China
Africa
Explore chapters and articles related to this topic
Genetics of diabetic pregnancy
Published in Moshe Hod, Lois G. Jovanovic, Gian Carlo Di Renzo, Alberto de Leiva, Oded Langer, Textbook of Diabetes and Pregnancy, 2018
ABCC8, located on 11p15.1, codes for a receptor on the pancreatic beta cell involved in insulin secretion. Several variants within this gene have been associated with an increased risk of GDM and/or T2DM.48 In the Han Chinese population, for example, the C allele of the -3 T/C polymorphism in intron 24 and the A allele of the R1273R in exon 31 were strongly associated with an increased susceptibility to gestational DM.49
Precision medicine in diabetes mellitus
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Sandhiya Selvarajan, Akila Srinivasan, Nishanthi Anandabaskar, Sadishkumar Kamalanathan, Melvin George
Numerous studies have been done to evaluate the association of various genes with the occurrence of diabetes. It has been found that the KATP channels present in β-cells have a SUR1 subunit encoded by the ABCC8 gene and a mutation in this gene has been associated with a twofold higher risk for diabetes mellitus with an earlier age of onset in Southwest American Indians (Baier et al., 2015). Apart from KATP channels, studies have been done to explore the role of PPAR-gamma mutations as a risk factor for the onset of type 2 diabetes mellitus, however, with contradictory results. It has been observed that PPAR-gamma, germ line loss-of-function mutations are associated with an early onset of insulin resistance type 2 diabetes mellitus and hypertension (Barroso et al., 1999). Similarly the presence of proline allele of PPAR-gamma has been shown to be associated with a greater risk for type 2 diabetes. On the contrary, the presence of Pro12Ala polymorphism of PPAR-gamma has been found to be protective against the development of type 2 diabetes mellitus in Caucasians (Altshuler et al., 2000). However, a similar study done by Radha et al. (2006) among Caucasians and South Asians in Texas and South Asians in Chennai showed that the PPAR-gamma Pro12Ala polymorphism provides protection against the occurrence of type 2 diabetes only in Caucasians but not so in South Asians. In addition, the transcription factor 7-like 2 (TCF7L2) gene present in most of the tissues including beta cells of the pancreas has been found to have reduced expression in fat deposits of obese type 2 diabetic patients compared to people with normal blood glucose (Cauchi et al., 2006). A study has identified 6 SNPs (single nucleotide polymorphisms) that are associated with elevated risk for type 2 diabetes mellitus, as shown in Table 14.3 (Zyriax et al., 2013). These findings suggest a robust contribution of genes in the occurrence of type 2 diabetes.
Congenital hyperinsulinism
Published in Demetrius Pertsemlidis, William B. Inabnet III, Michel Gagner, Endocrine Surgery, 2017
Christopher A. Behr, Stephen E. Dolgin
The two subunits of the KATP channel, the sulfonylurea receptor 1 and the inwardly rectifying potassium channel (Kir6.2), are encoded by ABCC8 and KCNJ11, respectively [15–17]. While an autosomal dominant mutation in one of these two genes causes a mild, medically responsive hyperinsulinism, the recessive inactivating mutations result in the more severe and often medically resistant form. Examining the mechanism of action of diazoxide, the principal medical treatment for CH, it becomes clear why this is the case. Diazoxide works as an agonist for the KATP channel in beta cells, specifically with the sulfonylurea receptor–potassium internal rectifier receptor complex (SUR-Kir). In normal beta cells, it causes an opening of the KATP channel and halts the release of insulin. Not surprisingly, approximately 80% of the diazoxide treatment-unresponsive cases (the most severe form) are due to either ABCC8 or KCNJ11 inactivating mutations [4, 14]. These recessive mutations most often result in the diffuse form of CH. In contrast, the focal form of CH has been shown to be the result of a different genetic process, paternal uniparental disomy. Both the ABCC8 gene and the KCNJ11 gene are located on chromosome 11p15. The focal loss of the maternal allele with subsequent replacement by the paternal copy on the short arm of chromosome 11 at position 15.1 can lead to a clone of beta cells that develop into a focal lesion in the pancreas. If this paternal copy of the allele possesses a mutation in either the ABCC8 or the KCNJ11 gene, then the hemi- or homozygosity results in hyperinsulinemia of this focal lesion [3, 4, 21, 22]. It is this paternal mutation and subsequent somatic loss of function of the maternal gene that is used clinically to differentiate between the diffuse and focal forms. Current genetic diagnostic testing allows the clinician to distinguish between a recessive homozygous mutation, and therefore diffuse disease, and a paternal mutation and subsequent loss of function of the maternal copy, indicating a focal disease. This, combined with recent advances in radiological imaging techniques, has made it possible to identify and localize these focal lesions, thus significantly changing the surgical management of CH.
