High-sensitivity CRP discriminates HNF1A-MODY from other subtypes of diabetes

OBJECTIVE

Maturity-onset diabetes of the young (MODY) as a result of mutations in hepatocyte nuclear factor 1-α (HNF1A) is often misdiagnosed as type 1 diabetes or type 2 diabetes. Recent work has shown that high-sensitivity C-reactive protein (hs-CRP) levels are lower in HNF1A-MODY than type 1 diabetes, type 2 diabetes, or glucokinase (GCK)-MODY. We aim to replicate these findings in larger numbers and other MODY subtypes.

RESEARCH DESIGN AND METHODS

hs-CRP levels were assessed in 750 patients (220 HNF1A, 245 GCK, 54 HNF4-α [HNF4A], 21 HNF1-β (HNF1B), 53 type 1 diabetes, and 157 type 2 diabetes).

RESULTS

hs-CRP was lower in HNF1A-MODY (median [IQR] 0.3 [0.1–0.6] mg/L) than type 2 diabetes (1.40 [0.60–3.45] mg/L; P < 0.001) and type 1 diabetes (1.10 [0.50–1.85] mg/L; P < 0.001), HNF4A-MODY (1.45 [0.46–2.88] mg/L; P < 0.001), GCK-MODY (0.60 [0.30–1.80] mg/L; P < 0.001), and HNF1B-MODY (0.60 [0.10–2.8] mg/L; P = 0.07). hs-CRP discriminated HNF1A-MODY from type 2 diabetes with hs-CRP <0.75 mg/L showing 79% sensitivity and 70% specificity (receiver operating characteristic area under the curve = 0.84).

CONCLUSIONS

hs-CRP levels are lower in HNF1A-MODY than other forms of diabetes and may be used as a biomarker to select patients for diagnostic HNF1A genetic testing.Maturity-onset diabetes of the young (MODY) is a rare monogenic form of diabetes and is often misdiagnosed as type 1 diabetes or type 2 diabetes (1,2). A correct genetic diagnosis of MODY is important for predicting the clinical course of disease, risk to relatives, and optimizing treatment. Therefore, cheap and novel biomarkers that help identify these patients are desirable.The CRP gene has hepatocyte nuclear factor 1-α (HNF1A) binding sites in its promoter, and common variants in and around HNF1A are associated with circulating high-sensitivity C-reactive protein (hs-CRP) levels (3,4). Recently, Owen et al. (5) demonstrated that hs-CRP levels were reduced in 31 HNF1A-MODY patients compared with type 1 diabetes, type 2 diabetes, glucokinase (GCK) MODY, and normal control subjects, making it potentially a useful clinical test.We aim to replicate this initial study in a larger cohort of patients and assess whether the reduction in hs-CRP is also seen in patients with mutations of other genes encoding hepatic nuclear factors (hepatocyte nuclear factor 4-α [HNF4A] and hepatocyte nuclear factor 4-β [HNF1B]).     

The long-term impact on offspring of exposure to hyperglycaemia in utero due to maternal glucokinase gene mutations

Aims/hypothesis There is strong evidence that maternal diabetes while offspring are in utero results in offspring beta cell dysfunction and diabetes or glucose intolerance. Offspring born to mothers with a mutation in the glucokinase gene (GCK) are a good model for studying exposure to moderate hyperglycaemia, as mutation carriers have fasting hyperglycaemia throughout life including during pregnancy. We assessed the long term effects of exposure to maternal hyperglycaemia in utero on beta cell function and glucose tolerance in adult offspring. Materials and methods We studied 86 adult offspring (mean age 40 years), 49 born to glucokinase mothers (exposed to hyperglycaemia in utero) and 37 born to glucokinase fathers (controls). We measured glucose tolerance during an OGTT and beta cell function using early insulin response (EIR); we also measured anthropometric data including birthweight. Results Offspring of glucokinase mothers had a higher birthweight by 450 g (p < 0.001), but no evidence of deterioration in glucose tolerance (2-h glucose 9.1 vs 8.6 mmol/l p = 0.50) or reduced beta cell function (log EIR 1.40 vs 1.26, p = 0.11) compared with offspring born to glucokinase fathers. Conclusions/interpretation The marked increase in birthweight shows that offspring born to affected mothers were exposed to increased glycaemia in utero. Despite this, there was no evidence of altered beta cell function or glucose tolerance. As previous human examples of marked programming by hyperglycaemia in utero have been in genetically predisposed offspring, we propose that our finding reflects the lack of genetic predisposition in the offspring to progressive beta cell dysfunction.     

