Phenotypic features, prevalence of KCNJ11-MODY in Chinese patients with early-onset diabetes and a literature review.

OBJECTIVE: Gain-of-function (GOF) variants of KCNJ11 cause neonate diabetes and maturity-onset diabetes of the young (KCNJ11-MODY), while loss-of-function (LOF) variants lead to hyperinsulinemia hypoglycemia and subsequent diabetes. Given the limited research of KCNJ11-MODY, we aimed to analyse its phenotypic features and prevalence in Chinese patients with early-onset type 2 diabetes (EOD). DESIGN, PATIENTS AND MEASUREMENTS: We performed next-generation sequencing on 679 Chinese EOD patients to screen for KCNJ11 exons variants. Bioinformatics prediction and the American College of Medical Genetics and Genomics guidelines was used to determine the pathogenicity and diagnosed KCNJ11-MODY. A literature review was conducted to investigate the phenotypic features of KCNJ11-MODY. RESULTS: We identified six predicted deleterious rare variants in six EOD patients (0.88%). They were classified as uncertain significance (variant of uncertain significance [VUS]), but more common in this EOD cohort than a general Chinese population database, however, without significant difference (53/10,588, 0.50%) (p = .268). Among 80 previously reported patients with KCNJ11-MODY, 23.8% (19/80) carried 9 (32.1%) LOF variants, who had significantly older age at diagnosis, higher birthweight and higher fasting C-peptide compared to patients with GOF variants. Many patients carrying VUS were not correctly diagnosed. CONCLUSIONS: Some rare variants of KCNJ11 might contribute to the development of Chinese EOD, although available evidence has not enough power to support them as cause of KCNJ11-MODY. The clinical features of LOF variants were different from GOF variants in KCNJ11-MODY patients. It is necessary to evaluate the pathogenicity of VUS through function experiments.

The Effects of Supervised Exercise Training on Weight Control and Other Metabolic Outcomes in Patients With Type 2 Diabetes: A Meta-Analysis.

Few studies have investigated the dose-response relationship between exercise and weight control. This study aimed to assess the effects of different types of supervised exercise training on weight control and other metabolic outcomes in patients with type 2 diabetes mellitus and explore the dose-response relationship between exercise volume/duration and these outcomes. PubMed/MEDLINE, Embase, and Cochrane databases were searched for studies between January 1980 and June 2019. Randomized control trials in type 2 diabetes mellitus patients with supervised exercise training versus control treatment were included. The primary outcome was changes in body weight (kg). The secondary outcomes included changes in waist circumference (cm) and total body fat percentage (%). Forty-two randomized control trials, including 3,625 patients with type 2 diabetes mellitus were included. Overall, exercise treatment was associated with significant reduction in body weight (weighted mean differences, -1.10 kg; 95% CI [-1.58, -0.62], p < .01), waist circumference (weighted mean differences, -2.51 cm; 95% CI [-3.25, -1.77], p < .01), and total body fat (weighted mean differences, -1.16%; 95% CI [-1.58%, -0.75%], p < .01). The percentage of total body fat was reduced by all types of exercise, with a significant difference between aerobic exercise and resistance exercise (p = .02) and a significant difference between combined exercise and resistance exercise (p < .01). A higher volume of aerobic exercise and a higher volume of resistance exercise were superior in reducing body weight. In conclusion, supervised exercise training improved metabolic outcomes in general, while different types and volume of exercises have their own merits.

Hypoglycemic Response to Dorzagliatin in a Patient With GCK-MODY.

OBJECTIVE: Metformin, insulin, and insulin secretagogues do not alter HbA1c levels in glucokinase maturity-onset diabetes of the young (GCK-MODY). However, the efficacy of the new hypoglycemic drugs on GCK-MODY remains unclear. RESEARCH DESIGN AND METHODS: We describe a case of GCK-MODY with unchanged blood glucose under different therapies during an 8 years' follow-up. His HbA1c and biochemical indices under different hypoglycemic treatments were recorded. RESULTS: Oral glucose-lowering drugs, including thiazolidinediones, dipeptidyl peptidase 4 inhibitor, α-glucosidase inhibitor, and sodium-glucose cotransporter 2 inhibitor that had not been evaluated previously, did not improve the HbA1c level in this patient. However, the glucokinase activator dorzagliatin effectively and safely lowered his HbA1c level. CONCLUSIONS: Dorzagliatin was effective and safe in this patient with GCK-MODY, providing potential application prospects for precise treatment of GCK-MODY with dorzagliatin.

A Comparison of Daily Glucose Fluctuation Between GCK-MODY and Type 2 Diabetes Using Continuous Glucose Monitoring Technology.

Glucokinase variant-induced maturity-onset diabetes of the young (GCK-MODY) exhibits the unique clinical features of mild fasting hyperglycemia. However, formal studies of its glucose excursion pattern in daily life in comparison with those with or without other types of diabetes are lacking. We conducted a case-control study including 25 patients with GCK-MODY, 25 A1C-matched, drug-naive patients with type 2 diabetes (T2DM), and 25 age-, BMI-, and sex-matched subjects with normal glucose tolerance (NGT). All the subjects wore flash glucose monitoring (FGM) sensors for 2 weeks, and glucose readings were masked. Glucose excursion was significantly lower in the GCK-MODY than that in A1C-matched T2DM during the daytime, but was similar during the nighttime. The daytime coefficient of variation (CV) driven by postprandial glucose could separate GCK-MODY from well-controlled T2DM, but the nighttime CV could not. In discriminating between GCK-MODY and T2DM, the area under the curve of the CV was 0.875. However, in GCK-MODY and NGT subjects, the CVs were similar at 24 h, whereas the other four excursion parameters were significantly higher in GCK-MODY than those in NGT subjects. FGM confirmed the stability and mildness of hyperglycemia in GCK-MODY patients. Postprandial regulation is a key driver of the difference in excursion between GCK-MODY and T2DM.