Diabetes – A Silent Killer: A Threat for Cardiorespiratory Fitness

Abstract

Type 2 Diabetes Mellitus (T2DM) is a noncommunicable, lifestyle-related chronic metabolic disorder of global involvement, characterized by elevated blood sugar levels, manifested by hyperglycaemia, polyuria, polydipsia and polyphagia. DM is associated with acute and chronic complications which lead to reduced quality of life, premature morbidity and mortality. T2DM is linked with overweight, obesity, reduced physical activity and a genetic component. T2DM is named a silent killer because the primary disease is silent at the early stage and usually gets diagnosed when presenting with a vascular event such as stroke or heart attack. Impaired cardiorespiratory fitness plays a crucial role in acceleration of cardiovascular complications resulting in premature organ damage, morbidity and mortality. Regular physical activity, resistance training and reduction in sedentary life style along with diet control and drugs help to control DM and prevent or delay complications. This chapter deals with diabetes as a disease, its prevalence, risk factors, signs and symptoms, pathophysiology, pathogenesis and underlying mechanisms, acute and chronic complications, along with measures to enhance cardiorespiratory fitness and control DM and a word of caution to the younger generation to be aware of the silent killer.

1. Introduction

Diabetes Mellitus (DM) is a chronic, metabolic disease characterized by chronically elevated circulating blood glucose levels (hyperglycaemia, FBS>126 mg%) which occurs when the body becomes resistant to insulin or doesn't make enough insulin. There are two types of diabetes: Type 1 Diabetes Mellitus (T1DM) and Type 2 Diabetes Mellitus (T2DM). Type 1 DM usually begins in youth and is an autoimmune disorder resulting in complete destruction of pancreatic beta cells, and thereby no insulin is produced. The person has to depend on external insulin supply lifelong. T2DM accounts for 95% of cases seen in adults, characterized by insulin resistance, where the response to insulin in the muscles, liver and fat cells is inadequate. This condition is amenable to exercise and diet to enhance insulin sensitivity. Insulin is essential for muscle, liver and adipose tissue cells to store glucose. Insulin resistance and insulin deficiency lead to hyperglycaemia or increased levels of circulating blood glucose which can damage the blood vessels and nerve. As a result, serious damage can happen to the heart, blood vessels, eyes, kidneys and nerves [1, 2]. Type 2 DM was once considered as a disease of the economically affluent ‘western countries’ that occurred by middle age, but today, it is increasingly seen affecting the younger generation. Diabetes damages the large and small blood vessels resulting in end organ damage. Uncontrolled diabetes leads to increased risk of vascular disease caused by macrovascular (cardiovascular (CV), cerebrovascular and peripheral artery disease) and microvascular (diabetic retinopathy, nephropathy and neuropathy) complications [3]. Long-term complications of this noncommunicable, chronic lifestyle disease are a leading cause of end stage renal failure, adult-onset blindness and non-traumatic amputations. Diabetes leads to atherosclerotic cardiovascular disease, a major cause of disability, reduced quality of life, morbidity, mortality and premature death [4]. Treatment of diabetic complications often is more expensive and disheartening than diabetes itself. The burden of DM is often unaffordable to the common man in a developing country where free medical service is unavailable to all citizens.

2. Prevalence of diabetes mellitus

According to WHO, noncommunicable disease accounts for 74% of death globally. The global prevalence of DM increased from 108 million in 1980 to 422 million in 2019 and accounted for 1.6 million deaths and the ninth leading cause of global mortality. By 2035, nearly 592 million people are predicted to die of diabetes [5]. In developing countries, undiagnosed diabetes accounts for more than 50%, which means 231.9 million (one in two) adults are with undiagnosed diabetes worldwide. An urgent need for diabetes screening, treatment and preventive initiatives along with population education exists worldwide.

At national level, India stands second to China in the global diabetic population with 77 million people with diabetes. About 57% (43.9 million) of adults having diabetes are undiagnosed in India. Besides, 25.2 million adults are assessed to have Impaired Glucose Tolerance (IGT), and that is expected to reach 35.7 million by the year 2045 [6]. An estimated number of diabetes patients in the 20–79 age group was 74.2 million in 2021 and is likely to increase to 124.8 million in 2045 [7]. In 2019, India was reported to have 77 million cases of diabetes and 54% cases of undiagnosed diabetes with the cases of DM projected to reach 134 million by the year 2045 if unchecked.

