Precision Diagnosis of Maturity-Onset Diabetes of the Young with Next-Generation Sequencing: Findings from the MODY-IST Study in Adult Patients.

Maturity-onset diabetes of the young (MODY) is a highly heterogeneous group of monogenic and nonautoimmune diseases. Misdiagnosis of MODY is a widespread problem and about 5% of patients with type 2 diabetes mellitus and nearly 10% with type 1 diabetes mellitus may actually have MODY. Using next-generation DNA sequencing (NGS) to facilitate accurate diagnosis of MODY, this study investigated mutations in 13 MODY genes (HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, and KCNJ11). In addition, we comprehensively investigated the clinical phenotypic effects of the genetic variations identified. Fifty-one adult patients with suspected MODY and 64 healthy controls participated in the study. We identified 7 novel and 10 known missense mutations localized in PDX1, HNF1B, KLF11, CEL, BLK, and ABCC8 genes in 29.4% of the patient sample. Importantly, we report several mutations that were classified as "deleterious" as well as those predicted as "benign." Notably, the ABCC8 p.R1103Q, ABCC8 p.V421I, CEL I336T, CEL p.N493H, BLK p.L503P, HNF1B p.S362P, and PDX1 p.E69A mutations were identified for the first time as causative variants for MODY. More aggressive clinical features were observed in three patients with double- and triple-heterozygosity of PDX1-KLF11 (p.E69A/p.S182R), CEL-ABCC8-KCNJ11 (p.I336, p.G157R/p.R1103Q/p.A157A), and HNF1B-KLF11 (p.S362P/p.P261L). Interestingly, the clinical effects of the BLK mutations appear to be exacerbated in the presence of obesity. In conclusion, NGS analyses of the adult patients with suspected MODY appear to be informative in a clinical context. These findings warrant further clinical diagnostic research and development in different world populations suffering from diabetes with genetic underpinnings.

Evaluation of the relationship between serum apelin levels and vitamin D and mean platelet volume in diabetic patients.

OBJECTIVES: It was reported that Vitamin D deficiency was associated with a greater risk of cardiometabolic diseases, obesity, impaired glucose tolerance and diabetes mellitus type 2, arterial hypertension, and dyslipidemia. Apelin is an adipocytokine suspected to have a role in skeletal muscle glucose utilization and glycemic regulation which may be a promising treatment modality for diabetes. It was recently reported that increased mean platelet volume (MPV) was emerging as an independent risk factor for thromboembolism, stroke, and myocardial infarction. In patients with diabetes, MPV was higher compared with the normal glycemic controls; in addition, it has been proposed that an increase in MPV may play a role in the micro- and macro-vascular complications related to diabetes. We postulated that deficiency in Vitamin D levels might be associated with higher MPV and lower serum apelin levels leading a further increase in insulin resistance in diabetic patients. So, we aimed to investigate Vitamin D levels, MPV and serum apelin levels in diabetic patients and their correlations between each other. MATERIALS AND METHOD: This is a cross-sectional study design. Seventy-eight patients with Diabetes Mellitus type 2, admitted to our outpatient clinic of internal medicine department at Bezmialem Vakif University, were included in our study. Forty-one patients were female; 37 patients were male. Serum apelin levels, fasting glucose levels, urea, creatinine, triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), fasting serum insulin level, HbA1c, free T3, free T4, TSH, vitamin D (25-OH Vitamin D) and complete blood counts were analyzed in all subjects. RESULTS: Each sex was analyzed separately. We found that a positive correlation existed between serum apelin levels and BMI in female patients. (r: 0.380, P: 0.014) There was also a significant positive correlation between MPV and HbA1c and fasting glucose levels and a negative correlation between MPV and PLT. (r: 0.377, P: 0.021; r: 0.395, P: 0.014; r: -0.401, P: 0.011; respectively) We failed to show a significant relationship between serum vitamin D levels, serum apelin levels and MPV in patients with diabetes mellitus type 2. CONCLUSION: We failed to show an association between vitamin D, apelin and MPV higher volumes of which may have a role in cardiovascular complications related to diabetes by increasing platelet activation.

Vaspin and lipocalin-2 levels in severe obsructive sleep apnea.

BACKGROUND: Vaspin and lipocalin-2 are less-known recent members of adipocytokine family. There are ongoing studies investigating the role of vaspin ve lipocalin-2 in metabolic syndrome (MS). Obstructive sleep apnea syndrome (OSAS) is independently associated with an increased prevalence of MS. We aimed to measure the levels of vaspin and lipocalin-2 which are secreted from adipocytes in patients with severe OSAS and examine the relationship between these two adipocytokines and OSAS. METHODS: THE STUDY CONSISTED OF TWO GROUPS: severe OSAS patients with an apnea-hypopnea index (AHI) of >30/h (OSAS group, 34 subjects) and age-matched healthy volunteers with a AHI <5/h (control group, 25 subjects) Serum levels of vaspin and lipocalin-2 in these two groups were compared. RESULTS: Serum levels of vaspin were significantly lower in OSAS group; patients with severe OSAS compared with control group; healthy volunteers (OSAS group: 0.69±0.5 vs. control group: 1.24±1.13; P=0.034). The difference between the two groups in terms of serum levels of lipocalin-2 has not reached statistical significance (OSAS group: 61.6±18.2 vs. control group: 68.5±20.1; P=0.17). CONCLUSIONS: We found that serum vaspin levels were significantly lower in patients with severe OSAS compared with healthy controls. Lipocalin-2 levels were similar. The decrease in serum vaspin levels in severe OSAS patients may be important in diagnosis and follow-up of these patients.

Effect of vildagliptin add-on treatment to metformin on plasma asymmetric dimethylarginine in type 2 diabetes mellitus patients.

AIMS: A close association has been demonstrated between increased cardiovascular risk and high asymmetric dimethylarginine (ADMA) levels in type 2 diabetes mellitus (DM) patients. We planned to measure serum ADMA levels in type 2 DM patients using vildagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor. MATERIALS AND METHODS: A total of 68 type 2 DM patients who were on metformin were enrolled in the study. Based on the glycemic levels of patients, vildagliptin was added on to treatment in 33 patients. Patients were followed for 6 months. Serum ADMA, C-reactive protein, and fibrinogen levels were compared in groups of patients using metformin or metformin + vildagliptin, after 6 months. RESULTS: Serum ADMA levels were found to be significantly lower in the group using vildagliptin compared to the group using metformin + vildagliptin (P<0.001). However, serum C-reactive protein and fibrinogen levels were statistically similar in the two study groups (P=0.34 and P=0.23, respectively). CONCLUSION: Metformin + vildagliptin treatment was observed to lower serum ADMA levels in type 2 DM patients. Our findings notwithstanding, large-scale prospective randomized controlled studies are warranted to conclude that vildagliptin provides cardiovascular protection along with diabetes regulation.