Cardiometabolic Risk Factors Associated With Type 2 Diabetes Mellitus: A Mechanistic Insight

Overview of cardiometabolic risk factor

Cardiometabolic risk factors are a group of condition that raises the possibility of metabolic diseases like T2DM and several CVD. The predominant cardiometabolic factors that enhance the probability of CVD occurrence include hypertension, dyslipidemia, obesity, IR, impaired glucose tolerance and unhealthy lifestyle. ⁷

A significant cardiometabolic risk factor, obesity is characterized by an excessive buildup of body fat. It is linked to IR, adipose tissue malfunction, and a chronic low-grade inflammatory state by releasing several pro-inflammatory cytokines that majorly includes tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), IL-12, IL-1b, Elastases, cathepsin G, and Proteinase-3. ⁸ Another significant component of cardiometabolic risk is IR that alludes to decreased cellular receptivity to insulin’s effects impairing glucose uptake and utilization along with promoting hyperuricemia, hypertension, elevated serum inflammatory markers and also develops a prothombic state. Genetic predispositions, obesity, lack of exercise, and persistent inflammation can all have an impact on IR. ⁹ As a result, there is compensatory hyperinsulinemia, which worsens the deregulation of lipid metabolism and encourages the growth of atherosclerosis. In dyslipidemia, the bloodstream’s lipid (cholesterol and triglyceride) levels are abnormal. ¹⁰ Atherosclerosis, which is characterized by the buildup of plaque in the artery walls, is a condition made worse by dyslipidemia. Atherosclerotic plaques can develop as a result of deposition of cholesterol in the artery intima causing inflammation and impaired blood flow. ¹¹ High blood pressure also known as hypertension is a significant CVD risk factor. Increased peripheral vascular resistance, suboptimal endothelial function and anomalies in the Renin-Angiotensin-Aldosterone System (RAAS) are a few of the processes that it may be brought on by hypertension. Hypertension also encourages vascular damage, speeds up atherosclerosis, and puts more strain on the heart, which all help to cause heart disease. ¹² Cardiometabolic risk factors frequently overlap and influence the onset and course of metabolic and CVDs synergistically. A nutritious diet, frequent exercise, and weight control are all essential lifestyle changes that can significantly lower these risk factors.

Understanding diabetes

T2DM involves 2 factors: malfunction in insulin secretion by pancreatic β cells and impaired insulin sensitivity thereby failing to cope up with metabolic necessities. ¹³ T2DM is a complex amalgamation of genetic, metabolic and environmental risk factors that contributes to the prevalence of the disease. Under healthy physiological state, insulin produced by β-cell is triggered to be released once the blood glucose level is abnormally high. The adenosine triphosphate (ATP) dependent potassium channel and cyclic adenosine monophosphate (cAMP) that balance the intracellular calcium ion (Ca²⁺) concentration induce insulin secretion.^14,15 Several mechanisms have been reveals that are responsible for the dysfunction of pancreatic β cells, thus impairs insulin^16,17

Adipose tissue alterations that occur with obesity lead to an increase in the release of free fatty acids into the circulation. The insulin signaling in muscle and liver cells can be disrupted by these raised amounts of FFA, which can result in decreased glucose uptake and increased gluconeogenesis. ¹⁸ Anomalies in the insulin receptors themselves can lead to IR as well. These receptors are surface-addressed proteins that bind to insulin to start the signaling chain that leads to glucose absorption. Cells may occasionally become less sensitive to insulin if there are fewer insulin receptors or changes to their structure or function. ¹⁹ Numerous intracellular signaling pathways are used by insulin to affect target cells. The phosphoinositide 3-kinase (PI3K)/Akt pathway is one significant route. Defects in this pathway can happen at a number of different levels in IR. Impairment of PI3K activation, lower Akt activity, and disruptions in insulin receptor substrate (IRS) phosphorylation can all result in impaired insulin signaling and IR. Reduced glucose transporter protein type 4 (GLUT4) translocation to the cell membrane is another common cause of IR. In reaction to insulin, GLUT4 promotes glucose uptake into cells. This translocation process can be interfered with by impaired insulin signaling, which lowers the efficiency of glucose uptake by cells, notably muscle and adipose cells.^20,21 Blood glucose levels are maintained in part by the liver. The liver promotes gluconeogenesis in T2DM, raising blood sugar levels. Under normal physiologic condition insulin inhibits gluconeogenesis, but during IR gluconeogenesis is boosted in liver. ²²

