Maturity onset diabetes of the young and fibrin-related thrombosis risk.

BACKGROUND: Fibrin network characteristics determine predisposition to cardiovascular disease (CVD). Individuals with type 1 (T1DM) and type 2 diabetes mellitus (T2DM) have higher risk of CVD and display deranged fibrin network structure. Those with maturity onset diabetes of the young (MODY) may also be at increased risk but their fibrin clot properties have not been studied. METHODS: Plasma clots properties from 13 individuals with HNF1A-MODY, 12 matched-individuals with T2DM and 12 with T1DM were studied using a validated turbidimetric assay and confocal microscopy. Plasma levels of fibrinogen, plasminogen activator inhibitor-1, complement C3 and C-reactive protein were also measured. RESULTS: MODY clot maximum absorbance was 0.37 ± 0.03 AU, similar to T1DM (0.32 ± 0.03 AU; p = 0.26), but lower than T2DM (0.49 ± 0.03 AU; p = 0.02), with confocal microscopy confirming structural differences. Clot lysis time in MODY was similar to T1DM (456 ± 50 and 402 ± 20 s, respectively; p = 0.09) but shorter than T2DM (588 ± 58 s; p = 0.006). Comparing inflammatory/thrombotic proteins in HNF1A-MODY and T2DM, C3 levels were lower in MODY than T2DM (0.58 ± 0.09 and 0.80 ± 0.1 mg/ml, respectively; p < 0.01). CONCLUSIONS: HNF1A-MODY fibrin network alterations are at least as pronounced as in T1DM but less thrombotic than T2DM clots. Differences in fibrin clot characteristics comparing HNF1A-MODY and T2DM may, in part, relate to lower C3 levels.

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

BACKGROUND: 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. CASE REPORTS: In case 1, the patient was hyperglycaemic at diagnosis (glucose > 30 mmol/l) and elevated glucose levels > 10 mmol/l persisted after withdrawal of insulin therapy. The patient in case 2 was also hyperglycaemic at diagnosis [HbA1c > 86 mmol/mol (10%)], which improved with the introduction of oral hypoglycaemic agents. These clinical features were not consistent with GCK-MODY. Both patients had a single nucleotide variant that prevented multiplex ligation-dependent probe analysis, which generated a false positive result of a GCK exon 10 deletion. CONCLUSION: False positive genetic results in these two unrelated cases were attributable to the presence of a rare single nucleotide variant that prevented ligation of the probe in the multiplex ligation-dependent probe analysis kit used and falsely indicated deletion of exon 10 within GCK. Both cases had clinical features that did not tally with the typical GCK-MODY phenotype. These cases emphasize the need to interpret the results of definitive genetic tests within the specific clinical context. Increased medical sequencing is likely to lead to more reports of novel mutations of uncertain significance. If genetic investigations do not agree with the clinical picture, clinicians should exercise caution when making therapeutic changes based on these results.

RD Lawrence lecture 2012: assessing aetiology in diabetes: how C-peptide, CRP and fucosylation came to the party!

Assigning the correct aetiology in diabetes is important for treatment, understanding prognosis and for follow-up of family members. Despite these benefits, many are missing out on the opportunity to have testing for monogenic forms of diabetes. This review gives the clinical features of the commoner forms of monogenic diabetes and examines which clinical and biological markers can be used to identify those at highest risk of having Maturity onset diabetes of the young (MODY). MODY is characterised by young-onset, familial diabetes which is C-peptide positive, ß-cell antibody negative and not associated with metabolic syndrome. Differentiating from type 1 and type 2 diabetes can be challenging due to the overlap of clinical features. In type 1 diabetes, insulin production ceases after the honeymoon period. Thus C-peptide can be used to detect those with persisting insulin secretion who might have a different cause for their diabetes. In type 2 diabetes, most have insulin resistance, so absence of metabolic syndrome could be used to identify those most likely to have MODY. Another approach is to look for non-pancreatic features associated with mutations in MODY genes. Following results from Genome-wide association studies, we have shown that those with HNF1A mutations (the commonest form of MODY) have decreased serum levels of highly-sensitive C-reactive protein (hsCRP) and altered patterns of plasma protein fucosylation. These features can differentiate HNF1A-MODY from common forms of diabetes with a high degree of discriminative accuracy. Using combinations of clinical features and new biomarkers in diagnostic pathways will help increase diagnosis rates of MODY.

