A young maturity-onset diabetes of the young type 3 (MODY 3) in a non- HNF 1α-mutation family——case report

DOI: https://doi.org/10.21203/rs.3.rs-2233747/v1

Abstract

Young maturity-onset diabetes of the young type3(MODY3) as a special type of diabetes, the probability of being diagnosed is low. This article reports a case and reviews the relevant knowledge of the disease. We report an 11-year-and-11-month-old girl whose grandmother died of diabetic complications while the rest of the families were non-diabetes. The proband initially treated with insulin and metformin but inefficient. After exome-targeted capture sequencing test, she was diagnosed with maturity-onset diabetes of the young type 3 (MODY3), and sulfonylureas makes sense. The key to the treatment of mody is correct and timely diagnosis, which is contribute to help patients overcome the problems of MODY3, especially for blood sugar control.

Background

MODY was first found in 1970s, and 14 subtypes were identified. MODY3 is the most common subtype of MODY.The typical age of onset is 6 months to 35 years[1].MODY3 results from pathogenic effect of gene (high allelic heterogene -HNF1α) mutations, characterised by progressive insulin secretion defect, decreased renal threshold for glucose reabsorption, lean, on-autoimmunity mediated, onset of noninsulin-dependent diabetes mellitus (NIDDM) at an early age. This onozygotic autosomal dominant form of diabetes features of significant fasting and prandial hyperglycemia, sensitivity to sulfonylurea therapy, and the frequent development of end-organ complications (including microvascular and macrovascular complications), and liver adenomatosis in rare families. The clinical manifestation of HNF1A-MODY varies a lot, even within one family, such as polyuria and polydipsia.

The prevalence of Mody is 50–100/million[1], and the specific proportion of HNF1A-MODY varies by country and region, with 0,0066% in Croatia[2] and 3.6% in the UK[3].Proportion of MODY3 in Mody also changes a lot. Over-lapping features constantly lead to misdiagnosis as T1DM or T2DM. Therefore, the article aims to help physicians improve their diagnostic awareness of mody3.

Case Presentation

An 11-year-and-11-month-old girl referred to us form Endocrinology clinic on August 26,2021, owing to hyperglycemia complaints of polyuria and polydipsia more than ten days. She was found hyperglycemia after an accident resulting in a fracture of the left femoral neck more than 8 months with ago. At that time, her fasting plasma glucose was 8.9mmol/L, postprandial glucose was 12.0mmol/L, and glycated hemoglobin (HbA1c) was 6.7%, but no diabetes symptoms. Without hypoglycemic therapy, the proband was discharged after surgical operation.

On admission, her postprandial glucose was 16.2mmol/L, her fasting plasma glucose was 8.2mmol/L, glycated hemoglobin (HbA1c) was 7.8%, fasting C-peptide was 1.35ng/ml, levels of TG and hs-CRP was 0.77mmol/L and 0.95 mg/L, her glucose in urine displayed 4+, with the increasing of bacteria, leukocytes and erythrocytes in urine. Diabetes autoantibody spectrum (GAD, IA, IA2, IC and ZnT8) was negative. Other biochemical indexes were within the normal range, with normal weight for age.

The proband was treated with metformin (500mg a day) and Insulin Detemir (8IU before sleeping). The girl had no significant hypoglycemia during hospitalization. However, combinating the results of hs-CRP with fasting C-peptide and diabetes autoantibody spectrum, we believe that the proband lacks the relevant characteristics of T1DM. Considering her age, BMI (19.40kg/) and record, absence of micro- or macrovascular complications, and no ketosis, we supposed she was not T2DM.

The proband is the third child in the family. Her maternal mother had no history of gestational diabetes mellitus. However, her grandmother died of diabetic complications. With consent from her parents, Beijing MyGenostics Institute of Medical Laboratory finished High-throughput sequencing for the proband and her families. MODY3 was diagnosed with heterozygous mutation nomenclature according to accession number NM_0005 45,exon4,of c.788G > A(missense mutations)and protein p.R263H.According to ACMG guidelines, the variation was preliminarily determined as pathogenic variation(PS2 + PS4 + PM1 + PM2 + PM5 + PP3).Sanger validation shows father, mother and two sisters of the proband are non-mutant individuals. Due to monogenic autosomal-dominant inheritance, her parents have no relevant gene mutation, it is speculated that her grandmother is not a MODY3 patient.

With ambulatory follow-up by outpatient clinic of the endocrinology department, she discharged 6 days later, keeping the treatment plan maintain diabetic diet. After discharge, she was advised to continue the current treatment. But Insulin Detemir was abandoned by her parents. Treatment was retained with Metformin 500 mg twice a day and keeps her at a good blood sugar level with 6.7mmol/L of fasting and 8.9mmol/L of postprandial. We captured her High-throughput sequencing report nearly a month later, which prompts MODY3.

Thus, after the remaining drugs ran out, the patient changed the protocol to glimepiride 4mg per day. At present, the patient's fasting blood glucose fluctuates at 5-6mmol / L. due to poor dietary control, the patient's postprandial blood glucose is controlled at 9-10mmol / L. The good news is that there were no hypoglycemic events found.Her father was very satisfied with the ability of controlling blood sugar, convenience and low price of glimepiride.

Discussion And Conclusions

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.

Abbreviations

MODY 3:A young maturity-onset diabetes of the young type 3 

Declarations

Ethics approval and consent to participate

Not applicable

Consent for publication

Because the patient is a minor, the consent to publish is obtained from the father of the patient.

Availability of data and materials

Not applicable

Competing interes

The authors declare that they have no competing interests.

Funding

No funding.

Acknowledgements

Not Applicable

Contribution statement

Co-author details

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Affiliation

E-mail

Author Contributions

Corresponding author

WZ

General Hospital Of The Western War Zone Of The Chinese People’s Liberation Army

[email protected]

Guidance、Revising it critically for intellectual content

First author

PHR

Chengdu Medical College

[email protected]

Paper Writing、take public responsibility for appropriate portions of the content

Second author

LJB

Southwest Medical University

[email protected]

Data acquisition、Follow-up

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