Distelmaier, Klaus

Context:Numerous factors are purported to influence insulin sensitivity including age, adiposity, mitochondrial function, and physical fitness. Univariate associations cannot address the complexity of insulin resistance or the interrelationship among potential determinants.Objective:The objective of the study was to identify significant independent predictors of insulin sensitivity across a range of age and adiposity in humans.Design, Setting, and Participants:Peripheral and hepatic insulin sensitivity were measured by two stage hyperinsulinemic-euglycemic clamps in 116 men and women (aged 19–78 y). Insulin-stimulated glucose disposal, the suppression of endogenous glucose production during hyperinsulinemia, and homeostatic model assessment of insulin resistance were tested for associations with 11 potential predictors. Abdominal subcutaneous fat, visceral fat (AFVISC), intrahepatic lipid, and intramyocellular lipid (IMCL) were quantified by magnetic resonance imaging and spectroscopy. Skeletal muscle mitochondrial respiratory capacity (state 3), coupling efficiency, and reactive oxygen species production were evaluated from muscle biopsies. Aerobic fitness was measured from whole-body maximum oxygen uptake (VO2 peak), and metabolic flexibility was determined using indirect calorimetry.Results:Multiple regression analysis revealed that AFVISC (P < .0001) and intrahepatic lipid (P = .002) were independent negative predictors of peripheral insulin sensitivity, whereas VO2 peak (P = .0007) and IMCL (P = .023) were positive predictors. Mitochondrial capacity and efficiency were not independent determinants of peripheral insulin sensitivity. The suppression of endogenous glucose production during hyperinsulinemia model of hepatic insulin sensitivity revealed percentage fat (P < .0001) and AFVISC (P = .001) as significant negative predictors. Modeling homeostatic model assessment of insulin resistance identified AFVISC (P < .0001), VO2 peak (P = .001), and IMCL (P = .01) as independent predictors.Conclusion:The reduction in insulin sensitivity observed with aging is driven primarily by age-related changes in the content and distribution of adipose tissue and is independent of muscle mitochondrial function or chronological age.

Caloric restriction (CR) improves insulin sensitivity and reduces the incidence of diabetes in obese individuals. The underlying mechanisms whereby CR improves insulin sensitivity are not clear. We evaluated the effect of 16 weeks of CR on whole-body insulin sensitivity by pancreatic clamp before and after CR in 11 obese participants (BMI = 35 kg/m2) compared with 9 matched control subjects (BMI = 34 kg/m2). Compared with the control subjects, CR increased the glucose infusion rate needed to maintain euglycemia during hyperinsulinemia, indicating enhancement of peripheral insulin sensitivity. This improvement in insulin sensitivity was not accompanied by changes in skeletal muscle mitochondrial oxidative capacity or oxidant emissions, nor were there changes in skeletal muscle ceramide, diacylglycerol, or amino acid metabolite levels. However, CR lowered insulin-stimulated thioredoxin-interacting protein (TXNIP) levels and enhanced nonoxidative glucose disposal. These results support a role for TXNIP in mediating the improvement in peripheral insulin sensitivity after CR.

AbstractBackgroundRecent data suggest that acute coronary syndromes (ACS) and acute myocardial infarction (AMI) are characterized by an inflammatory subset of thrombosis. We have previously described the accumulation of neutrophils at the coronary culprit lesion site. In this work, we assessed the prognostic value of culprit site (CS) neutrophil accumulation on long‐term mortality in patients with AMI.Materials and methodsIn this prospective study, 417 AMI patients were enrolled after thrombectomy during primary percutaneous coronary intervention. The optimal cut‐off for CS neutrophil accumulation for predicting 4‐year all‐cause mortality was calculated using time‐dependent receiver operator characteristic curve analyses.ResultsThe median follow‐up time was 39 months interquartile range (IQR 21·4–54·6 months) corresponding to 1217 patient years of follow‐up. The cut‐off for CS neutrophil accumulation (difference between culprit neutrophil counts and systemic neutrophil counts) was 0·25 Giga/l. CS neutrophil accumulation occurred in 195 patients (47%) and was independently associated with mortality (hazard ratio 1·88 (95%CI 1·02–3·41, P = 0·043)). In patients with CS neutrophil accumulation, 1‐year mortality (10·8% vs. 7·2%) and 4‐year mortality (19·8% vs. 10·4%) were markedly increased compared with patients without local neutrophil accumulation. Concordance index for CS neutrophil accumulation and mortality was 0·64 (95% CI 0·51–0·77; P = 0·035). Patients with CS neutrophil accumulation had significantly more often nonobstructive lesions compared with patients without neutrophil accumulation (32·6% vs. 22·4%; P = 0·024).Conclusions Neutrophil accumulation at the coronary culprit lesion site is a strong and independent predictor of mortality in patients with ACS/AMI.