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- Klannemark, Mia
(author)
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Genetics of type 2 diabetes and the metabolic syndrome
- 2001
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Doctoral thesis (other academic/artistic)abstract
- Type 2 diabetes and the metabolic syndrome are highly prevalent disorders with severe complications such as cardiovascular disease. The aetiology of type 2 diabetes and the metabolic syndrome is not known, but the interaction between genetic factors and environmental triggers is important. The aim this thesis was to identify genetic factors that may increase susceptibility to these disorders by investigating candidate genes regulating lipolysis (hormone-sensitive lipase, HSL, lipoprotein lipase, LPL and phosphodiesterase 3B, PDE3B), thermogenesis (uncoupling protein 2, UCP2) and adipogenesis (peroxisome proliferator-activated receptor gamma, PPARG). Four of the genes were screened for mutations and identified variants were tested for association in large intra-familial and case-control association studies. Variability in the UCP2 gene was not associated with alterations in basal metabolic rate or with obesity. The gene encoding HSL was associated with type 2 diabetes in a case-control study, and the LIPE marker of the HSL gene showed distorted transmission to abdominally obese offspring. The PDE3B gene was associated with hyperinsulinaemia in genotype-discordant siblings. Haplotypes including several variants on chromosome 11 were unequally transmitted to offspring with abnormal glucose tolerance. The studies also provided evidence for an interaction between a variant in the LPL gene and insulin sensitivity. In a large, family-based multi-step study we could show that genetic variability in the gene encoding PPARG is associated with a reduced risk for diabetes, supported by the consistent results in a meta-analysis on the same variant. In conclusion, variability in genes regulating lipolysis and adipogenesis increase susceptibility to type 2 diabetes and the metabolic syndrome. Prospective studies will be helpful to establish the risk associated with the potential genetic riskfactors presented in this thesis.
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| 2. |
- Klannemark, Mia, et al.
(author)
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Interaction between the Asn291Ser variant of the LPL gene and insulin resistance on dyslipidaemia in high risk individuals for Type 2 diabetes mellitus
- 2000
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In: Diabetic Medicine. - : Wiley. - 1464-5491 .- 0742-3071. ; 17:8, s. 599-605
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Journal article (peer-reviewed)abstract
- AIMS: Lipoprotein lipase (LPL) is a major regulator of triglyceride clearance. A genetic variant of the LPL gene on chromosome 8p22, Asn291Ser, has previously been associated with dyslipidaemia and an increased frequency of cardiovascular disease as well as familial disorders of lipoprotein metabolism. The aim of this study was to test whether the phenotypic expression of the LPL Asn291Ser variant is dependent upon glucose tolerance and insulin resistance. Therefore, the Asn291Ser variant was examined in 192 patients with Type 2 diabetes, 278 subjects with normal glucose tolerance who are first degree relatives of patients with Type 2 diabetes and 226 healthy control spouses without family history of diabetes. METHODS: The subjects were genotyped with an allele-specific mini-sequencing method. Insulin resistance was estimated using the homeostasis model assessment (HOMA) index. RESULTS: The frequency of the Asn/Ser genotype was significantly increased in normoglycaemic subjects with hypertriglyceridaemia (> 1.7 mmol/1), and was associated with dyslipidaemia and increased systolic blood pressure. There was a significant interaction between Asn291Ser and insulin resistance in normoglycaemic subjects, indicating that dyslipidaemia is more severe in Asn/ Ser carriers with reduced insulin sensitivity. The frequency of the Asn/Ser genotype was not increased in diabetic subjects with hypertriglyceridaemia, but was associated with increased systolic blood pressure. CONCLUSIONS: The Asn/Ser genotype of the LPL gene is associated with dyslipidaemia in normoglycaemic subjects, and the dyslipidaemic phenotype is more severe in insulin-resistant subjects. This association is not seen in diabetic subjects.
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| 3. |
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| 4. |
- Lindholm, Eero, et al.
(author)
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Putative role of polymorphisms in UCP1-3 genes for diabetic nephropathy.
