Search

OBJECTIVE—Statins may exert pleiotropic effects on insulin action that are still controversial. We assessed effects of high-dose simvastatin therapy on peripheral and hepatic insulin sensitivity, as well as on ectopic lipid deposition in patients with hypercholesterolemia and type 2 diabetes. RESEARCH DESIGN AND METHODS—We performed a randomized, double-blind, placebo-controlled, single-center study. Twenty patients with type 2 diabetes received 80 mg simvastatin (BMI 29 ± 4 kg/m2, age 55 ± 6 years) or placebo (BMI 27 ± 4 kg/m2, age 58 ± 8 years) daily for 8 weeks and were compared with 10 healthy humans (control subjects; BMI 27 ± 4 kg/m2, age 55 ± 7 years). Euglycemic-hyperinsulinemic clamp tests combined with d-[6,6-d2]glucose infusion were used to assess insulin sensitivity (M) and endogenous glucose production (EGP). 1H magnetic resonance spectroscopy was used to quantify intramyocellular and hepatocellular lipids. RESULTS—High-dose simvastatin treatment lowered plasma total and LDL cholesterol levels by ∼33 and ∼48% (P < 0.005) but did not affect M, intracellular lipid deposition in soleus and tibialis anterior muscles and liver, or basal and insulin-suppressed EGP. In simvastatin-treated patients, changes in LDL cholesterol related negatively to changes in M (r = −0.796, P < 0.01). Changes in fasting free fatty acids (FFAs) related negatively to changes in M (r = −0.840, P < 0.01) and positively to plasma retinol-binding protein-4 (r = 0.782, P = 0.008). CONCLUSIONS—High-dose simvastatin treatment has no direct effects on whole-body or tissue-specific insulin action and ectopic lipid deposition. A reduction in plasma FFAs probably mediates alterations in insulin sensitivity in vivo.

OBJECTIVE—Insulin resistance, the underlying pathophysiological mechanism of the metabolic syndrome, can not only predict type 2 diabetes development but also cardiovascular disease. Thus, precise insulin resistance measurement in individuals at risk for metabolic diseases would support clinical risk stratification. However, the gold standard for measuring insulin resistance, the hyperinsulinemic clamp test, is too labor intensive to be performed in large clinical studies/settings. RESEARCH DESIGN AND METHODS—Using plasma glucose and C-peptide concentrations from oral glucose tolerance tests (OGTTs), we developed the novel “clamp-like index” (CLIX) for insulin sensitivity calculation and compared CLIX to clamp glucose infusion rates (GIR) (100–120 min). We evaluated CLIX in 89 nondiabetic subjects (58 female and 31 male, aged 45 ± 1 years, BMI 27.5 ± 0.8 kg/m2) who underwent frequently sampled 3-h 75-g OGTTs and 2-h hyperinsulinemic-isoglycemic clamp (40 mU/min per m2) tests. RESULTS—CLIX, calculated as serum creatinine (×0.85 if male)/(mean AUCglucose × mean AUCC-peptide) × 6,600, was highly correlated (r = 0.670, P < 10−12) with and comparable to clamp GIRs100–120 min. In subgroup analyses, GIRs100–120 min were lower (P < 0.005) in type 2 diabetic offspring (6.2 ± 0.7 mg · min−1 · kg−1) than in sex-, age-, and BMI-matched subjects without a family history of type 2 diabetes (8.6 ± 0.5 mg · min−1 · kg−1), which was also reflected by CLIX (insulin-resistant offspring 6.4 ± 0.6 vs. those without a family history of type 2 diabetes 9.0 ± 0.5; P < 0.002). When compared with normal-weight subjects (GIR 8.8 ± 0.4 mg · min−1 · kg−1; CLIX 9.0 ± 0.5), both GIRs100–120 min and CLIX of obese (5.2 ± 0.9 mg · min −1 · kg−1; 5.7 ± 0.9) and morbidly obese (2.4 ± 0.4 mg · min −1 · kg−1; 3.3 ± 0.5) humans were lower (each P < 0.02). CONCLUSIONS—CLIX, a novel index obtained from plasma OGTT glucose and C-peptide levels and serum creatinine, without inclusion of anthropometrical measures to calculate insulin sensitivity in nondiabetic humans, highly correlates with clamp GIRs and reveals even slight insulin sensitivity alterations over a broad BMI range and is as sensitive as the hyperinsulinemic clamp test.

