OBJECTIVEShort leg length, a marker of early childhood deprivation, has been used in studies of the association of early life conditions with adult chronic disease risk. The objective of this study was to determine the cross-sectional associations of leg length with measures of insulin sensitivity and β-cell function.RESEARCH DESIGN AND METHODSSubjects (n = 462) at risk for type 2 diabetes were recruited into the PROspective Metabolism and ISlet cell Evaluation (PROMISE) longitudinal cohort. Leg length was calculated from sitting and standing height at the 3-year clinical examination. Glucose tolerance status was determined using an oral glucose tolerance test. Insulin sensitivity was assessed using homeostasis model assessment of insulin resistance (HOMA-IR) and the Matsuda insulin sensitivity index (ISI), while the insulinogenic index over HOMA-IR (IGI/IR) and the insulin secretion sensitivity index 2 (ISSI-2) determined β-cell function. Multiple linear regression analysis was conducted, adjusting for covariates including age, sex, ethnicity, family history of diabetes, waist, and weight.RESULTSLeg length and leg-to-height ratio were significantly associated with HOMA-IR (β = −0.037, β = −10.49, respectively; P < 0.0001), ISI (β = 0.035, β = 8.83, respectively; P < 0.0001), IGI/IR (β = 0.021, P < 0.05; β = 7.60, P < 0.01, respectively), and ISSI-2 (β = 0.01, P < 0.03; β = 3.34, P < 0.01, respectively) after adjustment for covariates. The association of shorter leg length with lower insulin sensitivity was most evident for those with high waist circumferences.CONCLUSIONSShorter legs were independently associated with lower insulin sensitivity and β-cell function, suggesting that early childhood deprivation may increase the risk of developing diabetes.
Total NEFA concentration was a strong predictor of lower beta cell function over 6 years. Our results suggest that the association with beta cell function is due to the absolute size of the serum NEFA fraction, rather than the specific fatty acid composition.
Metabolic alterations precede cardiometabolic disease onset. Here we present ceramide- and dihydroceramide-profiling data from a nested case-cohort (type 2 diabetes [T2D, n = 775]; cardiovascular disease [CVD, n = 551]; random subcohort [n = 1137]) in the prospective EPIC-Potsdam study. We apply the novel NetCoupler-algorithm to link a data-driven (dihydro)ceramide network to T2D and CVD risk. Controlling for confounding by other (dihydro)ceramides, ceramides C18:0 and C22:0 and dihydroceramides C20:0 and C22:2 are associated with higher and ceramide C20:0 and dihydroceramide C26:1 with lower T2D risk. Ceramide C16:0 and dihydroceramide C22:2 are associated with higher CVD risk. Genome-wide association studies and Mendelian randomization analyses support a role of ceramide C22:0 in T2D etiology. Our results also suggest that (dh)ceramides partly mediate the putative adverse effect of high red meat consumption and benefits of coffee consumption on T2D risk. Thus, (dihydro)ceramides may play a critical role in linking genetic predisposition and dietary habits to cardiometabolic disease risk.
Context Chronic inflammation arising from adipose tissue macrophage (ATM) activation may be central in type 2 diabetes etiology. Our objective was to assess the longitudinal associations of soluble CD163 (sCD163), a novel biomarker of ATM activation, with insulin sensitivity, β-cell function, and dysglycemia in high-risk subjects. Methods Adults at risk for type 2 diabetes in the Prospective Metabolism and Islet Cell Evaluation (PROMISE) study had 3 assessments over 6 years (n = 408). Levels of sCD163 were measured using fasting serum. Insulin sensitivity was assessed by HOMA2-%S and the Matsuda index (ISI). β-cell function was determined by insulinogenic index (IGI) over HOMA-IR and insulin secretion-sensitivity index-2 (ISSI-2). Incident dysglycemia was defined as the onset of impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes. Generalized estimating equations (GEE) evaluated longitudinal associations of sCD163 with insulin sensitivity, β-cell function, and incident dysglycemia adjusting for demographic and lifestyle covariates. Areas under receiver-operating-characteristic curve (AROC) tested whether sCD163 improved dysglycemia prediction in a clinical model. Results Longitudinal analyses showed significant inverse associations between sCD163 and insulin sensitivity (% difference per standard deviation increase of sCD163 for HOMA2-%S (β = −7.01; 95% CI, −12.26 to −1.44) and ISI (β = −7.60; 95% CI, −11.09 to −3.97) and β-cell function (ISSI-2 (β = −4.67; 95 %CI, −8.59 to −0.58) and IGI/HOMA-IR (β = −8.75; 95% CI, −15.42 to −1.56)). Increased sCD163 was associated with greater risk for incident dysglycemia (odds ratio = 1.04; 95% CI, 1.02-1.06; P < 0.001). Adding sCD163 data to a model with clinical variables improved prediction of incident dysglycemia (AROC=0.6731 vs 0.638; P < 0.05). Conclusions sCD163 was longitudinally associated with core disorders that precede the onset of type 2 diabetes.
ObjectiveTo evaluate multiple determinants of the longitudinal change in insulin clearance (IC) in subjects at high risk for type 2 diabetes (T2D).Research design and methodsAdults (n=492) at risk for T2D in the Prospective Metabolism and Islet Cell Evaluation cohort, a longitudinal observational cohort, had four visits over 9 years. Values from oral glucose tolerance tests collected at each assessment were used to calculate the ratios of both fasting C peptide-to-insulin (ICFASTING) and areas under the curve of C peptide-to-insulin (ICAUC). Generalized estimating equations (GEE) evaluated multiple determinants of longitudinal changes in IC.ResultsIC declined by 20% over the 9-year follow-up period (p<0.05). Primary GEE results indicated that non-European ethnicity, as well as increases in baseline measures of waist circumference, white cell count, and alanine aminotransferase, was associated with declines in ICFASTING and ICAUC over time (all p<0.05). There were no significant associations of IC with sex, age, physical activity, smoking, or family history of T2D. Both baseline and longitudinal IC were associated with incident dysglycemia.ConclusionsOur findings suggest that non-European ethnicity and components of the metabolic syndrome, including central obesity, non-alcoholic fatty liver disease, and subclinical inflammation, may be related to longitudinal declines in IC.
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