EDITORIAL (SEE CHAKERA ET AL., P. 1832)

Gestational Mellitus: Primum Non Nocere

aturity-onset diabetes of the progressively increase with age, long- pregnant women with previously undiag- M young (MODY) encompasses a term diabetes complications are uncom- nosed MODY 2 as having GDM. collection of distinct forms of di- mon (9,10). If, in keeping with the IADPSG di- abetes, which are inherited in an autosomal- MODY 2 does, however, have clinical agnostic criteria, a fasting level dominant mode from the maternal or implications in when there is below 92 mg/dL (5.1 mmol/L) was also paternal side of the family or occasion- discordance between the maternal and adopted as a management target in GDM, ally occur as a de novo . All the fetal genotype; statistically this occurs in this would be difficult to achieve in women involved affect either b-cell sensing 50% of all in which the with MODY 2 treated with diet alone, and or secretion (1). The clinical pre- mother or father carries the MODY mu- would inevitably necessitate insulin ther- sentations of MODY are heterogeneous, tation. When the mother is affected but apy. More importantly these more strin- reflecting the different not the fetus, maternal gent fasting glucose targets would be involved, and the glucose dysregulation causes fetal hyperinsulinemia and in- detrimental to fetal growth in half of all observed ranges from a relatively inno- creased birth weight (11). By contrast, pregnancies (12). cent rise in the fasting glucose to frank when the fetus carries the paternal The article by Chakera et al. (17) in Diabetes Care diabetes with neurological involvement MODY 2 gene, the levels of maternal this issue of provides (2,3). glycemia are insufficient to stimulate ade- proofofconceptthatpriorknowledge An exact MODY prevalence within quate fetal insulin to sustain optimal of the fetal genotype can help predict the general diabetes population has growth, and birth weight is approxi- fetal susceptibility to maternal hyper- proven difficult to assess because of glycemia and can therefore favorably mately 500 g lower than for an unaf- fl underrecognition and lack of routinely fected sibling (11). When both the in uence treatment in women with available and affordable diagnostic tools. mother and fetus share the MODY 2 mu- MODY 2. The article describes two preg- A further confounder is that the reported nancies in women with MODY 2 in whom fi tation, birth weight is normal, providing regional prevalence of speci cMODY the mother’s hyperglycemia is not treated, glycemic management was tailored on mutations varies considerably (4). Con- as the glucose threshold to trigger insulin the basis of fetal genotyping, performed servative estimates suggest that between following chorionic villus sampling secretion is similar in the mother and 0.14–1.8% of all cases of diabetes could undertaken for other indications. In both fetus, and fetal insulin levels remain nor- be attributable to MODY (4). It is to be pregnancies, the fetuses had inherited the mal. If, however, a mother with MODY 2 expected that among women screened maternal GCK mutation and were therefore has her hyperglycemia treated in preg- for mellitus (GDM) protected from the levels of maternal hy- nancy and the fetus also carries the GCK theprevalenceofMODYwillbehigher, perglycemia they were exposed to. Both reflecting both the proportionately mutation, birth weight can be severely women would have warranted active glyce- lower prevalence of in compromised (12). On the basis of these mic management by current guidelines women of this age group and the prob- observations, it has been recommended (18). Despite significant maternal hypergly- ability that those with undiagnosed to treat hyperglycemia in the mothers cemia and no treatment, both were MODY will screen positive (5). From with MODY 2 only when there is ultra- born at term with normal birth weights. the few population studies reported, sound evidence of accelerated fetal There are increasing numbers of mutations in the hepatocyte nuclear fac- growth (5). maternal genes being identified that in- tor 1 a (HNF1a)gene(MODY3)andglu- Maternal hyperglycemia at levels ob- fluence fasting blood glucose and fetal cokinase (GCK) gene (MODY 2) account served in women with MODY 2 has in growth (19). Our knowledge in this field for the majority of cases (6). observational and randomized trials been will expand with further subanalyses of MODY 2 is characterized by its high associated with adverse pregnancy out- maternal and fetal genes from the large penetrance, early onset, and lifelong fast- comes (13,14). These studies have pro- Hyperglycemia and Adverse Pregnancy ing hyperglycemia. It is due to mutations vided the evidence for the International Outcome (HAPO) cohort for which de- in the pancreatic GCK gene, which acts Association of the Diabetes and Preg- tailed biochemical, anthropometric, and as the b-cell glucose sensor, setting the nancy Study Groups (IADPSG) guidelines genetic data have been collected (19). In glucose threshold at which amplifica- on the diagnosis of GDM (15). In the the absence of this knowledge and the tion of insulin secretion occurs (7). In IADPSG guidelines, a fasting glucose ability to detect fetal genotype noninva- MODY 2, this is set at 18–45 mg/dL (1.0– value of $92 mg/dL (5.1 mmol/L) is sively during pregnancy, it must be ac- 2.5 mmol/L), higher than for unaffected considered diagnostic for GDM. As this knowledged that universally applied adults (7). Glucose tolerance can remain fasting value is set lower than other com- treatment guidelines will not be appro- stable over many years, provided that in- monly used diagnostic criteria, if adopted, priate for a minority of women with sulin sensitivity also remains stable (8). more women with GDM would be diag- GDM. However as 15–20% of today’s Although MODY 2 is associated with nosed (16). In addition, the lower fasting antenatal population has GDM using lifelong fasting hyperglycemia that may value by IADPSG criteria would label all the IADPSG criteria, this minority will care.diabetesjournals.org DIABETES CARE, VOLUME 35, SEPTEMBER 2012 1811 Editorial