- 2004
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In: Journal of Diabetes and its Complications. - 1873-460X. ; 18:2, s. 103-107
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Journal article (peer-reviewed)abstract
- Increased production of reactive oxygen species (ROS) has been suggested as a cause of diabetic complications. Uncoupling proteins (UCPs) have been ascribed a role in reducing the formation of ROS, and genetic variation in genes encoding for UCPs could thus be putative candidate genes for diabetic nephropathy. To test this hypothesis we searched for association between the A→G (−3862) variant in UCP1, the insertion/deletion (I/D) polymorphism in exon 8 in UCP2, and the C→T (−55) polymorphism in UCP3 and diabetic nephropathy in 218 diabetic patients with normal urinary albumin excretion rate (AER), 216 with micro- or macroalbuminuria, and in 106 control subjects without a family history of diabetes. We did not find any association between the different polymorphisms and diabetic nephropathy, nor did we observe any difference in AER among carriers of different UCP1–3 genotypes. We could, however, confirm the reported association between BMI and the UCP3 −55 C→T polymorphism; patients carrying the T allele had higher BMI than patients homozygous for the C allele (26.4±4.2 vs. 25.3±4.3 kg/m2; P=.01). We conclude that studied polymorphisms in the UCP1–3 genes do not play a major role in the development of micro- or macroalbuminuria in Scandinavian diabetic patients.
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| 5. |
- Orho-Melander, Marju, et al.
(author)
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Variants in the calpain-10 gene predispose to insulin resistance and elevated free fatty acid levels.
- 2002
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 51:8, s. 2658-2664
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Journal article (peer-reviewed)abstract
- The calpain-10 gene (CAPN10) has been associated with type 2 diabetes, but information on molecular and physiological mechanisms explaining this association is limited. Here we addressed this question by studying the role of CAPN10 for phenotypes associated with type 2 diabetes and free fatty acid (FFA) metabolism. Among 395 type 2 diabetic patients and 298 nondiabetic control subjects from Finland, the SNP-43 allele 1 (P = 0.011), SNP-63 allele 2 (P = 0.010), and the haplotype combination SNP-44/43/19/63 1121/1121 (P = 0.028) were associated with type 2 diabetes. The SNP-43 genotypes 11 and 12 were associated with higher fasting insulin and homeostasis model assessment (HOMA) insulin resistance index among control subjects (P = 0.021 and P = 0.0076) and with elevated FFA among both control subjects (P = 0.0040) and type 2 diabetic patients (P = 0.0025). Multiple regression analysis further indicated that SNP-43 is an independent predictor of FFA levels (P = 0.0037). Among 80 genotype discordant sibling pairs, the SNP-43 allele 1 was associated with elevated fasting serum insulin and HOMA index (P = 0.013 and P = 0.0068). None of the four SNPs showed distorted transmission of alleles to patients with type 2 diabetes in a qualitative transmission disequilibrium test, including 108 trios. Because FFA and insulin resistance are known to predict type 2 diabetes, the finding that variation in the CAPN10 gene influences FFA levels and insulin resistance may provide an explanation for how the CAPN10 gene increases susceptibility to type 2 diabetes.
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| 6. |
- Ridderstråle, Martin, et al.
(author)
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FOXC2 mRNA Expression and a 5' Untranslated Region Polymorphism of the Gene Are Associated With Insulin Resistance.
- 2002
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 51:12, s. 3554-3560
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Journal article (peer-reviewed)abstract
- The human transcription factor FOXC2 has recently been shown to protect against diet-induced insulin resistance in transgenic mice. We investigated the expression of FOXC2 in fat and muscle and performed a genetic analysis in human subjects. FOXC2 mRNA levels were increased in visceral compared with subcutaneous fat from obese subjects (12 ± 4-fold; P = 0.0001), and there was a correlation between whole-body insulin sensitivity and FOXC2 mRNA levels in visceral fat (fS-insulin R = −0.64, P = 0.01, and homeostasis model assessment of insulin resistance [HOMA-IR] R = −0.68, P = 0.007) and skeletal muscle (fS-insulin R = −0.57, P = 0.03, and HOMA-IR R = −0.55, P = 0.04). Mutation screening of the FOXC2 gene identified a common polymorphism in the 5′ untranslated region (C-512T). The T allele was associated with enhanced insulin sensitivity (HOMA-IR P = 0.007) and lower plasma triglyceride levels in females (P = 0.007). Also, the higher expression of FOXC2 in visceral than in subcutaneous fat was restricted to subjects homozygous for the T allele (P = 0.03 vs. P = 0.7). Our data suggest that increased FOXC2 expression may protect against insulin resistance in human subjects and that genetic variability in the gene may influence features associated with the metabolic syndrome.
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