Also the phenomenon of fatty pancreas, characterized by the accumulation of excess fat within the pancreatic tissue, has emerged as a significant player in the realm of insulin resistance and T2DM pathogenesis that not only mirrors peripheral insulin resistance but also contributes to a unique aspect of the disease. A key concept in understanding this intricate relationship is the twin-cycle hypothesis according to which, excess free fatty acids in the bloodstream resulting from obesity and poor dietary choices, lead to both peripheral insulin resistance and an increased influx of fatty acids into the liver. Within the liver, these fatty acids are metabolized, generating lipid metabolites and promoting hepatic insulin resistance. Simultaneously, these lipid metabolites find their way back to the pancreas interfering with the normal βcell function, impairing insulin secretion. This dual hit insulin resistance in peripheral tissues and impaired insulin secretion due to fatty infiltration in the pancreas creates a vicious cycle, further exacerbating the progression of T2DM. Understanding this twin-cycle hypothesis sheds light on the intricate relationship between fatty pancreas and insulin resistance, offering valuable insights for targeted interventions aimed at breaking this detrimental cycle and managing T2DM more effectively. ²³

Lipid abnormalities in diabetes

Even before the clinical diagnosis of T2DM, hypertriglyceridemia, low HDL-C, and elevated small dense LDL can be found in insulin-resistant, prediabetic people with acceptable glucose levels, so hyperglycemia cannot entirely account for the lipid alteration. Although the main cause of diabetic dyslipidemia is IR. ⁵¹ A key factor in determining the distinctive lipid profile of diabetic dyslipidemia is hypertriglyceridemia, which is regarded as the predominant lipid abnormality in insulin resistant individual. Increased synthesis and poor clearance of triglyceride-rich lipoproteins in both fasting and non-fasting stages lead to elevated triglyceride levels. IR involves an increased synthesis of very low-density lipoprotein cholesterol (VLDL-C), the primary carrier of fasting triglycerides. ⁵² VLDL-C can be divided into large, triglyceride-rich VLDL1 and small, dense VLDL2. VLDL 1 is reported to have greater triglyceride amount and has been found to be a significant predictor of plasma triglyceride levels as well as associated with insulin sensitivity. IR which is a key characteristic of T2DM, leads to dyslipidemia by several mechanisms. Insulin’s capacity to inhibit lipolysis is impaired by IR, increasing the release of FFA into the bloodstream, which in turn cause excessive production of VLDL-C by liver and carry triglycerides to the tissues in the periphery. As a result, this raises the amount of triglycerides in the blood.^50,52,53 Hypertriglyceridemia is a result of both an increase in VLDL-C synthesis as well as their reduced clearance rate that is linked to postprandial triglyceride-rich chylomicrons, decreased hepatic uptake of VLDL-C, and impaired lipoprotein lipase activity. ⁵⁴

Small, dense LDL becomes increasingly prevalent in T2DM patients and is more atherogenic than bigger LDL particles with a higher propensity to pierce the artery wall and is more vulnerable to oxidation, leading to the development of atherosclerotic plaques. Furthermore, the elevated cholesterol ester transfer protein (CETP) activity in hypertriglyceridemic patients facilitates the exchange of triglycerides from VLDL and LDL particles for cholesterol esters from HDL particles causing them to become enriched with triglycerides and depleted of cholesterol. As a result, these HDL particles become less effective at removing cholesterol from the bloodstream and also get more susceptible to degradation and clearance from the bloodstream. Consequently, the overall functionality of HDL particles is compromised, leading to lower levels of functional HDL cholesterol in T2DM patients. ⁵⁵ Chronic low-grade inflammation also leads to aberrant lipid levels is a hallmark of T2DM. People with T2DM have higher levels of inflammatory mediators like CRP, IL-6, and TNF-α which worsens IR and encourages the development of hepatic VLDL particles resulting in dyslipidemia.^56,57

Risk of CVD in diabetic dyslipidemia

Dyslipidemia is reported to elevate the risk of CVD in T2DM patients. Not only Hypertriglyceridemia, low HDL-C and elevated small dense LDL-C concentrations associate themselves in enhancing CVD risk. In comparison with non-diabetic people, T2DM patients might not show an elevated LDL-C concentration but have significantly greater number of small dense LDL particles, signifying the presence of greater atherogenic risk factor. ⁵⁸ Even when LDL-C levels are below 130 mg/dl, the limit set by the National Cholesterol Education Program, LDL-C is still considered a potent independent predictor of CVD in T2DM. According to the Strong Heart Study, every 10 mg/dl rise in LDL-C was associated with a 12% increase in the risk of CVD in diabetes participants.^59,60