Apolipoprotein M can discriminate HNF1A-MODY from Type 1 diabetes.

AIMS: Missed diagnosis of maturity-onset diabetes of the young (MODY) has led to an interest in biomarkers that enable efficient prioritization of patients for definitive molecular testing. Apolipoprotein M (apoM) was suggested as a biomarker for hepatocyte nuclear factor 1 alpha (HNF1A)-MODY because of its reduced expression in Hnf1a(-/-) mice. However, subsequent human studies examining apoM as a biomarker have yielded conflicting results. We aimed to evaluate apoM as a biomarker for HNF1A-MODY using a highly specific and sensitive ELISA. METHODS: ApoM concentration was measured in subjects with HNF1A-MODY (n = 69), Type 1 diabetes (n = 50), Type 2 diabetes (n = 120) and healthy control subjects (n = 100). The discriminative accuracy of apoM and of the apoM/HDL ratio for diabetes aetiology was evaluated. RESULTS: Mean (standard deviation) serum apoM concentration (µmol/l) was significantly lower for subjects with HNF1A-MODY [0.86 (0.29)], than for those with Type 1 diabetes [1.37 (0.26), P = 3.1 × 10(-18) ) and control subjects [1.34 (0.22), P = 7.2 × 10(-19) ). There was no significant difference in apoM concentration between subjects with HNF1A-MODY and Type 2 diabetes [0.89 (0.28), P = 0.13]. The C-statistic measure of discriminative accuracy for apoM was 0.91 for HNF1A-MODY vs. Type 1 diabetes, indicating high discriminative accuracy. The apoM/HDL ratio was significantly lower in HNF1A-MODY than other study groups. However, this ratio did not perform well in discriminating HNF1A-MODY from either Type 1 diabetes (C-statistic = 0.79) or Type 2 diabetes (C-statistic = 0.68). CONCLUSIONS: We confirm an earlier report that serum apoM levels are lower in HNF1A-MODY than in controls. Serum apoM provides good discrimination between HNF1A-MODY and Type 1 diabetes and warrants further investigation for clinical utility in diabetes diagnostics.

Identification of risk factors for traumatic injury in the general horse population of north-west England, Midlands and north Wales.

REASONS FOR PERFORMING STUDY: Traumatic injuries are a major cause of morbidity and mortality in the horse and consequently pose a serious threat to horses' wellbeing. To date, there have been no published studies assessing the frequency of injuries in the general horse population of the UK. OBJECTIVES: To obtain information regarding husbandry management strategies and injury prevalence in horses aged ≤15 years, with the aim of identifying predisposing risk factors for injury. METHODS: A postal questionnaire was distributed to a randomly selected sample of horse owners across north-west England, Midlands and north Wales. Factors associated with injury were assessed using univariable and multivariable logistic regression analysis performed with the binary outcome variable defined as whether or not the horse had sustained an injury within the previous 12 months. RESULTS: A usable questionnaire response rate of 68% (652/953) was achieved. Forty percent of horses had sustained a traumatic injury within the past year, of which 62% occurred in the field and 13% during ridden exercise. Factors identified as being associated with an increased risk of traumatic injury included the following: breed other than cob or pony (P = 0.001), shorter duration of ownership (P = 0.002), being turned out with an increasing number of horses (P = 0.001), being used for competitive (P = 0.001) or Parelli (P = 0.006) purposes. Stabling at all times during the spring (P = 0.005), the use of wood fencing in paddocks (P = 0.05) and being prone to becoming distressed if left alone in a field (P = 0.04) were also found to be associated with an increased risk of injury. Stabling at all times during winter was associated with a decreased risk of injury (P = 0.006). CONCLUSIONS AND POTENTIAL RELEVANCE: Risk factors for sustaining injuries have been identified in association with management practices. This information may be used to educate owners regarding management of their horse(s) in order to prevent injury.

A large multi-centre European study validates high-sensitivity C-reactive protein (hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes.

