Our study, a population-based investigation, estimates the prevalence of MODY3 and describes clinical features of the disease. Previous studies mainly discussed MODY3 in the European population. Few studies have focused on the incidence and characters of this subtype of diabetes in China. Meanwhile, MODY3 is often misdiagnosed asT1DM orT2DM owning to the similar symptoms. Our study is of great significance for doctors to reduce the frequency of wrong diagnosis and provide appropriate treatment for patients with MODY3 in the future.
Fifty percent clinically suspected MODY cases had missense mutations in HNF-1A, p.I27L, p.S487N and p.G574S. The result showed that patients with mutations located in the transactivation domain (B-III:9 and C-III:7) were diagnosed later than those carrying mutations in the dimerization/DNA-binding domains (A-III:4, D-III:8 and E-III:8), which is consistent with previous studies. Our study showed no negative correlation between the duration of MODY3 and the islet function. Patient B-III:9 had MODY3 for 15 years, the longest period among five patients, however, the islet function of that patient was better than patient D-III:8 and patient E-III:8 who only suffered from MODY3 for 4 years and 1 year separately. The duration of the disease was the same in patients A-III:4, C-III:7 and E-III:8, but the islet function of patient C-III:7 was obviously the best. The difference might be caused by different mutation sites. Mutations in the transactivation domain may have less effect on the islet function, which need to be verified by future research. Another impact of mutation site is the risk of angiopathy in MODY3. Both patients with mutations in the transactivation domain had angiopathy secondary to MODY3, opposite to patients with mutations in the dimerization/DNA-binding domains. The study indicated patients with mutations in the transactivation domain could have later onset age and better islet function, but could also have higher susceptibility of complications such as angiopathy.
The onset age in the study is similar to the prior literature. Previous research showed that patients with MODY3 lacked clinical features of insulin resistance, such as obesity and dyslipidaemia, which was different from patients with T2DM[2, 5]. However, insulin resistance existed in the five MODY3 patients in the current study. The average BMI, TG and LDL-C was over normal value. All patients had dyslipidemia. Four patients (80%) had fatty liver. As all patients in our study were from Yunnan province, they might carry some similar modifying genes which could be different to genes carried by patients from other districts in China and other parts in the world. The difference of clinical features in the present study might be caused by these specific modifying genes. The overlap of clinical symptoms between MODY3 and T2DM brought the difficulty in making a correct diagnosis. In our study, the average age of diagnosis was 4.2 years later than the average onset age. Before patients being diagnosed correctly, insulin was used in all five patients, of which three patients also used antidiabetic drugs which not including sulfonylureas. The control of diabetes was poor as the average HbA1c, FPG and PPG were still beyond the normal range. Therefore, early diagnosis and appropriate treatment of MODY3 are vital for effective control of blood glucose and decreasing complications related to diabetes.
Genetic testing is specific for MODY3, but due to the high expense, it is not feasible as a routine examination for all diabetic patients. Previous research recommended genetic testing only for young diabetic patients with strong family histories of diabetes, which was also the criteria in our study to select suspected MODY3 patients[18, 19]. However, it was estimated that more than half of MODY cases were missed in the real practice as some patients could not meet these criteria. Therefore, sensitive and specific biomarkers are needed to select proper patients for diagnostic genetic testing. N-glycan profile and high-sensitivity C-reactive protein (hs-CRP) have been reported to have a role in identifying diabetic patients with high risk of carrying HNF-1A mutations, which could improve diagnosis rates of MODY3. At present, low dose sulfonylureas are recommended as first-line therapy for patients with MODY3[2, 22, 23]. Some recent studies reported that nateglinide alone or DPP-4 inhibitor linagliptin as add-on therapy to glimepiride could better control glycemic fluctuations without increasing risk of hypoglycemia in MODY3 patients, which need to be verified by randomized multicenter trials[24, 25].