C. Carette

The Type and the Position of HNF1A Mutation Modulate Age at Diagnosis of Diabetes in Patients with Maturity-Onset Diabetes of the Young (MODY)-3

OBJECTIVE—The clinical expression of maturity-onset diabetes of the young (MODY)-3 is highly variable. This may be due to environmental and/or genetic factors, including molecular characteristics of the hepatocyte nuclear factor 1-α (HNF1A) gene mutation. RESEARCH DESIGN AND METHODS—We analyzed the mutations identified in 356 unrelated MODY3 patients, including 118 novel mutations, and searched for correlations between the genotype and age at diagnosis of diabetes. RESULTS—Missense mutations prevailed in the dimerization and DNA-binding domains (74%), while truncating mutations were predominant in the transactivation domain (62%). The majority (83%) of the mutations were located in exons 1- 6, thus affecting the three HNF1A isoforms. Age at diagnosis of diabetes was lower in patients with truncating mutations than in those with missense mutations (18 vs. 22 years, P = 0.005). Missense mutations affecting the dimerization/DNA-binding domains were associated with a lower age at diagnosis than those affecting the transactivation domain (20 vs. 30 years, P = 10−4). Patients with missense mutations affecting the three isoforms were younger at diagnosis than those with missense mutations involving one or two isoforms (P = 0.03). CONCLUSIONS—These data show that part of the variability of the clinical expression in MODY3 patients may be explained by the type and the location of HNF1A mutations. These findings should be considered in studies for the search of additional modifier genetic factors.

Clinical characteristics and diagnostic criteria of maturity-onset diabetes of the young (MODY) due to molecular anomalies of the HNF1A gene.

CONTEXT The diagnosis of maturity-onset diabetes of the young type 3 (MODY3), associated with HNF1A molecular abnormalities, is often missed. OBJECTIVE The objective of the study was to describe the phenotypes of a large series of MODY3 patients and to reassess parameters that may improve its diagnosis. DESIGN, SETTING, AND PATIENTS This retrospective multicenter study included 487 unrelated patients referred because of suspicion of MODY3. Genetic analysis identified 196 MODY3 and 283 non-MODY3 cases. Criteria associated with MODY3 were assessed by multivariate analysis. The capacity of the model to predict MODY3 diagnosis was assessed by the area under the receiver-operating characteristic curve and was further validated in an independent sample of 851 patients (165 MODY3 and 686 non-MODY3). RESULTS In the MODY3 patients, diabetes was revealed by clinical symptoms in 25% of the cases and was diagnosed by screening in the others. Age at diagnosis of diabetes was more than 25 yr in 40% of the MODY3 patients. There was considerable variability and overlap of all assessed parameters in MODY3 and non-MODY3 patients. The best predictive model was based on criteria available at diagnosis of diabetes, including age, body mass index, number of affected generations, presence of diabetes symptoms, and geographical origin. The area under the curve of the receiver-operating characteristic analysis was 0.81. When sensitivity was set to 90%, specificity was 49%. CONCLUSIONS Differential diagnosis between MODY3 and early-onset type 2 diabetes remains difficult. Whether the proposed model will improve the pick-up rate of MODY3 diagnosis needs to be confirmed in independent populations.

Diabetes mellitus and glucose-6-phosphate dehydrogenase deficiency: From one crisis to another

