Differential Pathophysiological Mechanisms in Heart Failure With a Reduced or Preserved Ejection Fraction in Diabetes

State-of-the-art Review

Milton Packer, MD


JACC Heart Fail. 2021;9(7):535-549. 

In This Article

Nutrient Excess Signaling, Autophagy Suppression, and Cardiomyocyte Stress in Diabetic Hearts

The health and viability of cardiomyocytes is determined by the balance between cellular processes that promote growth and those that prioritize homeostasis and survival. During states of nutrient excess, cells enhance their capacity to synthesize new subcellular constituents, and by doing so, place organelles (particularly mitochondria) under stress, increasing the production of reactive oxygen species and potentially undermining the health of key cellular constituents. In contrast, during states of nutrient deprivation, cells shift into a prosurvival mode and activate mechanisms that minimize cytosolic stress and promote the emergence of healthy organelles.[21] The critical cellular process that is activated during nutrient deprivation but is suppressed during nutrient excess is autophagy, a cellular housekeeping program that targets damaged organelles and potentially injurious cytosolic debris for disposal through a lysosome-dependent process.[22,23] The formation of autophagic vacuoles and their fusion with lysosomes disposes of misfolded proteins (as well as injurious glucose and lipid intermediates), thus reducing endoplasmic reticulum stress, and the autophagic clearance of deranged mitochondria and peroxisomes mitigates oxidative stress. Loss of autophagy allows for the accumulation of damaged organelles and misfolded proteins, which are the major source of oxidative and endoplasmic reticulum stress in cardiomyocytes.[24] Dissipation of these cellular stresses is essential to cardiomyocytes, because nonproliferating cells cannot use cell division to dilute intracellular debris or replace cells that have died.

Interplay of Nutrient Sensors in the Diabetic Heart

Protein kinase B (Akt) and mammalian target of rapamycin complex 1 (mTORC1) are serine/threonine protein kinases that are activated during nutrient surplus and promote cell growth and proliferation. By influencing hundreds of downstream effectors, Akt/mTORC1 signaling stimulates anabolic pathways, and by suppressing autophagy, it directs the priorities of the cell away from homeostasis and survival. The combination of these effects drives the mitochondrial production of reactive oxygen species to facilitate innate immunity and cellular replication, while enhancing the expression of a senescence phenotype that is essential to the cellular disposal required for effective organ growth. However, when disease states trigger cardiomyocyte stresses, activation of Akt/mTORC1 limits the ability of cells to defuse oxidative and endoplasmic reticulum stresses that cause dysfunction and death. Accordingly, mTORC1 is required for cardiomyocyte replication during fetal development, but it contributes to maladaptive cardiac hypertrophy when hearts are stressed in adulthood.[25,26] In experimental models, cardiac-specific overactivation of the Akt/mTOR pathway induces heart failure, whereas suppression of Akt signaling ameliorates maladaptive hypertrophy and fibrosis and retards the development of heart failure.[27] Activation of Akt in the human myocardium distinguishes the transition from well-compensated LV hypertrophy to decompensated heart failure.[28]

Opposing the actions of Akt/mTORC1 is sirtuin 1 (SIRT1), one of a family of redox-sensitive nicotinamide adenine dinucleotide-dependent deacetylases, which is activated by nutrient deprivation and (through its ability to promote autophagy) mediates the ability of caloric restriction to preserve organ function and prolong organismal survival.[21] Activation of SIRT1 in cardiomyocytes reduces oxidative stress, enhances mitochondrial health and biogenesis, and diminishes proinflammatory pathways to promote cell survival.[29] SIRT1 also mediates the ability of redox modulators and inflammasome suppressors to attenuate cardiac hypertrophy and to reduce cell senescence and death following cardiac injury.[30] Cardiac-specific deletion or down-regulation of SIRT1 augments mitochondrial production of reactive oxygen species, enhances oxidative and endoplasmic reticulum stress, and sensitizes the heart to injury, leading to cardiac dysfunction and cardiomyopathy both in experimental models and human cardiomyocytes.[31,32] Conversely, SIRT1 activation improves cardiac function and prevents adverse ventricular remodeling following experimental infarction, mitigates cardiac injury produced by diverse cellular stresses, and ameliorates fibrosis produced by pressure overload.[33,34] The effects of SIRT1 are mediated (in part) by its downstream effectors—proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) and fibroblast growth factor 21 (FGF21)—and are potentiated by the actions of adenosine monophosphate-activated protein kinase (AMPK).[21,35] Activated by caloric restriction, AMPK discerns the balance between cytosolic levels of ATP and AMP, and its effects oppose the actions of the Akt/mTORC1 pathway.[26]

Type 2 diabetes is characterized by hyperglycemia, the accumulation of intracellular glucose and lipid intermediates, and the expansion of adipose tissue within and surrounding visceral organs—thus, it is perceived as a state of nutrient excess. Accordingly, type 2 diabetes is accompanied by decreased activation of SIRT1/PGC-1a/FGF21 and AMPK as well as suppression of autophagy (Figure 1).[35–38] However, it is noteworthy that autophagic flux is increased (not decreased) in type 1 diabetes, both in the heart and the kidney,[39,40] presumably because it is the hyperinsulinemia of type 2 diabetes—rather than the hyperglycemia—that causes down-regulation of autophagy under conditions of glucose intolerance. In fact, insulin directly suppresses autophagic flux, possibly as a result of its effect to inhibit SIRT1 and activate the Akt/mTORC1 signaling.[41,42] Suppression of SIRT1/AMPK signaling and autophagic flux has been implicated in the pathogenesis of cardiac disease in type 2 diabetes.[38,39] A deficiency of SIRT1/AMPK activation and impairment in autophagy allows for the persistence of deleterious intracellular glucose and lipid intermediates and misfolded proteins (that can lead to endoplasmic reticulum stress) as well as dysfunctional mitochondria and peroxisomes (that lead to oxidative stress); these are the cellular hallmarks of diabetic heart disease.[43] Conversely, enhancement of SIRT1/AMPK signaling or autophagic flux mitigates the cardiac dysfunction of experimental diabetes.[33,44]

Figure 1.

Type 2 Diabetes Causes Up-Regulation of Nutrient Surplus Sensors and Down-Regulation of Nutrient Deprivation Sensors Leading to Increased Cardiomyocyte Oxidative and Endoplasmic Reticulum Stress
Type 2 diabetes represent a state of nutrient surplus, which leads activation of nutrient surplus sensor and suppression of nutrient deprivation signaling, leading to suppression of autophagy, organellar dysfunction, and activation of intracellular proinflammatory pathways. AMPK = adenosine monophosphate-activated protein kinase; FGF21 = fibroblast growth factor 21; mTORC1 = mammalian target of rapamycin complex 1; PGC-1α = proliferator-activated receptor-gamma coactivator 1-alpha; SIRT1 = sirtuin 1.

These observations, taken together, suggest that diabetes may promote the development of HFrEF by virtue of the actions of hyperinsulinemia to activate Akt/mTORC1 and inhibit SIRT1/PGC-1α/FGF21, thus suppressing autophagy and thereby promoting endoplasmic reticulum and oxidative stress and mitochondrial dysfunction in diabetic cardiomyocytes.