AIMS/HYPOTHESIS: An accurate molecular diagnosis of diabetes subtype confers clinical benefits; however, many individuals with monogenic diabetes remain undiagnosed. Biomarkers could help to prioritise patients for genetic investigation. We recently demonstrated that high-sensitivity C-reactive protein (hsCRP) levels are lower in UK patients with hepatocyte nuclear factor 1 alpha (HNF1A)-MODY than in other diabetes subtypes. In this large multi-centre study we aimed to assess the clinical validity of hsCRP as a diagnostic biomarker, examine the genotype-phenotype relationship and compare different hsCRP assays. METHODS: High-sensitivity CRP levels were analysed in individuals with HNF1A-MODY (n = 457), glucokinase (GCK)-MODY (n = 404), hepatocyte nuclear factor 4 alpha (HNF4A)-MODY (n = 54) and type 2 diabetes (n = 582) from seven European centres. Three common assays for hsCRP analysis were evaluated. We excluded 121 participants (8.1%) with hsCRP values >10 mg/l. The discriminative power of hsCRP with respect to diabetes aetiology was assessed by receiver operating characteristic curve-derived C-statistic. RESULTS: In all centres and irrespective of the assay method, meta-analysis confirmed significantly lower hsCRP levels in those with HNF1A-MODY than in those with other aetiologies (z score -21.8, p < 5 × 10(-105)). HNF1A-MODY cases with missense mutations had lower hsCRP levels than those with truncating mutations (0.03 vs 0.08 mg/l, p < 5 × 10(-5)). High-sensitivity CRP values between assays were strongly correlated (r (2) ≥ 0.91, p ≤ 1 × 10(-5)). Across the seven centres, the C-statistic for distinguishing HNF1A-MODY from young adult-onset type 2 diabetes ranged from 0.79 to 0.97, indicating high discriminative accuracy. CONCLUSIONS/INTERPRETATION: In the largest study to date, we have established that hsCRP is a clinically valid biomarker for HNF1A-MODY in European populations. Given the modest costs and wide availability, hsCRP could translate rapidly into clinical practice, considerably improving diagnosis rates in monogenic diabetes.

Sequencing PDX1 (insulin promoter factor 1) in 1788 UK individuals found 5% had a low frequency coding variant, but these variants are not associated with Type 2 diabetes.

AIM: Genome-wide association studies have identified >30 common variants associated with Type 2 diabetes (>5% minor allele frequency). These variants have small effects on individual risk and do not account for a large proportion of the heritable component of the disease. Monogenic forms of diabetes are caused by mutations that occur in <1:2000 individuals and follow strict patterns of inheritance. In contrast, the role of low frequency genetic variants (minor allele frequency 0.1-5%) in Type 2 diabetes is not known. The aim of this study was to assess the role of low frequency PDX1 (also called IPF1) variants in Type 2 diabetes. METHODS: We sequenced the coding and flanking intronic regions of PDX1 in 910 patients with Type 2 diabetes and 878 control subjects. RESULTS: We identified a total of 26 variants that occurred in 5.3% of individuals, 14 of which occurred once. Only D76N occurred in >1%. We found no difference in carrier frequency between patients (5.7%) and control subjects (5.0%) (P=0.46). There were also no differences between patients and control subjects when analyses were limited to subsets of variants. The strongest subset were those variants in the DNA binding domain where all five variants identified were only found in patients (P=0.06). CONCLUSION: Approximately 5% of UK individuals carry a PDX1 variant, but there is no evidence that these variants, either individually or cumulatively, predispose to Type 2 diabetes. Further studies will need to consider strategies to assess the role of multiple variants that occur in <1 in 1000 individuals.

Retrospective study of palmar/plantar annular ligament injury in 71 horses: 2001-2006.

REASON FOR PERFORMING STUDY: Constriction of the digital flexor tendon sheath (DFTS) and its contents by the palmar/plantar annular ligament (PAL) is well recognised. However, primary injury of the PAL has not been well documented. OBJECTIVES: To describe the clinical features of PAL injury, determine its prevalence with or without subcutaneous fibrosis and/or concurrent injury within the DFTS, and assess response to treatment. METHODS: Horses were selected for inclusion based upon clinical features consistent with PAL injury and the presence of a thickened PAL (> or =2 mm) verified ultrasonographically. A retrospective analysis of case records from 3 clinics was performed. Details of breed, age and use, and results of clinical and ultrasonographic assessments and response to treatment were recorded. Horses were treated conservatively or surgically by desmotomy of the PAL, with or without tenoscopic evaluation of the DFTS. A telephone questionnaire was performed to assess response to treatment. RESULTS: Seventy-one horses were included in the study and middle aged or older general purpose riding horses predominated. PAL desmopathy occurred more frequently in hind- than in forelimbs. The method of treatment, thickness of the PAL or presence of subcutaneous fibrosis did not significantly affect prognosis; however, <50% of horses were able to return to athletic function. There was a trend for horses with PAL desmopathy alone to have the best outcome. Bilateral thickening of the PAL or concurrent fore- and hindlimb injuries had a negative effect on prognosis, as did the simultaneous presence of subcutaneous fibrosis and lesions within the DFTS. CONCLUSIONS AND CLINICAL RELEVANCE: PAL injury is characterised by a convex contour of the palmar/plantar aspect of the fetlock, associated with thickening of the ligament with or without subcutaneous fibrosis. Bilateral PAL thickening is common in older horses, ponies and cobs; however, bilateral PAL enlargement is often present with only unilateral lameness. Treatment methods used in this study did not appear to influence outcome significantly.

