Abstract
Introduction: Scientists are considering the possibility of treating diabetes mellitus (DM) using a personalized approach in which various forms of the diseases will be treated based on the causal gene and its pathogenesis. To this end, scientists have identified mutations in certain genes as probable causes of Type 2 diabetes mellitus (T2DM) with diverse mechanisms.
Aim: This review was aimed at articulating already identified T2DM genes with their mechanisms of action and phenotypic presentations for the awareness of all stakeholders.
Method: The Google search engine was used to retrieve relevant information on the subject from reliable academic databases such as PubMed, Medline, and Google Scholar, among others.
Results: At least seventy (70) genes are currently being suspected in the biogenesis of T2DM. However, mutations in, or variants of KCNJ11, PPARG, HNF1B and WFS1 genes, are the most suspected and reported in the pathogenesis of the disease. Mutations in these genes can cause disruption of insulin biosynthesis through the destruction of pancreatic beta cells, change of beta cell morphology, destruction of insulin receptors, among others. These cellular events may lead to insulin resistance and hyperglycemia and, along with environmental triggers such as obesity and overweight, culminate in T2DM. It was observed that each identified gene has its distinct mechanism by which it interacts with other genes and environmental factors to cause T2DM.
Conclusion: Healthcare providers are advised to formulate T2DM drugs or treatment by targeting the causal genes along with their mechanisms.
Keywords: Beta cells, hyperglycemia, insulin resistance, mutation, obesity, type 2 diabetes.
[1]
Hameed I, Masoodi SR, Mir SA, Nabi M, Ghazanfar K, Ganai BA. Type 2 diabetes mellitus: From a metabolic disorder to an inflammatory condition. World J Diabetes 2015; 6(4): 598-612.
[2]
Weir GC, Bonner-Weir S. Five stages of evolving beta-cell dysfunction during progression to diabetes. Diabetes 2004; 53(suppe 3): S16-21.
[3]
Adeshara AK, Diwan AK, Tupe RS. Diabetes and complications: cellular signaling pathways, current understanding and targeted therapies. Curr Drug Targets 2016; 17(11): 1309-28.
[4]
Cho NH, Shaw JE, Karuranga S, et al. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract 2018; 138: 271-81.
[5]
Bommer C, Heesemann ECN, Sagalova V, et al. The global economic burden of diabetes in adults aged 20-79: A cost-of-illness study. Lancet Diabetes Endocrinol 2017; 5(6): 423-30.
[6]
Meur G, Simon A, Harun N, et al. Insulin gene mutations resulting in early-onset diabetes: marked differences in clinical presentation, metabolic status, and pathogenic effect through endoplasmic reticulum retention. Diabetes 2010; 59: 653-61.
[8]
Kitada M, Koya D. SIRT1 in Type 2 Diabetes: Mechanisms and Therapeutic Potential. Diabetes Metab J 2013; 37(5): 315-25.
[9]
Haigis MC, Mostoslavsky R, Haigis KM, et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 2006; 126: 941-54.
[10]
Ahuja N, Bjoern S, Stefania C, et al. Regulation of Insulin Secretion by SIRT4, a Mitochondrial ADP-ribosyltransferase. J Biol Chem 2007; 282: 33583-92.
[11]
Chiefari E, Tanyolaç S, Paonessa F, et al. Functional Variants of the HMGA1 Gene and Type 2 Diabetes Mellitus. JAMA 2011; 305(9): 903-12.
[12]
Kiriyama Y, Nochi H. Role and cytotoxicity of amylin and protection of pancreatic islet β- cells from amylin cytotoxicity. Cell 2018; 7(95): 1-13.
[13]
Cauchi S, Froguel P. TCF7L2 genetic defect and type 2 diabetes. Curr Diabetes Rep 2008; 8: 149.
[14]
Johnson JD, Han Z, Otani K, et al. RyR2 and Calpain-10 delineate a novel apoptosis pathway in pancreatic islets. J Biol Chem 2004; 279: 24794-802.
[15]
Odom DT, Zizlsperger N, Gordon DB, et al. Control of pancreas and liver gene expression by HNF transcription factors. Science 2004; 303: 1378-81.
