Objective Clinically, type 2 diabetes mellitus (T2DM) is heterogeneous, but the prevailing pathophysiologic hypothesis nevertheless contends that components of metabolic syndrome are central to all cases of T2DM. Here, we reevaluated this hypothesis. Research Design and Methods We conducted a cross-sectional analysis of 138 women from the monocenter, post gestational diabetes study PPSDiab, 73 of which had incident prediabetes or T2DM. Additionally, we examined all the 412 incident cases of T2DM in phases 3-9 of the Whitehall II Study in comparison to healthy controls. Our analysis included a medical history, anthropometrics, oral glucose tolerance testing, and laboratory chemistry in both studies. Additional analyses from the PPSDiab Study consisted of cardiopulmonary exercise testing, magnetic resonance imaging, auto-antibody testing, and the exclusion of glucokinase maturity-onset diabetes of the young. Results We found that 33 (45%) of the women with prediabetes or T2DM in the PPSDiab Study displayed no components of metabolic syndrome. They reached no point for metabolic syndrome in the NCEP ATP3 score other than hyperglycemia and, moreover, had levels of liver fat content, plasma triglycerides, hdl cholesterol, c-reactive protein, and blood pressure that were comparable to healthy controls. In the Whitehall II Study, 62 (15%) of the incident T2DM cases fulfilled the same criteria. In both studies, these cases without metabolic syndrome revealed insulin resistance and inadequately low insulin secretion. Conclusions Our results contradict the hypothesis that components of metabolic syndrome are central to all cases of T2DM. Instead, they suggest the common occurrence of a second, unrelated pathophysiology.

Background The myokine myostatin regulates muscle mass and has been linked to insulin resistance and metabolic syndrome. However, data on its role in humans is still limited. We, therefore, investigated the associations of serum myostatin with muscle mass, physical fitness, and components of the metabolic syndrome in a cohort of premenopausal women. Methods We undertook a cross-sectional analysis of 233 women from the monocenter study PPSDiab, conducted in Munich, Germany. Participants had recently completed a pregnancy with or without gestational diabetes. Our analysis included medical history, anthropometrics, oral glucose tolerance testing, laboratory chemistry, cardiopulmonary exercise testing, and magnetic resonance imaging (n=142) of visceral fat volume, left quadriceps muscle mass, and muscle fat content. Serum myostatin was quantified by a competitive enzyme-linked immunosorbent assay. Results We observed positive correlations of serum myostatin with body mass index (ρ=0.235; p=0.0003), body fat percentage (ρ=0.166; p=0.011), waist circumference (ρ=0.206; p=0.002), intraabdominal fat volume (ρ=0.182; p=0.030) and high-sensitivity C-reactive protein (ρ=0.175; p=0.008). These correlations were reproduced in linear regression analyses with adjustment for age and time after delivery. We saw no correlations with muscle mass, physical fitness, insulin sensitivity, triglycerides, HDL cholesterol, and blood pressure. Conclusions Our observation of elevated serum myostatin in women with a higher body fat percentage, visceral obesity, and elevated c-reactive protein suggests that this myokine contributes to the altered muscle-adipose tissue crosstalk in metabolic syndrome. Elevated myostatin may advance this pathophysiologic process and could also impair the efficacy of exercise interventions. Further mechanistic studies, therefore, seem warranted.

Introduction Skeletal muscle contributes significantly to insulin sensitivity in humans. However, which non-invasive measurement best reflects this contribution remains unknown. Consequently, this paper compares morphologic and functional measurements. Research methods and design We conducted a cross-sectional analysis of 144 premenopausal women enrolled in the “Prediction, Prevention, and Sub-classification of Type 2 Diabetes” (PPSDiab) cohort study. For the analysis, we quantified insulin sensitivity by oral glucose tolerance testing and, in a subgroup of 30 women, euglycemic clamp. To assess skeletal muscle, we measured volume by magnetic resonance imaging, intramyocellular lipid content by magnetic resonance spectroscopy, and physical fitness by cardiopulmonary exercise testing. Results The mean age of the cohort was 35.7 ± 4.1 years and 94 participants (65%) had a history of gestational diabetes mellitus. Of the morphologic and functional muscle parameters, the maximum workload achieved during cardiopulmonary exercise testing associated most closely with insulin sensitivity (standardized beta = 0.39; p < .001). Peak oxygen uptake also demonstrated significant associations, whereas muscle volume and intramyocellular lipid content displayed none. Conclusion Functional measurements provided a better assessment of the muscular contribution to insulin sensitivity than morphologic measurements in premenopausal women. In particular, exercise testing rendered an easy and cost-effective method applicable in clinical settings and other human studies.