Gaya Thanabalasingham

Diagnosis and management of maturity onset diabetes of the young (MODY).

#### Summary points Maturity onset diabetes of the young (MODY) comprises a heterogeneous group of monogenic disorders characterised by β cell dysfunction. It is estimated to be the underlying cause of diabetes in 1-2% of patients diagnosed with diabetes, but prevalence estimates will not be accurate until large population screening studies are performed.1 It is important to distinguish MODY from type 1 and type 2 diabetes because optimal treatments are different. Furthermore, first degree relatives have a 50% probability of inheriting the same mutation, which confers a greater than 95% lifetime risk of developing diabetes.2 Distinguishing people who have rare forms of diabetes such as MODY from those with type 1 or type 2 diabetes is a diagnostic challenge because clinical features are similar. In this review we discuss when the general physician might suspect MODY and how to identify which patients with diabetes should be offered genetic testing. We focus on the recognition of the common forms of MODY in people diagnosed with diabetes in the age range 10-45 years, drawing mainly on evidence from small trials and cross …

Assessment of High-Sensitivity C-Reactive Protein Levels as Diagnostic Discriminator of Maturity-Onset Diabetes of the Young Due to HNF1A Mutations

OBJECTIVE Despite the clinical importance of an accurate diagnosis in individuals with monogenic forms of diabetes, restricted access to genetic testing leaves many patients with undiagnosed diabetes. Recently, common variation near the HNF1 homeobox A (HNF1A) gene was shown to influence C-reactive protein levels in healthy adults. We hypothesized that serum levels of high-sensitivity C-reactive protein (hs-CRP) could represent a clinically useful biomarker for the identification of HNF1A mutations causing maturity-onset diabetes of the young (MODY). RESEARCH DESIGN AND METHODS Serum hs-CRP was measured in subjects with HNF1A-MODY (n = 31), autoimmune diabetes (n = 316), type 2 diabetes (n = 240), and glucokinase (GCK) MODY (n = 24) and in nondiabetic individuals (n = 198). The discriminative accuracy of hs-CRP was evaluated through receiver operating characteristic (ROC) curve analysis, and performance was compared with standard diagnostic criteria. Our primary analyses excluded ∼11% of subjects in whom the single available hs-CRP measurement was >10 mg/l. RESULTS Geometric mean (SD range) hs-CRP levels were significantly lower (P ≤ 0.009) for HNF1A-MODY individuals, 0.20 (0.03–1.14) mg/l, than for any other group: autoimmune diabetes 0.58 (0.10–2.75) mg/l, type 2 diabetes 1.33 (0.28–6.14) mg/l, GCK-MODY 1.01 (0.19–5.33) mg/l, and nondiabetic 0.48 (0.10–2.42) mg/l. The ROC-derived C-statistic for discriminating HNF1A-MODY and type 2 diabetes was 0.8. Measurement of hs-CRP, either alone or in combination with current diagnostic criteria, was superior to current diagnostic criteria alone. Sensitivity and specificity for the combined criteria approached 80%. CONCLUSIONS Serum hs-CRP levels are markedly lower in HNF1A-MODY than in other forms of diabetes. hs-CRP has potential as a widely available, cost-effective screening test to support more precise targeting of MODY diagnostic testing.

Mutations in HNF1A Result in Marked Alterations of Plasma Glycan Profile

A recent genome-wide association study identified hepatocyte nuclear factor 1-α (HNF1A) as a key regulator of fucosylation. We hypothesized that loss-of-function HNF1A mutations causal for maturity-onset diabetes of the young (MODY) would display altered fucosylation of N-linked glycans on plasma proteins and that glycan biomarkers could improve the efficiency of a diagnosis of HNF1A-MODY. In a pilot comparison of 33 subjects with HNF1A-MODY and 41 subjects with type 2 diabetes, 15 of 29 glycan measurements differed between the two groups. The DG9-glycan index, which is the ratio of fucosylated to nonfucosylated triantennary glycans, provided optimum discrimination in the pilot study and was examined further among additional subjects with HNF1A-MODY (n = 188), glucokinase (GCK)-MODY (n = 118), hepatocyte nuclear factor 4-α (HNF4A)-MODY (n = 40), type 1 diabetes (n = 98), type 2 diabetes (n = 167), and nondiabetic controls (n = 98). The DG9-glycan index was markedly lower in HNF1A-MODY than in controls or other diabetes subtypes, offered good discrimination between HNF1A-MODY and both type 1 and type 2 diabetes (C statistic ≥0.90), and enabled us to detect three previously undetected HNF1A mutations in patients with diabetes. In conclusion, glycan profiles are altered substantially in HNF1A-MODY, and the DG9-glycan index has potential clinical value as a diagnostic biomarker of HNF1A dysfunction.

