Metabolic dysregulation and chronic inflammation in T2D

A number of theories have been proposed to explain the pathophysiology of the metabolic dysregulation, insulin resistance and development of endothelial dysfunction in adults with T2D and obesity.²⁰ A chronic inflammatory state is induced by mitochondrial dysfunction and driven by chronic excess of nutrients, in particular the free fatty acids.^21–23 Mitochondrial nutrient overload results in metabolic shifts towards generation of reactive oxygen species (ROS), which activate endothelial cytokine production, leading to direct endothelial damage and alterations of insulin signalling.²⁴ This theory is based on the observation of higher and persistently elevated baseline levels of proinflammatory cytokines in obese individuals with T2D and insulin resistance as compared with lean controls.^25–31 Furthermore, endothelial inflammation exerts pro-atherogenic effects, further compounding the cardiovascular risk in this cohort.^22,32 In addition to promoting fatty streak deposition within the arterial wall, mitochondrial ROS results in reduced bioavailability of nitric oxide, which is essential to normal vascular homeostasis.²⁶ The resultant impaired endothelial vasomotor mechanics are the hallmark of endothelial dysfunction and a key mechanism behind microvascular dysfunction, which is responsible for a range of the pathological sequelae of T2D, including left ventricular (LV) diastolic dysfunction.^32–36 ROS toxicity leads to diastolic dysfunction by two mechanisms: first, ROS-mediated cardiomyocyte damage results in inflammation, apoptosis and fibrosis, directly contributing to LV diastolic dysfunction through remodeling,²² and second, ROS interact with endoplasmic reticulum, altering its structure and function primarily by altering the activity of the sarcoplasmic reticulum calcium pump, which is responsible for calcium sequestration during cardiomyocyte relaxation, thus leading to diastolic dysfunction.³⁷ However, a recent systematic review of 11 studies did not show an association between exercise and reduced levels of inflammatory markers in adults with T2D.³⁸

The volume and type of adipose tissue seems to have a significant effect on the propagation of the proinflammatory response. Brown adipose tissue and white adipose tissue play specific roles in energy metabolism and insulin homeostasis.³⁹ Brown adipose tissue has an important role in regulating energy and glucose homeostasis, and has been associated with peripheral insulin resistance and glucose levels.⁴⁰ Visceral white adipose tissue (around the trunk, upper body or abdomen) appears to be the major source of inflammatory markers in T2D, responsible for the production of inflammatory cytokines, thus contributing to the systemic inflammation and insulin resistance.⁴⁰ Although insulin resistance has been associated with reduced VO_2peak, this association has been described mainly from univariate analyses of small sample subjects with a risk of significantly overfitting the regression models.⁴¹ Although some older studies have shown association between glycaemic control (expressed as HbA1c) and exercise capacity,⁴² newer studies have not confirmed this association.²² Strict glycaemic control alone has not been shown to improve cardiovascular outcomes in patients with T2D.⁴²

Changes within the systemic micro- and macro-vasculature play an important role in maintaining exercise capacity. In a study of 134 asymptomatic adults with T2D, reduced capillary blood flow to skeletal muscle was found and was positively correlated with VO_2peak independent of mean arterial pressure and cardiac output.¹⁵ This association was driven by capillary blood velocity reserve rather than capillary blood volume reserve, suggesting impaired endothelial vasomotive response to exercise.¹³ Furthermore, the association of capillary blood flow with VO_2peak was independent of mean arterial pressure, cardiac output reserve and other cardiac covariates, suggesting that pre-capillary factors, particularly endothelium-mediated vasodilation, may be responsible.¹³ In another study, which compared 20 uncomplicated T2Ds with 20 T2Ds with microvascular complications, the latter group had abnormal skeletal muscle capillary responses to periodic contractile exercise,⁴³ thus reflecting an underlying abnormality in microvascular recruitment.²⁰ These findings again implicate endothelium-mediated vasodilation, which is responsible for exercise hyperaemia and known to be impaired in diabetes.¹⁷ Insulin increases limb blood flow in a dose dependent fashion; however, this mechanism is ineffective in the presence of insulin resistance and is compounded by reduced local availability of nitric oxide, as present in microvascular dysfunction.¹¹

The pathophysiological mechanisms leading to development of diabetic cardiomyopathy

The pathological myocardial alterations characteristic of diabetic cardiomyopathy begin early in the course of T2D and are present in otherwise asymptomatic individuals, suggesting a latent phase of cardiovascular dysfunction.³ Cardiac dysfunction in diabetes is thought to lie on a continuum ranging from asymptomatic diastolic dysfunction though subclinical systolic dysfunction and then overt HF.⁵⁵ Reduction in exercise tolerance is amongst the first marker of stage B HF (defined as structural or functional LV alterations in the absence of symptoms) in diabetic cardiomyopathy and a 10% reduction in an individual’s exercise tolerance in the presence of detectable cardiomyopathic changes would automatically class them as stage-II HF by the New York Heart Association (NYHA).⁵⁶ Figure 2 summarizes the stages of progression of diabetic cardiomyopathy, based on the presence of cardiomyopathic changes and symptomatology, with reference to the American College of Cardiology/American Heart Association (ACC/AHA) and NYHA HF classification scores, and Table 2 summarizes cardiac predictors of reduced exercise capacity.

