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Forskargrupp Tillväxt och metabolism

Harvest F. Gu is responsible for genetic and functional analyses in diabetes, obesity and diabetic complications especially nephropathy.

A. Genetic and epigenetic studies of diabetes and diabetic nephropathy with focus on IGF-IGFBP pathway

Diabetes and diabetic nephropathy are influenced by genetic and environmental factors. This research program is focused on genetic and epigenetic analyses of the IGF-IGFBP (insulin-like growth factors and their binding proteins) elements in diabetes and diabetic nephropathy. This pathway includes transcription factors, receptors, binding proteins etc. which not only control the properties of growth and development but also play important role on glucose regulation and pathogenesis of diabetes and diabetic nephropathy. We investigate DNA polymorphisms and methylation levels of the candidate genes in this system and also analyse the gene expression at protein levels. We aim to evaluate the genetic and epigenetic effects of the IGF-IGFBP genes in diabetes and diabetic nephropathy. The information from our studies will be useful for better understanding the pathogenesis of the diseases.

Selected publications:

1. Gu T, Gu HF, Hilding A, Sjöholm LK, Ostenson CG, Ekström TJ, Brismar K. Increased DNA methylation levels of the insulin-like growth factor binding protein 1 gene are associated with type 2 diabetes in Swedish men. Clin Epigenetics. 2013 5(1):21.

2. Gu HF, Gu T, Hilding A, Zhu Y, Kärvestedt L, Ostenson CG, Lai M, Kutsukake M, Frystyk J, Tamura K, Brismar K. Evaluation of IGFBP-7 DNA methylation changes and serum protein variation in Swedish subjects with and without type 2 diabetes. Clin Epigenetics. 2013 5(1):20.

3. Gu T, Horová E, Möllsten A, Seman NA, Falhammar H, Prázný M, Brismar K, Gu HF. IGF2BP2 and IGF2 genetic effects in diabetes and diabetic nephropathy. J Diabetes Complications. 2012 26(5):393-8.

4. Strawbridge RJ, Dupuis J, Prokopenko I,…Gu HF,…Langenberg C,Hamsten A, Florez JC. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes. Diabetes. 2011 60(10):2624-34.

B. Search for biomarkers in diabetic nephropathy

The natural history of diabetic nephropathy is a process that progresses gradually over the years. The process is categorized into the stages from normoalbuminuria, microalbuminuria, proteinuria and end stage renal disease (ESRD). Genetic and environmental factors are involved in the development of the diseases. Currently, urinary albumin excretion values are used as biomarkers for prediction of diabetic nephropathy. The markers, however, are late and subsequently less useful for early diagnosis and prediction in the prevention program of diabetic nephropathy. In this project, we investigate genomic DNA polymorphisms, methylation changes and plasma/serum protein variation in type 1 diabetes, type 2 diabetes with and without diabetic nephropathy. The information from our studies will be useful for further evaluation of novel biomarkers in diabetic nephropathy.

Selected publications:

1. Gu HF, Zheng X, Abu Seman N, Gu T, Botusan IR, Sunkari VG, Lokman EF, Brismar K, Catrina SB. Impact of the Hypoxia-Inducible Factor-1 α (HIF-1α) Pro582Ser Polymorphism on Diabetes Nephropathy. Diabetes Care. 2013 36(2):415-21.

2. Sandholm N, Salem RM, McKnight AJ, ...Falhammar H,…Gu HF, Brismar K ...Godson C, Florez JC, Groop PH, Maxwell AP. New susceptibility Loci associated with kidney disease in type 1 diabetes. PLoS Genet. 2012 8(9):e1002921.

3. Gu HF, Ma J, Gu KT, Brismar K. Association of intercellular adhesion molecule 1 (ICAM1) with diabetes and diabetic nephropathy. Front Endocrinol (Lausanne).2013 3:179-185.

4. Gu HF, Brismar K. Genetic association studies in diabetic nephropathy. Curr Diabetes Rev. 2012 8(5):336-44. Review.

5. Zhang D, Gu T, Forsberg E, Efendic S, Brismar K, Gu HF. Genetic and functional effects of membrane metalloendopeptidase on diabetic nephropathy development. Am J Nephrol. 2011 34(5):483-90.

6. Gu HF. Genetic studies of diabetic nephropathy. In Nephropathy Diagnosis and Treatment 2012 (Nova, New York). Pages 379-398, Book chapter.

C. Evaluation of AC3 as a novel target for anti-obesity drug development

Adenylyl cyclases (ACs) are enzymes that catalyze the synthesis of cAMP from ATP. We for the first time demonstrated that AC3 genetic polymorphisms are associated with obesity in normal glucose tolerance subjects and type 2 diabetic patients but not with fasting plasma glucose and insulin levels in type 2 diabetic patients in a Swedish population. We replicated genetic study and found that the AC3 genetic polymorphisms are associated with decreased risk of obesity among adults, but not in children in a Chinese population and suggested that AC3 may interact with factors related to ageing and environment. Moreover, AC3 knockout mice are found to develop obesity when ageing. We have very recently analysed the AC3 gene expression displays in visceral, omental and thigh fat tissues collected from Swedish type 2 diabetes patients, obese and lean subjects. The aims are to investigate the important role of AC3 in abdominal obesity and to evaluate the possibility of anti-obesity drug development.

Related references:

1. Seed Ahmed M, Kovoor A, Nordman S, Abu Seman N, Gu T, Efendic S, Brismar K, Östenson CG, Gu HF. Increased expression of adenylyl cyclase 3 in pancreatic islets and central nervous system of diabetic Goto-Kakizaki rats: a possible regulatory role in glucose homeostasis. Islets. 2012 4(5):343-8.

2. Gu HF. Open Diabetes J 2010 3:11-13.

3. Wang H, Wu M, Zhu W, Shen J, Shi X, Yang J, Zhao Q, Ni C, Xu Y, Shen H, Shen C, Gu HF. Evaluation of the association between the AC3 genetic polymorphisms and obesity in a Chinese Han population. PLoS One. 2010 5(11):e13851.

4. Wang Z, Li V, Chan GC, Phan T, Nudelman AS, Xia Z, Storm DR. Adult type 3adenylyl cyclase-deficient mice are obese. PLoS One. 2009 4(9):e6979.

5. Nordman S, Abulaiti A, Hilding A, Långberg EC, Humphreys K, Ostenson CG,Efendic S, Gu HF. Genetic variation of the adenylyl cyclase 3 (AC3) locus and its influence on type 2 diabetes and obesity susceptibility in Swedish men. Int J Obes (Lond). 2008 32(3):407-12.

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