Katherine V. Williams

The Effect of Short Periods of Caloric Restriction on Weight Loss and Glycemic Control in Type 2 Diabetes

OBJECTIVE To determine whether an intermittent very-low-calorie diet (VLCD) improves weight loss and glycemic control more than moderate caloric restriction alone. RESEARCH DESIGN AND METHODS Individuals with type 2 diabetes (n = 54) who were ≥ 20% over ideal body weight participated in a 20-week behavioral weight control program. Subjects were randomized to either a standard behavioral therapy (SBT) group or to one of two VLCD groups. SBT subjects received a 1,500−1,800 kcal/day diet throughout. Both VLCD groups followed a VLCD for 5 consecutive days during week 2, followed by either intermittent VLCD therapy for 1 day/week for 15 weeks (1-day) or for 5 consecutive days every 5 weeks (5-day), with a 1,500−1,800 kcal/day diet at other times. RESULTS Both VLCD groups lost more weight than the SBT group over the 20 weeks (P = 0.04). Although the groups did not differ in fasting plasma glucose (FPG) changes at 20 weeks, more subjects in the 5-day group attained a normal HbA1c when compared with the SBT group (P = 0.04). This benefit was independent of the effects of weight loss. The best predictor of overall change in FPG and HbA1c was the FPG response during the first 3 weeks of the program. CONCLUSIONS Periodic VLCDs improved weight loss in diabetic subjects. A regimen with intermittent 5-day VLCD therapy seemed particularly promising, because more subjects in this group attained a normal HbA1c. Moreover, the glucose response to a 3-week period of diet therapy predicted glycemic response at 20 weeks, and it was a better predictor of the 20-week response than initial or overall weight loss.

Subclinical Atherosclerosis and Estimated Glucose Disposal Rate as Predictors of Mortality in Type 1 Diabetes

PURPOSE To investigate the usefulness of ischemic resting electrocardiogram (ECG), ankle brachial index (ABI) <0.8, ankle brachial difference (ABD) > or = 75 mm Hg (a marker of peripheral medial arterial wall calcification), and estimated glucose disposal rate (eGDR) (a marker for insulin resistance) for predicting mortality risk in the context of standard risk factors. METHODS Data are from participants in the Pittsburgh Epidemiology of Diabetes Complications Study of 658 subjects with childhood onset Type 1 diabetes of mean age 28 years (range 8-48) and duration of diabetes 19 years (range 7-37) at baseline. Deaths were confirmed by death certificates. RESULTS There were 68 deaths from all causes during 10 years follow-up. In univariate analysis, the mortality hazard ratios and 95% confidence intervals associated with ischemic ECG (6.7, 3.7-12.1), the lowest quintile of eGDR (i.e., the most insulin resistant) (6.7, 4.1-10.9), ABI <0.8 (2.5, 1.1-5.9), and ABD > or = 75 mm Hg (6.7) were only marginally less than those conveyed by pre-existing coronary artery disease (8.4, 4.7-15.2) or overt nephropathy (7.6, 4.5-12.9). Ischemic ECG and eGDR were independent mortality predictors, together with duration of diabetes, coronary artery disease, overt nephropathy, nonhigh density lipoprotein cholesterol, and smoking history. If serum creatinine was available, it entered, and glycosylated hemoglobin replaced eGDR. CONCLUSIONS Estimated GDR and ECG ischemia are strong predictors of mortality in type 1 diabetes and may be useful in the identification of those at risk.

