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Diabetes - Ursachen und Behandlung

Diabetes Typ 2 und Vererbung

Neben den zahlreichen Lebensstil-bedingten Faktoren, die eine Diabetes-Erkrankung vom Typ 2 fördern, spielen auch genetische Faktoren eine Rolle für das individuelle Diabetes-Risiko. Ist ein naher Verwandter an Diabetes Typ 2 erkrankt, steigt das Risiko, ebenfalls an Diabetes zu erkranken, um das 3,5fache an. Welche Gene das Diabetes-Risiko erhöhen, ist noch weitgehend ungeklärt.

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Der Transkriptionsfaktor TCF7L2

Der Transkriptionsfaktor TCF7L2 (synonym: HTCF-4; jede Farbe steht für eine Aminosäure). PDB-Code: 1JDH.

Bereits länger bekannt ist, dass eine bestimmte Variante des TCF7L21) mit einem höheren Diabetes-Risiko verbunden ist und vermutlich eine reduzierte Insulin-Ausschüttung der β-Zellen der Bauchspeicheldrüse verursacht. Kanadische Wissenschaftler, die fast 400.000 single nucleotide polymorphisms (SNPs) untersuchten, identifizierten zwei weitere Genorte, die mit Diabetes assoziiert sind - einen Zink-Transporter SLC30A8, der nur in Insulin-produzierenden β-Zellen exprimiert wird, und einen Bereich des Genoms, der mit der Entwicklung oder Funktion der β-Zellen zu tun hat.

In der EPIC2)-Potsdam-Studie wurden mit einem speziellen Fragebogen zwischen 1994 und 1998 insgesamt mehr als 27.500 Teilnehmer im Alter von 35 bis 65 Jahren untersucht - unter anderem, um neben Faktoren wie Übergewicht, Ernährung und Lebensstil auch den Einfluss genetischer Faktoren auf das Diabetes-Risiko zu überprüfen (Link zum Diabetes Risiko Score). Der Test auf genetische Faktoren wurde mit zunächst 2.500 Teilnehmern durchgeführt, bei denen zusätzlich zum deutschen DRS3) 20 Gene anhand von SNPs analysiert wurden, die als Indikatoren für einen möglichen Diabetes Typ 2 gelten.

Nach sieben Jahren stellte sich heraus, dass die allgemeinen Risikofaktoren aufgrund eines bestimmten Lebensstils (Bewegungsmangel, Rauchen, Alkohol, Ernährung, die alle in den DRS Eingang gefunden haben) sehr gut geeignet sind, Risikopatienten zu identifizieren, nicht aber genetische Faktoren auf der Basis der 20 getesteten Marker. Dieses Ergebnis bedeutet nicht, dass diese genetische Faktoren keinen Einfluss auf das Risiko, Diabetes zu entwickeln, haben - es bedeutet lediglich, dass aufgrund der Vielzahl der an Diabetes beteiligten Gene derzeit keine Aussagen möglich sind, wie hoch das genetisch bedingte Risiko einer Person wirklich ist.

Weitere Information zu genetischen Faktoren des Diabetes finden Sie u.a. auf der Webseite des Deutschen Instituts für Ernährungsforschung Potsdam-Rehbrücke (DIfE).