[16]
Kim EK, Lee JS, Cheong HI, Chung SS, Kwak SH, Park KS. Identification and functional characterization of P159L mutation in HNF1B in a family with maturity-onset diabetes of the young 5 (MODY5). Genomics Inform 2014; 12(4): 240-6.
[17]
Florez JC, Burtt N, De Bakker PI, et al. Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region. Diabetes 2004; 53: 1360-8.
[18]
Zhou C, Dhall D, Nissen NN, Chen CR, Yu R. Homozygous P86S mutation of the human glucagon receptor is associated with hyperglucagonemia, alpha cell hyperplasia, and islet cell tumor. Pancreas 2009; 38(8): 941-6.
[19]
Gloyn AL, Weedon MN, Owen KR, et al. Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Hum Genet 2003; 52: 568-72.
[20]
Mattu RK, Trevelyan J, Needham EWA, et al. Lipoprotein lipase gene variants relate to presence and degree of microalbuminuria in Type II diabetes. Diabetologia 2002; 45: 905-13.
[21]
Muller YL, Bogardus C, Beamer BA, et al. A functional variant in the peroxisome proliferator-activated receptor gamma2 promoter is associated with predictors of obesity and type 2 diabetes in Pima Indians. Diabetes 2003; 52: 1864-71.
[22]
Thauvin-Robinet C, Auclair M, Duplomb L, et al. PIK3R1 Mutations Cause Syndromic Insulin Resistance with Lipoatrophy. The American Journal of Human Genetics 2013; 93: 141-9.
[23]
Bagnati M, Ogunkolade BW, Marshall C, et al. Glucolipotoxicity initiates pancreatic β-cell death through TNFR5/CD40-mediated STAT1 and NF-κB activation. Cell Death Dis 2016; 7(8)e2329
[24]
Xiang J, Xiao-Ying L, Min X, et al. Zinc Transporter-8 Gene (SLC30A8) Is Associated with Type 2 Diabetes in Chinese. The J Clin Endocrinol Metab 2008; 93(10): 4107-12.
[25]
Zhang C, Moriguchi T, Kajihara M, et al. MafA is a key regulator of glucose-stimulated insulin secretion. Mol Cell Biol 2005; 25(12): 4969-76.
[26]
Pal A, Barber TM, Van de Bunt M, et al. PTEN mutations as a cause of constitutive insulin sensitivity and obesity. N Engl J Med 2012; 367(11): 1002-11.
[27]
Al-Quobaili1 F,Montenarh M. Pancreatic duodenal homeobox factor-1 and diabetes mellitus type 2. Int J Mol Med 2008; 21: 399-404.
[29]
Bernadette N, Martin E, Fernandez-Zapico V. Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function. PNAS 2005; 102(13): 4807-12.
[30]
Wang L, Tong X, Gu F, et al. The KLF14 transcription factor regulates hepatic gluconeogenesis in Mice. J Biol Chem 2017; 292: 21631-42.
[31]
Yanqing Z, Genevieve E, Hongjun W, et al. PAX4 gene transfer induces α-to-β cell phenotypic conversion and confers therapeutic benefits for diabetes treatment. Mol Ther 2016; 24(2): 251-60.
[32]
Mitchell RK, Marie-Sophie NT, Pauline C, et al. The transcription factor Pax6 is required for pancreatic β cell identity, glucose-regulated ATP synthesis, and Ca2+ dynamics in adult mice. J Biol Chem 2017; 292: 8892-906.
[33]
Gutiérrez GD, Aaron S, Bender VC, et al. Pancreatic β cell identity requires continual repression of non-β cell programs. Clin Invest 2017; 127(1): 244-59.
[34]
Brandon L, Taylor FL, Maike S. Nkx6.1 is essential for maintaining the functional state of pancreatic beta cells. Cell Rep 2013; 4(6): 1262-75.
[35]
Laura V, Elisa R, Raquel A, et al. GATA6 controls insulin biosynthesis and secretion in adult β-Cells. Diabetes 2018; 67(3): 448-60.
[36]
Xianjie W, Yisheng Y. Emerging roles of GLIS3 in neonatal diabetes, type 1 and type 2 diabetes. J Mol Endocrinol 2017; 58: R73-85.