1 still represent a sizable number of preg- SHIVANI MISRA, MRCP candidate genes in 22 Spanish families. J Clin 2 – nancies (16). ANNE DORNHORST, FRCP Endocrinol Metab 2002;87:2532 2539 Identifying and managing pregnan- 10. Velho G, Blanché H, Vaxillaire M, et al. 1 Identification of 14 new muta- cies appropriately when either the moth- From the Department of Metabolic Medicine, Im- fi er or the father carries the MODY2 gene perial Healthcare NHS Trust, London, U.K.; and tions and description of the clinical pro le the 2Department of Medicine, Imperial College of 42 MODY-2 families. Diabetologia 1997; requires a higher level of clinical suspicion Healthcare NHS Trust, London, U.K. 40:217–224 among family physicians, diabetologists, Corresponding author: Shivani Misra, s.misra@ 11. Hattersley AT, Beards F, Ballantyne E, and obstetricians and greater access to the imperial.ac.uk. Appleton M, Harvey R, Ellard S. Muta- necessary diagnostic tools. Until there are DOI: 10.2337/dc12-0689 tions in the glucokinase gene of the fetus advances in the noninvasive genotyping of © 2012 by the American Diabetes Association. result in reduced birth weight. Nat Genet Readers may use this article as long as the work is – fetal DNA, for example using cell free fetal properly cited, the use is educational and not for 1998;19:268 270 DNA, genotyping the fetus will require fi 12. Spyer G, Hattersley AT, Sykes JE, Sturley pro t, and the work is not altered. See http:// fl opportunistic use of CVS if undertaken creativecommons.org/licenses/by-nc-nd/3.0/ for RH, MacLeod KM. In uence of maternal for alternative indications. details. and fetal glucokinase mutations in gesta- The optimal treatment during preg- tional diabetes. Am J Obstet Gynecol 2001;185:240–241 — fl nancy of women with other monogenic Acknowledgments Nopotentialcon icts of 13. Crowther CA, Hiller JE, Moss JR, McPhee formsofdiabeteshasnotbeenwell interest relevant to this article were re- AJ, Jeffries WS, Robinson JS; Australian evaluated. Permanent neonatal diabetes ported. Carbohydrate Intolerance Study in Preg- is believed to affect approximately 1 in nant Women (ACHOIS) Trial Group. Ef- 200,000 births; however, the condition cccccccccccccccccccccccc fect of treatment of gestational diabetes is often misdiagnosed as . References mellitus on pregnancy outcomes. N Engl J A variety of genes have been implicated 1. American Diabetes Association. Diagno- Med 2005;352:2477–2486 including activating mutations in the sis and classification of diabetes mellitus. 14. Landon MB, Spong CY, Thom E, et al.; gene encoding the Kir6.2 subunit of Diabetes Care 2010;33(Suppl. 1):S62– Eunice Kennedy Shriver National Institute the b-cell ATP-sensitive K channel S69 of Child Health and Human Development KCNJ11 2. Tattersall RB. Mild familial diabetes with Maternal-Fetal Medicine Units Network. ( ) (20). Good glycemic control A multicenter, randomized trial of treat- with a lower risk of can dominant inheritance. Q J Med 1974;43: 339–357 ment for mild gestational diabetes. N Engl be achieved in patients with the Kir6.2 3. Rubio-Cabezas O, Minton JA, Kantor I, J Med 2009;361:1339–1348 mutations using treatment with sulfo- Williams D, Ellard S, Hattersley AT. Ho- 15. Metzger BE, Gabbe SG, Persson B, et al.; nylureas rather than insulin (21). How- mozygous mutations in NEUROD1 are International Association of Diabetes and ever, the safety of use in responsible for a novel syndrome of per- Pregnancy Study Groups Consensus Panel. pregnancy has not been clearly estab- manent neonatal diabetes and neuro- International association of diabetes and lished, and though some evidence ex- logical abnormalities. Diabetes 2010;59: pregnancy study groups recommendations fi ists on the use of glyburide, the safety 2326–2331 on the diagnosis and classi cation of hy- of other agents such as gliclazide is un- 4. Shields BM, Hicks S, Shepherd MH, perglycemia in pregnancy. Diabetes Care Colclough K, Hattersley AT, Ellard S. 2010;33:676–682 known (22). 16. Sacks DA, Hadden DR, Maresh M, et al.; Gathering together sufficient num- Maturity-onset diabetes of the young (MODY): how many cases are we miss- HAPO Study Cooperative Research Group. bers of women with permanent neonatal ing? Diabetologia 2010;53:2504–2508 Frequency of gestational diabetes mellitus diabetes in pregnancy to establish the 5. Colom C, Corcoy R. Maturity onset dia- at collaborating centers based on IADPSG optimal therapy will depend on observa- betes of the young and pregnancy. Best consensus panel-recommended crite- tional data from those few specialized Pract Res Clin Endocrinol Metab 2010; ria: the Hyperglycemia and Adverse Preg- centers that look after these women. 24:605–615 nancy Outcome (HAPO) Study. Diabetes Because of the general paucity of data, the 6. Estalella I, Rica I, Perez de Nanclares G, Care 2012;35:526–528 two case reports by Gaal et al. (23) of et al.; Spanish MODY Group. Mutations 17. Chakera AJ, Carleton VL, Ellard S, et al. women with KCNJ11 mutations treated in GCK and HNF-1alpha explain the ma- Antenatal diagnosis of fetal genotype jority of cases with clinical diagnosis of determines if maternal hyperglycemia due exclusively during pregnancy with the sul- to a glucokinase mutation requires treat- fonylurea glicazide, is a small but helpful MODY in Spain. Clin Endocrinol (Oxf) 2007;67:538–546 ment. Diabetes Care 2012;35:1832–1834 contribution, which when added to other 7. Byrne MM, Sturis J, Clément K, et al. In- 18. Metzger BE, Buchanan TA, Coustan DR, anecdotal reports (24) will begin to sulin secretory abnormalities in subjects et al. Summary and recommendations establish a knowledge base from which with hyperglycemia due to glucokinase of the Fifth International Workshop- guidelines can be formed. However, until mutations. J Clin Invest 1994;93:1120– Conference on Gestational Diabetes Mellitus. safety data on the use of gliclazide in 1130 Diabetes Care 2007;30(Suppl. 2):S251–S260 pregnancy is established, its use cannot 8. Martin D, Bellanné-Chantelot C, Deschamps 19. Freathy RM, Hayes MG, Urbanek M, et al.; be routinely advocated in these circum- I,FroguelP,RobertJJ,VelhoG.Long-term HAPO Study Cooperative Research Group. stances. follow-up of oral - Hyperglycemia and Adverse Pregnancy derived glucose tolerance and insulin Outcome (HAPO) study: common genetic The reports from Chakera et al. and variants in GCK and TCF7L2 are associ- Gaal et al. both highlight that treating all secretion and insulin sensitivity indexes in subjects with glucokinase mutations ated with fasting and postchallenge glucose women with hyperglycemia in pregnancy (MODY2). Diabetes Care 2008;31:1321– levels in pregnancy and with the new con- using generic evidenced-based algorithmic 1323 sensus definition of gestational diabetes guidelines may not necessarily be in the 9. Barrio R, Bellanné-Chantelot C, Moreno mellitus from the International Association best interests of all mothers and their JC, et al. Nine novel mutations in matu- of Study Groups. babies. rity-onset diabetes of the young (MODY) Diabetes 2010;59:2682–2689