Polymorphisms in glucose homeostasis genes are associated with cardiovascular and renal parameters in patients with diabetic nephropathy
Published in Annals of Medicine, 2022
Sonia Mota-Zamorano, Luz M. González, Nicolás R. Robles, José M. Valdivielso, José C. Arévalo-Lorido, Juan López-Gómez, Guillermo Gervasini
A critical step in glucose homeostasis is its transport across the cells of the proximal tubule through two different classes of transporters, namely glucose transporters GLUT1 and 2, encoded by the SLC2A1-2 genes, and sodium-dependent glucose transporters SGLT1 and 2, encoded by SLC5A1-2 [12] (Supplementary Figure S1). Several SNPs in these loci, such as rs9934336, rs3813008, rs371505974 or rs200406921, have been related to impaired glucose homeostasis [13], the risk of DN [14,15] and CVD [16]. In addition, two proteins, namely Kir6.2 (potassium channel subunit) (KCNJ11 gene) and SUR1 (sulfonylurea receptor-1) (ABCC8 gene), form together an ATP-sensitive potassium channel that is key in glucose-induced insulin secretion by pancreatic beta cells (Supplementary Figure S1). Genetic variability in these two genes, most notably rs5219, has also been associated with glucose imbalance, T2DM and CVD [17–20].
The role of sulfonylureas in the treatment of type 2 diabetes
Published in Expert Opinion on Pharmacotherapy, 2022
Brian Tomlinson, Nivritti Gajanan Patil, Manson Fok, Paul Chan, Christopher Wai Kei Lam
Maturity-onset diabetes of the young (MODY) due to dominant mutations in one of at least 13 different genes occurs in <5% of people with diabetes and usually manifests before the age of 25 years [116,117]. MODY3 caused by mutations in the gene for hepatocyte nuclear factor 1 α (HNF1A) is the most common form of MODY, accounting for more than half the cases of MODY. Patients with this condition and with MODY1 caused by mutations in HNF1A and MODY12 caused by mutations in ABCC8 are extremely sensitive to sulfonylureas, which are considered first-line therapy in these patients [117–119]. Patients with HNF1A MODY had a 5.2-fold greater reduction in fasting plasma glucose with gliclazide than with metformin and 3.9-fold greater response to gliclazide than those patients with T2D [120].
Emerging therapeutic targets for cerebral edema
Published in Expert Opinion on Therapeutic Targets, 2021
Ruchira M. Jha, Sudhanshu P. Raikwar, Sandra Mihaljevic, Amanda M. Casabella, Joshua S. Catapano, Anupama Rani, Shashvat Desai, Volodymyr Gerzanich, J. Marc Simard
Despite the unclear role of CRISPR/Cas9 technology in clinical treatment of cerebral edema, given the limitations above, it is being used to further understand edema pathobiology in preclinical models. Recently, AQP4ex (the extended isoform of AQP4a containing a 29 amino-acid C terminal extension), has been identified in vitro as the potential modulator of supramolecular organization and regulation of water channel activity [332]. CRISPR/Cas9 technology was used to generate an AQP4ex–/ – mouse. In these mice, although total AQP4 protein expression was unchanged, removal of AQP4ex completely suppressed the location of AQP4 at the astrocyte endfeet [333]. Similarly, although the number of AQP4 orthogonal arrays of particles (OAP) remained unchanged, the OAP size was markedly reduced. This has important implications for cerebral edema generation and may valuably inform future targeted therapies. Both homozygous and heterozygous ABCC8 (encoding SUR1) mutant cell lines have been generated using CRISPR/Cas9 technology[334,335]. These were generated to evaluate effects of ABCC8 genetic mutations on congenital hyperinsulinism and revealed defective KATP channels unresponsive to diazoxide. Nonetheless, this technique may be valuable for understanding the biological consequences of important ABCC8 genetic variation contributing to cerebral edema and hemorrhage progression (described in Section III-E).