Maturity-onset diabetes of the young type 6 in China and the utility of semaglutide: A case report

Abstract

BACKGROUND

Sulfonylureas and insulin constitute the standard therapy for patients with maturity-onset diabetes of the young 6 (MODY6) caused by mutation in neurogenic differentiation 1 gene but are characterized by an increased risk of hypoglycemia. Although glucagon-like peptide-1 receptor agonist (GLP-1 RA) may represent an effective treatment option, the utility of GLP-1 RA therapy in MODY6 has not been reported.

CASE SUMMARY

We report the case of a young man with MODY6 who was affected a mutation p.Asp331Glu in the neurogenic differentiation 1 gene and effectively and safely treated with semaglutide, which led to significant improvements in glycemic management and weight loss.

CONCLUSION

Our case report supports the classification of the p.Asp331Glu mutation as a likely pathogenicity of MODY6. And the use of GLP-1 RA under controlled conditions may represent an effective treatment option for patients with MODY6.

Key Words: Maturity-onset diabetes of the young; Neurogenic differentiation 1 gene; Glucagon-like peptide-1 receptor agonist; Semaglutide; Case report

Core Tip: Maturity-onset diabetes of the young type (MOD) 6, as a subtype of MODY caused by mutations in the neurogenic differentiation 1 gene, has been poorly reported, and its clinical features and treatments remain unclear. We report the case of a young man with MODY6 who was affected a mutation p.Asp331Glu in the neurogenic differentiation 1 gene and effectively and safely treated with semaglutide, which led to significant improvements in glycemic management and weight loss.

INTRODUCTION

Maturity-onset diabetes of the young (MODY) is a form of rare, monogenic nonautoimmune diabetes mellitus, which is characterized by hyperglycemia due to β-cell dysfunction and autosomal dominant inheritance; the typical onset age is usually less than age 25 years[1]. There are 14 MODY subtypes according to the Online Mendelian Inheritance in Man database[2], of which MODY6 is an uncommon form of diabetes and is caused by either a homozygous or heterozygous mutation in the Neurogenic differentiation 1 (NEUROD1) gene[3]. NEUROD1 functions as a transcription factor that transactivates the insulin gene and plays a vital role in order to maintain normal glucose homeostasis[4]. Details of the phenotypic characteristics and treatment of the disease are relatively scarce and remain to be elucidated. Emerging evidence suggests that glucagon-like peptide-1 receptor agonist (GLP-1 RA) treatment may be beneficial for hepatocyte nuclear factor 4 alpha-MODY[5], hepatocyte nuclear factor 1 alpha-MODY[6] and ATP binding cassette subfamily C member 8-MODY[7]. To the best of our knowledge, the utility of GLP-1 RA therapy for MODY6 has not yet been reported. Here, we present a case of MODY6 caused by a novel heterozygous missense mutation in the NEUROD1 gene in a Chinese family and the use of GLP-RA therapy during its management.

CASE PRESENTATION

Chief complaints

A 21-year-old male was admitted to the hospital with polyuria, polydipsia, and weight loss over 1 month prior to his diagnosis of diabetes.

History of present illness

His initial random blood glucose was found to be 21.41 mmol/L and was admitted to the Department of Endocrinology and Metabolism for further treatment. His other medical history was unremarkable.

History of past illness

The patient had a history of asthma for 9 years, though it did not relapse in the past year.

Personal and family history

The patient reported that his father was diagnosed with diabetes during physical examinations at 39 years but did not receive medical treatment.

Physical examination

The patient was sane and conscious. His blood pressure was 143/101 mmHg, body mass index (BMI) was 25.6 kg/m², and waist circumference was 96 cm.

Laboratory examinations

At admission, his biochemical analyses were as follows: Arterial blood gas test indicated that pH was 7.48, PO₂ was 96.90 mmHg, bicarbonate was 14.6 mmol/L. His glycosylated hemoglobin (HbA1c) was 9.68%. Fasting blood glucose was 13.62 mmol/L, 2-hour postprandial blood glucose was 22.51 mmol/L. And his fasting C-peptide was 0.3 nmol/L, 2-hour postprandial C-peptide was 0.68 nmol/L. The autoimmune form of diabetes was screened using glutamic acid decarboxylase autoantibody, insulinoma-associated-2 autoantibody, and zinc transporter 8 autoantibody, the 3 antibodies that were tested were negative. His urine ketone level was significantly elevated. Blood lipid testing revealed the following: Triglyceride (TG), 96.99 mmol/L, total cholesterol, 11.62 mmol/L, low-density lipoprotein cholesterol of 7.07 mmol/L. Seven days after admission, blood lipid retesting indicated that TG levels had dropped to 7.89 mmol/L.

