Persistent elevations in circulating INS DNA among subjects with longstanding type 1 diabetes

Area of Science:

• Endocrinology
• Immunology
• Metabolic Diseases

Background:

• Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing beta cells.
• While beta cell destruction is central to T1D pathogenesis, the persistence of this process in later disease stages remains an area of investigation.

Purpose of the Study:

• To determine if beta cells continue to undergo apoptosis in individuals with long-standing type 1 diabetes.
• To investigate potential therapeutic targets for preserving beta cell function in advanced T1D.

Main Methods:

• Analysis of fasting and stimulated serum samples from 90 participants with longstanding T1D (median 9 years) and 54 non-diabetic controls.
• Quantification of unmethylated and methylated preproinsulin (INS) DNA using digital droplet PCR.
• Classification of T1D participants as C-peptide negative (C-peptide -) or C-peptide positive (C-peptide +) based on mixed-meal tolerance testing.

Main Results:

• Elevated levels of circulating unmethylated INS DNA were observed in both C-peptide (-) and C-peptide (+) individuals with longstanding T1D compared to controls.
• A significant correlation was found between unmethylated and methylated INS DNA levels, with both being elevated in T1D subjects.
• Mixed-meal stimulation showed variable effects on DNA levels, with a decrease in fasting levels in the highest quartiles.

Conclusions:

• The presence of elevated INS DNA suggests ongoing beta cell death in individuals with longstanding T1D, irrespective of C-peptide status.
• These findings support the potential benefit of therapies aimed at enhancing beta cell survival in patients with advanced type 1 diabetes.