An association analysis of the HLA gene region in latent autoimmune diabetes in adults.

AIMS/HYPOTHESIS: Pathophysiological similarities between latent autoimmune diabetes in adults (LADA) and type 1 diabetes indicate an overlap in genetic susceptibility. HLA-DRB1 and HLA-DQB1 are major susceptibility genes for type 1 diabetes but studies of these genes in LADA have been limited. Our aim was to define patterns of HLA-encoded susceptibility/protection in a large, well characterised LADA cohort, and to establish association with disease and age at diagnosis. MATERIALS AND METHODS: Patients with LADA (n = 387, including 211 patients from the UK Prospective Diabetes Study) and non-diabetic control subjects (n = 327) were of British/Irish European origin. The HLA-DRB1 and -DQB1 genes were genotyped by sequence-specific PCR. RESULTS: As in type 1 diabetes mellitus, DRB1 0301_DQB1 0201 (odds ratio [OR] = 3.08, 95% CI 2.32-4.12, p = 1.2 x 10(-16)) and DRB1 0401_DQB1 0302 (OR = 2.57, 95% CI 1.80-3.73, p = 4.5 x 10(-8)) were the main susceptibility haplotypes in LADA, and DRB1 1501_DQB1 0602 was protective (OR = 0.21, 95% CI 0.13-0.34, p = 4.2 x 10(-13)). Differential susceptibility was conferred by DR4 subtypes: DRB1 0401 was predisposing (OR = 1.79, 95% CI 1.35-2.38, p = 2.7 x 10(-5)) whereas DRB1 0403 was protective (OR = 0.37, 95% CI 0.13-0.97, p = 0.033). The highest-risk genotypes were DRB1 0301/DRB1 0401 and DQB1 0201/DQB1 0302 (OR = 5.14, 95% CI 2.68-10.69, p = 1.3 x 10(-8); and OR = 6.88, 95% CI 3.54-14.68, p = 1.2 x 10(-11), respectively). These genotypes and those containing DRB1 0401 and DQB1 0302 associated with a younger age at diagnosis in LADA, whereas genotypes containing DRB1 1501 and DQB1 0602 associated with an older age at diagnosis. CONCLUSIONS/INTERPRETATION: Patterns of susceptibility at the HLA-DRB1 and HLA-DQB1 loci in LADA are similar to those reported for type 1 diabetes, supporting the hypothesis that autoimmune diabetes occurring in adults is an age-related extension of the pathophysiological process presenting as childhood-onset type 1 diabetes.

Syndromic obesity and diabetes: changes in body composition with age and mutation analysis of ALMS1 in 12 United Kingdom kindreds with Alstrom syndrome.