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Figure 2.

Pathological alterations leading to diabetic cardiomyopathy in relation to stages of progression of heart failure.

ACC/AHA, American College of Cardiology/American Heart Association; HF, heart failure; LA, left atrium; LV, left ventricular; NYHA, New York Heart Association; T2D, type 2 diabetes mellitus.

Table 2.

Cardiac predictors of exercise capacity in T2D.

Author	T2D group(s)	Inclusion/exclusion criteria	Method of assessment	Predictors of ↓ VO2peak	Comments
Gulsin et al.47	N=247 T2D age 51.8±11.9years, 55% M, HbA1c 7.4±1.1%	Incl.: T2D, asymptomatic	CMR for MPR	MPR (β=0.822, p=0.006) and E/e′ (β=–0.388, p=0.001) were independently associated with VO2peak in subjects with T2D	In subjects with T2D, significant correlations were observed between VO2peak and age, T2D duration, BP, absolute and indexed LV volumes, LV EF, LV mass, LV GLS, average E/e′ and MPR
		Excl.: T1D, IHD, HF, CKD	TTE for E/e′
			CPET for VO2peak
Vukomanovic et al.48	N=70 T2D, uncomplicated, age 52±7years, 56% M, HbA1c 7.5±1.2 Controls	Incl.: T2D	CPET for VO2peak	GLS (−21.6±2.8 versus -18.4±2.3%, p<0.001) and circumferential strain (−22.0±2.9 versus −19.5±2.6%, p<0.001) were reduced in T2D versus controls. VO2peak significantly lower in T2D (27.0±4.3 versus 20.7±4.0mL/kg per min, p<0.001).	Age and sex were not forced into the regression model. Furthermore, regression was calculated combined with controls
		Excl.: HTN, HF, CAD	Echo for GLS and GCS
Kosmala et al.49	N=510 (292 T2D)	Incl.: asymptomatic patients with T2D, HTN and BMI30 kg/m2	Diastolic dysfunction (E/e′ >13) or strain>18%	↓VO2peak associated with LV strain and presence of LVH (p<0.001),	↓VO2peak correlated with ↑components of abnormal values; however, not adjusted for age or sex
	Stage A HF: T2D (n=186, 70%), HbA1c 7±1.6%, log HOMA-IR 0.41±0.36
				Multivariate: presence of stage B HF independently associated with ↓VO2peak. Stage B HF (>1 imaging variable present) associated with lower VO2peak (beta ¼ 0.20; p<0.0001) and METs (beta ¼ 0.21; p<0.0001
		Excl.: complications of T2D, IHD	CPET for VO2peak
	Stage B HF: T2D (N=106, 44%) HbA1c (7±1.4%), log HOMA-IR 0.47±0.27
Fang et al.44	N=170, 53% M, age 56±10years	Incl.: T2D	Abnormal EC defined as: METs=18×0.15×age Abnormal HRR: 18 beats.min−1, echo: strain, Em	Univariate: ↓EC associated with ↓diastolic function.↑ EC: males (r=0.26, p<0.001), preserved Em (r=0.43, p<0.001) and preserved HRR (r=0.42, p<0.001).	NS correlation in univariate analysis between METs, LV EF, insulin or cardiovascular drugs
		Excl.: LV EF <50%, IHD

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BMI, body mass index; BP, blood pressure; CAD, coronary artery disease; CKD, chronic kidney disease; CMR, cardiac magnetic resonance; CPET, cardiopulmonary exercise test; EC, exercise capacity; E/E′, ratio of early mitral inflow velocity and mitral annular early diastolic velocity; EF, ejection fraction; Em, early mitral inflow velocity; GCS, global circumferential strain; GLS, global longitudinal strain; HF, heart failure; HOMA-IR, homeostatic model assessment of insulin resistance; HRR, heart rate recovery; HTN, hypertension; IHD, ischaemic heart disease; LV, left ventricle; LVH, left ventricular hypertrophy; M, male; MET, metabolic equivalent of task; MPR, myocardial perfusion reserve; T1D, type 1 diabetes; T2D, type 2 diabetes; TTE, transthoracic echocardiography; VO_2peak, peak oxygen consumption.

The pathogenesis of diabetic cardiomyopathy is complex and incompletely understood.³ Myocardial steatosis, altered myocardial energetics, and impaired calcium handling have all been implicated. In vivo studies have confirmed elevated myocardial triglyceride content in T2D^57,58 and myocardial steatosis has been linked to both diastolic and systolic strain,⁵⁹ linking steatosis with development of cardiac dysfunction. Myocardial energy metabolism (as assessed by the myocardial Creatinine phosphate/ATP ratio) is reduced in T2D and this is exacerbated by exercise.⁶⁰ Abnormalities of myocardial calcium handling via impairments in the sarcoplasmic reticulum Ca²⁺ ATPase (SERCA) have been implicated in HF, but not in T2D. SERCA2a activity declines in late stage HF⁶¹ and decreased levels of SERCA2a have been found in cardiac tissues isolated from humans and animals with HF.⁶² Importantly, low SERCA2 levels have been correlated to poor clinical outcomes.^62,63 Therapeutic approaches aiming to boost the myocardial SERCA2a levels have produced disappointing results.^61,64 No studies, however, have directly evaluated links between myocardial steatosis, calcium handling, or energetics and impaired aerobic exercise capacity.

