MODY3 accounts for about 50% of all Mody subtypes[1, 4, 5], generally including significant prandial and fasting hyperglycemia,polyuria,polydipsia,polyphagia and weight-losing. A low renal threshold for glucose reabsorption presents apparent glycosuria. HNF1A-MODY is non-insulin-dependent diabetes but sensitivity to sulfonylureas. However, long course of disease reveals the pros and cons of the best first-line medications for MODY3 patients.
China was reported ranking first in the amount of diabetes. However, this does not match with the few reports on MODY3 in Chinese. This phenomenon implies numbers of mody3 sufferers are mistakenly classified as T1DM, T2DM or undiagnosed, contributing to Indistinguishable symptoms, clinical experience and affordable testing methods. Exact diagnosis depends on molecular genetic test, which is costly and not available in grassroots hospitals. Misdiagnosis and missed diagnosis lead to misguided pharmacological intervention resulting in micro- and macro-vascular complications—including 47% of retinopathy,19% nephropathy and 4% neuropathy[5].
During the childhood HNF1A mutation carriers could be normoglycemic in plasma but glycosuria. And in several individuals diabetes manifests after a phase of neonatal transient hyperinsulinemia hypoglycemia[6, 7]. Once maternal was diagnosed HNF1A-MODY before pregnancy, onset of their children were at younger age compared to others. Moreover, the younger one diagnosed, the shorter their life expectancy will be. Offspring of MODY3 parents have 50% chance of getting sick due to monogenic autosomal-dominant inheritance. Fasting blood glucose increased with age. It is explained by a progressive loss in beta-cell function adding to the physiological impairment in insulin release and glucose tolerance, causing microvascular complications. But John Wiley et al.’s experiment contradicts this age-related trend[8].
Approximate 80 percent MODY patients were divided into T1DM or T2DM[9].However,HNF1A defects increase the synthesis of bile acid and the levels of total cholesterol, HDL-C, and LDL-C[10].Apolipoprotein M has been suggested as a discriminator between MODY3 and T1DM[11].And HDL-cholesterol differentiates MODY3 with T2D for a higher level of HNF1A-MODY nearing to non-diabetic patients[12] but by no means a low cardiovascular risk. Besides, bodies of evidence shows High-sensitivity CRP (hs-CRP) levels were significantly lower in MODY3 patients compared with T2DM and T1DM or non-diabetes and discriminates MODY3 well from T2DM[13, 14] for mutations in HNF1A. C-peptide is lower than in Non-diabetic patients, but higher than T1DM[10].Combination of hs-CRP with fasting C-peptide,MODY3 patients distinguished significantly from T1DM(AUC of 1.0)[10]. Nevertheless, some researchers claim that hs-CRP is not useful for distinguishing HNF1A-MODY from young-onset T2DM.It increases during the infection and decreases after statin therapy[7]. The positive rate of diabetes autoantibodies affirmed to distinguish Mody and T1DM to some extent deserving high clinical suspicion[15].
HNF1 is a protein with 631 amino acids composed of three functional domains: a dimerization domain (amino acids 1–32),a DNA-binding domain (91–276),and a carboxyl-terminal transactivation domain[16].This protein regulates a complex regulatory network important for the differentiation and function of beta-cells as a transcription factor. The HNF1A gene is localized in the chromosome 12q24.31,spanning a region of 120 kb with 10 exons expressed in the pancreas,liver,and kidneys and encodes in order to regulate expression of the genes involved in glucose metabolism, glucose transportation, and the insulin gene as well as liver-specific genes[17]. It is oriented on the plus strand. The proportions of different mutation types in functional domains differ. The HNF1A(A) isoform comprises the 10 exons, whereas the HNF1A(B) and HNF1A(C) isoforms contain the first seven and first six exons, respectively. In terms of diagnostic age, different mutation types in the same functional domain and the same mutation type in different functional domains may be quite different.
Diet without saccharides excess is probably curative when glycosylated hemoglobin is lower than 6.5% (about one third patients were adviced non drug treatment). But low doses of Sulfonylureas (SUs) are the best first-line pharmacological treatment when uncontrol. Benefit from Sulfonylureas (SUs) bind to a membrane protein closely related to the ATP-dependent potassium (K+) channel (KATP channel) in the B-cell. Thereby closing it causing membrane depolarization, leading to the opening of the voltage-gated calcium (Ca2+) channel and increasing intracellular Ca2+ concentration, increase insulin secretion. Because of the particular mechanism, hypoglycemia often related with Sulfonylureas even in a low dose[18].Hypersensitivity to sulfonylureas and increasing body weight embarrass the adolescent patients needing physical exercise. Sulfonylureas combine the DPP-4 inhibitor linagliptin reduce glycemic variability and HbA1c without increasing the risk of hypoglycemia or other adverse events[19]. Otherwise, Sulfonylureas is usually effective for several decades, once severe decrease in B-cell insulin production, exogenous insulin is needed.
The Glucagon-like peptide-1 (GLP-1) receptor makes hypoglycemia rare and allows weight reduction. Furthermore,GLP-1 promotes the generation of pancreatic β-cells and to suppress their apoptosis[20] Although the cAMP pathway is affected by the production of ATP by glucose metabolism, GLP-1 can still amplify the cAMP-mediated insulin secretion pathway. It might be efficacious for patients with HNF1A diabetes, but lack of adequate evidence. And liraglutide was proved effective for avoiding hypoglycemia. Many HNF1A patients treated with Sulfonylureas (SUs) well, but GLP-1RA monotherapy can not. Thus, GLP-1 often substitute for Sus when frequent hypoglycemia or serious overweight.
A small dose of nateglinide prevents from postprandial hyperglycemia better than glibenclamide and with less stimulation of peak insulin concentrations and less hypoglycemic symptoms in patients with MODY3. Some research reported Dipeptidyl Peptidase-4 inhibitors in patients with HNF1A diabetes when combined with other oral glucose-lowering drugs (14,15) or with liraglutide as adjunct therapy to SU and basal insulin[21].
This paper describes a new patient with HNF mutation in a HNF 1α (-) family. The physician usually judge the possibility of Mody through family HNF mutation history. However, this method is not particularly friendly for newly mutated individuals in negative families. In this case, it is suggested that family history should be taken as a supplementary consideration, and more emphasis should be placed on the characteristics of patients and clinical indicators, so as to distinguish T1DM from T2DM.
Poor glycaemic control is associated with a twofold to threefold increased risk among MODY3 patients of developing microalbuminuria and retin-opathy, respectively. More than this, poor blood glucose control may cause a variety of vascular complications. Furthermore, hypoglycemia is dangerous and has long term damage. It is essential for blood glucose control. Genetic test is the only way to diagnose MODY3, which leads to optimized treatment. Doctors should be familiar with the key points of distinguishing MODY3 from T1DM and T2DM, specially show solicitude for patient characteristics, clinical indicators and genetic history. Suggesting gene testing in time is of great help to patients.