CONTEXT: Alström syndrome (AS) is a monogenic form of infancy-onset obesity and insulin resistance, caused by ALMS1 mutations. The natural history of the insulin resistance is unknown, in particular how this relates to changes in body composition. It is also unclear how ALMS1 mutations relate to the characteristic phenotype. OBJECTIVES: Our objectives were to characterize body composition and metabolic parameters, to establish ALMS1 mutation spectrum of United Kingdom AS patients, and to determine whether a genotype-phenotype correlation exists. DESIGN AND PATIENTS: We conducted a cross-sectional cohort study of 12 unrelated subjects with AS. Age-standardized body composition was assessed by anthropometry and dual-energy x-ray absorptiometry and insulin sensitivity by homeostasis model assessment. The exons and intron-exon boundaries of ALMS1 were directly sequenced. SETTING: The study was performed during the annual Alström Syndrome UK multidisciplinary screening clinic. RESULTS: AS patients have early-onset obesity, but body mass index, waist circumference, and body fat from dual-energy x-ray absorptiometry were negatively correlated with age (r = -0.37, P = 0.2; r = -0.84, P = 0.002; and r = -0.6, P = 0.05). Despite this, insulin resistance increased, demonstrated by raised fasting insulin and fall in homeostasis model assessment insulin sensitivity with age (r = -0.64, P = 0.02). ALMS1 mutations were identified in 10 of 12 patients, with a potential founder mutation in exon 16 present in five [np 10775del (C); Del3592fs/ter3597]. No genotype-phenotype correlation was observed. CONCLUSIONS: We identified mutations in ALMS1 in more than 80% of patients with no genotype-phenotype correlation. In AS, severe childhood obesity, waist circumference, and body fat decrease with age, whereas insulin resistance increases. The abdominal obesity, insulin resistance, diabetes, hypertriglyceridemia, and hypertension suggest that AS could represent a monogenic model for the metabolic syndrome.

Large-scale studies of the association between variation at the TNF/LTA locus and susceptibility to type 2 diabetes.

AIMS/HYPOTHESIS: The proinflammatory cytokine TNF-alpha has been implicated in the pathogenesis of insulin resistance and type 2 diabetes, and variation in the gene encoding TNF-alpha (TNF) has shown inconsistent associations with susceptibility to both conditions. Additionally, the coding non-synonymous variant T60N in the neighbouring LTA gene has been reported to be associated with type 2 diabetes. The present study aimed to obtain a robust assessment of the role of variation in the tightly linked TNF/LTA region in diabetes susceptibility by genotyping TNF and LTA variants in large case-control resources. MATERIALS AND METHODS: The G-308A and G-238A TNF promoter variants and the LTA T60N polymorphism were genotyped in two UK case samples that were ascertained for positive family history and/or early onset of type 2 diabetes (combined n=858) and in 1,257 ethnically matched controls. RESULTS: There were no significant associations between the T60N, G-308A or G-238A genotype and type 2 diabetes in the combined analysis (exact Cochran-Mantel-Haenszel statistic for ordered genotypes for T60N, p=0.69; for G-308A, p=0.51; for G-238A, p=0.16). CONCLUSIONS/INTERPRETATION: The present study, one of the largest association analyses yet reported at this locus, provides no evidence that the specific TNF or LTA variants examined influence susceptibility to type 2 diabetes. More comprehensive studies of the TNF/LTA locus in substantially larger sample sets are required to establish whether genome sequence variation at this locus truly influences susceptibility to type 2 diabetes.

Examining the relationships between the Pro12Ala variant in PPARG and Type 2 diabetes-related traits in UK samples.

AIMS: The Pro12Ala polymorphism in the PPARG gene alters amino acid sequence and has shown consistent association with susceptibility to Type 2 diabetes in several populations. The present study makes use of large, well-characterized case-control resources to enhance understanding of this susceptibility effect by examining related traits, such as body mass index (BMI), waist-hip ratio and age at diagnosis. METHODS: The Pro12Ala variant was genotyped in two UK case samples, ascertained for positive family history and/or early onset of Type 2 diabetes (combined n=971); and in 1257 ethnically matched control subjects. RESULTS: There were significant associations of the Pro12Ala single nucleotide polymorphism (SNP) genotypes with diabetes in both case-control comparisons (P=0.025 and P=0.039). Comparing individuals homozygous for the Pro allele, with those carrying an Ala allele, the combined odds ratio for diabetes was 1.40 (95% CIs, 1.12-1.76, P=0.0031). There was no association between the variant and either waist-hip ratio or age at diagnosis. Proline homozygosity was associated with increased BMI in one patient group (P=0.013) and decreased BMI in the other (P=0.038). CONCLUSIONS: This study confirms that variation within PPARG influences susceptibility to Type 2 diabetes in UK samples. However, the relationship between PPARG variation and BMI is more complex, and studies in much larger sample sets will be required to more precisely characterize the effect of this variant on adiposity.

Analysis of the contribution to type 2 diabetes susceptibility of sequence variation in the gene encoding stearoyl-CoA desaturase, a key regulator of lipid and carbohydrate metabolism.