[37]
Sivitskaya L, Nina D, Zoya Z, et al. HFE gene mutation associated with the severity of gestational diabetes mellitus in belarusian women. OJEMD 2013; 3: 13-7.
[38]
Zhang H, Wang WP, Guo T, et al. The LIM-homeodomain protein ISL1 activates insulin gene promoter directly through synergy with BETA2. J Mol Biol 2009; 392(3): 566-77.
[39]
Tan K, Kimber WA, Luan J, et al. Analysis of genetic variation in Akt2/PKB-beta in severe insulin resistance, lipodystrophy, type 2 diabetes, and related metabolic phenotypes. Diabetes 2007; 56(3): 714-9.
[40]
Schäfer SA, Müssig K, Staiger H, et al. A common genetic variant in WFS1 determines impaired glucagon-like peptide-1-induced insulin secretion. Diabetologia 2009; 52: 1075.
[41]
Zhang J, Lindsay B, McKenna CW, et al. The diabetes gene Hhex maintains δ-cell differentiation and islet function. Genes and Dev 2014; 28: 829-34.
[42]
Palmer CJ, Bruckner RJ, Paulo JA, et al. Cdkal1, a type 2 diabetes susceptibility gene, regulates mitochondrial function in adipose tissue. Mol Metab 2017; 6(10): 1212-25.
[43]
Zeggini E, Weedon MN, Lindgren CM, et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 2007; 316: 1336-41.
[44]
Kamura Y, Iwata M, Maeda S, et al. FTO Gene polymorphism is associated with type 2 diabetes through its effect on increasing the maximum BMI in Japanese men. PLoS One 2016; 11(11) e0165523
[45]
Yoshiuchi I. Two SNPs associated with type 2 diabetes and obesity at melanocortin-4 receptor gene loci exhibited high fst values and natural selection. J Diabetes Metab 2013; S11: 005.
[46]
Perry JRB, Fralyin TM. New gene variants alter type 2 diabetes risk predominantly through reduced beta-cell function. Curr Opin Clin Nutr Metab Care 2008; 11: 371-7.
[47]
Boesgaard WT, Gjesing AP, Grarup N, et al. Variant near ADAMTS9 known to associate with type 2 diabetes is related to insulin resistance in offspring of type 2 diabetes patients—EUGENE2 study. PLoS One 2009; 4(9)e7236
[48]
Simonis-Bik AM, Nijpels G, van Haeften TW, et al. Gene variants in the novel type 2 diabetes loci CDC123/CAMK1D, THADA, ADAMTS9, BCL11A, and MTNR1B affect different aspects of pancreatic beta-cell function. Diabetes 2009; 59(1): 293-301.
[49]
Alharbi HK, Khan IA, Syed R, et al. Association of JAZF1 and TSPAN8/LGR5 variants in relation to type 2 diabetes mellitus in a Saudi population. Diabetol Metab Syndr 2015; 7: 92.
[50]
Rasheed MA, Kantoush N, Abd El-Ghaffar N, et al. Expression of JAZF1, ABCC8, KCNJ11and Notch2 genes and vitamin D receptor polymorphisms in type 2 diabetes, and their association with microvascular complications. J Clin Endocrinol Metab 2017; 8(6): 97-108.
[51]
Langenberg C, Pascoe L, Mari A, et al. Common genetic variation in the melatonin receptor 1B gene (MTNR1B) is associated with decreased early-phase insulin response. Diabetologia 2009; 52(8): 1537-42.
[52]
Singh S. Genetics of type 2 diabetes: advances and future prospect. J Diabetes Metab 2015; 6: 518.
[53]
Bhatia S, Bansal P, Mani S. Mitochondrial diabetes: differential diagnostic features and its possible management. JIMSA 2014; 27: 4.
[54]
Maassen JA, Hart LM, Van Essen E, et al. Mitochondrial diabetes: molecular mechanisms and clinical presentation. Diabetes 2004; 53(Suppl. 1): S103-9.
[55]
Hertel KJ, Johansson S, Midthjell ON, et al. Type 2 diabetes genes - Present status anddata from Norwegian studies. Nor Epidemiol 2013; 23(1): 9-22.
