Table 2.

Modulation of signaling pathways as promising targets.

Sl no.	Targets/Agents	Mechanisms	References
1	Cardiac PI3K (p110α) signaling pathway	Increased activation of the p110α pathway leads to improved diastolic dysfunction, cardiomyocyte hypertrophy, myocardial fibrosis, and programmed cell death in diabetic subjects, thus preserving ventricular function as well as augmenting cardiac structural remodeling. The beneficial effect of recombinant adeno-associated viral vectors carrying a constitutively active PI3K construct (rAAV6-caPI3K) in T2DM animals was studied. rAAV6-caPI3K gene-bearing animals showed a reduction in diabetes-induced cardiac remodeling by preventing cardiac fibrosis and cardiomyocyte hypertrophy. Additionally, LV reactive oxygen species and ER stress were reduced.	[22,162,163]
2	Long-chain 3-ketoacyl-CoA thiolase inhibitors	Trimetazidine (TMZ) is a competitive inhibitor of the long-chain 3-ketoacyl-CoA thiolase involved in the β-oxidation of fatty acids, which potentially improves myocardial metabolic or substrate utilization and reduces calcium overload, and ROS-induced cell injury. It reduces FFA utilization and enhances glucose oxidation along with decreasing insulin resistance. TMZ has been shown to be cardioprotective in DCM. TMZ treatment reciprocated LV dysfunction, cardiac hypertrophy, fibrosis, inflammation, and oxidative stress in the myocardium. Additionally, TMZ treatment inhibited diabetes-associated structural and functional alterations by inhibiting NADPH oxidase 2 and transient receptor potential channel 3. Furthermore, the administration of TMZ in an early stage of diabetes may inhibit the progression of DCM by inhibiting myocardial fibrosis and cardiomyocyte apoptosis and enhancing autophagy. TMZ has been found to reverse myocardial remodeling and reduce the deposition of collagen I and III content.	[164,165,166]
3	Metallothioneins (MTs)	MTs involved in the regulation of the intracellular zinc concentration have received significant attention due to the fact that supplementation with zinc has been found to be beneficial in the management of T2DM. MTs are considered a key regulator of zinc metabolism, and the redox process controlled by them causes the simultaneous release and regeneration of zinc-binding capacity. MTs have been found to be involved in the attenuation of oxidative stress by the scavenging of superoxide and hydroxyl radicals. MT prevents DCM and increases the expression of proteins associated with glucose metabolism. MT has been found to preserve Akt2 activity and cardiac function by inhibiting tribbles pseudokinase 3 (TRB3). Cardiac MT overexpression in Akt2 knockout mice was found to prevent pathological changes associated with DCM.	[167,168,169]
4	E3 ubiquitin ligase	The E3 ubiquitin ligases (E3s), the components of the ubiquitin-proteasome system, are believed to play a key role in the progression of DCM due to their involvement in cardiac hypertrophy, increased apoptosis, fibrosis, and altered insulin metabolism. In animal models of T2DM, it has been seen that there is an increase in the expression of E3s in the cardiac tissue, leading to proteasomal degradation of the insulin receptor and insulin receptor substrates, converging to a state of insulin resistance.	[170,171]
5	A novel curcumin analog, C66, in the management of DCM	C66[(2E,6E)-2,6-bis(2-(trifluoromethyl)benzylidene)cyclohexanone], a curcumin analogue, could be beneficial in the management of DCM. It has been reported to reduce hypertriglyceridemia in diabetic animals, along with reducing plasma and cardiac triglyceride levels. Additionally, it also inhibits Jun NH2-terminal kinase (JNK) and NF-κB activation in the heart.	[172,173]
6	Neuregulins (NRG)	NRG-1 is involved in cardiac damage adaptability, as well as maintenance of the shape of cardiomyocytes to limit apoptosis and increase cardiomyocyte proliferation. NRG-1 promotes mitochondrial homeostasis and stability and is considered to be an agent with the potential to ameliorate heart failure and other metabolic dysregulation and inflammation-related diseases such as obesity and T2DM.	[96,174,175]