OBJECTIVE The autonomic nervous system (ANS) regulates both the cardiovascular system and energy balance and is disturbed in diabetes and obesity. The effect of different approaches of caloric restriction on ANS function has not been assessed in individuals with diabetes. Thus, we sought to determine whether low-energy diets differing in fiber, red meat, and coffee intake exert differential effects on cardiac autonomic function. RESEARCH DESIGN AND METHODS In this randomized parallel-group pilot trial, obese patients with type 2 diabetes were randomly allocated to consume either a diet high in cereal fiber, free of red meat, and high in coffee (n = 13) or a diet low in fiber, high in red meat, and coffee free (n = 15) over 8 weeks. Eight measures of heart rate variability (HRV) indicating vagal and/or sympathetic modulation over 3 h and inflammatory markers were determined during a hyperinsulinemic-euglycemic clamp. RESULTS After 8 weeks, both dietary interventions resulted in a mean weight loss of 5–6 kg, a mean decline in heart rate of 4–6 bpm, and improvement in vagally mediated HRV. However, the changes in HRV parameters from baseline to 8 weeks did not differ between the groups. In the entire study cohort, incremental HRV from baseline to 8 weeks was associated with enhanced oxidative glucose utilization (P < 0.05), but not with insulin sensitivity and inflammatory markers. CONCLUSIONS In obese patients with type 2 diabetes, energy restriction per se over 8 weeks contributed to improved cardiac vagal function in relation to improved oxidative glucose utilization. This preliminary finding should be verified in a confirmatory trial.

OBJECTIVE—In response to hyperglycemia, β-cells release insulin and C-peptide, as well as islet amyloid pancreatic polypeptide, which is involved in glucose homeostasis. After successful pancreas-kidney transplantation (PKT), type 1 diabetic patients may revert to a nondiabetic metabolism without exogenous insulin therapy and re-secrete all β-cell hormones. RESEARCH DESIGN AND METHODS—Using mathematical models, we investigated hormone (amylin, insulin, C-peptide) and metabolite (glucose, free fatty acids) kinetics, β-cell sensitivity to glucose, and oral glucose insulin sensitivity index (OGIS) in 11 nondiabetic type 1 diabetic patients after PKT (BMI 25 ± 1 kg/m2, 47 ± 2 years of age, 4 women/7 men, glucocorticoid-free), 6 matching nondiabetic patients after kidney transplantation (25 ± 1 kg/m2, 50 ± 5 years, 3 women/3 men, on glucocorticoids), and 9 matching nondiabetic control subjects (24 ± 1 kg/m2, 47 ± 2 years, 4 women/5 men) during a 3-h 75-g oral glucose tolerance test (OGTT). RESULTS—PKT patients had higher fasting amylin (19 ± 3 vs. control subjects: 7 ± 1 pmol/l) and insulin (20 ± 2 vs. control subjects: 10 ± 1 μU/ml; each P < 0.01) levels. Kidney transplant subjects showed increased OGTT plasma insulin at 90 min and C-peptide levels (each P < 0.05). In PKT patients, plasma glucose from 90 to 150 min was 9–31% higher (P < 0.05 vs. control subjects). Amylin clearance was comparable in all groups. Amylin’s plasma concentrations and area under the concentration curve were up to twofold higher in PKT patients during OGTT (P < 0.05). OGIS was not significantly different between groups. β-Cell sensitivity to glucose was reduced in PKT patients (−64%, P < 0.009). Fasting plasma amylin was inversely associated with β-cell sensitivity to glucose (r = −0.543, P < 0.004). CONCLUSIONS—After successful PKT, type 1 diabetic patients with nondiabetic glycemia exhibit increased fasting and post–glucose load plasma amylin, which appears to be linked to impaired β-cell function. Thus, higher amylin release in proportion to insulin might also reflect impaired β-cell function in type 1 diabetic patients after PKT.

