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3. Genetic risk factors affecting mitochondrial function are associated with kidney disease in people with Type 1 diabetes.

Author

Swan, E, Salem, Rany, Sandholm, N, Tarnow, L, Rossing, P, Lajer, M, Groop, P, Maxwell, A, and McKnight, A

Subjects
Adult, Aged, Case-Control Studies, Diabetes Mellitus, Type 1, Diabetic Nephropathies, Female, Genetic Predisposition to Disease, Genome, Mitochondrial, Humans, Kidney Failure, Chronic, Male, Middle Aged, Mitochondria, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic
Abstract

AIM: To evaluate the association with diabetic kidney disease of single nucleotide polymorphisms (SNPs) that may contribute to mitochondrial dysfunction. METHODS: The mitochondrial genome and 1039 nuclear genes that are integral to mitochondrial function were investigated using a case (n = 823 individuals with diabetic kidney disease) vs. control (n = 903 individuals with diabetes and no renal disease) approach. All people included in the analysis were of white European origin and were diagnosed with Type 1 diabetes before the age of 31 years. Replication was conducted in 5093 people with similar phenotypes to those of the discovery collection. Association analyses were performed using the plink genetic analysis toolset, with adjustment for relevant covariates. RESULTS: A total of 25 SNPs were evaluated in the mitochondrial genome, but none were significantly associated with diabetic kidney disease or end-stage renal disease. A total of 38 SNPs in nuclear genes influencing mitochondrial function were nominally associated with diabetic kidney disease and 16 SNPS were associated with end-stage renal disease, secondary to diabetic kidney disease, with meta-analyses confirming the same direction of effect. Three independent signals (seven SNPs) were common to the replication data for both phenotypes with Type 1 diabetes and persistent proteinuria or end-stage renal disease. CONCLUSIONS: Our results suggest that SNPs in nuclear genes that influence mitochondrial function are significantly associated with diabetic kidney disease in a white European population.

Published
2015

4. Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes

Author

Albrechtsen, A, Grarup, N, Li, Y, Sparsø, T, Tian, G, Cao, H, Jiang, T, Kim, SY, Korneliussen, T, Li, Q, Nie, C, Wu, R, Skotte, L, Morris, AP, Ladenvall, C, Cauchi, S, Stančáková, A, Andersen, G, Astrup, A, Banasik, K, Bennett, AJ, Bolund, L, Charpentier, G, Chen, Y, Dekker, JM, Doney, ASF, Dorkhan, M, Forsen, T, Frayling, TM, Groves, CJ, Gui, Y, Hallmans, G, Hattersley, AT, He, K, Hitman, GA, Holmkvist, J, Huang, S, Jiang, H, Jin, X, Justesen, JM, Kristiansen, K, Kuusisto, J, Lajer, M, Lantieri, O, Li, W, Liang, H, Liao, Q, Liu, X, Ma, T, Ma, X, Manijak, MP, Marre, M, Mokrosiński, J, Morris, AD, Mu, B, Nielsen, AA, Nijpels, G, Nilsson, P, Palmer, CNA, Rayner, NW, Renström, F, Ribel-Madsen, R, Robertson, N, Rolandsson, O, Rossing, P, Schwartz, TW, Slagboom, PE, Sterner, M, D.E.S.I.R. Study Group, Tang, M, Tarnow, L, the DIAGRAM Consortium, Tuomi, T, van’t Riet, E, van Leeuwen, N, Varga, TV, Vestmar, MA, Walker, M, Wang, B, Wang, Y, Wu, H, Xi, F, Yengo, L, Yu, C, Zhang, X, Zhang, J, Zhang, Q, Zhang, W, Zheng, H, Zhou, Y, Altshuler, D, ‘t Hart, LM, Franks, PW, Balkau, B, Froguel, P, McCarthy, MI, Laakso, M, Groop, L, Christensen, C, and Brandslund, I

Subjects
Diabetes, Human Genome, Nutrition, Genetics, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Diabetes Mellitus, Type 2, Exome, Gene Frequency, Genotype, High-Throughput Nucleotide Sequencing, Humans, Hypertension, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Exome sequencing, Genetic epidemiology, Lipids, Next-generation sequencing, Obesity, Type 2 diabetes, D.E.S.I.R. Study Group, DIAGRAM Consortium, Clinical Sciences, Paediatrics and Reproductive Medicine, Public Health and Health Services, Endocrinology & Metabolism
Abstract

Aims/hypothesisHuman complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes.MethodsThe study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p 1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10(-10)).Conclusions/interpretationWe applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.

Published
2013

5. The effect of metformin versus placebo in combination with insulin analogues on bone mineral density and trabecular bone score in patients with type 2 diabetes mellitus: a randomized placebo-controlled trial

Author

Nordklint, A. K., Almdal, T. P., Vestergaard, P., Lundby-Christensen, L., Boesgaard, T. W., Breum, L., Gade-Rasmussen, B., Sneppen, S. B., Gluud, C., Hemmingsen, B., Jensen, T., Krarup, T., Madsbad, S., Mathiesen, E. R., Perrild, H., Tarnow, L., Thorsteinsson, B., Vestergaard, H., Lund, S. S., and Eiken, P.