Imaging examinations

Because of the high TG levels, we performed amylase and lipase testing and upper abdominal computed tomography examination to rule out acute pancreatitis; the results were negative, and the patient was administered fluid replacement, insulin, and lipid-lowering treatment at admission until urine ketone levels returned to normal.

MULTIDISCIPLINARY EXPERT CONSULTATION

The proband’s father

He was 51 years old with a BMI of 25.05 kg/m² and a waist circumference of 90 cm. His blood pressure was 130/80 mmHg. The oral glucose tolerance test showed 0-120 min blood glucose levels of 5.96-8.55 mmol/L and C-peptide levels of 0.86-4.99 nmol/L. His HbA1c was 5.84%. Laboratory tests revealed a TG level of 2.99 mmol/L, total cholesterol level of 5.90 mmol/L, and low-density lipoprotein cholesterol level of 3.67 mmol/L. Liver and kidney function tests were within normal ranges. Unfortunatly, diabetes autoantibody test was not performed. Currently, he is managed with diet and exercise, with good glycemic control.

Next-generation sequencing

Considering these clinical features, namely young age, normal islet function, and negative pancreatic antibodies, the Exeter MODY Probability Calculator was used to calculate the possibility of MODY, and the results indicated a 58% likelihood of having MODY. After obtaining informed consent, a venous blood (5 mL) was collected from the proband and his parents and performed next-generation sequencing. Whole-exome sequencing identified a heterozygous missense mutation (NM_002500.5: C.993C > A,p.Asp331Glu) in the coding sequence of the NEUROD1 gene in this patient and his father (Figure 1). This has not been reported in any literature. Based on the interpretation guidelines developed by the American College of Medical Genetics and Genomics to classify the pathogenic of the variant, the novel NEUROD1 mutation identified in this family was considered to be “likely pathogenic”, based on the evidence framework of PM2 (pathogenic moderate; i.e., not found in polymorphism databases), PM5 (pathogenic moderate; i.e., the new missense mutation leads to an amino acid change, and this variation has not been reported before[8]. However, at the same site, another amino acid variation that causes a disease has been confirmed to be pathogenic), PP3 (pathogenic supporting; i.e., multiple lines of computational evidence predict that this variant will have a deleterious effect on the gene or its product (CADD score: 21.3; Fathmm Score: -3.59 and meta-voting prediction score: 0.97) and PP4 (pathogenic supporting; i.e., the phenotype or family history of the variant carrier is highly consistent with a particular monogenic inherited disorder). The findings revealed that he had a heterozygous missense mutation (NM_002500.5: C.993C > A,p.Asp331Glu) in the coding sequence of the NEUROD1 and supported the classification of the this mutation as a cause of MODY6.

Figure 1  Gene sequencing results of proband and his family.

FINAL DIAGNOSIS

Grounded in the clinical and genetic findings, a diagnosis of MODY6 was established.

TREATMENT

Because of his relatively high BMI and normal islet function, the patient was initiated on once-weekly subcutaneous semaglutide at a starting dose of 0.25 mg after obtaining ethics approval and informed consent. The patient experienced mild nausea and reduced appetite after the first dose; however, these symptoms resolved within 3 days. The dose was gradually increased at monthly intervals until a dose of 0.75 mg weekly was reached.

OUTCOME AND FOLLOW-UP

The patient attended monthly follow-up visits at our outpatient clinic. Approximately 3 months after discharge, his glycemic indices improved significantly, as evidenced by a decrease in HbA1c levels from 9.68% to 7.20%, and his BMI decreased from 25.6 kg/m² to 24.2 kg/m². Approximately 6 months after discharge, a carbohydrate-rich meal (50 g carbohydrates; 350 kcal) was administered to evaluate his islet cell function. His HbA1c was 6.70%, and fasting and 2 hours postprandial blood glucose concentration were 6.18 mmol/L and 11.20 mmol/L, respectively. The fasting and postprandial serum C-peptide levels were 0.68 nmol/L and 1.23 nmol/L, respectively, indicating a considerable improvement in islet cell function. The patient tolerated semaglutide well and did not report any adverse events except mild nausea and reduced appetite after first dose. These symptoms resolved within 3 days after first dose. The complete timeline of patient’s clinical progression is shown in Figure 2.

Figure 2 The whole timeline of clinical progression. HbA1c: Glycosylated hemoglobin.