As discussed earlier, atherosclerosis is most primary factor for the rise of any CVD that includes CAD, PAD and stroke. Dyslipidemia in T2DM promotes the development and progression of atherosclerosis by forming atherosclerotic plaques when levels of LDL-C, especially small dense LDL particles are elevated. ⁶¹ These small LDL-C particles can easily pass through the artery wall and are particularly susceptible to oxidation, encouraging the build up of cholesterol, inflammatory cells, and smooth muscle cells once penetrate the artery wall resulting in the development of fatty streaks followed by fibrous plaques. These plaques may rupture, developing blood clots that can result in MI or stroke. ⁶² Epidemiological and clinical research reports an inverse relationship between HDL-C concentration and CVD and considers HDL-C as the “good” lipoprotein due to its antiatherogenic function of reverse cholesterol transport as well as its cardioprotective functions that includes anti-inflammatory, anti-oxidative and endothelium-dependent vasodilatory effects and dyslipidemia is characterized with decreased HDL-C level.^63,64 Endothelial function is also hampered by elevated LDL-C and other lipid abnormalities that encourage oxidative stress and inflammation in the arterial wall. The production of NO, a vasodialator is reduced in endothelial dysfunction, whereas the production of endothelin-1, a vasoconstrictor is enhanced thus unbalancing vascular tonicity.^65,66 Additionally, dyslipidemia also affects the body’s fibrinolytic and anticoagulant mechanisms, which increase the probability of thrombus formation and makes blood clot dissolution less effective. ⁶⁷ Figure 1 summarize the pathway depicting association between CVD and diabetic dyslipidemia. Alterations in lifestyle are essential for minimizing CVD risk and rebalancing lipid profiles that includes adhering to a healthy diet with diminished cholesterol, processed carbohydrates and saturated trans fats maintaining the body weight. ⁶⁸ Improvement in insulin sensitivity, glycemic management, and lipid profile are linked to moderate weight loss (5% of body weight) and reportedly increase HDL-C and lowers triglyceride levels. Fruits, vegetables, whole grains, lean meats, and healthy fats are encouraged to be consumed along with regular exercise, such as strength training and aerobic workouts that improves insulin sensitivity, lowers triglyceride levels and elevates HDL-C level. ⁶⁹

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Figure 1.

Summarized pathway representing the manifestation of cardiovascular disorder due to dyslipidemia in patients with T2DM. Abbreviations: FFA, free fatty acid; HDL, high density lipoprotein; HL, hepatic lipoprotein; IL, interleukin; LDL, low density lipoprotein; LDL-C, low density lipoprotein cholesterol; NO, nitric oxide; Sd-LDL, small dense low density lipoprotein; TG/TGA, triglyceride; TNF-α, tumor necrosis factor-α; VLDL, very-low density lipoprotein.

Hypertension and diabetes

Hypertension impacted by a number of dysregulated physiological systems that elevates cardiac output and blood volume resulting in elevated blood pressure. T2DM is linked to a number of metabolic abnormalities, including IR, hyperglycemia, and dyslipidemia, which cause hypertension and in turn manifests CVD. ⁷² Diabetes-related metabolic complications, vascular disorder, and hormonal disorders interact intricately and elevates the blood pressure. ⁷³ IR acts as a major factor in the emergence of hypertension by an array of interconnected mechanisms. Increased activity in the sympathetic nervous system is related to IR which arises because of defective insulin signaling to the regions of the brain that control sympathetic outflow. Also RAAS that controls and maintain electrolyte homeostasis, fluid balance, and blood pressure is compromised in faulty insulin signaling. ⁷⁴