[56]
Chen T, Xu J, Liu G, et al. PTPRD silencing by DNA hypermethylation decreases insulin receptor signaling and leads to type 2 diabetes. Oncotarget 2016; 7(46): 76101-7.
[57]
Barroso I, Luan J, Middelberg RPS, et al. Candidate gene association study in type 2 diabetes indicates a role for genes involved in β-cell function as well as insulin action. PLoS Biol 2003; 1(1)e20
[58]
Golshani H, Haghani K, Dousti M, et al. Association of TNF-α 308 G/A polymorphism with type 2 diabetes: a case-control study in the iranian kurdish ethnic group. Osong Public Health Res Perspect 2015; 6(2): 94-9.
[59]
Beale GA, Hammer ER, Antoine B, et al. Disregulated glyceroneogenesis: PCK1 as a candidate diabetes and obesity gene. Trends Endocrinol Metab 2004; 15(3): 125-35.
[60]
Helaly MA, Hatata EZ, Abu-Elmagd M, et al. Association of IL-10 and IL-6 gene polymorphisms with type 2 diabetes mellitus among Egyptian Patients. Eur J Gen Med 2013; 10(3): 158-62.
[61]
Bacci S, De Cosmo S, Prudente S, et al. ENPP1 gene, insulin resistance and related clinical outcomes. Curr Opin Clin Nutr Metab Care 2007; 10(4): 403-9.
[62]
Maruccia A, Cozzolino F, Dimatteo C, et al. Role of GALNT2 in the modulation of ENPP1 expression, and insulin signaling and action: GALNT2: A novel modulator of insulin signaling. Biochimicaet Biophysica Acta (BBA). Mol Cell Res 2013; 1833(6): 1388-95.
[63]
Inagaki N, Gonoi T, Clement JT, et al. Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Science 2003; 270: 1166-70.
[64]
Haghvirdizadeh P, Mohamed Z, Abdullah NA, Haghvirdizadeh P, Haerian MS, Haerian BS. KCNJ11: genetic polymorphisms and risk of diabetes mellitus. J Diabetes Res 2015; 2015 908152
[65]
van Dam RM, Hoebee B, Seidell JC, Schaap MM, de Bruin TWA, Feskens EJM. Common variants in the ATP-sensitive K+ channel genes KCNJ11 (Kir6.2) and ABCC8 (SUR1) in relation to glucose intolerance: population-based studies and meta-analyses. Diabet Med 2005; 22: 590-8.
[66]
Hart LM, van Haeften TW, Dekker JM, et al. Variations in insulin secretion in carriers of the E23K variant in the KIR6.2 subunit of the ATP-sensitive K(+) channel in the beta- cell. Diabetes 2002; 51: 3135-8.
[67]
Schwanstecher C, Neugebauer B, Schulz M, et al. The common single nucleotide polymorphism E23K in K (IR) 6.2 sensitizes pancreatic beta-cell ATP-sensitive potassium channels toward activation through nucleoside diphosphates. Diabetes 2002; 51: 363-7.
[68]
Riedel MJ, Boora P, Steckley D, et al. Kir6.2 polymorphisms sensitize beta-cell ATP- sensitive potassium channels to activation by acyl CoAs: a possible cellular mechanism for increased susceptibility to type 2 diabetes. Diabetes 2003; 52: 2630-5.
[69]
Nielsen EM, Hansen L, Carstensen B, et al. The E23K variant of Kir6.2 associates with impaired post-OGTT serum insulin response and increased risk of type 2 diabetes. Diabetes 2003; 52: 573-7.
[70]
Qiu L, Na R, Xu R, et al. Quantitative assessment of the effect of KCNJ11 gene polymorphism on the risk of type 2 diabetes. PLoS One 2014; 9(4)e93961
[71]
Miki T, Minami K, Zhang L, et al. ATP-sensitive potassium channels participate in glucose uptake in skeletal muscle and adipose tissue. Am J Physiol Endocrinol Metab 2002; 283(6): E1178-84.
[72]
Miki T, Seino S. Roles of KATP channels as metabolic sensors in acute metabolic changes. J Mol Cell Cardiol 2005; 38: 917-25.