Maturity-onset diabetes of the young: clinical heterogeneity explained by genetic heterogeneity

Maturity-onset diabetes of the young (MODY) can be defined by the clinical characteristics of early-onset Type 2 (non-insulin-dependent) diabetes and autosomal dominant inheritance. Mutations in four genes have been shown to cause MODY: glucokinase, hepatic nuclear factor 1 alpha (HNF1α), hepatic nuclear factor 4 alpha (HNF4α) and insulin protein factor 1 (IPF1). In white Caucasians it is now possible to define the gene in most patients with a clinical diagnosis of MODY. Each gene involved in MODY has its own specific clinical and physiological characteristics. Patients with mutations of the glucokinase gene have mild fasting hyperglycaemia throughout life, and rarely require medication or develop microvascular complications. The principle pathophysiology is stable beta-cell dysfunction characterized by reduced sensing of glucose by the pancreas. Patients with mutations in HNF1α have normal glucose tolerance in early childhood and usually present with symptomatic diabetes in their late teens or early adulthood. They show increasing hyperglycaemia and treatment requirements with frequent microvascular complications. The underlying defect is progressive beta-cell failure, with the early lesion characterized by failure to increase insulin secretion with increasing glucose levels. Patients with HNF4α and IPF1 mutations show a similar clinical picture to HNF1α although diabetes may be diagnosed later. There are other patients with MODY in whom the genetic defect is still unknown. Molecular genetic testing in patients with diabetes offers the possibility of making a firm diagnosis of MODY and allows prediction of the future clinical course. The role of predictive testing in non-diabetic subjects within families is uncertain at present. Preliminary evidence suggests that maintaining insulin sensitivity by avoiding obesity and regular physical exercise may help delay the onset of diabetes © 1998 John Wiley & Sons, Ltd.     

Heterozygous ABCC8 mutations are a cause of MODY

Aims/hypothesis  

The ABCC8 gene encodes the sulfonylurea receptor 1 (SUR1) subunit of the pancreatic beta cell ATP-sensitive potassium (K_ATP) channel. Inactivating mutations cause congenital hyperinsulinism (CHI) and activating mutations cause transient neonatal diabetes (TNDM) or permanent neonatal diabetes (PNDM) that can usually be treated with sulfonylureas. Sulfonylurea sensitivity is also a feature of HNF1A and HNF4A MODY, but patients referred for genetic testing with clinical features of these types of diabetes do not always have mutations in the HNF1A/4A genes. Our aim was to establish whether mutations in the ABCC8 gene cause MODY that is responsive to sulfonylurea therapy.     

Type 1 diabetes phenotype in white and South Asian people with young onset diabetes in the UK: results from the MY DIABETES study

Background

Differentiating type 1 diabetes from other subtypes in ethnic groups is challenging. Non-white young adults are assumed to be more likely to develop type 2 diabetes, although the characteristics of type 1 diabetes have not been studied in non-white ethnic groups. Data suggest that second generation migrant populations adopt the local risk for type 1 diabetes, but the phenotype in these groups remains unexplored. We aimed to investigate the phenotype of type 1 diabetes in a UK multi-ethnic population.

Precision diabetes: learning from monogenic diabetes

The precision medicine approach of tailoring treatment to the individual characteristics of each patient or subgroup has been a great success in monogenic diabetes subtypes, MODY and neonatal diabetes. This review examines what has led to the success of a precision medicine approach in monogenic diabetes (precision diabetes) and outlines possible implications for type 2 diabetes. For monogenic diabetes, the molecular genetics can define discrete aetiological subtypes that have profound implications on diabetes treatment and can predict future development of associated clinical features, allowing early preventative or supportive treatment. In contrast, type 2 diabetes has overlapping polygenic susceptibility and underlying aetiologies, making it difficult to define discrete clinical subtypes with a dramatic implication for treatment. The implementation of precision medicine in neonatal diabetes was simple and rapid as it was based on single clinical criteria (diagnosed <6 months of age). In contrast, in MODY it was more complex and slow because of the lack of single criteria to identify patients, but it was greatly assisted by the development of a diagnostic probability calculator and associated smartphone app. Experience in monogenic diabetes suggests that successful adoption of a precision diabetes approach in type 2 diabetes will require simple, quick, easily accessible stratification that is based on a combination of routine clinical data, rather than relying on newer technologies. Analysing existing clinical data from routine clinical practice and trials may provide early success for precision medicine in type 2 diabetes.