According to an ICMR study, India DIABetes, prevalence of diabetes has increased from 3.5 to 8.7% in rural and from 5.8 to 15.5% in urban areas, and the prevalence of prediabetes was reported as 5.8–14.7% in rural to 7.2–16.2% in urban areas. The number of cases of prediabetes exceeds that of diabetes and will become full-blown diabetes in a short span of 10 years. This will have a detrimental effect on the nation.

The situation within Indian states is no different; South Indian states such as Tamil Nadu and Kerala were reported to have a prevalence of 21.9% in 2016, while incidence of prediabetes in Kerala was found to be 36.7% [8]. A prospective study on lifestyle disease from Alleppey, Kerala, found incidence rate of T2DM as 24.5 per 1000 person-years and impaired fasting glucose (IFG) as 45.01 per 1000 persons [9]. The heavy disease burden of diabetes is fuelled by overweight, obesity, inadequate physical activity and unhealthy eating and lifestyle practices. Diabetes is a silent killer which remains asymptomatic at early stages and goes undetected until presented with a vascular event such as angina or myocardial infarction or stroke.

Although insulin is found to be a remedy for diabetes, the place of physical activity is superior to insulin for effective action on insulin receptors. Unfortunately, subjects with diabetes appear to be sedentary or related to disease itself, but exhibit reduced cardiorespiratory fitness [10].

3. Risk factors of Type 2 diabetes

Most of the risk factors except genetic causes are lifestyle-related and thus modifiable. Economic evolution and increased standard of living have replaced bicycle riders and pedestrians with motorized vehicles for quicker transport. Children are discouraged from walking and cycling to school, and commutation is replaced with school bus. Games or physical training sessions are restricted or non-existent in many schools with some schools having no playgrounds at all. Additional tuition classes for high academic achievements and the competition to get admission to schools and colleges take away the after-school play time from children.

Advanced technology and digitalization have changed activity pattern at work and during leisure time to energy-saving measures. Considerable time is spent on sedentary pursuits, with television, movie watching, video games, internet surfing and telephone gossip sessions. The advent of the smartphone has again further contributed to people developing sedentary habits. With the advent of COVID-19 pandemic, smart phone has become an inevitable tool for teaching and learning, exposing the young generation to a prolonged screen time. Pandemic also promoted social isolation, lock down, virtual communication and increased sedentarism. All these have indirectly contributed to physical inactivity and impaired cardiorespiratory fitness.

Significant association was reported with overweight and obesity, while lack of physical activities, prolonged TV watching/playing computer games, frequent consumption of fast food/junk food and frequent consumption of calorie dense food items were found to be contributory factors to developing DM. Higher socioeconomic family status and familial obesity also play a significant role among risk factors [11]. Mendenhall et al. found that the higher-income group conveyed ‘tension’ or stress associated with children's futures, financial security and family dynamics, whereas depression was most common among the poorest, the middle (38%) and the high-income (29%) group [12]. Significant risk factors for T2DM among adolescents are found to be obesity, positive family history, female gender, puberty and being a low-birth-weight baby. Presence of T2DM among a first- or second-degree relative is reported in 75–100% of patients.

Prevalence of T2DM increased from 36% to 54% when there was a positive family history of diabetes on the non-diabetic parental side also. When both parents were diabetic, the prevalence rate was as high as 62% [13]. Genetics plays a significant role for T2DM in children. Children born to mothers with T2DM are particularly at increased risk for the disease when compared with children whose fathers had T2DM. The risk is higher for boys than for girls. A strong positive family history of diabetes (FHD) is present in 45%–80% of children with T2DM. However, research explains only 10% of the heritability of type 2 DM. The appearance of T2DM at a very young age like childhood and adolescence is distressing as it consumes the most productive years of life, and its consequences on society, public and mental health are dreadful. For a healthy nation and economy, healthy individuals and healthy families are essential.