Lipoprotein composition in HNF1A-MODY: Differentiating between HNF1A-MODY and Type 2 diabetes.

INTRODUCTION The young-onset diabetes seen in HNF1A-MODY is often misdiagnosed as Type 2 diabetes. Type 2 diabetes, unlike HNF1A-MODY, is associated with insulin resistance and a characteristic dyslipidaemia. We aimed to compare the lipid profiles in HNF1A-MODY, Type 2 diabetes and control subjects and to determine if lipids can be used to aid the differential diagnosis of diabetes sub-type. METHODS 1) 14 subjects in each group (HNF1A-MODY, Type 2 diabetes and controls) were matched for gender and BMI. Fasting lipid profiles and HDL lipid constituents were compared in the 3 groups. 2) HDL-cholesterol was assessed in a further 267 patients with HNF1A-MODY and 297 patients with a diagnosis of Type 2 diabetes to determine its discriminative value. RESULTS 1) In HNF1A-MODY subjects, plasma-triglycerides were lower (1.36 vs. 1.93 mmol/l, p = 0.07) and plasma-HDL-cholesterol was higher than in subjects with Type 2 diabetes (1.47 vs. 1.15 mmol/l, p = 0.0008), but was similar to controls. Furthermore, in the isolated HDL; HDL-phospholipid and HDL-cholesterol ester content were higher in HNF1A-MODY, than in Type 2 diabetes (1.59 vs. 1.33 mmol/L, p = 0.04 and 1.10 vs. 0.83 mmol/L, p = 0.019, respectively), but were similar to controls (1.59 vs. 1.45 mmol/L, p = 0.35 and 1.10 vs. 1.21 mmol/L, p = 0.19, respectively). 2) A plasma-HDL-cholesterol > 1.12 mmol/L was 75% sensitive and 64% specific (ROC AUC = 0.76) at discriminating HNF1A-MODY from Type 2 diabetes. CONCLUSION The plasma-lipid profiles of HNF1A-MODY and the lipid constituents of HDL are similar to non-diabetic controls. However, HDL-cholesterol was higher in HNF1A-MODY than in Type 2 diabetes and could be used as a biomarker to aid in the identification of patients with HNF1A-MODY.

Metabolic Profiling in Maturity-Onset Diabetes of the Young (MODY) and Young Onset Type 2 Diabetes Fails to Detect Robust Urinary Biomarkers

It is important to identify patients with Maturity-onset diabetes of the young (MODY) as a molecular diagnosis determines both treatment and prognosis. Genetic testing is currently expensive and many patients are therefore not assessed and are misclassified as having either type 1 or type 2 diabetes. Biomarkers could facilitate the prioritisation of patients for genetic testing. We hypothesised that patients with different underlying genetic aetiologies for their diabetes could have distinct metabolic profiles which may uncover novel biomarkers. The aim of this study was to perform metabolic profiling in urine from patients with MODY due to mutations in the genes encoding glucokinase (GCK) or hepatocyte nuclear factor 1 alpha (HNF1A), type 2 diabetes (T2D) and normoglycaemic control subjects. Urinary metabolic profiling by Nuclear Magnetic Resonance (NMR) and ultra performance liquid chromatography hyphenated to Q-TOF mass spectrometry (UPLC-MS) was performed in a Discovery set of subjects with HNF1A-MODY (n = 14), GCK-MODY (n = 17), T2D (n = 14) and normoglycaemic controls (n = 34). Data were used to build a valid partial least squares discriminate analysis (PLS-DA) model where HNF1A-MODY subjects could be separated from the other diabetes subtypes. No single metabolite contributed significantly to the separation of the patient groups. However, betaine, valine, glycine and glucose were elevated in the urine of HNF1A-MODY subjects compared to the other subgroups. Direct measurements of urinary amino acids and betaine in an extended dataset did not support differences between patients groups. Elevated urinary glucose in HNF1A-MODY is consistent with the previously reported low renal threshold for glucose in this genetic subtype. In conclusion, we report the first metabolic profiling study in monogenic diabetes and show that, despite the distinct biochemical pathways affected, there are unlikely to be robust urinary biomarkers which distinguish monogenic subtypes from T2D. Our results have implications for studies investigating metabolic profiles in complex traits including T2D.

Atypical phenotype associated with reported GCK exon 10 deletions: Clinical judgement is needed alongside appropriate genetic investigations.

