Mutations in the human insulin gene (INS) usually cause permanent neonatal diabetes, and can rarely cause a form of maturity onset diabetes of the young (MODY). Both conditions form because the pancreas can’t produce enough of its own insulin. INS-related neonatal diabetes often looks a lot like type 1 diabetes. However, type 1 diabetes is an autoimmune condition, and INS-related neonatal diabetes is a genetic condition.
INS is the gene that codes for insulin, the signaling molecule released from cells in the pancreas (beta cells) that prompt other cells in the body to take in glucose (sugar) from the blood. A normal insulin protein undergoes several stages of processing before it is released as fully-functional insulin. Mutations in the INS gene can cause this processing to go wrong. In the most severe mutations, these changes in the protein cause processing to stop in one of the intermediate stages. The broken, unprocessed protein will then build up inside of the cell, causing stress and eventually cell death. These mutations will therefore result in gradual beta cell death and, ultimately, total loss of insulin production. This process appears to be the most common result of INS gene mutations, but some people may have slower or faster disease progression depending on several factors, including their environment, lifestyle, and exact mutation type.
There are currently over 70 mutations in the insulin gene identified. Each of these unique mutations (pictured below) will cause a slightly different change in the insulin protein, sometimes causing differences in the resulting diabetes.
The vast majority of INS gene mutations will result in permanent neonatal diabetes, diabetes that develops in the first year of life. Babies with these mutations (represented as black circles below) will usually develop extremely high blood sugars before their first birthday.
Features common of neonatal diabetes due to an INS gene mutation include:
- Below average birth weight
- Lack of beta-cell autoantibodies that would be expected in type 1 diabetes
- Low or undetectable C-peptide (meaning the body is not making very much, if any, of its own insulin)
- Diabetic ketoacidosis (DKA) or extremely high blood sugar at diagnosis
- Insulin dependence
While rare, insulin gene mutations can also result in more mild diabetes that develops later in life. Individuals with these mutations are usually diagnosed with maturity onset diabetes of the young (MODY). People with these mutations (represented by purple circles above) might still produce some of their own insulin.
People with INS mutations will require insulin therapy since the body is not making enough insulin of its own. Insulin can be given through multiple daily injections or by an insulin pump.
Mutations can occur spontaneously but usually are passed on from a parent to a child. If a parent has an INS gene mutation, there is a 50% chance that a child will inherit the mutation and also have monogenic diabetes. Finding an INS gene mutation in a patient’s family may reveal other family members who also have monogenic diabetes, even if they were previously diagnosed with another form of diabetes.
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