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Tandi E Matsha,1,* Shanel Raghubeer,1,* Abegail M Tshivhase,1 Saarah FG Davids,1 Gloudina M Hon,1 Lise Bjørkhaug,2 Rajiv T Erasmus1 1SAMRC/Cardiometabolic Health Research Unit, Department of Biomedical Sciences, Faculty of Health & Wellness Sciences, Cape Peninsula University of Technology, Bellville Campus, Cape Town 7530, South Africa; 2Department of Safety, Chemistry, and Biomedical Laboratory Sciences, Western Norway University of Applied Sciences, Bergen, Norway*These authors contributed equally to this workCorrespondence: Shanel RaghubeerSAMRC/CPUT/Cardiometabolic Health Research Unit, Department of Biomedical Sciences, Faculty of Health & Wellness Sciences, Cape Peninsula University of Technology, Bellville Campus, Cape Town 7530, South AfricaTel +27 21 959 6015Email shanelraghubeer@gmail.comBackground and Aim: Maturity-onset diabetes of the young (MODY) is the result of single gene variants. To date, fourteen different MODY subtypes have been described. Variants in genes coding for glucokinase (GCK, MODY2) and hepatic nuclear factor 1 alpha (HNF1A, MODY3) are most frequently encountered. MODY patients are often misdiagnosed with type 1 or type 2 diabetes, resulting in incorrect treatment protocols. At the time of reporting, no data are available on MODY prevalence in populations from Africa. Our study aimed to investigate and report on the incidence of MODY-related variants, specifically HNF1A variants, in a population from the Western Cape.Methods: Study participants were recruited (1643 in total, 407 males, 1236 females) and underwent anthropometric tests. Thereafter, blood was collected, and real-time PCR was used to screen for specific variants in HNF1A and GCK genes.Results: Ninety-seven individuals (5.9%) were identified with a specific HNF1A gene polymorphism (rs1169288) and twelve (0.9%) with a GCK polymorphism (rs4607517).Conclusion: In total, 6.6% of the study population expressed MODY variants. To our knowledge, we are the first to report on MODY incidence in Africa. This research provides the basis for MODY incidence studies in South Africa, as well as data on non-Caucasian populations.Keywords: MODY, HNF1A, GCK, diabetes mellitus, monogenic diabetes, South Africa

Victoria L Rudland1,21Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, NSW, Australia; 2Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, AustraliaAbstract: Glucokinase–maturity-onset diabetes of the young (GCK-MODY) is an autosomal dominant disorder caused by heterozygous inactivating GCK gene mutations. GCK-MODY is one the most common MODY subtypes, affecting 0.1% of the population and 0.4–1% of women with gestational diabetes mellitus. Glucokinase is predominantly expressed in pancreatic beta cells and catalyzes the phosphorylation of glucose to glucose-6-phosphate. The unique kinetics of glucokinase enable it to change the rate of glucose phosphorylation according to the glucose concentration, thereby regulating insulin secretion. Individuals with GCK-MODY have mildly elevated fasting blood glucose levels (5.5–8.0 mmol/L) and regulate glucose perturbations to a higher set-point, resulting in a relatively flat glucose profile on a 75 g oral glucose tolerance test. The hyperglycemia is usually subclinical and may only be detected on incidental glucose testing. It is important to correctly identify GCK-MODY as the clinical course and management differs substantially from other types of diabetes. Diabetes-related complications are relatively uncommon, so glucose-lowering treatment is not usually required. The exception is pregnancy, where fetal growth and therefore glucose-lowering treatment are predominantly determined by whether or not the fetus inherits the GCK mutation. The fetal genotype is not usually known but can be inferred from serial fetal ultrasound measurements. If there is evidence of accelerating fetal abdominal circumference on serial ultrasounds, the fetus is assumed to not have the GCK mutation and treatment of maternal hyperglycemia is indicated to reduce the risk of macrosomia, Caesarean section and neonatal hypoglycemia. If there is no evidence of accelerating fetal growth, the fetus is assumed to have inherited the GCK mutation and will have a similarly elevated glucose set-point as their mother, so maternal hyperglycemia is not treated. With recent advances in genetic technology, such as next-generation sequencing and noninvasive fetal genotyping, the detection and management of GCK-MODY in pregnancy should continue to improve.Keywords: GCK, MODY, genetics, mutation, gestational diabetes, fetal

Maturity onset diabetes of the young (MODY) is a heterogeneous group of disorders that result in β-cell dysfunction. It is rare, accounting for just 1%-2% of all diabetes. It is often misdiagnosed as type 1 or type 2 diabetes, as it is often difficult to distinguish MODY from these two forms. However, diagnosis allows appropriate individualized care, depending on the genetic etiology, and allows prognostication in family members. In this review, we discuss features of the common causes of MODY, as well as the treatment and diagnosis of MODY.