DISCUSSION

Herein, we report the effective and safe use of GLP-RA therapy in a patient with MODY6. MODY is a monogenic and non-autoimmune form of diabetes mellitus that accounts for 0.4% of all cases of diabetes and 1%-5% of young onset diabetes cases[9], but 80% of MODY cases are misdiagnosed as type 1 or 2 because of similar clinical presentation, low awareness, and availability of testing[3,10,11]. There are 14 MODY subtypes according to the Online Mendelian Inheritance in Man database[2], of which MODY1, 2, 3, and 5 may be the most common and their aggregate exceeds over 90% of the total MODY cases[3]; in contrast, MODY6 is a much more uncommon form of diabetes and is caused by either a homozygous or heterozygous mutation in the NEUROD1 gene[3]. NEUROD1 functions as a transcription factor that transactivates insulin and plays a vital role in maintaining normal glucose homeostasis[4]. The clinical features of MODY6, including age at diagnosis, clinical manifestations, and BMI, exhibit significant heterogeneity. Notably, most patients with MODY6 are diagnosed before the age of 25 years and present with episodes of diabetic ketosis, consistent with the findings in our patient. Over 50% of patients with MODY6 are reported to have an elevated BMI or obesity; although this prevalence may vary by ethnicity. In contrast to our patient, patients with MODY6 reported in China and Japan generally have a normal BMI[12], which may be due to the westernization of lifestyle in China.

NEUROD1 is a type II basic helix loop helix transcription factor expressed in the pancreas, which regulate insulin gene transcription[4]. Moreover, NEUROD1 is also known to bind and activate the promoter of the glucokinase[13], the glucose-6-phosphatase catalytic subunit-related protein[14], sulfonylurea receptor 1 (SUR1)[15], and paired box gene 6[16]. The treatment for MODY6 patients is diverse and should be tailored based on individual circumstances. Oral hypoglycemic agents such as sulfonylureas and insulin are currently the preferred treatment options for MODY6[17]. As a pancreas-specific transcriptional activator, NEUROD1 regulates insulin secretion by modulating the expression of the SUR1 gene[18]. As the agonist for SUR1, sulfonylurea drugs are widely used for blood glucose control in MODY6 patients. Other oral hypoglycemic agents such as metformin or thiazolidinediones are also used in patients who are insensitive to sulfonylureas[19]. Insulin is usually required in patients with unsatisfactory blood glucose control when treated with oral hypoglycemic agents or in those with severe diabetic complications. Emerging evidence suggests that treatment with a GLP-1 RA may be beneficial in hepatocyte nuclear factor 4 alpha-MODY[5], hepatocyte nuclear factor 1 alpha-MODY[6] and ATP binding cassette subfamily C member 8-MODY[7]. To the best of our knowledge, the utility of GLP-1 RA therapy for NEUROD1-MODY has not yet been reported. Owing to his relatively high BMI and normal islet function, we selected semaglutide for treatment and found that MODY6 could be managed with semaglutide, leading to significant improvements in glycemic management and weight loss.

Another concern of our study was the patient’s markedly elevated TG level upon admission. A previous study re a reported a prevalence of severe hyper hypertriglyceridemia of 8% among adults with severe hyperglycemia[8], Therefore, we considered the patient’s hypertriglyceridemia to represent a secondary lipid metabolism disorder and initiated treatment with fenofibrate. Repeat blood lipid testing indicated that TG levels had dropped to 7.89 mmol/L by 7 days after admission. Fenofibrate was discontinued 1 month after discharge after follow-up lipid testing indicated a normal TG level.

Although our study reported the effective and safe use of GLP-RA therapy in a patient with MODY6 and the results are promising, owing to the limitation of only a single patient and relatively short follow-up duration. Moreover, lack of a comparator treatment group and absence of long-term safety observations limited the generalizability of our findings. More extensive studies are needed to assess the long-term safety of this treatment in patients with MODY6.

CONCLUSION

In conclusion, we provide evidence for the classification of the c.993C > A, p.Asp331Glu missense mutation in the NEUROD1 gene as likely pathogenicity of MODY6. Our findings suggest that the use of GLP-1 RA may represent an effective treatment option for patients with MODY6under controlled conditions, for example, patients with relatively high BMI and normal islet function. However, further research is required to adequately assess the effectiveness and safety of glucagon-like peptide-1 agonists in the glycemic management of such patients.

ACKNOWLEDGEMENTS

The authors gratefully acknowledge the patient and family members that agreed to participate in this study.