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  • 1
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    Online Resource
    Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes
    American Diabetes Association ; 2011
    In:  Diabetes Vol. 60, No. 10 ( 2011-10-01), p. 2624-2634
    Details
    In: Diabetes, American Diabetes Association, Vol. 60, No. 10 ( 2011-10-01), p. 2624-2634
    Abstract: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS Nine SNPs at eight loci were associated with proinsulin levels (P & lt; 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db11-0415
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2011
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  • 2
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    Relationship Between Testosterone Levels, Insulin Sensitivity, and Mitochondrial Function in Men
    American Diabetes Association ; 2005
    In:  Diabetes Care Vol. 28, No. 7 ( 2005-07-01), p. 1636-1642
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 28, No. 7 ( 2005-07-01), p. 1636-1642
    Abstract: OBJECTIVE— The goal of this study was to examine the relationship between serum testosterone levels and insulin sensitivity and mitochondrial function in men. RESEARCH DESIGN AND METHODS—A total of 60 men (mean age 60.5 ± 1.2 years) had a detailed hormonal and metabolic evaluation. Insulin sensitivity was measured using a hyperinsulinemic-euglycemic clamp. Mitochondrial function was assessed by measuring maximal aerobic capacity (Vo2max) and expression of oxidative phosphorylation genes in skeletal muscle. RESULTS—A total of 45% of subjects had normal glucose tolerance, 20% had impaired glucose tolerance, and 35% had type 2 diabetes. Testosterone levels were positively correlated with insulin sensitivity (r = 0.4, P & lt; 0.005). Subjects with hypogonadal testosterone levels (n = 10) had a BMI & gt;25 kg/m2 and a threefold higher prevalence of the metabolic syndrome than their eugonadal counterparts (n = 50); this relationship held true after adjusting for age and sex hormone–binding globulin but not BMI. Testosterone levels also correlated with Vo2max (r = 0.43, P & lt; 0.05) and oxidative phosphorylation gene expression (r = 0.57, P & lt; 0.0001). CONCLUSIONS—These data indicate that low serum testosterone levels are associated with an adverse metabolic profile and suggest a novel unifying mechanism for the previously independent observations that low testosterone levels and impaired mitochondrial function promote insulin resistance in men.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/diacare.28.7.1636
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2005
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  • 3
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    Morning or Bedtime NPH Insulin Combined With Sulfonylurea in Treatment of NIDDM
    American Diabetes Association ; 1992
    In:  Diabetes Care Vol. 15, No. 7 ( 1992-07-01), p. 831-834
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 15, No. 7 ( 1992-07-01), p. 831-834
    Abstract: To compare the effect of morning and bedtime NPH insulin combined with daytime sulfonylurea on glycemic control in non-insulin-dependent diabetes mellitus (NIDDM) patients no longer responding to treatment with sulfonylureas alone. Research Design and Methods Twenty-four NIDDM patients who fulfilled these criteria were randomized to treatment with Protaphan human insulin in the morning or at bedtime (22 ± 1 IU) plus 3.5 mg glibenclamide twice a day. Results Morning and bedtime NPH insulin resulted in equal reduction of HbA1 (from 13.5 ± 0.3 to 9.4 ± 0.1 and 9.6 ± 0.2%, respectively) and mean self-monitored blood glucose (9.2 ± 0.5 vs. 10.1 ± 0.4 mM). Bedtime insulin resulted in lower morning blood glucose (7.8 ± 0.5 vs. 9.1 ± 0.4 mM; P & lt; 0.01), whereas morning insulin resulted in lower evening blood glucose (10.1 ± 0.6 vs 12.1 ± 0.6 mM, P & lt; 0.01). Conclusions Morning and bedtime NPH insulin combined with glibenclamide are equipotent in the treatment of NIDDM patients with secondary failure to sulfonylurea. However, this treatment regimen normalizes blood glucose only in a small group of patients. Therefore, more intensified insulin therapy seems to be required to achieve this goal.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/diacare.15.7.831
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 1992
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  • 4
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    A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
    American Diabetes Association ; 2017
    In:  Diabetes Vol. 66, No. 7 ( 2017-07-01), p. 2019-2032
    Details
    In: Diabetes, American Diabetes Association, Vol. 66, No. 7 ( 2017-07-01), p. 2019-2032
    Abstract: To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db16-1329
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2017
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  • 5
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    Online Resource
    Depressive Symptoms, Antidepressant Medication Use, and Insulin Resistance
    American Diabetes Association ; 2011
    In:  Diabetes Care Vol. 34, No. 12 ( 2011-12-01), p. 2545-2547
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 34, No. 12 ( 2011-12-01), p. 2545-2547
