the AcAc/3-BOH ratio was 0.72 ± 0.06 in control subjects, whereas in NIDDM patients, the ratio was 1.61 ± 0.13 at baseline (P < 0.001 vs. control subjects), 1.66 ± 0.15 during placebo, 1.57 ± 0.09 during glibenclamide (NS vs. baseline), and 1.51 ± 0.23 during glibenclamide plus placebo FFAs. Both the AcAc interconversion rate to 3-BOH and the 3-BOH interconversion rate to AcAc were significantly lower in NIDDM patients than in control subjects. In conclusion, in NIDDM patients the major portion of overall ketogenesis must be ascribed to AcAc production. 3-BOH production is decreased because of an impaired interconversion between the two ketones. A direct effect of glibenclamide on ketogenesis in vivo is disputable because blood KB concentrations increase to a similar extent for a given plasma FFA concentration in the presence or absence of this drug.

Reduction of Hyper- and Hypoglycemia during Two Months with a Wearable Artifi cial Pancreas from Dinner to Breakfast in Patients with Type 1 Diabetes

929-P Patient Responses to Interim Data from Cardiovascular Outcomes Trials: Results from an Online Patient Survey MANU V. VENKAT, RICHARD S. WOOD, ADAM S. BROWN, PHIN YOUNGE, LISA S. ROTENSTEIN, KELLY L. CLOSE, San Francisco, CA, Boston, MA The disclosure of interim data from ongoing clinical trials is usually discouraged, as it can alter participant behavior and threaten trial integrity. Current U.S. regulatory guidance requires long-term cardiovascular outcomes trials (CVOTs) for new T2DM drugs, but allows interim data to be disclosed to support approval. The purpose of this study was to examine how such disclosure could influence enrollment dynamics in a CVOT. An online survey from the diabetes market research company dQ&A was distributed to a panel of adult T2DM patients. Of the 1,984 total respondents with T2DM, 1,542 reported a history of CVD and/or being told by their healthcare provider that they are at elevated CVD risk. This represents a patient subgroup that is targeted for enrollment in most diabetes CVOTs. In the survey, respondents were described a hypothetical CVOT. Next, they were randomized to receive scenarios in which evidence of either an increase or decrease in CVD incidence was disclosed during the trial. In both scenarios, the drug was approved. All participants selected one of four choices regarding their subsequent actions (see table below).

Glucose and ketone body turnover in carnitine-palmitoyl-transferase deficiency

Most of the patients with carnitine-palmitoyl-transferase deficiency (CPT) show reduced levels of blood ketone bodies in the postabsorptive state. In the present study, we have evaluated ketone body and glucose kinetics in patients with CPT deficiency. Intermediate metabolites of carbohydrate and lipid metabolism have also been studied. Ketone body (KB) turnover was measured by means of sequential intravenous bolus injections of 3-14C acetoacetate and 3-14C D(-) 3-hydroxybutyrate in four patients with liver, platelet, and muscle deficiency of CPT system and in eight normal overnight fasting subjects. 6-3H glucose was also injected, along with 3-14C ketone bodies to measure glucose turnover rate. Three out of four CPT deficiency patients had normal KB turnover, despite a marked reduction in liver CPT activity. Only one subject, with severe defect of CPT activity in liver, showed a significantly reduced, but still present rate of de novo synthesis of acetoacetate and 3-hydroxybutyrate (40 and 51 mumol/m-2/min-1 respectively) in comparison with control subjects (103 +/- 14 and 157 +/- 22 mumol/m-2/min-1). Blood concentrations of dicarboxylic adipic and suberic acids were significantly higher in CPT deficiency patients (0.035 +/- 0.007 and 0.021 +/- 0.005, mmol/L respectively) than in control subjects (0.008 +/- 0.008 and 0.006 +/- 0.003 respectively). Basal glucose turnover was increased in CPT deficiency patients (505 +/- 13 mumol/m-2/min-1) in comparison with normal subjects (433 +/- 18 mumol/m-2/min-1; P less than .01) as well as clearance rates (127 +/- 3 mL/m-2/min-1 and 91 +/- 11 mL/m-2/min-1, respectively; P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Development of metabolic syndrome and electrocardiographic features of left ventricular hypertrophy in middle-aged working subjects

Background and aims: Metabolic syndrome (MS) leads to excess cardiovascular disease, including heart failure. Left ventricular hypertrophy (LVH) is common in MS patients, but it is unknown whether onsets of MS and LVH coincide. Herein, we tested the association between development of MS and of electrocardiographic LVH in a cohort of middle-aged individuals. Methods: We included 303 working subjects (mean age 43.0±6.2; 41% males), follo wed-up for 4.3±0.8 yr. ATP-III MS components were determined. Electrocardiographic LVH features were assessed by Sokolow and Cornell voltage indexes and Romhilt-Estes (RE) score. Results: At baseline, Cornell index was significantly higher in subjects with (no.=55; 18.2%) than in those without MS (12.8±6.4 vs 10.9±5.4 mm; p=0.023), while Sokolow index and RE score were not different. At follow-up, individuals who developed (no.=51) compared to those who did not develop MS showed a significant increase in Cornell voltage index (1.0±0.6 vs −0.55±0.3 mm; p=0.035) and RE score (0.17±0.17 vs −0.08±0.04; p=0.028). The change in Cornell index over time was directly correlated with the change in the number of MS components (r=0.133; p=0.02) and in homeostasis model assessment of insulin resistance (r=0.117; p=0.046). The association between MS onset and the increase in Cornell index/RE score was independent from confounders. Conclusions: In a young population of working subjects, the development of MS is associated with worsening features of LVH. Early LVH electrocardiographic screening in young subjects who develop MS should be considered and performed using Cornell voltage index.