Over the years, different forms of maturity-onset diabetes of the young (MODY) have been identified, with mutations in a number of different genes associated with a MODY-like phenotype. Depending on the genetic etiology, the genetic subtypes differ in terms of age of onset, pattern of hyperglycemia, response to treatment, and extrapancreatic manifestations. The prevalence of MODY varies across different countries, very often as a result of differences in screening practices in the different countries. S U L F O N Y L U R E A S A N D T H E E V O LV I N G L A N D S C A P E O F T Y P E 2 D I A B E T E S Sulfonylureas in specific clinical situations: maturity-onset diabetes of the young (MODY) by J. Vassallo, Malta Josanne VASSALLO, Address for correspondence: www.medicographia.com Maturity-onset diabetes of the young (MODY) is a heterogeneous group of monogenic disorders that lead to -cell dysfunction and is often misdiagnosed as type 1 or type 2 diabetes mellitus. Common clinical features of MODY include young age at presentation, lean body, evidence of continued insulin production, absence of -cell autoimmunity, absence of insulin resistance, parental history of diabetes mellitus, and an autosomal mode of transmission. Depending on the genetic alteration present, provision of appropriate individualized care and determination of the prognosis for affected individuals and their families is possible. In this review, the management of the more common forms of MODY will be discussed, with particular reference to HNF1A-MODY (MODY3), HNF4A-MODY (MODY1), and glucokinase-mody (MODY2). The rationale for the use of sulfonylureas in these forms of MODY, as well as the particular challenges faced, will be discussed. Although there are no large-scale clinical trials about management of the different forms of MODY, reports in the literature based on real-life experience of the response to treatment in MODY patients provide compelling evidence in favor of the use of sulfonylureas in the most common forms of MODY, namely MODY1 and MODY3. The management of pregnancy in MODY will also be discussed, with an emphasis on maternal and fetal outcomes. Medicographia. 2018;40:152-157 Introduction A 152 MEDICOGRAPHIA, Vol 40, No. 4, 2018 Sulfonylurea use in MODY Vassallo
Table I. Features of the most frequent types of maturity-onset diabetes of the young (MODY) compared with common forms of diabetes. Abbreviations: GCK, glucokinase; HNF1A, hepatocyte nuclear factor 1- ; HNF4A, hepatocyte nuclear factor 4- ; hscrp, high-sensitivity C-reactive protein; MODY, maturity-onset diabetes of the young. After reference 6: Owen et al. Clin Med (Lond.). 2013;13(3):278-281. (Table I), SELECTED ABBREVIATIONS AND ACRONYMS HNF1A HNF1B HNF4A MODY MODY1 MODY2 MODY3 SGLT2 T1DM T2DM Sulfonylurea use in MODY Vassallo MEDICOGRAPHIA, Vol 40, No. 4, 2018 153
(Figure 1). (Figure 2). (Figure 1). HNF1A-MODY (MODY3) HNF1A Figure 1. Monogenic forms of diabetes mellitus. Abbreviations: 6q24, a region on the 6th chromosome; ABCC8, ATP-binding cassette transporter subfamily C member 8; APPL1, adaptor protein, phosphotyrosine interaction, PH domain, and leucine zipper containing 1; BLK, BLK proto-oncogene, Src family tyrosine kinase; CEL, carboxyl ester lipase; CFTR, cystic fibrosis transmembrane conductance regulator; EIF2AK3, eukaryotic translation initiation factor 2 kinase 3; FOXP3, forkhead box P3 (also known as scurfin); GATA6, GATA binding protein 6; GCK, glucokinase; GLIS3, GLIsimilar zinc finger protein 3; HNF1A, hepatocyte nuclear factor 1- ; HNF1B, hepatocyte nuclear factor 1- ; HNF4A, hepatocyte nuclear factor 4- ; HFE, encodes HFE protein, also known as human hemochromatosis protein; IER3IP1, immediate early response 3 interacting protein 1; IL2RA, interleukin 2 receptor subunit ; INS, insulin; KCNJ11, potassium voltage-gated channel subfamily J member 11; KLF11, Kruppel-like factor 11; LMNA, lamin A/C; MODY, maturity-onset diabetes of the young; MNX1, motor neuron and pancreas homeobox protein 1; MT-TE, mitochondrially encoded trna glutamic acid; MT-TK, mitochondrially encoded trna lysine; MT-TL1, mitochondrially encoded trna leucine 1; NDM, neonatal diabetes mellitus; NEUROD1, neurogenic differentiation 1; NEUROG3, neurogenin 3; NKX2.2, NK2 homeobox 2; PAX4, paired box 4; PAX6, paired box 6; PDX1, pancreatic and duodenal homeobox 1 (also known as insulin promoter factor 1); PPARG, peroxisome proliferator activated receptor ; PTF1A, pancreas transcription factor 1 subunit ; RFX6, regulatory factor X6; SLC2A2, solute carrier family 2 member 2; SLC19A2, solute carrier family 19 member 2 (also known as thiamine carrier 1); TRMT10A, trna methyltransferase 10A; WFS1, wolframin; ZFP57, ZFP57 zinc finger protein. After reference 8: Flannick et al. Nat Rev Endocrinol. 2016;12(7):394-406. HNF1A 154 MEDICOGRAPHIA, Vol 40, No. 4, 2018 Sulfonylurea use in MODY Vassallo
Figure 2. Glucose-stimulated insulin secretion from pancreatic -cells and depiction of the most commonly implicated transcription factor genes in MODY. Abbreviations: ATP, adenosine triphosphate; Ca 2+, calcium; HNF1A, hepatocyte nuclear factor 1- ; HNF1B, hepatocyte nuclear factor 1- ; HNF4A, hepatocyte nuclear factor 4- ; PDX1, pancreatic and duodenal homeobox 1 (also known as insulin promoter factor 1); K +, potassium; MODY, maturity-onset diabetes of the young; NEUROD1, neurogenic differentiation 1. After reference 9: Fajans et al. N Engl J Med. 2001; 345(13):971-980. HNF1A HNF1A. HNF4A-MODY (MODY1) HNF4A HNF4A Sulfonylurea use in MODY Vassallo MEDICOGRAPHIA, Vol 40, No. 4, 2018 155
Potential mechanisms to explain the increased sensitivity to sulfonylureas in MODY1 and MODY3 patients HNF1B HNF1A HNF1A Nonsulfonylurea oral hypoglycemic agents in the treatment of MODY ABCC8, Glucokinase-MODY (MODY2) The management of MODY during pregnancy Conclusions 156 MEDICOGRAPHIA, Vol 40, No. 4, 2018 Sulfonylurea use in MODY Vassallo
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