AIMS/HYPOTHESIS: Stearoyl-CoA desaturase (SCD) is emerging as a key regulator of lipid and carbohydrate metabolism. Scd-null mice display a beneficial metabolic phenotype characterised by resistance to obesity, diabetes and hyperlipidaemia. The human homologue, SCD, maps to a region of chromosome 10 linked to type 2 diabetes, and SCD activity correlates with insulin sensitivity. Given this strong positional and biological candidacy, the present study sought to establish whether sequence variation in SCD influences susceptibility to type 2 diabetes and related traits. METHODS: The SCD gene was resequenced in 23 diabetic subjects. Six variants within coding and adjacent sequence, including a non-synonymous SNP in exon 5 (M224L), were selected for genotyping in a primary set of 608 diabetic subjects and 600 control subjects. RESULTS: There was no association (at the allele, genotype or haplotype level) with type 2 diabetes, although genotype frequencies at the +14301 A>C SNP in the 3' untranslated region showed borderline association (p~0.06) when evidence for linkage was taken into account. However, replication studies (350 young-onset diabetic patients; 747 controls) failed to confirm any relationship with diabetes for this variant. No significant associations were seen for diabetes-related traits including BMI and waist-to-hip ratio. CONCLUSIONS/INTERPRETATION: The present study, the first reported analysis of this gene, indicates that the SCD variants typed do not explain chromosome-10-encoded susceptibility to type 2 diabetes. Although this study provided no evidence that SCD sequence variation influences diabetes susceptibility or related traits, SCD remains a major target for pharmaceutical and/or environmental manipulation.

Adolescent onset Type 2 diabetes in a non-obese Caucasian patient with an unbalanced translocation.

BACKGROUND: Childhood onset Type 2 diabetes in the UK has been reported in obese, insulin-resistant subjects. Investigation is necessary to exclude other aetiologies including genetic causes. The co-existence of diabetes and a chromosomal breakpoint may indicate the position of novel diabetes genes. CASE REPORT: We describe a novel unbalanced translocation between Xq and 10p associated with amenorrhoea and onset of Type 2 diabetes in a non-obese Caucasian adolescent. There was no evidence of an autoimmune or known genetic aetiology for the diabetes and the phenotype was not typical of youth-onset Type 2. We therefore hypothesize that the translocation is implicated in the aetiology of the diabetes. This is supported by previous reports of diabetes as a feature of Xq deletions and Turner's syndrome and linkage to the Xq region in a genome-wide scan for Type 2 genes. CONCLUSION: That this region may harbour a gene predisposing to Type 2 diabetes and that cytogenetic studies may be useful in investigating diabetes in children and young adults.

Heterogeneity in young adult onset diabetes: aetiology alters clinical characteristics.

AIMS: To describe the characteristics of hepatocyte nuclear factor (HNF) 1 alpha mutation carriers diagnosed with diabetes after 25 years and compare them with young-onset Type 2 diabetic patients (YT2D) diagnosed at the same age. SUBJECTS AND METHODS: We studied 44 (21 male, 23 female) patients with HNF-1 alpha mutations diagnosed with diabetes at ages 25-45 years and 44 YT2D subjects matched for sex and age of diagnosis. RESULTS: Median age of onset of diabetes was 35 years in both groups. The HNF-1 alpha group demonstrated: lower body mass index (25.1 vs. 30.7 kg/m2; P < 0.001) and lower fasting triglycerides (1.37 vs. 2.96 mmol/l; P = 0.001) with similar fasting cholesterol level. They had lower glycated haemoglobin A1c (7.3 vs. 8.5%; P = 0.015) despite greater duration of diabetes (24 vs. 16 years; P = 0.02) and less frequent treatment with insulin (21% vs. 55%; P = 0.002). They were less likely to be treated for hypertension (13.3% vs. 56.3%; P = 0.009). Importantly, no difference was observed in reported parental history of diabetes between the two groups (65.9% vs. 63.6%; P = 0.92). Logistic regression showed that triglyceride levels and presence of anti-hypertensive treatment were the most important independent variables. CONCLUSIONS: Patients with HNF-1 alpha mutations may present with diabetes as young adults between the ages of 25-45 years. In this age range a wide differential diagnosis of diabetes is observed. Conventional criteria of age of onset and family history will not differentiate HNF-1 alpha mutation carriers from YT2D subjects in this age range, but features of the metabolic syndrome, in particular fasting triglycerides and hypertension, are helpful. In patients diagnosed before 45 years without features of insulin resistance the diagnosis of HNF-1 alpha should be considered.