Monogenic diabetes, hyperinsulinemia, and monogenic hypoglycemia [124 genes]

Glucose metabolism disorders are a group of disorders recognized as one of the main risk factors for the development and complication of cardiometabolic diseases.

The relationship between alterations in glucose metabolism and cardiometabolic diseases is complex and is mediated by multiple dysregulated pathways. Insulin resistance is the main factor that determines the alteration of glucose homeostasis and is strongly associated with obesity and metabolic syndrome. In turn, metabolic syndrome is characterized by metabolic disorders including glucose intolerance, abdominal obesity, decreased HDL-C, and increased triglycerides, and it is also associated with a procoagulant, proinflammatory, and prooxidant state. Therefore, metabolic syndrome associated with insulin resistance further increases the likelihood of developing cardiovascular and cerebrovascular ischemic disease.

Among glucose metabolism disorders are diabetes, hyperinsulinemia, and other causes of hypoglycemia. The two most common forms of monogenic diabetes are known as MODY and neonatal diabetes.

Hyperinsulinemia is related to insulin resistance. In this scenario, the pancreas generates more insulin to overcome resistance, leading to higher blood insulin levels. Hyperinsulinemia can be related to metabolic syndrome, gestational diabetes, and type 2 diabetes and can therefore be associated with cardiovascular diseases and other conditions that are more prevalent among metabolic syndrome patients. It is also an independent risk factor for a number of conditions such as diet-induced obesity, arthrosis, certain types of cancer, Alzheimer disease, and other dementias.

Congenital hyperinsulinism (CHI) is the most frequent cause of severe and persistent hypoglycemia in newborns and lactating infants, although it can also present during early adulthood depending on the severity of hypoglycemia. It encompasses a heterogeneous group of genetic disorders that alter the mechanism that regulates insulin secretion, thus leading to higher insulin production than necessary and triggering severe and persistent hypoglycemias. Neonatal onset is the most frequent, and newborns (who are often macrosomic) show feeding problems, fasting intolerance, and persistent hypoglycemia. Hypoglycemic episodes range from mild (hypotonia, lethargy, and irritability) to severe (apnea, seizures, coma, and arrhythmia). Severe episodes can have major neurological effects due to the irreversible damage caused by exposure to hypoglycemia. Patients with a later onset show typical recurrent hypoglycemias (paleness, excessive sweating, and tachycardia). The diagnosis of CHI is not easy and requires a high degree of suspicion. An underlying genetic cause is identified in up to 40% of children with the disease.

1. MODY: 1:10,000 in adults and 1:23,000 in children.
2. Neonatal diabetes: 1:120,000
3. Congenital hyperinsulinism has a global incidence of 1:30,000-50,000 live newborns (or 1:2,500 in communities with a high degree of consanguinity).

Genetic testing can confirm the diagnosis of diseases related to the genes included in our study. It is particularly important for the diagnosis of monogenic diabetes and congenital hyperinsulinism, as it has implications for therapeutic prognosis and strategy. The identification of a mutation in the index case allows screening the family and identifying other relatives at risk who still have not presented with any clinical manifestations.

Aimed at the study of patients with different forms of monogenic diabetes. It is also useful to explore other conditions associated with glucose metabolism disorders, such as hyperinsulinemias and hypoglycemias.