Low serum level of high‐sensitivity C‐reactive protein in a Japanese patient with maturity‐onset diabetes of the young type 3 (MODY3)

High‐sensitivity C‐reactive protein (hs‐CRP) levels in European populations are lower in patients with maturity‐onset diabetes of the young type 3 (MODY3) than in those with type 2 diabetes. hs‐CRP levels have been suggested to be useful for discriminating MODY3 from type 2 diabetes. As hs‐CRP levels are influenced by various factors including race and body mass index, it is worthwhile to examine whether hs‐CRP can serve as a biomarker for MODY3 in Japanese. Here we describe the case of a Japanese MODY3 patient with a nonsense mutation in the HNF1A gene. Two measurements showed consistently lower hs‐CRP levels (<0.05 and 0.09 mg/L) than in Japanese patients with type 1 and type 2 diabetes. Hepatic expression of Crp messenger ribonucleic acid was significantly decreased in Hnf1a knockout mice. The hs‐CRP level might be a useful biomarker for MODY3 in both Japanese and European populations.     

Treatment implications of a delayed diagnosis of maturity‐onset diabetes of the young

Maturity‐onset diabetes of the young (MODY) is a rare form of monogeneic diabetes that classically presents as non‐insulin requiring diabetes with evidence of autosomal dominant inheritance in individuals who are typically young and lean. However, these criteria do not capture all cases and can also overlap with other types of diabetes. The hepatocyte nuclear factor‐1 alpha (HNF1A) mutation is a common cause of MODY and is highly sensitive to sulphonylureas, which should be first‐line therapy. Our case represents the diagnostic challenges of HNF1A MODY and the implications of a delayed diagnosis, which can lead to reduced success of sulphonylurea treatment.     

Phenotypical aspects of maturity‐onset diabetes of the young (MODY diabetes) in comparison with Type 2 diabetes mellitus (T2DM) in children and adolescents: experience from a large multicentre database

Aims To analyse and compare clinical characteristics in young patients with maturity‐onset diabetes of the young (MODY) and Type 2 diabetes mellitus (T2DM). Methods We conducted an observational investigation using the DPV‐Wiss database containing clinical data on 40 757 diabetic patients < 20 years of age from Germany and Austria. Results Three hundred and thirty‐nine cases were clinically categorized as MODY (0.83%); 562 patients were diagnosed as T2DM (1.4%). In 20% of cases, the diagnosis of MODY was based on clinical findings only. Of the 272 subjects where genetic testing was available, 3% did not carry mutations in the three examined MODY genes. Glucokinase‐MODY was commoner than HNF1A‐MODY and HNF4A‐MODY. Age at diagnosis was younger in MODY patients. The body mass index of T2DM was significantly higher compared with all MODY subgroups. Macrovascular risk factors such as dyslipidaemia and hypertension were commoner in T2DM, but 23% of MODY patients had dyslipidaemia and 10% hypertension. Glycaemic control was within the therapeutic target (HbA_1c < 7.5%) in 86% of MODY and 70% of T2DM patients. Conclusions The prevalence of MODY in children and adolescents in Germany and Austria is lower than that of T2DM in this age group. Dyslipidaemia and hypertension are less frequent in MODY compared with T2DM patients, but do occur.     

HbA1c‐based diabetes diagnosis among patients with glucokinase mutation (GCK‐MODY) is affected by a genetic variant of glucose‐6‐phosphatase (G6PC2)

Aims Genetic variation at the rs560887 locus of the glucose‐6‐phosphatase, catalytic 2 gene (G6PC2) is known to affect regulation of fasting glycaemia. We determined the rs560887 genotype of patients with monogenic diabetes and glucokinase gene mutations (GCK‐MODY) and correlated the genotypes with HbA_1c levels. Methods Patients from families with GCK‐MODY were recruited from two large cohorts from Poland (n = 128) and the Czech Republic (n = 154). Genotypes at the rs560887 polymorphic site in G6PC2 were examined using real‐time quantitative polymerase chain reaction. The effect of rs560887 genotype on age at diagnosis of GCK‐MODY and initial HbA_1c levels were evaluated separately within both cohorts. Following that, a meta‐analysis of rs560887 genotype–HbA_1c associations of both Polish and Czech cohorts was performed to confirm homogeneity of findings and validate cohort‐specific results. Results GG homozygosity at rs560887 was associated with marginally elevated HbA_1c levels (P = 0.07 in both cohorts). The effects observed in both groups were very homogeneous (Q = 0.18; P = 0.68). Meta‐analysis showed that GG homozygosity at rs560887 was associated with mean HbA_1c levels higher by 2.4 mmol/mol (0.24%), 95% CI 0.5–4.4 mmol/mol (0.05–0.44%) than in individuals with other genotypes. Additionally, meta‐analysis of both cohorts showed that GG homozygous individuals had higher odds of reaching the 48 mmol/mol (6.5%) diagnostic threshold of diabetes; (odds ratio 1.90; 95% CI 1.07–3.36; P = 0.03). No such effects were observed for age at diagnosis of diabetes. Conclusions Variation at the rs560887 locus of G6PC2 is associated with worse glycated haemoglobin levels in individuals with GCK mutations; GG homozygotes are more likely to meet diagnostic criteria for diabetes based on HbA_1c level.     

