IntroductionK ATP channels respond to changes in the intracellular ATP content by altering a cell's membrane potential (1, 2). K ATP channels are widely expressed in neural, endocrine, and muscle tissues where they are inhibited by ATP and stimulated by ADP. K ATP channels are an octameric complex consisting of four potassium channel subunits, either Kir6.1 or Kir6.2, and four sulfonylurea receptor subunits, SUR1 or SUR2 (3-9). SURs, named for their ability to bind with high affinity the hypoglycemic sulfonylurea agents, are members of the ATP-binding cassette (ABC) transporter family of transmembrane proteins. SUR1 and SUR2 are 70% identical proteins encoded by different genes. SUR2 undergoes differential splicing altering its carboxy-terminal 42 amino acids, yielding channels with unique pharmacologic properties.In cardiomyocytes, where K ATP channels modulate protection from ischemia, SUR1 and SUR2 are coexpressed (10, 11). In smooth muscle and voluntary striated muscle, only SUR2 is expressed (11). The physiology and pharmacology of K ATP channels have been most extensively studied in the pancreatic β cell. Here, sulfonylurea agents such as glibenclamide inhibit K ATP channels by binding to SUR1, which results in the closure of the channel and the stimulation of insulin release (3). In vascular smooth muscle, potassium channel openers, such as nicorandil, implicate K ATP channels in the regulation of tonic vasomotor activity. These agents, useful in the treatment of hypertension and angina, open K ATP channels leading to potassium efflux, membrane hyperpolarization, and vasodilation (12-14). Potassium channel openers alter membrane potential through K ATP channels and thereby activate voltage-dependent calcium channels producing changes in vascular smooth muscle contractility (15). In skeletal muscle, K ATP channels affect glucose metabolism. Using mice with a targeted disruption of the Sur2 gene (16), we demonstrated that the loss of K ATP channels increased insulin responsiveness mediated by striated muscle.The diversity of responses to individual pharmacologic agents that act through K ATP channels derives in part from the tissue-specific expression of K ATP subunits and the composition of K ATP channels within a cell. Since pharmacologic agents act through the SUR subunit, the significant homology between SUR isoforms and their overlapping expression pattern complicates the interpretation of pharmacologic studies in This article was published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.
Objective: The aims of this study were: 1) to assess relationships among insulinmediated glucose uptake with standard clinical outcomes and deep-phenotyping measures (including fatty acid [FA] rate of appearance [FA Ra] into the systemic circulation); and 2) to examine the contribution of adipocyte size, fibrosis, and proteomic profile to FA Ra regulation. Methods: A total of 66 adults with obesity (BMI = 34 [SD 3] kg/m 2 ) were assessed for insulin sensitivity (hyperinsulinemic-euglycemic clamp), and stable isotope dilution methods quantified glucose, FA, and glycerol kinetics in vivo. Abdominal subcutaneous adipose tissue (aSAT) and skeletal muscle biopsies were collected, and magnetic resonance imaging quantified liver and visceral fat content. Results: Insulin-mediated FA Ra suppression associated with insulin-mediated glucose uptake (r = 0.51; p < 0.01) and negatively correlated with liver (r = À0.36; p < 0.01) and visceral fat (r = À0.42; p < 0.01). aSAT proteomics from subcohorts of participants with low FA Ra suppression (n = 8) versus high FA Ra suppression (n = 8) demonstrated greater extracellular matrix collagen protein in low versus high FA Ra suppression. Skeletal muscle lipidomics (n = 18) revealed inverse correlations of FA Ra suppression with acyl-chain length of acylcarnitine (r = À0.42; p = 0.02) and triacylglycerol (r = À0.51; p < 0.01), in addition to insulin-mediated glucose uptake (acylcarnitine: r = À0.49; p < 0.01, triacylglycerol: r = À0.40; p < 0.01).Conclusions: Insulin's ability to suppress FA release from aSAT in obesity is related to enhanced insulin-mediated glucose uptake and metabolic health in peripheral tissues.
Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P<5x10-8) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.
Mitochondria are adaptable organelles with diverse cellular functions critical to whole-body metabolic homeostasis. While chronic endurance exercise training is known to alter mitochondrial activity, these adaptations have not yet been systematically characterized. Here, the Molecular Transducers of Physical Activity Consortium (MoTrPAC) mapped the longitudinal, multi-omic changes in mitochondrial analytes across 19 tissues in male and female rats endurance trained for 1, 2, 4 or 8 weeks. Training elicited substantial changes in the adrenal gland, brown adipose, colon, heart and skeletal muscle, while we detected mild responses in the brain, lung, small intestine and testes. The colon response was characterized by non-linear dynamics that resulted in upregulation of mitochondrial function that was more prominent in females. Brown adipose and adrenal tissues were characterized by substantial downregulation of mitochondrial pathways. Training induced a previously unrecognized robust upregulation of mitochondrial protein abundance and acetylation in the liver, and a concomitant shift in lipid metabolism. The striated muscles demonstrated a highly coordinated response to increase oxidative capacity, with the majority of changes occurring in protein abundance and post-translational modifications. We identified exercise upregulated networks that are downregulated in human type 2 diabetes and liver cirrhosis. In both cases HSD17B10, a central dehydrogenase in multiple metabolic pathways and mitochondrial tRNA maturation, was the main hub. In summary, we provide a multi-omic, cross-tissue atlas of the mitochondrial response to training and identify candidates for prevention of disease-associated mitochondrial dysfunction.
Introduction: Test performance screening measures for dysglycemia have not been evaluated prospectively in youth. This study evaluated the prospective test performance of random glucose (RG), 1-hour nonfasting glucose challenge test (1-h GCT), Hemoglobin A1c (HbA1c), fructosamine (FA), and 1,5-Anhydroglucitol (1,5-AG) for identifying dysglycemia. Methods: Youth ages 8-17 years with overweight or obesity (body mass index, BMI, ≥85th percentile) without known diabetes completed nonfasting tests at baseline (n=176) and returned an average of 1.1 years later for two formal fasting 2-hour oral glucose tolerance tests. Outcomes included glucose-defined dysglycemia (fasting plasma glucose ≥100 mg/dL or 2-hour plasma glucose ≥140 mg/dL) or elevated HbA1c (≥5.7%). Longitudinal test performance was evaluated using receiver operating characteristic (ROC) curves and calculation of area under the curve (AUC). Results: Glucose-defined dysglycemia, elevated HbA1c, and either dysglycemia or elevated HbA1c were present in 15 (8.5%), 11 (6.3%), and 23 (13.1%) participants at baseline, and 16 (9.1%), 18 (10.3%), and 28 (15.9%) participants at follow-up. For prediction of glucose-defined dysglycemia at follow-up, RG, 1-h GCT, and HbA1c had similar performance (0.68 (95% CI 0.55-0.80), 0.76 (95% CI 0.64-0.89), and 0.70 (95% CI 0.56-0.84)), while FA and 1,5-AG performed poorly. For prediction of HbA1c at follow-up, baseline HbA1c had strong performance (AUC 0.93 (95% CI 0.88-0.98)), RG had moderate performance (AUC 0.67 (0.54-0.79)), while 1-h GCT, FA, and 1,5-AG performed poorly. Conclusion: HbA1c and nonfasting glucose tests had reasonable longitudinal discrimination identifying adolescents at risk for dysglycemia, but performance depended on outcome definition.
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