Related Experiment Video

Updated: Jul 13, 2026

Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
09:34

Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease

Published on: April 4, 2018

33.6K

Case Report: Functional characterization of a missense variant in INSR associated with hypoketotic hypoglycemia

Herodes Guzman1,2, Lauren M Mitteer1, Pan Chen1

  • 1Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, United States.

Frontiers in Pediatrics
|November 1, 2024
PubMed

Insights

A genetic variant in the insulin receptor (INSR) gene caused persistent hypoglycemia in a child. This discovery highlights INSR gene defects as a cause of hypoglycemia, impacting treatment strategies.

Area of Science:

  • Endocrinology
  • Genetics
  • Molecular Biology

Background:

  • Persistent hypoglycemia in children is often due to dysregulated insulin secretion (hyperinsulinism).
  • Defects in the insulin signaling pathway are an alternative cause of hypoglycemia.
  • Differentiating these causes is crucial for appropriate clinical management.

Observation:

  • A 10-year-old female presented with recurrent fasting and postprandial hypoglycemia.
  • Whole exome sequencing revealed a heterozygous missense variant (c.1151A>G, p.Asn384Ser) in the insulin receptor (INSR) gene, inherited from her mother.
  • The mother exhibited postprandial hypoglycemia, suggesting a familial link.

Findings:

  • Functional studies using 3T3-L1 cells demonstrated that the mutant INSR leads to constitutive and enhanced activation of the insulin receptor.
  • Increased signaling through Akt and ERK1/2 pathways was observed in cells expressing the mutant INSR, even without insulin stimulation.
  • This hyperactivation of the insulin receptor explains the patient's severe hypoglycemia.

Implications:

  • Identifies a novel heterozygous missense variant in the INSR gene associated with both fasting and postprandial hypoglycemia.
  • Expands the genetic basis of hypoglycemia beyond hyperinsulinism to include insulin receptor signaling defects.
  • This finding may guide diagnostic approaches and therapeutic interventions for pediatric hypoglycemia.

Keywords:
beta cellsglucosehyperinsulinisminsulininsulin receptor

More Related Videos

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila00:06

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila

Published on: August 20, 2019

13.6K
Functional Characterization of Endogenously Expressed Human RYR1 Variants07:59

Functional Characterization of Endogenously Expressed Human RYR1 Variants

Published on: June 9, 2021

2.5K

Related Concept Videos

Glucose Transporters01:27

Glucose Transporters

Glucose transporters facilitate the transport of glucose across the cell membrane. In addition to glucose, some glucose transporters can also aid the movement of other hexoses such as fructose, mannose, and galactose.
Facilitated diffusion-glucose transporters (GLUTs) are encoded by the solute-linked carrier (SLC) family 2, subfamily A gene family, or SLC2A. The 14 GLUT protein members are distributed into three classes:
Inborn Errors of Metabolism01:20

Inborn Errors of Metabolism

Phenylketonuria (PKU) is a protein metabolism disorder characterized by high blood levels of the amino acid phenylalanine. This results from a mutation in the gene responsible for phenylalanine hydroxylase, an enzyme that converts phenylalanine into tyrosine. When this enzyme is deficient, phenylalanine builds up in the blood, leading to symptoms such as vomiting, rashes, seizures, growth deficiency, and severe mental retardation. An early diagnosis and a diet restricting phenylalanine intake...
Type II Diabetes I: Introduction01:26

Type II Diabetes I: Introduction

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance, in which target tissues such as the liver, muscle, and adipose tissue respond poorly to insulin. It is also associated with inadequate compensatory insulin secretion, where pancreatic β-cells fail to produce sufficient insulin. Together, these abnormalities lead to persistent hyperglycemia.EtiologyT2DM develops through a complex interaction of genetic predisposition and environmental or...
Hypoglycemia01:26

Hypoglycemia

Hypoglycemia is a blood glucose level below 70 mg/dL. It commonly occurs in individuals using insulin or insulin-secreting drugs, but may also arise in non-diabetic conditions. People with type 1 diabetes are at the highest risk because they depend on exogenous insulin. People with type 2 diabetes are also at risk, especially when treated with insulin or medications such as sulfonylureas, which increase insulin release regardless of blood glucose levels. It develops when insulin levels exceed...
Hyperglycemia01:29

Hyperglycemia

Hyperglycemia is an abnormally high blood glucose level. It is diagnosed by fasting glucose ≥126 mg/dL, 2-hour oral glucose tolerance test (or OGTT) ≥200 mg/dL, random glucose ≥200 mg/dL with symptoms, or HbA1c ≥6.5%. However, HbA1c results may be unreliable in certain conditions, such as anemia or hemoglobinopathies, and the diagnosis should be confirmed unless classic symptoms are present. Postprandial hyperglycemia is typically considered significant when glucose levels exceed 180 mg/dL two...
Diabetic Ketoacidosis ll: Pathophysiology01:22

Diabetic Ketoacidosis ll: Pathophysiology

Diabetic ketoacidosis (DKA) is a metabolic emergency characterized by hyperglycemia, ketonemia, and metabolic acidosis. It results from severe insulin deficiency and an excess of counterregulatory hormones, leading to uncontrolled lipolysis, ketogenesis, and widespread electrolyte and fluid disturbances.Pathophysiology The central event in DKA is a profound loss of insulin action. Without insulin, glucose uptake in insulin-dependent tissues is impaired, while hepatic glucose production...