506 research outputs found
The transcription factor 7-like 2 gene and increased risk of type 2 diabetes: an update.
No full textPURPOSE OF REVIEW: The purpose of this review is to provide a comprehensive evaluation of the most important type 2 diabetes gene to date, transcription factor 7 like-2. RECENT FINDINGS: An important step to find genetic causes of type 2 diabetes in 2006 was the identification of the fact that variants in the gene encoding transcription factor 7 like-2 reproducibly increase susceptibility to type 2 diabetes in almost all populations studied. This gene has since then emerged as the most important type 2 diabetes gene. Genetic variants in transcription factor 7 like-2 confer a strong risk of type 2 diabetes possibly mediated by altering expression of transcription factor 7 like-2 in pancreatic islets. Risk variants in the transcription factor 7 like-2 influence insulin secretions both in vitro and in vivo. The risk T allele of this single nucleotide polymorphism also seems to have effects on the enteroinsular axis and the relationship between the incretin hormone glucose-dependent insulinotropic peptide and its target hormones, glucagon and insulin. Given transcription factor 7 like-2s' central role in the Wnt signaling pathway, it would be important to define whether the variant is associated with increased or decreased Wnt signaling. SUMMARY: The fact that transcription factor 7 like-2 is by far the strongest type 2 diabetes susceptibility gene to date emphasizes the importance of exploring the potential of manipulating this pathway in future treatment of the disease
A Variant of GJD2, Encoding for Connexin 36, Alters the Function of Insulin Producing β-Cells.
No full textSignalling through gap junctions contributes to control insulin secretion and, thus, blood glucose levels. Gap junctions of the insulin-producing β-cells are made of connexin 36 (Cx36), which is encoded by the GJD2 gene. Cx36-null mice feature alterations mimicking those observed in type 2 diabetes (T2D). GJD2 is also expressed in neurons, which share a number of common features with pancreatic β-cells. Given that a synonymous exonic single nucleotide polymorphism of human Cx36 (SNP rs3743123) associates with altered function of central neurons in a subset of epileptic patients, we investigated whether this SNP also caused alterations of β-cell function. Transfection of rs3743123 cDNA in connexin-lacking HeLa cells resulted in altered formation of gap junction plaques and cell coupling, as compared to those induced by wild type (WT) GJD2 cDNA. Transgenic mice expressing the very same cDNAs under an insulin promoter revealed that SNP rs3743123 expression consistently lead to a post-natal reduction of islet Cx36 levels and β-cell survival, resulting in hyperglycemia in selected lines. These changes were not observed in sex- and age-matched controls expressing WT hCx36. The variant GJD2 only marginally associated to heterogeneous populations of diabetic patients. The data document that a silent polymorphism of GJD2 is associated with altered β-cell function, presumably contributing to T2D pathogenesis
From association to function : MTNR1B
No full textThe discovery that variants in the melatonin receptor 2 (MTNR1B) gene were associated with glucose levels, insulin secretion, and risk for type 2 diabetes (T2D) in genome-wide association studies (GWAS) reinforced the previously suggested link between glucose homeostasis and circadian rhythmicity. Diurnal secretion of melatonin has reported to be altered in people with diabetes and rodent models of T2D. The proposed underlying mechanisms by which altered melatonin signaling could predispose to progression to T2D and gestational diabetes mellitus (GDM) involve altered expression of MTNR1B in pancreatic beta cells, leading to impaired insulin secretion, consequent increased fasting glucose concentrations, and eventually overt T2D. Thus blocking the inhibition of insulin secretion may have potential clinical implications, and these effects could be more pronounced in individuals carrying risk genotypes. Finally, given that melatonin could emerge as an attractive treatment for a variety of conditions including pregnancies associated with GDM, preeclampsia, and intrauterine growth retardation, pharmacogenetic studies are warranted to determine treatment response and side effects according to genotype
Genetics of diabetes-associated microvascular complications
No full textDiabetes is associated with excess morbidity and mortality due to both micro- and macrovascular complications, as well as a range of non-classical comorbidities. Diabetes-associated microvascular complications are those considered most closely related to hyperglycaemia in a causal manner. However, some individuals with hyperglycaemia (even those with severe hyperglycaemia) do not develop microvascular diseases, which, together with evidence of co-occurrence of microvascular diseases in families, suggests a role for genetics. While genome-wide association studies (GWASs) produced firm evidence of multiple genetic variants underlying differential susceptibility to type 1 and type 2 diabetes, genetic determinants of microvascular complications are mostly suggestive. Identified susceptibility variants of diabetic kidney disease (DKD) in type 2 diabetes mirror variants underlying chronic kidney disease (CKD) in individuals without diabetes. As for retinopathy and neuropathy, reported risk variants currently lack large-scale replication. The reported associations between type 2 diabetes risk variants and microvascular complications may be explained by hyperglycaemia. More extensive phenotyping, along with adjustments for unmeasured confounding, including both early (fetal) and late-life (hyperglycaemia, hypertension, etc.) environmental factors, are urgently needed to understand the genetics of microvascular complications. Finally, genetic variants associated with reduced glycolysis, mitochondrial dysfunction and DNA damage and sustained cell regeneration may protect against microvascular complications, illustrating the utility of studies in individuals who have escaped these complications
Genome-wide association study for type 2 diabetes: clinical applications.
No full textPURPOSE OF REVIEW: Dissecting the genetics of complex polygenic diseases in which environmental factors interact with genetic variants in the predisposition to the disease has not been a trivial task and success has been limited. The purpose of this review is to provide insights into recent advances in genetics of type 2 diabetes. RECENT FINDINGS: In the past year, together the consortia of several genome-wide association studies for type 2 diabetes have identified 19 common variants increasing susceptibility to disease. Most novel loci seem to influence the capacity of beta-cells to increase insulin secretion in response to increase in insulin resistance or body weight. Combined genetic information ultimately might aid in personalized prediction of disease risk; however, genetic tests cannot be offered yet to predict disease. The main reason is that the increased risk associated with each risk variant is small. We have only begun to explore the role of rare variants with stronger effects or copy number variations in the pathogenesis of type 2 diabetes. SUMMARY: Rapid progress in the genetics of type 2 diabetes has significantly improved our understanding of disease pathogenesis and provided promising opportunities for drug discoveries over the coming years
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