The predominant HF phenotype in people with T2D is HFpEF, which accounts for up to 83% of newly diagnosed cases of HF.⁶⁵ In two contemporary large-scale HF trials of angiotensin-neprilysin inhibitor sacubitril-valsartan – PARAGON-HF⁵² and PARADIGM-HF⁵ – prevalence of diabetes was 44% and 35%, respectively, and in our own HFpEF cohort 54% of 140 patients had T2D.⁶⁶ People with T2D appear to be particularly prone to development of diastolic LV impairment, although systolic LV impairment often co-exists. A significant proportion of patients with diastolic impairment are asymptomatic, which poses a clinical challenge as diastolic dysfunction even in isolation is associated with poor outcomes.^3,67 Over the past three decades, the rapid evolution of advanced non-invasive cardiac imaging techniques has enabled detailed evaluation of cardiovascular structure and function in vivo. Application of these techniques has provided key insights to the relationship between cardiovascular function and exercise capacity in T2D, shedding light on early perturbations that may lead to HF (Table 2).

Weight loss and exercise

Weight loss confers a number of clinically important benefits in patients with T2D.

Weight loss achieved through bariatric surgery^97,98 or low-calorie meal replacement diet⁵⁸ results in remission to a non-diabetic state, with a strong correlation between the extent of weight loss and reversal of T2D. However, the same effects are not seen in more advanced T2D (defined by insulin therapy) or with longer disease duration.^58,97,98 Sustained weight loss also confers direct beneficial cardiovascular effects in obese adults without T2D, with reductions in LV mass, volumes, arterial stiffness and diastolic function as measured by CMR.³ Improved diastolic function, energetics and reduced myocardial triglyceride content, which may confer benefit to exercise tolerance, have been reported in obese individuals following bariatric surgery-mediated weight loss.⁹⁹ Importantly, bariatric surgery can achieve sustained weight loss (in up to one-fifth of patients), sustained remission of diabetes (in up to one-third of patients) and lower rates of major adverse cardiovascular events (including HF) in people with T2D and obesity.

In addition to benefits on cardiac function, weight loss simply improves physical function in adults with T2D by reducing the biomechanical burden of moving around.⁴⁷ However, the cardiovascular benefits of weight loss alone do not directly translate to significant improvements in objective measures of aerobic exercise capacity. In fact, a number of studies have reported reduced strength and VO_2max in individuals exposed to caloric restriction alone.⁴⁷ In a study of 52 obese individuals, daily calorific reduction of 20% mediated weight loss of approximately 7% of body mass over a 12 week period and corresponded to an approximately 6% reduction in absolute VO_2max, an effect that was attenuated by exercise.^99–101 Conversely, exercise alone resulted in 15% improvement in the VO_2max, even in the absence of weight loss. The combination of modest exercise (4.4±0.5h/week) and 20% calorific reduction attenuated the reduction in lean mass and aerobic capacity that occurred with calorific reduction alone. Weight loss achieved through exercise confers the greatest benefits on preservation of lean mass and increase in VO_2max, but the required amount of exercise to cause weight loss is substantial (7.4±0.5h/week) and may be challenging to achieve in deconditioned, overweight individuals in the real world.¹⁰⁰

Our group has also assessed the impact of lifestyle interventions on cardiac function and exercise capacity in younger obese adults with T2D.¹⁰² We undertook a 12-week randomized trial comparing a supervised exercise programme or low energy meal replacement diet. A significant improvement in the primary outcome of diastolic function was observed in the exercise arm, despite only small reductions in weight, BMI and exercise capacity. By contrast, in the diet arm there was dramatic overall weight loss (median 13.6kg and fall in BMI of 4.8kg/m²) accompanied by a mean HbA1c decrease of 0.75%, with 83% of participants achieving T2D remission. However, only a small increase in VO_2peak when corrected for body weight (1.9mL/kg per min) was observed, but there was no change in absolute VO_2peak.¹⁰³ There were no significant improvements in myocardial perfusion or remodelling with exercise.¹⁰³ Although exercise has been found to improve endothelial function, it is possible that the small sample size and short duration (12weeks) of follow-up precluded these effects from fully manifesting in this study. The lack of improvement in VO_2peak may be explained by loss of lean tissue mass.¹⁰³ Even in obese individuals, weight loss resulting from calorific restriction results in loss of lean tissue as fat free mass in a 1:4 ratio with adipose tissue. The predominant site of reduction in lean body mass is the skeletal muscle, which when coupled with possible reductions in the functional capacity of the musculature with weight loss, limit the magnitude of benefits realized.¹⁰³