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

Current treatments for type 1 diabetes (T1D) focus on insulin replacement. We demonstrated the therapeutic potential of a secreted protein fraction from embryonic brown adipose tissue (BAT) that mediates insulin receptor-dependent recovery of euglycemia in a T1D, nonobese diabetic (NOD) mouse model, by suppressing glucagon secretion. This fraction promoted white adipocyte differentiation and browning, maintained healthy BAT, and enhanced glucose uptake in adipose tissue, skeletal muscle, and liver. We identified nidogen-2 as a critical BAT-secreted protein that reverses hyperglycemia in NOD mice, inhibits glucagon secretion from pancreatic α-cells, and mimics other actions of the entire secreted fraction. Secretions from a BAT cell line with siRNA knockdown of nidogen-2 failed to inhibit glucagon secretion and restore euglycemia. These findings demonstrate that BAT-secreted peptides represent a novel therapeutic approach to diabetes management. Furthermore, our research reveals a novel signaling role for nidogen-2 beyond its traditional classification as an extracellular matrix protein. ARTICLE HIGHLIGHTS: Large embryonic brown adipose tissue-secreted proteins (CB-100) suppress glucagon and normalize glycemia in mice with type 1 diabetes (T1D) without changing insulin. CB-100 prevented T1D-induced whitening, promoted browning of adipose tissue, and enhanced glucose uptake via an insulin receptor-dependent pathway. Within CB-100, nidogen-2 regulated glucagon secretion and restored euglycemia in T1D. Nidogen-2 and CB-100 unveil a therapeutic strategy for diabetes management beyond insulin-centric paradigms by modulating glucagon secretion and enhancing glucose metabolism.