1812 DIABETES CARE, VOLUME 35, SEPTEMBER 2012 care.diabetesjournals.org Misra and Dornhorst

20. Rubio-Cabezas O, Klupa T, Malecki MT; median follow-up. Diabetes Technol Ther diabetes because of KCNJ11 mutation: CEED3 Consortium. Permanent neonatal di- 2010;12:387–391 a report of two cases. Diabetes Care 2012; abetes mellitus—the importance of diabetes 22. Langer O, Conway DL, Berkus MD, Xenakis 35:e40 differential diagnosis in neonates and in- EM, Gonzales O. A comparison of glyburide 24. Klupa T, Kozek E, Nowak N, et al. The fants. Eur J Clin Invest 2011;41:323–333 andinsulininwomenwithgestationaldi- first case report of sulfonylurea use in a 21. Klupa T, Skupien J, Mirkiewicz-Sieradzka abetes mellitus. N Engl J Med 2000; woman with permanent neonatal diabetes B, et al. Efficacy and safety of sulfonylurea 343:1134–1138 mellitus due to KCNJ11 mutation during a use in permanent neonatal diabetes due 23. Gaal Z, Klupa T, Kantor I, et al. Sulfo- high-risk pregnancy. J Clin Endocrinol to KCNJ11 gene mutations: 34-month nylurea use during entire pregnancy in Metab 2010;95:3599–3604

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