Socio-economic and cultural factors play an important role in childhood nutrition. Parental ignorance and dependency on various media such as television, radio and print advertising for information also can lead to erroneous food and lifestyle practices. Fewer working parents have the time and energy to prepare a full meal after working hours. And children of many working parents may be in the care of people who may not be much concerned about their charges due to various reasons. Food is the centre of most celebrations and a reward for desired behaviour. Many families believe that a fat baby is a healthy baby [13]. Not to mention that across the world, with income inequality and cultural norms, food distribution itself across societal strata as well as genders depends on purchasing power too.

Healthy organic food is a hard thing to find even for the affluent in many societies today.

Another scenario is where in urban nuclear families where both parents are working full time or in single-parent homes, children are kept engaged with electronic gadgets or digital games. Several hours may be spent on viewing television and snacking till parents return from work. Fewer children walk to school or play outside to save time and energy or due to safety reasons. In urban residential areas with multistorey buildings, people tend to use a lift. Progressive decline in physical activity is a key feature. Climbing few stairs makes an overweight or obese person short of breath, which is a true reflection of impaired cardiorespiratory fitness.

4. Pathophysiology of DM

Diabetes mellitus is a heterogeneous disorder defined by the presence of hyperglycaemia. Diagnostic criteria for diabetes include the following: (1) a fasting plasma glucose (FPG) of ≥126 mg/dL (7.0 mmol/L); (2) classic symptoms of hyperglycaemia plus a random plasma glucose of ≥200 mg/dL (11.1 mmol/L); (3) a 2-hour plasma glucose level ≥200 mg/dL following a standard 75 g oral glucose load (oral glucose tolerance test [OGTT]); or (4) a glycated haemoglobin (HbA1C) >6.5%. HbA1C(A1C) values reflect average blood glucose levels during the previous 2–3 months.

Hyperglycaemia results from inadequate insulin production or insulin resistance. An increase in the counter-regulatory hormones that oppose the effects of insulin also can result in hyperglycaemia. Type 1 DM is often seen in the younger age group below 30 years with peak incidence at puberty. It is characterized by the autoimmune destruction of pancreatic β cells leading to severe or absolute insulin deficiency, requiring insulin treatment lifelong. Patients present with symptoms of polyuria, polydipsia and weight loss with markedly elevated serum glucose concentrations. Absence of insulin leads to formation of Ketone bodies resulting in life-threatening acidosis (diabetic ketoacidosis [DKA]) which needs urgent intensive intervention.

Type 2 DM accounts for majority cases of diabetes (90–95%). It has a stronger genetic component; prevalence increases with age, occurring mostly in adults (18% of individuals older than 65 years worldwide and 33% in the United States). Insulin resistance is the hallmark of type 2 DM and is frequently (85%) associated with obesity. Increased prevalence of T2DM is associated with increase in obesity, increased insulin resistance as well as a decrease in insulin secretion by the pancreas. These patients are often asymptomatic and not diagnosed until 5–7 years after the actual onset of disease owing to the presence of varying amounts of residual insulin secretion, which prevents severe hyperglycaemia or ketosis. Once diagnosed with type 2 DM, majority (70%) are managed with lifestyle modifications (diet, exercise, weight management) alone or in combination.

After progressive decline in β-cell function, the disease manifests as an impairment in the acute insulin release that precedes sustained insulin secretion in response to a meal. Once the β-cell mass declines by 40%–60% owing to β-cell apoptosis, patients present with impaired fasting glucose and frank Type 2 DM, respectively. Chronic exposure to elevated free fatty acids, hyperglycaemia (glucolipotoxicity) and inflammatory cytokines contribute to impaired β-cell insulin secretion in a background of insulin resistance [14].

On a cellular level, mitochondrial dysfunction occurs which may be due to decreased activity, abnormal size or decreased biogenesis. However, these organelles are highly responsive to the stimulus created by muscle contraction and exercise and have a direct link to insulin action/inaction [15]. In a study among 18 diabetic patients, in vivo mitochondrial function among content and glucose disposal were restored following 12 weeks of exercise training (with 13% increased VO2max) [16].