In insulin resistant condition, renin release from kidney is stimulated increasing the conversion of angiotensinogen into angiotensin I. Angiotensin-converting enzyme (ACE), abundantly present in lungs and blood vessels further converts angiotensin I into angiotensin II. As a powerful vasoconstrictor, angiotensin II induces blood vessel constriction and develop peripheral resistance, thus bringing up resistance in blood flow and elevating blood pressure.^75,76 Further the secretion of aldosterone from the adrenal glands is also stimulated by angiotensin II that induces retention of both sodium and water expanding blood volume as a result blood pressure is raised. Angiotensin II also stimulate the sympathetic nervous system increasing the sympathetic activity which leads to excessive release of norepinephrine, enhancing vasoconstriction, and again elevates blood pressure.^77,78 Adipokines, the bioactive chemicals by adipose tissue is unbalanced in IR and with increased pro-inflammatory adipokine and decreased anti-inflammatory adipokine production along with other hormonal changes, development of hypertension is manifested. Adiponectin is an adipokine with anti-inflammatory and insulin-sensitizing properties. Insulin resistant individuals frequently reports decreased adiponectin level which is associated with increased inflammation, poor vasodilation, and endothelial dysfunction, triggering hypertension.^79,80 Another adipokine that affects appetite control and energy balance is leptin that is frequently elevated in obese and insulin resistant individual because of increased adipose tissue mass. Leptin levels when excessively elevated stimulates sympathetic nervous system, constricting blood vessels and elevates blood pressure. ⁸¹ Typically IR is associated with chronic low-grade inflammation in the body and inflammatory substances elevate vasoconstriction and impair blood vessel function, contributing to hypertension. ¹² In normal physiological condition insulin increases endothelial NO synthesis but in IR the production of NO is downregulated leading to vasoconstriction and elevated blood pressure that ultimately contributes to the development of endothelial dysfunction. ⁸² T2DM is associated with increased sodium retention by the kidneys into the bloodstream which occurs due to insulin’s diminished effect on kidney’s renal tubules. As reabsorption of water increases along with sodium chloride, the blood volume expands and blood pressure elevates. Further T2DM includes hormonal imbalances, such as increased levels of insulin, cortisol (a stress hormone), and aldosterone which is studied to exert direct effects on blood pressure regulation by causing electrolyte imbalance in body.^83,84 The sodium-potassium pump, a crucial mechanism for preserving cellular electrolyte balance, is activated by insulin. This pump’s function is compromised by IR causing intracellular sodium buildup and extracellular potassium depletion that triggers vasoconstriction, higher blood pressure and increased arterial stiffness ultimately triggering CVD. ⁸⁵

Cardiovascular consequence of hypertension in diabetes

T2DM is the most common cause of end-stage renal disease, blindness, and nontraumatic amputations and is linked to several cardiovascular complications. Glycemia is the constant variable that serves as a cardiovascular risk factor and hypertension alone is a significant risk factor for cardiovascular morbidity and mortality and their coexistence in the same patient is detrimental. ⁸⁶ Figure 2 summarize the overall impact and physiology of hypertension on the development of cardiovascular complication in presence of IR.

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Figure 2.

Crossover pathways in hypertension and IR that lead to the development of CVD. Abbreviations: ANG-I, Angiotensin-I; ANG-II, Angiotensin-II; H₂O, water; IR, insulin resistance; Na+, sodium ion; NO, nitric oxide; T2DM, Type 2 diabetes mellitus.

Impact on the vascular tree

T2DM and hypertension are both recognized contributors for atherogenesis and damage the vascular tree through an array of underlying factors. Endothelial dysfunction, a crucial early stage in the emergence of vascular problems in T2DM is exacerbated by hypertension. The endothelial cells that lines the blood arteries are subjected to greater degree of mechanical stress due to elevated blood pressure and compromise its capacity to control vascular tone, inflammation, and clotting factors, interfering with its standard functionality. ⁸⁷ Hyperglycemia, a hallmark of T2DM generates ROS in excess that also damages the vascular tonicity of endothelial lining. Also oxidative stress produce AGEs which contribute to endothelial dysfunction and vascular damage in diabetes.^88,89 The reduced availability of NO in endothelium in diabetic hypertensive condition is mediated by several factors. As was already established, elevated oxidative stress can inactivate NO by directly scavenging it. Furthermore, eNOS, the enzyme that produces NO is also impaired by high glucose levels. Vasoconstriction and endothelial dysfunction are caused by a combination of decreased production and increased degradation of NO ultimately enhancing peripheral resistance of the blood vessel and act as a contributing factor for atherosclerosis. ⁹⁰ In diabetic hypertension the endothelial barrier breaks down increasing the permeability. Because of the malfunctioned endothelial cells, plasma proteins and lipids, particularly LDL-C leaks into the blood vessel, accumulating plaque for arthrosclerosis development. ⁹¹ In hypertension the endothelial cells are stimulated to produce endothelin-1 (ET-1), a strong vasoconstrictor, which tightens blood vessels and increases vascular resistance and excessive rise in blood pressure leads to vascular complications. ⁹²

