Macrophage modulation with dipeptidyl peptidase-4 inhibitors: A new frontier for treating diabetic cardiomyopathy?

Table 1 Molecular mechanisms of macrophage dysfunction in diabetic cardiomyopathy

Mechanism	Consequence	Effect on heart function	Ref.
Increased M1 polarization by hyperglycemia: Activation of nuclear factor-kappaB and mitogen-activated protein kinases pathways	Increased production of pro-inflammatory cytokines (IL-1β, TNF-α) and enhanced generation of reactive oxygen species	Direct cardiomyocyte damage and impaired contractile function	[8,12]
Impaired M2 polarization by hyperglycemia: Downregulation of IL-10 and TGF-β signaling	Reduced production of anti-inflammatory cytokines and impaired clearance of apoptotic cells and tissue repair	Perpetuation of inflammation and delayed wound healing	[7]
NLRP3 inflammasome activation: Triggered by hyperglycemia and damage-associated molecular patterns	Processing and release of pro-inflammatory cytokine IL-1β	Amplification of inflammatory response and aggravated cardiac dysfunction	[12,13,22]
M1 macrophage-mediated cardiomyocyte injury: Release of pro-inflammatory cytokines and reactive oxygen species	Direct damage to cardiomyocytes	Reduced contractility and pump function	[23]
M1 macrophage-promoted fibrosis: Enhanced collagen deposition by fibroblasts	Myocardial stiffening and fibrosis	Impaired relaxation and filling of heart and decreased pump function	[11]
Impaired apoptotic/necrotic cell clearance: Dysfunctional macrophages	Accumulation of cellular debris	Sustained inflammatory response and hindered tissue repair	[10]

TNF: Tumor necrosis factor; IL: Interleukin; TGF: Transforming growth factor.

Table 2 Effects of antidiabetic drugs on macrophage function in diabetic cardiomyopathy

Drug class	Drug examples	Effects on macrophages	Related mechanisms	Ref.
Dipeptidyl peptidase-4 inhibitors	Teneligliptin, linagliptin, sitagliptin	Reduce pro-inflammatory cytokine production (IL-1β, IL-6), promote M2 polarization, and inhibit NLRP3 inflammasome activation	Increased glucagon-like peptide-1 levels, reduced oxidative stress, and modulation of nuclear factor-kappaB signaling pathway	[3,14,24]
Metformin	Metformin	Reduces M1 polarization, increases M2 polarization, suppresses nuclear factor-kappaB signaling, and inhibits mitochondrial dysfunction	AMPK activation, reduced reactive oxygen species generation, and modulation of metabolic pathways	[13,17]
Sodium-glucose cotransporter 2 inhibitors	Dapagliflozin, empagliflozin	May indirectly affect macrophage function through improved cardiac function and reduced inflammation	Sodium-glucose cotransporter 2 inhibition leads to diuresis and natriuresis, and may improve cardiac remodeling	[18,25]
Glucagon-like peptide-1 receptor agonists	Liraglutide, dulaglutide	Promote M2 polarization, reduce pro-inflammatory cytokine production, and may improve cardiac contractility	Reduce oxidative stress, and enhance insulin sensitivity	[26-28]
Thiazolidinediones	Pioglitazone	Have anti-inflammatory properties, and improve insulin sensitivity	Peroxisome proliferator-activated receptor-γ activation, and reduced nuclear factor-kappaB signaling	[29,30]

AMPK: AMP-activated protein kinase; IL: Interleukin.