[73]
Pocai A, Lam TK, Gutierrez-Juarez R, et al. Hypothalamic KATP channels control hepatic glucose production. Nature 2005; 434: 1026-31.
[74]
Gommers LLM, Hoenderop JGJ, Bindels RJM, de Baaij JHF. Hypomagnesemia in type 2 diabetes: a vicious circle? Diabetes 2016; 65: 3-13.
[75]
Arner PC. The adipocyte in insulin resistance: key molecules and the impact of the thiazolidinediones. Trends Endocrinol Metab 2003; 14: 137-45.
[76]
Altshuler D, Hirschhorn JN, Klannemark M, et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 2000; 26: 76-80.
[77]
Costa V, Amelia C, Katherine E, et al. Characterization of a novel polymorphism in pparg regulatory region associated with type 2 diabetes and diabetic retinopathy in Italy. J Biomed Biotechnol 2009; 2009: 1-7.
[78]
Stumvoll M, Haring H. The peroxisome proliferator-activated receptor-gamma2 Pro12Ala polymorphism. Diabetes 2002; 51: 2341-7.
[79]
Mittermayer F, Caveney E, De Oliveira C, et al. addressing unmet medical needs in type 2 diabetes: a narrative review of drugs under development. Curr Diabetes Rev 2015; 11(1): 7-31.
[80]
Corrales P, Vidal-Puig A, Medina-Gómez G. PPARs and metabolic disorders associated with challenged adipose tissue plasticity. Int J Mol Sci 2018; 19(7): 2124.
[81]
Pisani DF, Barquissau V, Chambard JC, et al. Mitochondrial fission is associated with UCP1 activity in human brite/beige adipocytes. Mol Metab 2018; 7: 35-44.
[82]
Bartelt A, Bruns OT, Reimer R, et al. Brown adipose tissue activity controls triglyceride clearance. Nat Med 2011; 17: 200-5.
[83]
Porter JR, Barrett TG. Monogenic syndromes of abnormal glucose homeostasis: clinical review and relevance to the understanding of the pathology of insulin resistance and β cell failure. J Med Genet 2005; 42: 893-902.
[84]
Zhang J, Qu P, Zhou C. MicroRNA-125b is a key epigenetic regulatory factor that promotes nuclear transfer reprogramming. The J Biol Chem 2017; 292(38): 15916-26.
[85]
De Vas MG, Kopp JL, Heliot C, Sander M, Cereghini S, Haumaitre C. HNF1B controls pancreasmorphogenesis and the generation of Ngn3+ endocrine progenitors. Development 2015; 142(5): 871-82.
[86]
Wang C, Hu C, Zhang R, et al. Common variants of hepatocyte nuclear factor 1beta are associated with type 2 diabetes in a Chinese population. Diabetes 2009; 58(4): 1023-7.
[87]
Furuta H, Furuta M, Sanke T, et al. Nonsense and missense mutations in the human hepatocyte nuclear factor-1 beta gene (TCF2) and their relation to type 2 diabetes in Japanese. J Clin Endocrinol Metab 2002; 87(8): 3859-63.
[88]
Coffinier C, Thépot D, Babinet C, Yaniv M, Barra J. Essential role for the homeoproteinv HNF1/HNF1 in visceral endoderm differentiation. Development 1999; 126(21): 4785-94.
[89]
Wang L, Coffinier C, Thomas MK, et al. Selective deletion of the Hnf1(MODY5) gene in-cells leads to altered gene expression and defective insulin release. Endocrinology 2004; 145(8): 3941-9.
[90]
Lipson LK, Fonseca SG, Ishigaki S, et al. Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1. Cell Metab 2006; 4(3): 245-54.
[91]
Franks PW, Rolandsson O, Debenham SL, et al. Replication of the association between variants in WFS1 and risk of type 2 diabetes in European populations. Diabetologia 2008; 51: 458.
[92]
Fonseca SG, Mariko F, Kathryn L, et al. WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic β-cells. J Biol Chem 2005; 280: 39609-15.
[93]
Yamada T, Ishihara H, Tamura A, et al. WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic β-cells. Hum Mol Genet 2006; 15(10): 1600-9.
Article Metrics
42
4