Regulation of Type 1 Diabetes via Brown Adipocyte-Secreted Proteins and the Novel Glucagon Regulator Nidogen-2.

Summary

A BAT-derived secretome normalized glycemia in T1D mice by suppressing glucagon secretion without increasing insulin. Nidogen-2 was identified as the key BAT-secreted protein that inhibits α-cell glucagon and recapitulates the secretome’s metabolic benefits; its knockdown abrogated these effects.

Key Findings

• BAT secreted protein fraction normalized glycemia in NOD T1D mice by suppressing glucagon without changing insulin.
• The secretome promoted white adipocyte browning and increased glucose uptake in adipose tissue, skeletal muscle, and liver via insulin receptor-dependent pathways.
• Nidogen-2 was identified as the key effector: it inhibited α-cell glucagon secretion and reversed hyperglycemia; siRNA knockdown of nidogen-2 abolished these effects.

Clinical Implications

While preclinical, targeting adipose-derived pathways that suppress glucagon (e.g., nidogen-2) could complement insulin-centric therapies in T1D and inspire new drug classes.

Limitations

• Preclinical mouse models; human translatability and pharmacokinetics of nidogen-2 are unknown
• Use of embryonic BAT-derived fractions may not reflect adult human BAT secretome

Future Directions

Define nidogen-2 receptor/signaling in α-cells, evaluate safety/efficacy in larger animals, and develop pharmacologic mimetics or delivery systems for clinical translation.