Published
2018
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15. Effect of metformin and insulin vs. placebo and insulin on whole body composition in overweight patients with type 2 diabetes:a randomized placebo-controlled trial

Author

Nordklint, A. K., Almdal, T. P., Vestergaard, P., Lundby-Christensen, L., Boesgaard, T. W., Breum, L., Gade-Rasmussen, B., Sneppen, S. B., Gluud, C., Hemmingsen, B., Perrild, H., Madsbad, S., Mathiesen, E. R., Tarnow, L., Thorsteinsson, B., Vestergaard, H., Lund, S. S., Eiken, P., Nordklint, A. K., Almdal, T. P., Vestergaard, P., Lundby-Christensen, L., Boesgaard, T. W., Breum, L., Gade-Rasmussen, B., Sneppen, S. B., Gluud, C., Hemmingsen, B., Perrild, H., Madsbad, S., Mathiesen, E. R., Tarnow, L., Thorsteinsson, B., Vestergaard, H., Lund, S. S., and Eiken, P.

Abstract

Summary: Some studies indicate potential beneficial effects of metformin on body composition and bone. This trial compared metformin + insulin vs placebo + insulin. Metformin treatment had a small but positive effect on bone quality in the peripheral skeleton, reduced weight gain, and resulted in a more beneficial body composition compared with placebo in insulin-treated patients with type 2 diabetes. Introduction: Glucose-lowering medications affect body composition. We assessed the long-term effects of metformin compared with placebo on whole body bone and body composition measures in patients with type 2 diabetes mellitus. Methods: This was a sub-study of the Copenhagen Insulin and Metformin Therapy trial, which was a double-blinded randomized placebo-controlled trial assessing 18-month treatment with metformin compared with placebo, in combination with different insulin regimens in patients with type 2 diabetes mellitus (T2DM). The sub-study evaluates the effects on bone mineral content (BMC), density (BMD), and body composition from whole body dual-energy X-ray absorptiometry (DXA) scans which were assessed at baseline and after 18 months. Results: Metformin had a small, but positive, (p < 0.05) effect on subtotal, appendicular, and legs BMC and BMD compared with placebo. After adjustment for sex, age, vitamin D, smoking, BMI, T2DM duration, HbA1c, and insulin dose, the effects on appendicular BMC and BMD persisted (p < 0.05 for both). The changes in appendicular BMC and BMD corresponded approximately to a 0.7% and 0.5% increase in the metformin group and 0.4% and 0.4% decrease in the placebo group, respectively. These effects were mostly driven by an increase in BMC and BMD in the legs and a loss of BMC and BMD in the arms. During 18 months, all participants increased in weight, fat mass (FM), FM%, and lean mass (LM), but decreased in LM%. The metformin group increased less in weight (subtotal weight (weight-head) − 2.4 [− 3.5, − 1.4] kg, p value

Published
2021

31. COMPARISON OF INSULIN DEGLUDEC AND GLARGINE U100 IN PATIENTS WITH TYPE 1 DIABETES PRONE TO SEVERE NOCTURNAL HYPOGLYCAEMIA

Author

Agesen, R., Alibegovic, A., Andersen, H., Beck-Nielsen, H., Gustenhoff, P., Hansen, T., Hedetoft, C., Jensen, T., Juhl, C., Kryger, A., Lerche, S., Norgaard, K., Parving, H. -H., Sørensen, A., Tarnow, L., Thorsteinsson, B., Pedersen-Bjergaard, U., Agesen, R., Alibegovic, A., Andersen, H., Beck-Nielsen, H., Gustenhoff, P., Hansen, T., Hedetoft, C., Jensen, T., Juhl, C., Kryger, A., Lerche, S., Norgaard, K., Parving, H. -H., Sørensen, A., Tarnow, L., Thorsteinsson, B., and Pedersen-Bjergaard, U.

Published
2020

45. Study rationale and design of the CIMT trial: The Copenhagen Insulin and Metformin Therapy Trial

Author

Lundby Christensen, L., Almdal, T., Boesgaard, T., Breum, L., Dunn, E., Gade-Rasmussen, B., Gluud, C., Hedetoft, C., Jarloev, A., Jensen, T., Krarup, T., Johansen, L. B., Lund, S. S., Madsbad, S., Mathiesen, E., Moelvig, J., Nielsen, F., Perrild, H., Pedersen, O., Roeder, M., Sneppen, S. B., Snorgaard, O., Tarnow, L., Thorsteinsson, B., Vaag, A., Vestergaard, H., Wetterslev, J., and Wiinberg, N.

Published
2009
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