    Abstract: Although insulin resistance (IR) may underlie associations between depressive symptoms and diabetes, previous findings have been contradictory. We examined whether depressive symptoms associate with IR and insulin secretion, and, additionally, whether antidepressant medication use may modulate such associations. RESEARCH DESIGN AND METHODS A total of 4,419 individuals underwent an oral glucose tolerance test (OGTT). Participants with previously or newly diagnosed diabetes are excluded from this sample. The homeostasis model assessment of IR (HOMA-IR) and corrected insulin response (CIR) were calculated. Depressive symptoms and antidepressant medication use were self-reported. RESULTS After controlling for confounding factors, depressive symptoms were associated with higher fasting and 30-min insulin during the OGTT and higher HOMA-IR but not CIR. Antidepressant medication use failed to modify these associations. CONCLUSIONS Depressive symptoms are associated with IR but not with changes in insulin response when corrected for IR in individuals without previously or newly diagnosed diabetes.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc11-0107
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2011
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  • 6
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    An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans
    American Diabetes Association ; 2017
    In:  Diabetes Vol. 66, No. 11 ( 2017-11-01), p. 2888-2902
    Details
    In: Diabetes, American Diabetes Association, Vol. 66, No. 11 ( 2017-11-01), p. 2888-2902
    Abstract: To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P & lt; 5 × 10−8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action–associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db16-1253
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2017
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  • 7
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    Impact of an Exercise Intervention on DNA Methylation in Skeletal Muscle From First-Degree Relatives of Patients With Type 2 Diabetes
    American Diabetes Association ; 2012
    In:  Diabetes Vol. 61, No. 12 ( 2012-12-01), p. 3322-3332
    Details
    In: Diabetes, American Diabetes Association, Vol. 61, No. 12 ( 2012-12-01), p. 3322-3332
    Abstract: To identify epigenetic patterns, which may predispose to type 2 diabetes (T2D) due to a family history (FH) of the disease, we analyzed DNA methylation genome-wide in skeletal muscle from individuals with (FH+) or without (FH−) an FH of T2D. We found differential DNA methylation of genes in biological pathways including mitogen-activated protein kinase (MAPK), insulin, and calcium signaling (P ≤ 0.007) and of individual genes with known function in muscle, including MAPK1, MYO18B, HOXC6, and the AMP-activated protein kinase subunit PRKAB1 in skeletal muscle of FH+ compared with FH− men. We further validated our findings from FH+ men in monozygotic twin pairs discordant for T2D, and 40% of 65 analyzed genes exhibited differential DNA methylation in muscle of both FH+ men and diabetic twins. We further examined if a 6-month exercise intervention modifies the genome-wide DNA methylation pattern in skeletal muscle of the FH+ and FH− individuals. DNA methylation of genes in retinol metabolism and calcium signaling pathways (P & lt; 3 × 10−6) and with known functions in muscle and T2D including MEF2A, RUNX1, NDUFC2, and THADA decreased after exercise. Methylation of these human promoter regions suppressed reporter gene expression in vitro. In addition, both expression and methylation of several genes, i.e., ADIPOR1, BDKRB2, and TRIB1, changed after exercise. These findings provide new insights into how genetic background and environment can alter the human epigenome.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db11-1653
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2012
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  • 8
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    Online Resource
    Stressful Life Events and the Metabolic Syndrome
    American Diabetes Association ; 2010
    In:  Diabetes Care Vol. 33, No. 2 ( 2010-02-01), p. 378-384
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 33, No. 2 ( 2010-02-01), p. 378-384
    Abstract: Stress may play a role in the pathogenesis of the metabolic syndrome. However, the scant evidence available is not population-based, restricting the external validity of the findings. Our aim was to test associations between stressful life events, their accumulation, and the metabolic syndrome in a large population-based cohort. We also tested associations between stress and the individual components related to the metabolic syndrome. RESEARCH DESIGN AND METHODS This was a population-based, random sample of 3,407 women and men aged 18–78 years residing in Western Finland. Metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III and International Diabetes Federation criteria. The severity of 15 stressful life events pertaining to finance, work, social relationships, health, and housing was self-rated. RESULTS In comparison with subjects not reporting any extremely stressful life events, those reporting work- or finance-related events had an increased odds for having the metabolic syndrome. The risk was further increased according to accumulation of stressful finance-related events and to having at least three stressful life events in any of the life domains assessed. Accumulation of stressful life events was associated with insulin resistance, obesity, and triglycerides. The associations were not confounded by sex, age, lifestyle, or family history of diabetes. CONCLUSIONS Life events perceived as stressful, particularly those related to finance and work, may be a signal for poor metabolic health.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc09-1027