Obesity is a major driver of the increased prevalence of diabetes and plays a critical role in its pathogenesis. Majority (85%) of patients with type 2 DM are obese. Even a 5–10% weight loss in obese individuals with type 2 DM can ameliorate or even terminate the disorder. Excess nutritional intake from any source eventually leads to increased free fatty acid (FFA) storage as triglyceride in adipose tissue. Subcutaneous tissue is the body’s major site of fat storage, but it is unable to expand and accommodate excess lipid in obesity. This leads to increased fat deposit in visceral (central) adipose tissue, which promotes insulin resistance owing to its high lipid turnover. Excess lipolysis from visceral stores directly feeds FFAs into the liver, thus contributing to hepatic lipid accumulation(steatosis), insulin resistance and increased hepatic gluconeogenesis, which raises the level of fasting glucose. Metformin, a first-line therapy for type 2 DM, is particularly effective in reversing these hepatic effects of insulin resistance.

The decreased rate of mitochondrial fat oxidation, excess lipid stores and insulin resistance with advanced ageing results in increased prevalence of type 2 DM. Besides, release of certain factors such as adiponectin, leptin and inflammatory cytokines such as tumour necrosis factor from visceral adipose in addition to FFA also drives insulin resistance. Hyperinsulinaemia can itself contribute to insulin resistance by downregulating insulin receptor levels and desensitizing downstream pathways.

5. Pathology and pathogenesis of DM

Regardless of origin, all types of diabetes result from a relative deficiency of insulin action. The degree of loss of insulin action determines the resultant metabolic derangements. Since the adipose tissue is highly sensitive to insulin action, low insulin levels suppress the excessive lipolysis and thereby enhance storage of fat. Liver liberates glucose in to circulation as a result of glucagon effects. In order to control the same, higher insulin levels are required. In a non-diabetic, healthy individual, basal levels of insulin activity mediate both these responses.

In a healthy person, the hepatic tissue is superbly responsive to changes in pancreatic insulin secretion owing to its high sensitivity and exposure to elevated levels of insulin in the portal circulation. However, stimulated secretion of additional insulin from the pancreas is required for the skeletal muscle to respond to a glucose load with insulin-mediated glucose uptake. Inability of the skeletal muscle to clear up its share of 85% of glucose due to mild insulin deficiency is reflected by postprandial hyperglycaemia.

When an additional loss of insulin action occurs, glucagon’s effects on the liver are insufficiently counter-balanced. In such situation, patients will present with both postprandial hyperglycaemia and fasting hyperglycaemia. Insulin deficiency causes hypertriglyceridemia in diabetes, owing to the increase in VLDL production and a decrease in VLDL clearance as a result of decrease in lipoprotein lipase, the enzyme mediating fatty acid storage in adipose tissue.

Insulin is responsible for amino acid uptake and protein synthesis in muscle. Hence, a decrease in insulin action results in decreased muscle protein synthesis among diabetic patients. Marked insulinopenia such as in type 1 DM can cause a negative nitrogen balance and marked protein wasting. Superimposition of stress-induced counter-regulatory hormones on already an insulinopenic state exacerbates the metabolic manifestations of deficient insulin action in both Type 1 and 2 DM. The stress of infection and decrease in insulin action in diabetes result in decreased muscle protein synthesis induced DKA in type 1 DM. In addition to all of the metabolic derangements listed, diabetes causes other chronic, progressive complications that are responsible for the high morbidity and mortality rates associated with this disease.

6. Diabetic complications and its mechanisms

Uncontrolled diabetes damages the nerves and blood vessels causing major organ damage, reduced quality of life, disability, premature morbidity and mortality. It also leads to increased disease burden for the family, community and the nation at large.