Maturity-onset diabetes of the young (MODY)

This review summarized aspects of the widening scope, phenotypic expression, natural history, recognition, pathogeneses, and heterogenous nature of maturity-onset diabetes of the young (MODY), an autosomal dominant inherited subtype of NIDDM, which can be recognized at a young age. There are differences in metabolic, hormonal, and vascular abnormalities in different ethnic groups and even among Caucasian pedigrees. In MODY patients with low insulin responses, there is a delayed and decreased insulin and C-peptide secretory response to glucose from childhood or adolescence, even before glucose intolerance appears; it may represent the basic genetic defect. The nondiabetic siblings have had normal insulin responses for decades. The fasting hyperglycemia of some MODY has been treated successfully with sulfonylureas for more than 30 years. In a few, after years or decades of diabetes, the insulin and C-peptide responses to glucose are so low that they may resemble those of early Type I diabetes. The rate of progression of the insulin secretory defect over time does distinguish between these two types of diabetes. In contrast are patients from families who have very high insulin responses to glucose despite glucose intolerance and fasting hyperglycemia similar to those seen in patients with low insulin responses. In many of these patients, there is in vivo and in vitro evidence of insulin resistance. Whatever its mechanism, the compensatory insulin responses to nutrients must be insufficient to maintain normal carbohydrate tolerance. This suggests that diabetes occurs only in those patients who have an additional islet cell defect, i.e., insufficient beta cell reserve and secretory capacity. In a few MODY pedigrees with high insulin responses to glucose and lack of evidence of insulin resistance, an insulin is secreted which is a structurally abnormal, mutant insulin molecule that is biologically ineffective. No associations have been found between specific HLA antigens and MODY in Caucasian, black, and Asian pedigrees. Linkage studies of the insulin gene, the insulin receptor gene, the erythrocyte/Hep G2 glucose transporter locus, and the apolipoprotein B locus have shown no association with MODY. Vascular disease may be as prevalent as in conventional NIDDM. Because of autosomal dominant transmission and penetrance at a young age, MODY is a good model for further investigations of etiologic and pathogenetic factors in NIDDM, including the use of genetic linkage strategies to identify diabetogenic genes.     

Maturity-onset diabetes of the young (MODY)

Maturity-onset diabetes of the young (MODY) is a rare but important differential diagnosis of diabetes presenting in childhood, adolescence or young adulthood. Common features of the 10 known MODY forms are autosomal dominant inheritance of mutations in genes involved, e.g. in the regulation of insulin secretion or β-cell development. The most common forms are MODY2 (glucokinase MODY) and MODY3 (HNF1A-MODY). Patients with MODY2 initially present with hyperglycemia during an incidental laboratory control without any clinical symptoms of diabetes and diet alone is usually sufficient for glycemic control. MODY3 is characterized by progressive hyperglycemia as a result of a decrease in insulin secretion capacity. Most patients are initially successfully treated with sulphonyl ureas but might later require insulin treatment. The other MODY forms occur much less frequently and can show specific clinical signs. Diagnosis of MODY has direct impact on the management of diabetes, genetic counselling and early diagnosing of diabetes in affected family members.     

Early onset of liver steatosis in a Japanese girl with maturity-onset diabetes of the young type 3 (MODY3)

Maturity-onset diabetes of the young type 3 (MODY3) is caused by heterozygous mutation in the HNF1A gene. Liver adenomatosis has been reported in MODY3 patients. The patient reported in this paper is a Japanese girl who first developed hepatomegaly, fatty liver, and hepatic dysfunction at age 5 years. Liver biopsy demonstrated steatosis and degeneration of hepatocytes. At that time, blood glucose and HbA1c levels were within normal ranges. Elevated HbA1c was noticed 4 years later, but islet cell and glutamic acid decarboxylase antibodies were not detected in the serum. Therefore, MODY3 was suspected and subsequent analysis of the HNF1A gene identified a heterozygous germline splice donor-site mutation in intron 9. MODY3 patients should be screened by non-invasive liver imaging, and careful follow-up of liver disease should be performed.