FoxO1 breaks diabetic heart.

The incidence of type 2 diabetes is increasing explosively around the world. Both hyperglycemia and insulin resistance can cause myocardial damages with coronary atherosclerosis in type 2 diabetes. In addition, some patients show cardiac functional disorder, characterized by diastolic dysfunction, without ischemia. In a large prospective study in the Framingham cohort, patients with diabetes showed a higher risk of congestive heart failure as compared with those without diabetes after adjusting for coronary artery disease. This cardiac damage found in diabetes is called ‘diabetic cardiomyopathy’. The pathology of diabetic cardiomyopathy was classically characterized by myocellular hypertrophy and myocardial interstitial fibrosis in autopsy specimens. Multiple factors (e.g. impairments of calcium homeostasis, upregulation of the renin–angiotensin system, glycation and metabolic derangements) have been implicated in the pathogenesis of diabetic cardiomyopathy.

Impaired energy use and abnormal lipid metabolism have emerged as important contributors to multiple organ damage in diabetes. With regard to heart failure, several diabetic animal models have shown abnormal lipid accumulation in the myocardium. In recent years, proton magnetic resonance spectroscopy enables us to evaluate the myocardial lipid accumulation non‐invasively. Several reports have shown that myocardial triacylglycerol accumulation is observed in individuals with diabetes or insulin resistance preceding heart failure. In practice, lipid droplets are observed in the myocardium of patients with diabetes or obesity1.

The major energy source (approximately two‐thirds) of the adult heart is β‐oxidation of fatty acids (FAs), with the remainder from glucose and lactate metabolism. FAs are mainly taken into cardiomyocytes through FA transporters (e.g. CD36 and FA transport protein 1 [FATP‐1]), and are subsequently converted to acyl‐CoA. The intracellular acyl‐CoA not used for adenosine triphosphate (ATP) production (β‐oxidation in mitochondria) are esterified into triacylglycerols and stocked in the cardiomyocytes. Decreased insulin signaling, based on both insulin resistance and deficiency, characteristically reduces glucose usage and enhances FA metabolism in diabetes. FA overloading and consequent activation of peroxisome proliferator‐activated receptor α (PPARα)/PPARγ co‐activator 1 (PGC‐1) accelerate the abnormal substrate usage in the diabetic heart. The imbalance between FA uptake and oxidation, increased uptake exceeding oxidation, gradually induces lipid accumulation, which can lead to various deleterious effects (e.g. mitochondrial uncoupling, reactive oxygen species production, diacylglycerol formation, endoplasmic reticulum stress and insulin resistance), so‐called ‘lipotoxicity’2.

A recent report from the Hill's laboratory3 in The Journal of Clinical Investigation provides new in vivo evidence for the important role of forkhead box protein O1 (FoxO1) in myocardial abnormal metabolism in diabetic cardiomyopathy. The FoxO family of transcription factors is expressed almost ubiquitously in mammalian cells, and plays pivotal roles in cell growth, metabolism and survival. Previous studies have shown that activation of FoxO (especially FoxO1) enhances hepatic glucose production, decreases pancreatic insulin secretion, increases white adipose tissue lipolysis and stimulates hypothalamic orexigenic signals. However, the role of FoxO in the diabetic heart has not been established yet.

FoxO proteins are well established as important downstream mediators of the phosphatidylinositol 3‐kinase (PI3K)/Akt pathway in insulin/insulin‐like growth factor 1 (IGF‐1) signaling. Akt‐dependent phosphorylation negatively regulates the ability of FoxO by inducing nuclear exclusion. Meanwhile, Hill et al. have pointed out that FoxO can mediate negative feedback control in insulin signaling at the same time. In a preceding study, Ni et al.4 showed that FoxO activation contributes to reduced insulin sensitivity and glucose metabolism impairment in primary cardiomyocytes through modulating Akt phosphorylation. In their recent report, Battiprolu et al.3 further showed that FoxO‐mediated feedback regulation of insulin signaling plays a pivotal role in diabetic cardiomyopathy through insulin receptor substrate 1 (IRS‐1) inactivation. These findings of the FoxO‐mediated vicious cycle of insulin resistance provide new insights into the pathogenesis of diabetic cardiomyopathy and other diabetic complications.