OBJECTIVE—To assess insulin sensitivity and β-cell function associated with lower maternal fasting plasma glucose levels at high altitude compared with sea level. RESEARCH DESIGN AND METHODS—We studied 215 pregnant women at 8–42 weeks of gestation in Peru. The women were recruited from Cerro de Pasco, which is situated 4,370 m (14,340 feet) above sea level, and Lima, which is at sea level. We also examined 53 nonpregnant control subjects (22 in Cerro de Pasco and 31 in Lima). Fasting plasma glucose, insulin, C-peptide, and proinsulin concentrations were measured in samples obtained from the antecubital vein between 8:00 a.m. and 10:00 a.m. after an overnight period of fasting for 10–14 h. Insulin resistance and β-cell function were calculated using homeostasis model assessment. RESULTS—Fasting C-peptide levels and β-cell function were similar, fasting concentrations of insulin and proinsulin were lower, and insulin sensitivity was higher at high altitude compared with sea level. CONCLUSIONS—Maternal fasting plasma glucose that is lower at high altitude than at sea level in the presence of similar insulin secretion is associated with higher peripheral insulin sensitivity. This may partly explain the lower birth weights at high altitudes.

Insulin resistance, the underlying pathophysiological mechanism of the metabolic syndrome, can not only predict type 2 diabetes development but also cardiovascular disease. Thus, precise insulin resistance measurement in individuals at risk for metabolic diseases would support clinical risk stratification. However, the gold standard for measuring insulin resistance, the hyperinsulinemic clamp test, is too labor intensive to be performed in large clinical studies/settings.Using plasma glucose and C-peptide concentrations from oral glucose tolerance tests (OGTTs), we developed the novel "clamp-like index" (CLIX) for insulin sensitivity calculation and compared CLIX to clamp glucose infusion rates (GIR) (100-120 min). We evaluated CLIX in 89 nondiabetic subjects (58 female and 31 male, aged 45 +/- 1 years, BMI 27.5 +/- 0.8 kg/m(2)) who underwent frequently sampled 3-h 75-g OGTTs and 2-h hyperinsulinemic-isoglycemic clamp (40 mU/min per m(2)) tests.CLIX, calculated as serum creatinine (x0.85 if male)/(mean AUC(glucose) x mean AUC(C-peptide)) x 6,600, was highly correlated (r = 0.670, P10(-12)) with and comparable to clamp GIRs(100-120 min). In subgroup analyses, GIRs(100-120 min) were lower (P0.005) in type 2 diabetic offspring (6.2 +/- 0.7 mg x min(-1) x kg(-1)) than in sex-, age-, and BMI-matched subjects without a family history of type 2 diabetes (8.6 +/- 0.5 mg x min(-1) x kg(-1)), which was also reflected by CLIX (insulin-resistant offspring 6.4 +/- 0.6 vs. those without a family history of type 2 diabetes 9.0 +/- 0.5; P0.002). When compared with normal-weight subjects (GIR 8.8 +/- 0.4 mg x min(-1) x kg(-1); CLIX 9.0 +/- 0.5), both GIRs(100-120 min) and CLIX of obese (5.2 +/- 0.9 mg x min (-1) x kg(-1); 5.7 +/- 0.9) and morbidly obese (2.4 +/- 0.4 mg x min (-1) x kg(-1); 3.3 +/- 0.5) humans were lower (each P0.02).CLIX, a novel index obtained from plasma OGTT glucose and C-peptide levels and serum creatinine, without inclusion of anthropometrical measures to calculate insulin sensitivity in nondiabetic humans, highly correlates with clamp GIRs and reveals even slight insulin sensitivity alterations over a broad BMI range and is as sensitive as the hyperinsulinemic clamp test.