AIM Epidemiological data suggest that glucose-6-phosphate dehydrogenase (G6PD) deficiency may be a risk factor for diabetes. Also, the occurrence of haemolysis in the context of diabetes crises has been reported in patients with G6PD deficiency. A unifying hypothesis could explain these associations. METHODS We report two patients in whom haemolytic crises occurred soon after acute diabetes decompensation, and revealed G6PD deficiency. We have reviewed the mechanisms that may link the two diseases. RESULTS One patient was admitted for decompensated ketosis-prone type-2 diabetes (KPT2D), but no acidosis, and was treated with insulin, then metformin and glibenclamide. The second patient had type-1 diabetes and ketoacidosis treated with insulin. Haemolytic crises were recognized 8 and 4 days after admission, respectively, and G6PD deficiency was confirmed in both patients. These patients and the other published cases share, as a unique characteristic, the occurrence of haemolysis after diabetes decompensation, whatever the treatment or associated conditions. Experimental data show that hyperglycaemia can reduce expression of the G6PD gene and activity of the enzyme. Conversely, G6PD deficiency can promote oxidative stress and impairment of insulin secretion by beta cells. CONCLUSION In patients at risk of G6PD deficiency, the possibility of haemolysis should be explored in case of diabetes crisis. In African patients with KPT2D diabetes, potentially oxidative hypoglycaemic agents should be avoided in the remission phase of the disease. G6PD deficiency and diabetes can aggravate each other, and diabetes could be aetiologically associated with G6PD deficiency.

HNF1B -related diabetes triggered by renal transplantation

Background. A 37-year-old man developed cholestasis-associated pruritus followed by overt hyperglycemia (blood glucose level 23 mmol/l), necessitating insulin treatment, within weeks of undergoing renal transplantation. He had a history of gout, but his fasting blood glucose and glycated hemoglobin concentrations had been normal before transplantation.Investigations. Physical examination; laboratory tests, including assessment of glycated hemoglobin, anti-glutamic-acid-decarboxylase and anti-islet-antigen-2 antibodies, liver enzymes, renal function, tacrolimus blood trough level, exocrine (fecal elastase) and endocrine (C-peptide) pancreatic function; abdominal CT scan; liver biopsy; and screening of the hepatocyte nuclear factor 1 homeobox B (transcription factor 2) gene, HNF1B.Diagnosis. New-onset diabetes after transplantation associated with a newly described deletion in HNF1B.Management. Minimization of tacrolimus exposure and withdrawal of steroids considerably reduced the patients insulin requirement, and cholestasis-related pruritus was dramatically improved by administration of ursodeoxycholic acid. Renal ultrasonography and screening for the HNF1B molecular abnormality were offered to the patients relatives.

Familial young-onset forms of diabetes related to HNF4A and rare HNF1A molecular aetiologies.

Diabet. Med. 27, 1454–1458 (2010)

Factors associated with the presence of glutamic acid decarboxylase and islet antigen-2 autoantibodies in patients with long-standing type 1 diabetes

AIM Glutamic acid decarboxylase (GAD) and/or islet antigen-2 (IA-2) autoantibodies (ab) are present in 90% of patients at the onset of type 1 diabetes (T1D). Few studies have shown that they may persist in the long-term. We analysed the frequency of GADab and IA-2ab and the factors associated with their persistency in patients with long-lasting T1D. METHODS This cross-sectional study included 430 adult patients with T1D of at least 10-year duration, consecutively seen over one year. GADab and IA-2ab were determined by radio-binding assays. Autoantibodies to thyroperoxydase, gastric parietal cells and transglutaminase were assessed in 418 patients, and HLA DRB1 genotyping in 359. Parameters associated with the persistency of antibodies were studied by multivariate analysis. RESULTS Median age at diagnosis of T1D was 12 years, and median diabetes duration was 19 years. Extrapancreatic autoimmunity was present in 38% of the patients, and associated autoimmune diseases in 21%. GADab and/or IA-2ab were found in 56% of the patients, and in 32% in those with more than 25-year diabetes duration. GADab were more frequent than IA-2ab. Female sex, an older age at diagnosis, and a shorter duration of diabetes were independently associated with the presence of ab. The same factors and the DR3 allele were associated with GADab, while only diabetes duration and the DR4 allele were associated with IA-2ab. CONCLUSION In a large proportion of the patients with T1D, the long-term persistency of diabetes-associated antibodies allows aetiological diagnosis, even far from the onset of hyperglycaemia.