For the treatment of monogenic diabetes, sulfonylurea hypoglycemic drugs have a better effect!

Type 2 diabetes mellitus (T2DM) is a group of chronic metabolic syndromes caused by the interaction of multiple genetic factors and environmental factors, but patients diagnosed with T2DM with clinical manifestations may still be a heterogeneous group in etiology, and some single-gene mutations may be hidden in it
.
At present, the single-gene mutation diabetes found is roughly the following four categories: adolescent-onset adult diabetes mellitus (MODY), diabetes mellitus caused by mitochondrial DNA mutation (MDM), diabetes caused by insulin gene mutation, and diabetes
caused by insulin receptor gene mutation.
Among them, MODY has been the most
studied.

First, the clinical classification of MODY

MODY is chronic hyperglycemic syndrome caused by mutations in one or several genes encoding proteins involved in the development and maturation of β cells and enzymes involved in insulin secretion, and is the most common type of
monogenic diabetes.
To date, 14 MODY subtypes have been identified, of which MODY3, MODY2 and MODY1 are the most common, accounting for more than
90% of all monogenic diabetes patients.
Patients are divided into different MODY subtypes according to genetic testing, and the clinical features are different
for different subtypes.
For example, patients with GCK-MODY have stable and mild increases in fasting blood glucose, while HNF1A has progressive hyperglycemia and positive urine glucose, patients with HNF4A often have hypoglycemia in macrosomia and newborns, and patients with HNF1B-MODY are often accompanied by renal and multi-organ developmental disorders
.

Different mody subtypes differ in treatment, with patients with GCK-MODY controlling mild hyperglycemia through diet alone, while patients with HNF4A-MODY and HNF1A-MODY should be treated with sulfonylurea as the first choice
.
Therefore, accurate typing, correct treatment, follow-up and active intervention of related complications through genetic testing will have a significant impact
on the prognosis of patients.

Second, the relevant mechanism of MODY3

MODY3 is caused by mutations in the HNF1A gene, located on chromosome 12, which is mainly expressed in pancreatic islet β cells, liver, and intestine, and is a key transcription factor
for insulin and sodium-dependent glucose transporter 2 (SGLT-2) in molded β cells 。 HNF1A mutation has a significant negative effect on the gene expression of glucose and glycolysis, and can cause progressive dysfunction of pancreatic islet β cells, including impaired expression of genes encoding insulin and SGLT-T2, decreased pyruvate kinase activity, decreased ATP formation, decreased SGLT-2 expression and insulin secretion, resulting in reduced renal glucose threshold and glucose intolerance, and decreased glucose reabsorption by the distal renal tubules, resulting in positive
urine glucose.

Patients with HNF1A mutations begin with relatively normal fasting blood glucose levels, although blood glucose levels increase sharply after OGTT 2 hours (typical elevation > 4.
5 mmol/l).

The occurrence of this phenomenon indicates that diabetic patients with HNF1A mutation have normal stress capacity
when blood sugar is less than 8mmol/L.
Glycosuria is the most obvious clinical feature
in patients with HNF1A mutations before they develop diabetes.
Patients who are positive for urine glucose after a high-sugar diet are advised to have OGTT and genetic testing
.

Third, MODY3 treatment is preferably sulfonylurea hypoglycemic drugs

Clinical studies have shown that sulfonylureas can significantly improve blood glucose control in MODY3 patients, and for patients with poor early glycemic control and prejuvenile diabetes, they can be controlled from lifestyle first, and sulfonylureas can be given after the initial treatment is ineffective
.
Diabetic patients with confirmed HNF1A mutations are very sensitive
to sulfonylurea therapy.
It is recommended that starting a small dose (e.
g.
, 20~40mg of gliclazide per day) of sulfonylurea therapy is the first-line treatment for these patients, and patients using other oral hypoglycemic agents or insulin should try sulfonylureas
.
Studies have also shown that the addition of dipeptidyl peptidase IV inhibitors to sulfonylureas is more effective in reducing glucose, but with age, the reduction of islet β cells and their progressive decline in function make hyperglycemia more and more obvious, and eventually insulin therapy
is still required.

Bacon et al.
studied
the efficacy and safety of sulfonylurea therapy in 60 MODY3 patients and 60 patients with type 1 diabetes mellitus matched by BMI, age, ethnicity, and diabetes duration.
The results of this study showed that glycated hemoglobin levels were significantly improved in patients treated with sulfonylureas in MODY3, the incidence of retinal was significantly lower than in patients with type 1 diabetes, and the incidence of microalbuminuria and cardiovascular disease was also lower
.

In recent years, it has been reported that some patients with MODY3 are not sensitive to a variety of hypoglycemic drug regimens, including sulfonylureas, so subsequent treatment plans should be decided according to the sensitivity of patients to different treatment regimens, and the sensitivity cannot be predicted
according to the duration of diabetes, pancreatic function, insulin sensitivity, and mutation site.

Therefore, for patients suspected of MODY3 in clinical diagnosis, single gene screening should be paid attention to to confirm the diagnosis, which is conducive to the reasonable selection of treatment regimen, prognosis judgment and risk assessment
of family members.
Sulfonylureas are currently recommended as first-line agents for treatment, but as the course of the disease gradually prolongs, insulin secretion continues to decrease, and eventually insulin therapy
is still required.

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SU Ying,CHEN Qian,YUAN Gang,YU Xuefeng,HE Wentao.
A case of monogenic diabetes mellitus MODY3 family[J].
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7.
Bacon S,Kyithar MP,Rizvi SR,et al.
Successful maintenance on sulphonylurea therapy and low diabetes complication rates in a HNF1A-MODY cohort[J].
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