6.1 Acute complications

6.1.1 Hyperglycaemia

When elevated glucose levels exceed the renal threshold for glucose reabsorption (approximately 200 mg/dL), glucosuria results. This causes an osmotic diuresis manifested clinically by polyuria, including nocturia resulting in dehydration and subsequent thirst that results in polydipsia. Glucosuria can lead to significant loss of calories from urinary glucose losses that can exceed 75 g/day. Polyphagia is followed by uncontrolled hyperglycaemia, the result of excessive caloric consumption. Cardinal symptoms of diabetes are three ‘polys’: polyuria (excessive urination), polydipsia (excessive thirst) and polyphagia (excessive hunger). These are present in type I DM and symptomatic type II DM patients. Loss of fluid and calories through urine (polyuria) results in weight loss. Changes in the water content of the lens of the eye in response to changes in osmolality can cause blurred vision. In women, glucosuria can lead to an increased incidence of candidal vulvovaginitis. In uncircumcised men, candidal balanitis (a similar infection of the glans penis) can occur.

6.1.2 Diabetic Ketoacidosis (DKA)

DKA can also occur in individuals with type 2 DM, particularly during infections, severe trauma or other causes of stress that increase levels of counter-regulatory hormones, thus producing a state of profound inhibition of insulin action. In the absence of insulin, lipolysis is stimulated, providing fatty acids that are favourably converted to ketone bodies in the liver by unopposed glucagon action. When the compensatory mechanism of osmotic diuresis fails, blood sugar can escalate to average of 500 mg/dL, a state of severe hyperglycaemia. Hyperglycaemia leads to increased osmolality, and an intracellular to extracellular fluid shift, inspired by thirst in an effort to maintain intravascular volume. If the polyuria is not controlled, compensatory mechanism fails to maintain circulating fluid volume. Besides, ketoacidosis is often accompanied by nausea and vomiting, resulting in fluid loss and consecutive dehydration and subsequent reduction in renal blood flow. This leads to reduced ability of the kidneys to excrete glucose. Hypovolemia stimulates counter-regulatory hormones, and it turns out into a vicious cycle. Profound cellular dehydration occurs in response to the marked increase in plasma osmolality. A severe loss of intracellular fluid in the brain leads to coma.

The increase in ketogenesis caused by a severe lack of insulin action results in increased serum levels of ketones and ketonuria. During ketoacidosis, liver produces ketone bodies mainly Acetoacetate and β-hydroxybutyrate, which are organic acids that cause metabolic acidosis resulting in a decrease in blood pH and serum bicarbonate levels. Partial compensatory mechanisms may increase the respiratory rates to compensate for the metabolic acidosis by reducing PCO2. As a result, when pH level is lower than 7.20, characteristic deep, rapid respirations occur (Kussmaul breathing). Although acetone is a minor product of ketogenesis, the ketosis of DKA is much more severe than ketosis due to starvation. Na+ is lost in addition to water during the osmotic diuresis accompanying DKA, resulting in low serum sodium. Total body stores of K+ are also depleted by diuresis and vomiting. Without treatment, K+ can fall to dangerously low levels, leading to potentially lethal cardiac arrhythmias. Marked hypertriglyceridemia can also accompany DKA because of the increased production and decreased clearance of VLDL that occurs in insulin-deficient states. Nausea and vomiting often accompany DKA, contributing to further dehydration. Abdominal pain, present in 30% of patients, may be due to gastric stasis and distention. DKA is treated by replacing water and electrolytes (Na+ and K+) and administering insulin.

6.1.3 Hyperosmolar coma

Decreased fluid intake, an intercurrent illness or elderly, debilitated patients who lack sufficient access to water and have abnormal renal function, thus hindering the clearance of excessive glucose loads and can lead to severe hyperosmolar states in the absence of ketosis in type 2 DM. Profound hyperglycaemia and dehydration occur when presented late; glucose levels often range from 800 to 2400 mg/dL, resulting in a higher incidence of coma. Mortality is 10 times higher than in DKA, which is often precipitated by co-morbidity.