LDL-C and other circulating lipids that are drawn to the damaged endothelium builds up and undergoes oxidation within the artery wall, causing an inflammatory reaction and draws immune cells to the area notably macrophages and which releases pro-inflammatory cytokines. The formation of atherosclerotic plaque in the artery is brought on by the lipid engulfment of the macrophages, forming foam cell.^93,94 The earliest detectable stage of atherosclerosis is a fatty stripe formed by inflammatory cells and lipid-filled foam cells over which a fibrous covering eventually forms as the fatty streak develops into an atheromatous plaque, a more complicated lesion. The unstable plaque with a thick lipid core and a thin fibrous cap is more likely to break and on rupture the highly thrombogenic components of the plaque, such as tissue factor and collagen, are made available to the bloodstream and platelets cling to the area formation blood clot, thereby obstructing the blood vessel that leads to ischemic events.^95,96 Furthermore, heart muscle cells enlarges due to the increased stain on the artery walls and deposition of extracellular protein on leading to remodeling and hypertrophy of the bigger arteries in diabetic hypertension. The arterial stiffness, decreased compliance, and compromised vasodilation that follow these anatomical alterations elevates blood pressure and raise stress on heart. ⁹⁷

Impact on the heart

As the atherosclerotic plaque developed within the artery wall ruptures that initiates a process of thrombus formation that block the coronary artery, decreasing blood flow to the heart muscle. Ischemia is the result of the narrowing or blockade of the heart arteries and if the blood flow is not quickly restored, it can result in symptoms like angina or more serious problems like MI. ⁹⁸ The heart must work harder to pump blood against more resistance which result in chronic hypertension and develop hypertrophy of its muscular walls. The heart’s ability to pump blood decline with time resulting in heart failure or arrhythmias.^99,100

Anomalies in the microcirculation are responsible for the severe degenerative alterations in the diabetic hypertensive heart. ¹⁰¹ Nonhemodynamic factors such as sodium intake, activity of growth-promoting hormones, activity of the sympathetic nervous system, RAAS, whole-blood viscosity glucose levels, and genetics contribute to the development of left ventricular hypertrophy that explains hypertensive cardiomyopathy in diabetic hypertension.^102,103 The widespread presence of extensive interstitial connective tissue throughout the myocardium appears to be one of the most noticeable microscopic learning of the hypertensive diabetic heart. Clinical research using echocardiography also revealed that patients with diabetes and hypertension had an enlarged left ventricular mass.^104,105 While nondiabetic hypertensive patients with comparable levels of hypertension only had a lower prevalence of left ventricular hypertrophy than hypertensive T2DM patients that partially clarify why T2DM patients have higher rates of morbidity and mortality. ¹⁰⁶

Diabetes and obesity

As a significant contributor to IR, obesity raises plasma FFA levels over time, both in the basal state and after a glucose load. Central-abdominal fat has a higher level of metabolic and lipolytic activity, which results in a greater release of FFAs into the bloodstream. Whole-body IR was seen in clinical tests in healthy participants with acutely elevated plasma FFA levels. ¹⁰⁸ Increased plasma FFAs impede glucose metabolism at the level of substrate competition, intermediates accumulation, enzyme regulation, intracellular signaling, and/or gene transcription by mass action to increase their cellular absorption and stimulate mitochondrial –oxidation. ¹⁰⁹ As observed by the rise in lipid oxidation, the predominance of lipid utilization at the expense of glucose causes skeletal muscle to absorb less glucose and produce less glycogen at a slower rate. This chronic hyperglycemia (glucotoxicity) condition reduces insulin sensitivity substantially. ¹¹⁰ AGEs are produced as a result of the pathological glycation of circulating proteins and compensatory hyperinsulinemia carried on by IR and glucose intolerance resulting in pancreatic beta cell secretory failure are the consequences of this process in the final stages. ¹¹¹ In addition to the liver, skeletal muscle, and pancreatic cells, which under normal circumstances do not store lipids, fat storage occurs inside and around these organs when the diet-derived fat intake is increased that ultimately leads to an excessive generation in the mitochondria of hazardous reactive lipid species that harm specific organs through oxidative stress and cellular malfunction, eventually developing into IR, poor glucose tolerance and T2DM. ¹¹² An increasing amount of research points to the pathophysiology of diabetes in obese patients being affected by chronic low-grade inflammation in adipose tissue. ¹¹³ Through Lipopolysaccharide (LPS)-related endotoxemia that affects gut microbiota, obesity causes inflammation. An upsurge in T-lymphocytes and M1 macrophages along with enhanced production of proinflammatory cytokines induce inflamation and contribute to the development of IR. Additionally, inflammatory signals linked to obesity impair endoplasmic reticulum performance and significantly activate JNK, specifically the JNK1 isoform in insulin-sensitive organs like the liver and fat which functions by serine phosphorylation of the insulin receptor substrate-1 and subsequent suppression of insulin action.^114,115

