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M aturity-onset diabetes of the young (MODY) is a heterogeneous groupof monogenic disorders that lead to -cell dysfunction and is oftenmisdiagnosed as type 1 or type 2 diabetes mellitus. Common clini-

cal features of MODY include young age at presentation, lean body, evidenceof continued insulin production, absence of -cell autoimmunity, absence ofinsulin resistance, parental history of diabetes mellitus, and an autosomalmode of transmission. Depending on the genetic alteration present, provisionof appropriate individualized care and determination of the prognosis for af-fected individuals and their families is possible. In this review, the manage-ment of the more common forms of MODY will be discussed, with particularreference to HNF1A-MODY (MODY3), HNF4A-MODY (MODY1), and glucoki-nase-MODY (MODY2). The rationale for the use of sulfonylureas in these formsof MODY, as well as the particular challenges faced, will be discussed. Al-though there are no large-scale clinical trials about management of the dif-ferent forms of MODY, reports in the literature based on real-life experience ofthe response to treatment in MODY patients provide compelling evidence infavor of the use of sulfonylureas in the most common forms of MODY, name-ly MODY1 and MODY3. The management of pregnancy in MODY will also bediscussed, with an emphasis on maternal and fetal outcomes.

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Introduction

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Over the years, different formsof maturity-onset diabetes of theyoung (MODY) have been identi-fied, with mutations in a number ofdifferent genes associated with aMODY-like phenotype. Dependingon the genetic etiology, the genet-ic subtypes differ in terms of ageof onset, pattern of hyperglycemia,response to treatment, and extra-pancreatic manifestations.The pre-valence of MODY varies acrossdifferent countries, very often as aresult of differences in screeningpractices in thedifferentcountries.”

Sulfonylureas in specificclinical situations:

maturity-onset diabetesof the young (MODY)

by J . Vassa l lo , Malta

Josanne VASSALLO,

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(Table I),

SELECTED ABBREVIATIONS AND ACRONYMS

HNF1A HNF1B HNF4A MODY MODY1 MODY2 MODY3 SGLT2 T1DM T2DM

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.

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(Figure 1).

(Fi-gure 2).

(Figure 1).

HNF1A-MODY (MODY3) HNF1A

HNF1A

Figure 1. Monogenic forms of diabetes mellitus.

Abbreviations: 6q24, a region on the 6th chromosome; ABCC8, ATP-binding cassette transporter subfamilyC member 8; APPL1, adaptor protein, phosphotyrosine interaction, PH domain, and leucine zipper contain-ing 1; BLK, BLK proto-oncogene, Src family tyrosine kinase; CEL, carboxyl ester lipase; CFTR, cystic fibrosistransmembrane 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, GLI-similar 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 hemochromatosisprotein; 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 factor11; LMNA, lamin A/C; MODY, maturity-onset diabetes of the young; MNX1, motor neuron and pancreashomeobox protein 1; MT-TE, mitochondrially encoded tRNA glutamic acid; MT-TK, mitochondrially encodedtRNA 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 factor1); 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 19member 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.

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HNF1A.

HNF1A

HNF4A-MODY (MODY1) HNF4A HNF4A

Figure 2. Glucose-stimulated insulin secre-tion from pancreatic -cells and depiction ofthe most commonly implicated transcriptionfactor genes in MODY. Abbreviations: ATP, adenosine triphosphate; Ca2+,calcium; HNF1A, hepatocyte nuclear factor 1- ;HNF1B, hepatocyte nuclear factor 1- ; HNF4A,hepatocyte nuclear factor 4- ; PDX1, pancreatic andduodenal homeobox 1 (also known as insulin promoterfactor 1); K+, potassium; MODY, maturity-onset dia-betes of the young; NEUROD1, neurogenic differen-tiation 1. After reference 9: Fajans et al. N Engl J Med. 2001;345(13):971-980.

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Potential mechanisms to explain the increasedsensitivity to sulfonylureas in MODY1 and MODY3patients HNF1BHNF1AHNF1A

Nonsulfonylurea oral hypoglycemic agents in thetreatment of MODY

ABCC8,

Glucokinase-MODY (MODY2)

The management of MODY during pregnancy

Conclusions

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Keywords: management; maturity-onset diabetes of the young; sulfonylurea