Literatur

Fisher, E.; Boeing, H.; Fritsche, A.; Doering, F.; Joost, H. G.; Schulze, M. B. (2009): Whole-grain consumption and transcription factor-7-like 2 (TCF7L2) rs7903146: gene - diet interaction in modulating type 2 diabetes risk. In: British Journal of Nutrition. 101 , 478-481
Titel des Artikels
Whole-grain consumption and transcription factor-7-like 2 (TCF7L2) rs7903146: gene - diet interaction in modulating type 2 diabetes risk
Abstract
Whole grains are known to influence postprandial glucose response and insulin demand and are inversely associated with diabetes risk. Genetic variation of the transcription factor-7-like 2 encoding gene (TCF7L2) is assumed to promote an early insulin secretory defect and has been consistently attributed to the risk of developing type 2 diabetes. The present study examined the hypothesis that the protective effect of whole grains might be attenuated in the presence of the rs7903146 risk-conferring T-allele. We employed a case–cohort study of 2318 randomised individuals and 724 incident type 2 diabetes cases from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort. Multivariate Cox regression was used to estimate relative risks of diabetes including product terms testing for the genotype-specific effect modification of dietary whole grain. Dietary intake of whole grains was assessed by a validated FFQ. The TCF7L2 rs7903146 T-allele was associated with type 2 diabetes (hazard ratio = 1·51; 95 % CI 1·21, 1·87) and modified the inverse association between whole-grain intake and diabetes risk (P = 0·016 for interaction). While whole-grain intake was inversely associated with diabetes risk among rs7903146 CC homozygote carriers (hazard ratio for 50 g portion per d = 0·86; 95 % CI 0·75, 0·99), the T-allele negated the protective effect of whole-grain intake (hazard ratio among T-allele carriers for 50 g portion per d = 1·08; 95 % CI 0·96, 1·23). These data provide evidence that the beneficial effect of whole-grain intake on diabetes risk is modified by TCF7L2 rs7903146.
Sladek, R.; Rocheleau, G.; Rung, J.; Dina, C.; Shen, L.; Serre , D.; Boutin, P.; Vincent, D.; Belisle, A.; Hadjadj, S.; Balkau, B.; Heude, B.; Charpentier, G.; Hudson, T. J.; Montpetit, A.; Pshezhetsky, A. V.; Prentki, M.; Posner, B. I.; Balding, D. J.; Meyre, D.; Polychronakos, C.; Froguel, P. (2007): A genome-wide association study identifies novel risk loci for type 2 diabetes. In: Nature. 445 , 881-5
Titel des Artikels
A genome-wide association study identifies novel risk loci for type 2 diabetes
Abstract
Type 2 diabetes mellitus results from the interaction of environmental factors with a combination of genetic variants, most of which were hitherto unknown. A systematic search for these variants was recently made possible by the development of high-density arrays that permit the genotyping of hundreds of thousands of polymorphisms. We tested 392,935 single-nucleotide polymorphisms in a French case-control cohort. Markers with the most significant difference in genotype frequencies between cases of type 2 diabetes and controls were fast-tracked for testing in a second cohort. This identified four loci containing variants that confer type 2 diabetes risk, in addition to confirming the known association with the TCF7L2 gene. These loci include a non-synonymous polymorphism in the zinc transporter SLC30A8, which is expressed exclusively in insulin-producing beta-cells, and two linkage disequilibrium blocks that contain genes potentially involved in beta-cell development or function (IDE-KIF11-HHEX and EXT2-ALX4). These associations explain a substantial portion of disease risk and constitute proof of principle for the genome-wide approach to the elucidation of complex genetic traits.
Schulze, M. B.; Hoffmann, K.; Boeing, H.; Joost, H. G. (2007): Der Deutsche Diabetes Risiko-Score (DRS). In: Ernährungs Umschau. 3 , 122-127
Schulze, M. B.; Weikert, C.; Pischon, T.; Bergmann, M. M.; Al-Hasani, H.; Schleicher, E.; Fritsche, A.; Häring, H. U.; Boeing, H.; Joost, H. G. (2009): Use of Multiple Metabolic and Genetic Markers to Improve the Prediction of Type 2 Diabetes: the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study. In: Diabetes Care . 11 , 2116-9
Titel des Artikels
Use of Multiple Metabolic and Genetic Markers to Improve the Prediction of Type 2 Diabetes: the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study
Abstract
OBJECTIVE: We investigated whether metabolic biomarkers and single nucleotide polymorphisms (SNPs) improve diabetes prediction beyond age, anthropometry, and lifestyle risk factors. RESEARCH DESIGN AND METHODS: A case-cohort study within a prospective study was designed. We randomly selected a subcohort (n = 2,500) from 26,444 participants, of whom 1,962 were diabetes free at baseline. Of the 801 incident type 2 diabetes cases identified in the cohort during 7 years of follow-up, 579 remained for analyses after exclusions. Prediction models were compared by receiver operatoring characteristic (ROC) curve and integrated discrimination improvement. RESULTS: Case-control discrimination by the lifestyle characteristics (ROC-AUC: 0.8465) improved with plasma glucose (ROC-AUC: 0.8672, P < 0.001) and A1C (ROC-AUC: 0.8859, P < 0.001). ROC-AUC further improved with HDL cholesterol, triglycerides, gamma-glutamyltransferase, and alanine aminotransferase (0.9000, P = 0.002). Twenty SNPs did not improve discrimination beyond these characteristics (P = 0.69). CONCLUSIONS: Metabolic markers, but not genotyping for 20 diabetogenic SNPs, improve discrimination of incident type 2 diabetes beyond lifestyle risk factors.
Chadt, A.; Leicht, K.; Deshmukh, A.; Jiang, L. Q.; Scherneck, S.; Bernhardt, U.; Dreja, T.; Vogel, H.; Schmolz, K.; Kluge, R.; Zierath, J. R.; Hultschig, C.; Hoeben, R. C.; Schürmann, A.; Joost, H. G.; Al-Hasani, A. (2008): Tbc1d1 mutation in lean mouse strain confers leanness and protects from diet-induced obesity.. In: Nat. Genet.. 11 , 1354-9
Titel des Artikels
Tbc1d1 mutation in lean mouse strain confers leanness and protects from diet-induced obesity.
Abstract
We previously identified Nob1 as a quantitative trait locus for high-fat diet-induced obesity and diabetes in genome-wide scans of outcross populations of obese and lean mouse strains. Additional crossbreeding experiments indicated that Nob1 represents an obesity suppressor from the lean Swiss Jim Lambert (SJL) strain. Here we identify a SJL-specific mutation in the Tbc1d1 gene that results in a truncated protein lacking the TBC Rab-GTPase-activating protein domain. TBC1D1, which has been recently linked to human obesity, is related to the insulin signaling protein AS160 and is predominantly expressed in skeletal muscle. Knockdown of TBC1D1 in skeletal muscle cells increased fatty acid uptake and oxidation, whereas overexpression of TBC1D1 had the opposite effect. Recombinant congenic mice lacking TBC1D1 showed reduced body weight, decreased respiratory quotient, increased fatty acid oxidation and reduced glucose uptake in isolated skeletal muscle. Our data strongly suggest that mutation of Tbc1d1 suppresses high-fat diet-induced obesity by increasing lipid use in skeletal muscle.

Zugang zur PubMed-Datenbank

1)TCF7L2: transcription factor 7-like 2
2)EPIC: European Prospective Investigation into Cancer and Nutrition
3)DRS: Diabetes Risiko Score
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