Cardiovascular consequences of obesity in T2DM

Hyperglycemia is brought on by poor glucose cellular uptake due to IR, where the formed AGEs rupture blood vessels and impair their function. Furthermore, increased plasma levels of FFAs in obese people aggravate IR and compromise glucose metabolism. ¹¹⁶ Low-grade inflammatory state developed in obesity is exacerbated in T2DM. Secretion of adipokines including leptin and resistin as well as pro-inflammatory cytokines encourage inflammation, promoting endothelial dysfunction. Also in obese T2DM condition elevated ROS weakens body’s antioxidant defense that induce oxidative damage to tissues, especially the vascular endothelium also contributing to endothelium dysfunction. ¹¹⁷ Endothelial dysfunction caused due to aforementioned condition induce hypertension and vascular injury as it decrease NO production, hence vascular tonicity disrupts. ¹¹⁸ Dyslipidemia in T2DM obese individual accelerates the development of atherosclerotic plaques within the arteries. These plaques may rupture or calcify over time, developing blood clots that partially or totally obstruct blood flow through the coronary arteries resulting in angina or MI. ¹¹⁹

Other than inflammatory cytokines, release of adipokine by adipose tissue in obese T2DM patient encourage sodium retention, vasoconstriction and enhance sympathetic nervous system activity that contribute to hypertension and systemic vascular resistance. ¹²⁰ Chronic inflammation, oxidative stress, and IR in obese T2DM patient damage the heart muscle hampering cardiovascular cellular ability to utilize glucose, resulting in fatigue. Pro-inflammatory cytokines and adipokines also promote structural and functional alterations in the heart by increasing ventricular stiffness and impaired diastolic function. Heart failure develops as a result of reduced cardiac contractility caused by these variables taken together. Obesity and diabetes accelerates the developmental procedure of atherosclerosis, which can alter the cerebral arteries and limit blood flow along with the development of prothrombic condition. Uncontrolled diabetes also causes small vessel disease, such as cerebral small vessel disease and microangiopathy, which raises the risk of an ischemic stroke.^121,122

Obese T2DM patients are more susceptible to CVD in which the heart undergoes structural and electrical remodeling. The normal electrical conduction is disrupted by the left ventricular hypertrophy, fibrosis, and dilatation that are linked to obesity. ¹²³ Ion channel function and cardiac electrical activity are also affected by IR and dyslipidemia leading to cardiac arrhythmia. Pro-inflammatory cytokines also promote fibrosis in the heart, creating arrhythmogenic substrate. Identifying important pathways and prospective targets for treatments is made easier by having a thorough understanding of the pathophysiology of each cardiovascular disease in diabetes obesity.^124,125 To slow the onset and progression of these cardiovascular problems, effective care should focus on managing diabetes, controlling obesity, managing hypertension, and addressing associated risk factors Figure 3 summarize the pathophysiology underlying the development of CVD in obese diabetic individuals.

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Figure 3.

Pathophysiology involved in the rise of CVD in obese diabetic individual. Abbreviations: AGE, advanced glycation end product; ANG-II, Angiotensin-II; FFA-Free fatty acid; IL6, interleukin6; ROS, Reactive Oxygen Species; TNF-α, tumor necrosis factor-α.

Diabetic nephropathy

The prime pathological alteration in DKD occurs in kidneys’ glomeruli, renal tubules, and interstitium. In DKD, the filtering units of the kidneys, glomeruli experience pathogenic alterations where the glomerular filtration rate (GFR) and renal blood flow initially rise. This hyperfiltration appears to be a compensatory reaction to the raised glucose levels and increased metabolic demands associated with T2DM. ¹²⁶ The glomeruli are under greater stress due to the elevated GFR and the glomerular filtration barrier becomes more permeable over time due hyperglycemia and GFR stress. Larger molecules, especially albumin leaks into urine due to this enhanced permeability causing albuminuria that is regarded as a glomerular filtration barrier degradation indicator and an early indicator of DKD.^127,128 The glomerular basement membrane thickens as a result of buildup of Collagen and other elements of the extracellular matrix resulting in reduction of glomeruli’s capacity for filtration. ¹²⁹

