Exercise preserves β-cell function in type 2 diabetes by reshaping intra-islet macrophage-β-cell crosstalk.

Area of Science:

• Immunology
• Metabolic disease
• Endocrinology

Background:

• Type 2 diabetes (T2D) involves beta-cell dysfunction and insulin resistance, with islet inflammation playing a key role.
• Macrophages are crucial regulators of the islet immune microenvironment in T2D.
• The effects of exercise on islet inflammation and beta-cell function in T2D are not fully understood.

Purpose of the Study:

• To investigate the impact of exercise intervention on islet inflammation and beta-cell function in a mouse model of obesity-associated T2D.
• To identify potential molecular mechanisms and circulating factors involved in exercise-mediated protection of islets.

Main Methods:

• Established a mouse model of T2D using high-fat diet (HFD) feeding and treadmill running.
• Assessed glucose tolerance, insulin sensitivity, islet morphology, immune cell infiltration, and gene expression.
• Utilized untargeted plasma proteomics to identify circulating factors.
• Analyzed a human cohort to correlate SPARC levels with T2D parameters.

Main Results:

• Exercise significantly improved glucose tolerance and insulin sensitivity in HFD-fed mice.
• Exercise mitigated HFD-induced beta-cell dysfunction, islet hypertrophy, and inflammation.
• Secreted protein acidic and rich in cysteine (SPARC) was identified as a circulating factor suppressed by exercise and linked to islet protection.
• Elevated circulating SPARC levels in human T2D patients correlated negatively with insulin sensitivity and beta-cell function, and positively with insulin resistance.

Conclusions:

• Exercise intervention effectively improves islet homeostasis and beta-cell function in a mouse model of T2D.
• SPARC is implicated in mediating beta-cell dysfunction, potentially via macrophage inflammasome signaling.
• SPARC represents a potential therapeutic target for T2D intervention.