In response to hyperglycemia, beta-cells release insulin and C-peptide, as well as islet amyloid pancreatic polypeptide, which is involved in glucose homeostasis. After successful pancreas-kidney transplantation (PKT), type 1 diabetic patients may revert to a nondiabetic metabolism without exogenous insulin therapy and re-secrete all beta-cell hormones.Using mathematical models, we investigated hormone (amylin, insulin, C-peptide) and metabolite (glucose, free fatty acids) kinetics, beta-cell sensitivity to glucose, and oral glucose insulin sensitivity index (OGIS) in 11 nondiabetic type 1 diabetic patients after PKT (BMI 25 +/- 1 kg/m2, 47 +/- 2 years of age, 4 women/7 men, glucocorticoid-free), 6 matching nondiabetic patients after kidney transplantation (25 +/- 1 kg/m2, 50 +/- 5 years, 3 women/3 men, on glucocorticoids), and 9 matching nondiabetic control subjects (24 +/- 1 kg/m2, 47 +/- 2 years, 4 women/5 men) during a 3-h 75-g oral glucose tolerance test (OGTT).PKT patients had higher fasting amylin (19 +/- 3 vs. control subjects: 7 +/- 1 pmol/l) and insulin (20 +/- 2 vs. control subjects: 10 +/- 1 microU/ml; each P0.01) levels. Kidney transplant subjects showed increased OGTT plasma insulin at 90 min and C-peptide levels (each P0.05). In PKT patients, plasma glucose from 90 to 150 min was 9-31% higher (P0.05 vs. control subjects). Amylin clearance was comparable in all groups. Amylin's plasma concentrations and area under the concentration curve were up to twofold higher in PKT patients during OGTT (P0.05). OGIS was not significantly different between groups. beta-Cell sensitivity to glucose was reduced in PKT patients (-64%, P0.009). Fasting plasma amylin was inversely associated with beta-cell sensitivity to glucose (r = -0.543, P0.004).After successful PKT, type 1 diabetic patients with nondiabetic glycemia exhibit increased fasting and post-glucose load plasma amylin, which appears to be linked to impaired beta-cell function. Thus, higher amylin release in proportion to insulin might also reflect impaired beta-cell function in type 1 diabetic patients after PKT.

This study examines the feasibility of deriving the 24-h insulin requirement of insulin-dependent diabetic patients who were devoid of any endogenous insulin release (IDD) from the insulin-production rate (IPR) of healthy man (basal, 17 mU/min; stimulated 1.35 U/12.5 g glucose). To this end, continuous intravenous insulin infusion (CIVII) was initiated at a precalculated rate of 41.2 +/- 4.6 (SD) U/24 h in IDD (N - 12). Blood glucose profiles were compared with those obtained during intermittent subcutaneous (s.c.) insulin therapy (IIT) and those of healthy controls (N = 7). Regular insulin (Hoechst CS) was infused with an adapted Mill Hill Infuser at a basal infusion rate of 1.6 U/h (6:00 a.m. to 8:00 p.m.), and of 0.8 U/h from 8:00 p.m. to 6:00 a.m. Preprandial insulin (3.2-6.4 U) was added for breakfast, lunch, and dinner. Daily individual food intake totaled 7688 +/- 784 kJ (1836 +/- 187 kcal)/24 h including 184 +/- 37 g of glucose. Proper control of blood glucose (BG) (mean BG 105 +/- 10 mg/dl; mean amplitude of glycemic excursions 54 +/- 18 mg/dl; and 1 h postprandial BG levels not exceeding 160 mg/dl) and of plasma concentrations of beta-hydroxybutyrate and lactate was maintained by 41.4 +/- 4.4 U insulin/24 h. Although BG values only approximated the upper normal range as seen in healthy controls, they were well within the range reported by others during CIVII. Therefore, we conclude that in adult IDD completely devoid of endogenous insulin (1) the IPR of normal man can be used during CIVII as an estimate for the patient's minimal insulin requirement per 24 h, and (2) this approach allows for a blood glucose profile close to the upper range of a normal control group. Thus, deriving a patient's daily insulin dose from the insulin production rate of healthy man may add an additional experimental protocol which aids in making general calculations of a necessary insulin dose instead of using trial and error or a closed-loop insulin infusion system.