Insulin regulation of glucose transport and phosphorylation in skeletal muscle assessed by PET

The current study examined in vivo insulin regulation of glucose transport and phosphorylation in skeletal muscle of healthy, lean volunteers. Positron emission tomography (PET) imaging and compartmental modeling of the time course of skeletal muscle uptake and utilization after a bolus injection of 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) was performed during metabolic steady-state conditions at four rates of euglycemic insulin infusion. Leg glucose uptake (LGU) was determined by arteriovenous limb balance assessments. The metabolism of [18F]FDG strongly correlated with skeletal muscle LGU ( r= 0.72, P < 0.01). On the basis of compartmental modeling, the fraction of glucose undergoing phosphorylation (PF) increased in a dose-responsive manner from 11% during basal conditions to 74% at the highest insulin infusion rate ( P < 0.001). The PF and LGU were highly correlated ( r = 0.73, P < 0.001). Insulin also increased the volume of distribution of nonphosphorylated [18F]FDG ( P < 0.05). In step-wise regression analysis, the volume of distribution of nonphosphorylated [18F]FDG and the rate constant for glucose phosphorylation accounted for most of the variance in LGU ( r = 0.91, P < 0.001). These findings indicate an important interaction between transport and phosphorylation in the control of insulin-stimulated glucose metabolism in skeletal muscle.The current study examined in vivo insulin regulation of glucose transport and phosphorylation in skeletal muscle of healthy, lean volunteers. Positron emission tomography (PET) imaging and compartmental modeling of the time course of skeletal muscle uptake and utilization after a bolus injection of 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) was performed during metabolic steady-state conditions at four rates of euglycemic insulin infusion. Leg glucose uptake (LGU) was determined by arteriovenous limb balance assessments. The metabolism of [(18)F]FDG strongly correlated with skeletal muscle LGU (r = 0.72, P < 0.01). On the basis of compartmental modeling, the fraction of glucose undergoing phosphorylation (PF) increased in a dose-responsive manner from 11% during basal conditions to 74% at the highest insulin infusion rate (P < 0.001). The PF and LGU were highly correlated (r = 0.73, P < 0.001). Insulin also increased the volume of distribution of nonphosphorylated [(18)F]FDG (P < 0.05). In step-wise regression analysis, the volume of distribution of nonphosphorylated [(18)F]FDG and the rate constant for glucose phosphorylation accounted for most of the variance in LGU (r = 0.91, P < 0.001). These findings indicate an important interaction between transport and phosphorylation in the control of insulin-stimulated glucose metabolism in skeletal muscle.

Celiac Autoimmunity is Associated with Lower Blood Pressure and Renal Risk in Type 1 Diabetes.

Context Though the long-term consequences of celiac disease (CD) in type 1 diabetes are unclear, CD has been associated with increased prevalence of end-stage renal disease (ESRD) independent of type 1 diabetes. Objective We evaluated whether celiac autoimmunity is related to the cumulative incidence of microalbuminuria [albumin excretion rate (AER) 20 to 200 µg/min], macroalbuminuria (AER >200 µg/min), and ESRD. Design, Patients, and Methods In the prospective follow-up of the Pittsburgh Epidemiology of Diabetes Complications study of childhood-onset type 1 diabetes, 618 participants were screened for tissue transglutaminase (tTG) antibodies with a clinical assay. Nephropathy outcomes were determined at 25 years of diabetes duration. Results Overall, the 33 subjects (5.3%) with strongly positive tTG levels (≥3 times the upper limit of normal) or a reported clinical history of CD had lower baseline blood pressure and lipid values. At 25 years of diabetes duration, a lower cumulative incidence of macroalbuminuria in strongly positive subjects compared with those with negative serology (3.6% vs 30.0%; P = 0.003) remained significant after adjustment for age, HbA1c, lipid measures, and blood pressure (adjusted P = 0.004). No considerable differences between these subjects and tTG-negative groups were found for microalbuminuria (40.0% vs 57.1%) or ESRD (0 vs 4.1%). Conclusions These findings show that strongly positive celiac autoimmunity status in individuals with childhood-onset type 1 diabetes is associated with lower baseline blood pressure and cholesterol measurements as well as lower macroalbuminuria risk after 25 years of type 1 diabetes duration with no increase in the risk of microalbuminuria or ESRD.