The accumulation of proteins, including type IV collagen develops Kimmelstiel-Wilson nodules and are the defining hallmark of advanced stage DKD. ¹³⁰ The renal tubules enlarge due to fluid buildup and atrophy characterized by the loss of tubular cells and renal function is further compromised. The renal vasculature is potentially impacted by diabetes where arterioles supplying the kidneys thickens and narrows causing arteriolar hyalinosis contributing to renal ischemia and further kidney tissue injury. ¹³¹ It’s significant to remember that DKD pathophysiology is not exclusive to the kidneys. Organs and systems throughout the body are affected by diabetes and DKD, including Cardiovascular System. The development of hypertension, atherosclerosis and the increased risk of heart disease and stroke are all influenced by the pathophysiological alteration in the kidneys. ¹³²

Linking cardiovascular disease and diabetic nephropathy

Endothelial dysfunction is linked to both DKD and CVD and due to prolonged hyperglycemia and metabolic imbalances. AGEs are produced in excess in hyperglycemia and activation of protein kinase C pathway worsens NO bioavailability, exacerbate oxidative stress and inflammation and manifest vasoconstriction. Ineffective vasodilation, increased arterial permeability and prothrombotic condition are developed endothelial dysfunction, which leads to atherosclerosis. ¹³³ Due to the endothelial dysfunction in DKD, inflammatory cells including monocytes and lymphocytes are drawn to and adhere to the vascular endothelium. Secretion of adhesion molecules and chemokines by activated endothelium helps inflammatory cells move into the vessel wall and exude cytokines and growth factors encouraging development of extracellular matrix components and vascular smooth muscle cell proliferation. Atherosclerotic plaques develop as a result, narrowing the artery lumen, decreasing blood flow and consecutively raising the risk of CVD. ¹³⁴

In DKD renin is released in excess from the juxtaglomerular cells as a result of poor sodium excretion and volume enlargement caused by renal injury. Angiotensin II is produced when RAAS is activated by renin that induces vasoconstriction, aldosterone release and sympathetic nervous system stimulation. These processes increase blood pressure, sodium and water retention and systemic vascular resistance. A vicious loop between renal impairment and cardiovascular issues is created by hypertension, which worsens already existing kidney disease. In addition to sodium and water retention, plasma volume expansion and raised blood pressure, Angiotensin II also increases the release of aldosterone that cause vascular remodeling and fibrosis by encouraging the growth of vascular smooth muscle cells. The risk of hypertension, atherosclerosis increases as a result of these modifications, which can result in heart failure and other cardiovascular problems.^135,136 The production of numerous cytokines and growth factors in diabetic nephropathy together with systemic variables like hypertension, oxidative stress, inflammation and metabolic irregularities bring about structural alteration of the heart. These modifications include diastolic dysfunction, myocardial fibrosis, and left ventricular hypertrophy. ¹³⁷ Myocardial fibrosis alters the natural structure of the myocardium, which impairs cardiac function and increases the risk of arrhythmias and heart failure. ¹³⁸ A vicious cycle is created by the interaction of both DKD and T2DM with renal damage being exacerbated by cardiovascular disease while DKD promotes the growth and advancement of the ailment. To lessen the effects of DKD on cardiovascular health, effective management techniques should prioritize optimizing glycemic control, blood pressure management, cholesterol management, and renin-angiotensin system blocking. Figure 4 show the pathophysiological pathway of the development of CVD in diabetic nephropathy.

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Figure 4.

Physiological pathway that lead to development of CVD in diabetic nephropathy patients. Abbreviations: ANG II- Angiotensin II; JG cells, Juxtaglomerular cells; Na+, sodium ion; T2DM, Type 2 diabetes mellitus.