Battiprolu et al.3 initially examined two different experimental models of type 2 diabetes, leptin receptor deficient db/db mice and high‐fat diet‐induced obese mice, and observed functional and morphological myocardial changes resembling diabetic cardiomyopathy in these models. As expected, they confirmed increased FoxO activity, in terms of decreased phosphorylation of FoxO proteins, increased nuclear localization and increased levels of FoxO's target genes. Furthermore, myocardium‐specific FoxO1 knock‐out (KO) mice were resistant to high‐fat diet‐induced cardiac hypertrophy and dysfunction.

Lipid accumulation, as a result of increased lipid uptake relative to utilization, is a major preceding feature of diabetic cardiomyopathy. Relative to wild‐type mice, FoxO1 KO mice showed lower lipid accumulation in the myocardium under a high‐fat diet by shifting their metabolic substrate usage from FA to glucose3. High‐fat diet‐induced abnormal gene expression patterns in glycolytic genes (decreased hexokinase 1 and glucose transporter 4 [GLUT‐4]) and lipid oxidative genes (decreased PGC‐1α and increased pyruvate dehydrogenase kinase 4 [PDK4]) were abrogated by FoxO1 depletion. In addition, FoxO1 KO tended to cancel the increased gene expression of CD36, a key FA transporter in cardiomyocytes, under a high‐fat diet. Puthanveetil et al.5 also showed that palmitate‐induced FoxO1 activation accel‐erates triacylglycerol accumulation in primary cardiomyocytes, accompanied by CD36 translocation to the plasma membrane with neither messenger ribonuclic acid (mRNA) nor protein augmentation. Further research in the intracellular localization of CD36 in FoxO1 KO cardiomyocytes is therefore of particular interest. Furthermore, IRS‐1 inactivation through FoxO1 might not only extend their preceding work in the link between FoxO1 and myocardial insulin resistance, but also elucidate the roles of FoxO1 in lipid accumulation and consequent lipotoxicity (Figure 1).

Figure 1

Possible pathogenesis for diabetic cardiomyopathy through forkhead box protein O1 (FoxO1). IRS‐1, insulin receptor substrate 1.

In this detailed in vivo study, FoxO1 was singled out as an important player in the myocardial metabolic disturbances in diabetic cardiomyopathy. However, as aforementioned, the pathogenesis of diabetic cardiomyopathy would be composed of a number of factors. A multimodal therapeutic approach should therefore be required for the prevention and control of diabetic cardiomyopathy. In addition to the molecular mechanism of FoxO1 underlying diabetic cardiomyopathy, an improved survival rate shown in the FoxO1 KO mice under a high‐fat diet is also of great interest. It implies that cardiac FoxO1 targeting therapy might reduce heart failure mortality in patients with type 2 diabetes.

What is an initial step for myocardial persistent FoxO1 activation in diabetes; systemic insulin resistance, elevated serum FAs, inflammatory cytokines or hyperglycemia per se? As well as insulin resistance, insulin deficiency is another important feature of diabetes, and cardiomyopathy is also found in type 1 diabetes, so another question is whether FoxO1 in cardiomyocytes plays identical roles in non‐obese insulin‐deficient diabetes. In addition, cardiomyopathy is not always observed in all patients with diabetes. FoxO1 function (e.g. differences in activity owing to its genetic polymorphism) might explain individual susceptibility for diabetic cardiomyopathy.

Taken together, the work by Hill et al.3 could be a clinical milestone for elucidating the pathogenesis of diabetic cardiomyopathy, as well as other diabetic complications. Further research in the roles of FoxO1 might relieve the heartbreak of patients with diabetes.