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2010
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  • 9
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    Expression of Phosphofructokinase in Skeletal Muscle Is Influenced by Genetic Variation and Associated With Insulin Sensitivity
    American Diabetes Association ; 2014
    In:  Diabetes Vol. 63, No. 3 ( 2014-03-01), p. 1154-1165
    Details
    In: Diabetes, American Diabetes Association, Vol. 63, No. 3 ( 2014-03-01), p. 1154-1165
    Abstract: Using an integrative approach in which genetic variation, gene expression, and clinical phenotypes are assessed in relevant tissues may help functionally characterize the contribution of genetics to disease susceptibility. We sought to identify genetic variation influencing skeletal muscle gene expression (expression quantitative trait loci [eQTLs]) as well as expression associated with measures of insulin sensitivity. We investigated associations of 3,799,401 genetic variants in expression of & gt;7,000 genes from three cohorts (n = 104). We identified 287 genes with cis-acting eQTLs (false discovery rate [FDR] & lt;5%; P & lt; 1.96 × 10−5) and 49 expression–insulin sensitivity phenotype associations (i.e., fasting insulin, homeostasis model assessment–insulin resistance, and BMI) (FDR & lt;5%; P = 1.34 × 10−4). One of these associations, fasting insulin/phosphofructokinase (PFKM), overlaps with an eQTL. Furthermore, the expression of PFKM, a rate-limiting enzyme in glycolysis, was nominally associated with glucose uptake in skeletal muscle (P = 0.026; n = 42) and overexpressed (Bonferroni-corrected P = 0.03) in skeletal muscle of patients with T2D (n = 102) compared with normoglycemic controls (n = 87). The PFKM eQTL (rs4547172; P = 7.69 × 10−6) was nominally associated with glucose uptake, glucose oxidation rate, intramuscular triglyceride content, and metabolic flexibility (P = 0.016–0.048; n = 178). We explored eQTL results using published data from genome-wide association studies (DIAGRAM and MAGIC), and a proxy for the PFKM eQTL (rs11168327; r2 = 0.75) was nominally associated with T2D (DIAGRAM P = 2.7 × 10−3). Taken together, our analysis highlights PFKM as a potential regulator of skeletal muscle insulin sensitivity.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db13-1301
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2014
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  • 10
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    Online Resource
    Metformin Normalizes Nonoxidative Glucose Metabolism in Insulin-Resistant Normoglycemic First-Degree Relatives of Patients With NIDDM
    American Diabetes Association ; 1992
    In:  Diabetes Vol. 41, No. 3 ( 1992-03-01), p. 354-358
    Details
    In: Diabetes, American Diabetes Association, Vol. 41, No. 3 ( 1992-03-01), p. 354-358
    Abstract: Many first-degree relatives of patients with non-insulin-dependent diabetes mellitus (NIDDM) are characterized by insulin resistance. Because metformin improves peripheral insulin sensitivity, we examined the acute effect of metformin and placebo on glucose and lipid metabolism in nine insulin-resistant first-degree relatives of NIDDM patients with the euglycemic insulin-clamp technique combined with indirect calorimetry and infusion of [3-3H]glucose. Either placebo or 500 mg metformin was taken in random order twice the day before and once 1 h before the clamp. Nine healthy individuals without family history of diabetes served as control subjects. Basal plasma glucose was normal and did not differ between the metformin and the placebo study (4.8 ± 0.2 vs. 5.0 ± 0.2 mM) and neither did basal hepatic glucose production (10.59 ± 0.54 vs. 10.21 ± 0.80 μmol · kg−1 · min−1). Insulin-stimulated glucose disposal was significantly increased by 25% after metformin compared with placebo (26.67 ± 2.87 vs. 21.31 ± 1.73 μmol kg−1 min−1 P & lt; 0.05). The enhancement in glucose utilization was primarily due to normalization of nonoxidative glucose disposal (from 8.02 ± 1.35 to 15.07 ± 2.69 μmol kg−1 min−1 P & lt; 0.01, vs. 15.65 ± 2.72 μmol kg−1 min−1 in control subjects). In contrast, glucose oxidation during the clamp was slightly lower after metformin compared with both placebo (11.59 ± 0.83 vs. 13.30 ± 1.00 μmol kg−1 min−1 P = 0.06) and healthy control subjects (15.68 ± 1.38 μmol kg−1 min−1 P & lt; 0.05). We conclude that acutely administered metformin improves peripheral insulin sensitivity in insulin-resistant normoglycemic individuals primarily by stimulating the nonoxidative pathway of glucose metabolism.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/diab.41.3.354
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 1992
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