Maturity‐onset diabetes of the young (MODY) caused by heterozygous mutations in the glucokinase (GCK) gene typically presents with lifelong, stable, mild fasting hyperglycaemia. With the exception of pregnancy, patients with GCK‐MODY usually do not require pharmacological therapy. We report two unrelated patients whose initial genetic test results indicated a deletion of GCK exon 10, but whose clinical phenotypes were not typical of GCK‐MODY.

Comparability of high-sensitivity CRP methods to detect maturity-onset diabetes of the young due to HNF1A mutations.

C-reactive protein (CRP) is an acute-phase protein synthesised in the liver that can rise rapidly in response to infection or tissue injury. The CRP methods may be categorised as those optimised for performance between 5 mg/L and 200 mg/L for detection and monitoring of inflammation and infection, and those applicable in the 1–20 mg/L range, so-called high-sensitivity assays, for application in cardiovascular risk assessment. An increased understanding of the role of genetic factors in CRP expression have led to suggestions that plasma CRP may provide a screening tool for the identification of patients with maturity-onset diabetes of the young (MODY) due to mutations in the HNF1A gene. Currently, HNF1AMODY is under-diagnosed due to restricted awareness and costs of genetic testing, and consequently many patients are mislabelled as having more common forms of diabetes and may receive suboptimal treatment. HNF1A regulates expression of CRP, so haploinsufficiency due to inactivating mutations results in lower plasma CRP concentrations in patients with HNF1A-MODY compared with other diabetes subtypes, but the absolute values appear CRP method-dependent. The present study clarifies method differences in the concentration range of relevance to this clinical application. Three CRP methods were obtained from Siemens Healthcare Diagnostics (Frimley, UK) and applied using the manufacturer’s recommendations. Two immunoturbidimetric assays, high-sensitivity CRP method (HCRP) and a widerange CRP method (WCRP) were applied on an ADVIA 2400 general chemistry analyser. The third method (ICRP) was a chemiluminescence immunoassay applied on an Immulite 2000 analyser. Each method had kit-specific calibration material. The immunoturbidimetric methods used six-point calibration, HCRP covering the range 0.16–10 mg/L and WCRP 0.02–164 mg/L. The ICRP method utilised a master curve over the range 0.2–100 mg/L with an on-instrument two-point adjustment. Lithium heparin plasma samples sent to the clinical biochemistry laboratory for CRP analysis were used for all studies. Intra-assay imprecision was assessed by analysing 11 samples in quadruplicate, inter-assay imprecision with three clinical samples measured in duplicate on 10 separate days. The limit of quantification (LOQ) was defined at an inter-assay imprecision of 20%. The method comparison utilised 121 samples with values evenly distributed between 0.02 mg/L and 5 mg/L. Spiked samples were used to assess the effect of common interferences: haemolysis (haemoglobin up to 0.68 mmol/L), lipaemia (triglycerides, in the form of intralipid, up to 26.7 mmol/L) and icterus (bilirubin up to 334 μmol/L). Effects of the interfering substances were considered significant if an absolute difference of >5% between spiked and unspiked samples was noted. Assessment of imprecision utilised geometric mean, standard deviation and percentage coefficient of variation (%CV). Method comparisons are presented as Bland-Altman plots and evaluated using Passing-Bablock regression using Analyse-It software within Excel. Intra-assay imprecision of clinical samples (n=11, measured in quadruplicate) between 0.05 mg/L and 2.5 mg/L was superior for HCRP (mean %CV: 1.5; range: 0.4–6.2%) compared to WCRP (mean %CV: 4.2; range: 0–13.3%) and ICRP (mean %CV: 3.9; range: 1.4–9.4%). Inter-batch imprecision for HCRP was 7.5% at 0.41 mg/L, 2.6% at Correspondence to: Professor Tim James

Acromegaly: Beyond surgery

Acromegaly is characterized by chronic, excess secretion of growth hormone (GH) from a pituitary adenoma, and elevated hepatic insulin-like growth factor 1 (IGF-1) levels. Significant progress has been made in the development of medical therapies to achieve biochemical and symptomatic control in acromegaly. In this review we discuss the three currently available medical therapies, which include somatostatin analogs, dopamine agonists and pegvisomant. We describe a step-wise approach in which a somatostatin analog is followed by the addition of a dopamine agonist, and then if required the addition of or replacement by pegvisomant. New somatostatin agonists such as pasireotide, and the introduction of new orally-acting somatostatin agonists, should increase the therapeutic choices available in the near future.