Lifestyle modification

By practicing weight management, lowering inflammation, regulating blood sugar levels, controlling blood pressure and cholesterol levels, lifestyle changes have an impact on cardiometabolic diseases inT2DM, consistent implementation of which can greatly lower the probability of cardiovascular problems and enhance general wellbeing in T2DM patients. T2DM patients must consume complex carbohydrates, high-fiber foods, and spreading their carbohydrate intake throughout the day to avoid blood sugar spikes and maintain stable glucose levels. Physical activity improves insulin sensitivity, glucose uptake into cells, raise metabolism and maintain lipid profile that assist lowering hyperglycemia and obesity. The risk of cardiometabolic disorders is decreased when a healthy weight is maintained because it eases the load on the heart and blood vessels.^139,140 People can minimize the risk of CVD and enhance blood vessel function by giving up smoking. ¹⁴¹ The release of stress hormones such cortisol, catecholamines and glucagon by the body during stress cause spike in blood sugar levels by boosting gluconeogenesis causing compromised glycemic control and IR in people with poor glucose metabolism. ¹⁴² The release of pro-inflammatory cytokines and the activation of immune cells are 2 features of low grade inflammatory reactions that chronic stress sets off in the body which is linked to the onset and development of CVD. ¹⁴³ The duration and quality of sleep also affect the ratio of hormones that control appetite, such as leptin and ghrelin. Lack of sleep can interfere with these hormonal signals, causing cravings for high-calorie meals and increased hunger leading to obesity and lipotoxicity which are risk factors for T2DM. ¹⁴⁴ In order to enhance glycemic control, lower IR, and lessen cardiovascular risks, comprehensive care for T2DM patients must include implementing effective stress management techniques and promoting healthy sleep habits.

Pharmacological interventions

In order to manage cardiovascular risk factors, regulate blood glucose levels, and lower the frequency of cardiovascular events, extensive pharmaceutical therapies are employed. The following section highlights the most widely used pharmaceutical treatments for T2DM’s cardiometabolic consequences.

Among oral antidiabetic medications the drug of choice for treating T2DM is metformin which promotes glucose absorption by peripheral tissues, raises insulin sensitivity, and decreases hepatic glucose synthesis. ¹⁴⁵ Sulfonylureas like glibenclamide, glimepiride and glipizide encourage pancreatic β cells to secrete more insulin. ¹⁴⁶ DPP-4 inhibitors that include sitagliptin, saxagliptin, and linagliptin improve glycemic management by increasing insulin production and decreasing glucagon release. ¹⁴⁷ Sodium-Glucose Co-Transporter 2 (SGLT2) inhibitors including empagliflozin, dapagliflozin, and canagliflozin decrease renal glucose reabsorption and increases urine glucose excretion and improve glycemic management as well as lowers cardiovascular mortality. ¹⁴⁸ Thiazolidinedione, in particular Pioglitazone are recommended as oral antidiabetic drug for increasing insulin sensitivity in peripheral tissues. ¹⁴⁹ Other than oral medication several injectables are also prescribed for glycemic control. Exenatide, liraglutide, and dulaglutide imitate the effects of glucagon-like peptide-1 (GLP-1), a hormone that increases the secretion of the insulin and glucagon while inhibiting the release of glucagon, delaying gastric emptying and lowers the risk of CVD, GLP-1 receptor agonists have positive effects on the cardiovascular system. ¹⁵⁰ Patients with T2DM who cannot achieve appropriate glycemic control with oral medicines require insulin therapy. ¹⁵¹ As part of the management of cardiometabolic problems in T2DM, antihypertensive medicines are frequently prescribed to control hypertension, a comorbidity that is frequently present in T2DM patients and lessen the load on the heart and blood vessels reducing the chances of CVD. To better manage blood pressure, many antihypertensive drugs of various kinds are frequently used in combination. When compared to a single medicine, combination therapy can reduce blood pressure more effectively due to its additive or synergistic effects. ¹⁵² Antihypertensive drug classes that are frequently prescribed include beta-blockers which majorly includes metoprolol and carvedilol that reduce heart rate and myocardial contractility, calcium channel blockers like amlodipine and verapamil that relax vascular smooth muscle cells, Angiotensin-converting enzyme inhibitors (ACE) and diuretics. ¹⁵³ The most commonly preferred lipid lowering drug is statin, that primarily function by blocking synthesis of cholesterol, lowers LDL-C level and slightly raise HDL-C levels lowering the risk of atherosclerosis. Statins with its anti-inflammatory property help to stabilize plaque and prevents rupture, avoiding heart attacks and strokes. ¹⁵⁴ Monoclonal antibodies evolocumab and alirocumab target proprotein convertase subtilisin/kexin type 9 (PCSK9) which breaks down LDL receptors and increase the number of LDL receptors thus increases LDL clearance and lowers the risk of CVD. ¹⁵⁵ T2DM patients are more likely to develop thrombosis. Antiplatelet drugs like aspirin and cloperedogel supports healthy clotting process by preventing the development of thrombi inside blood vessels. Antiplatelet drugs are prescribed to T2DM patients having coronary artery stenting or other cardiovascular procedures in order to prevent stent thrombosis. ¹⁵⁶ By lowering platelet activation and inflammation, antiplatelet medications not only reduce risk of CVD but also decrease progression of DKD.