6.1.4 Hypoglycaemia

A dangerous factor limiting the achievement of tight glucose control is a complication of insulin treatment in DM. It can also occur with oral hypoglycaemic drugs that stimulate glucose-independent insulin secretion (e.g. sulfonylureas). Hypoglycaemia often occurs during exercise or with fasting. It can be neurogenic symptoms, secondary to central nervous system (CNS)-mediated sympathoadrenal discharge; adrenergic (shaking, palpitations, anxiety) and cholinergic (sweating, hunger) responses that encourage carbohydrate-seeking behaviour. As glucose drops further, neuroglycopenic symptoms may occur from the direct effects of hypoglycaemia on CNS function (confusion, coma). A characteristic set of symptoms (night sweats, nightmares, morning headaches) also accompanies hypoglycaemic episodes that occur during sleep (nocturnal hypoglycaemia. Acute treatment of hypoglycaemia in diabetic individuals consists of the rapid oral administration of glucose at the onset of warning symptoms or the intramuscular administration of exogenous glucagon by another person when neuroglycopenic symptoms prohibit oral glucose self-treatment. Excessive glucose administration can lead to rebound hyperglycaemia by the action of counter-regulatory hormones (Somogyi phenomenon).

6.2 Chronic complications

Over time, diabetes results in damage and dysfunction in multiple organ systems by damaging the blood vessels and nerves. Both microvascular disease (retinopathy, nephropathy, neuropathy) and macrovascular disease (coronary artery disease, peripheral vascular disease), which occurs with increased frequency in diabetes, contribute to the high morbidity and mortality rates associated with diabetes mellitus. Peripheral Neuropathy where the sensory perception is impaired due to nerve damage, there is an increased risk of foot ulcers that lead to increased morbidity. Good glycaemic control plays a key role in preventing complications. Genetic factors also clearly play a role in complications.

6.2.1 Microvascular complications

Hyperglycaemia plays a critical role in microvascular disease. The high intracellular levels of glucose in cells that cannot downregulate glucose entry (the endothelium, glomeruli and nerve cells) result in microvascular damage. There is overproduction of mitochondrial-derived reactive oxygen species generated by an increased flux of glucose through the tricarboxylic acid (TCA) cycle. These changes in the microvasculature result in an increase in protein accumulation in vessel walls, endothelial cell dysfunction, loss of endothelial cells and, ultimately, occlusion. The formation of irreversibly glycated proteins called advanced glycosylation end-products (AGEs) also causes microvascular damage in diabetes. Elevated glucose leads to increased glycation of HbA within red blood cells. The measurement of HbA1c in diabetic patients serves as an index of glycaemic control over the preceding 3 months.

6.2.2 Retinopathy

Diabetes is a leading cause of blindness in developed countries occurring in two distinct stages: non-proliferative and proliferative. Microaneurysms of the retinal capillaries, appearing as tiny red dots, are the earliest clinically detectable sign of diabetic retinopathy (background retinopathy). The appearance of hard exudates in the area of the macula is often associated with macular oedema, which can occur at any stage of retinopathy progression and is the most common cause of blindness in type 2 DM, occurring in 7% of diabetics. Occlusion of capillaries and terminal arterioles causes areas of retinal ischemia that appear as hazy yellow areas with indistinct borders (cotton wool spots or soft exudates) at areas of infarction. Retinal haemorrhage can also occur, and retinal veins develop segmental dilation. Retinopathy can progress to a second, more severe stage characterized by the proliferation of new vessels (proliferative retinopathy). These capillary vessels are abnormal, and traction between new fibrovascular networks and the vitreous can result in vitreous haemorrhage or retinal detachment, both are potential causes of blindness in diabetic patients.

6.2.3 Nephropathy

Globally, the most common cause of ESRD is chronic, uncontrolled diabetes. A disordered glomerular function leads to diabetic nephropathy.

Basement membranes of the glomerular capillaries get thickened and obliterate the vessels. The mesangium surrounding the glomerular vessels is increased owing to the deposition of basement membrane-like material and can encroach on the glomerular vessels. The afferent and efferent glomerular arteries become sclerosed. Histological alterations of renal glomeruli are accompanied by early microalbuminuria, which is not revealed on a routine urinalysis dipstick method. Albuminuria is thought to be due to a decrease in the heparan sulfate content of the thickened glomerular capillary basement membrane. As the glomerular lesion progresses, proteinuria rises and nephropathy becomes evident. Presence of heavy proteinuria (>300 mg/day) that can be spotted on a routine urine examination signifies diabetic nephropathy. Proteinuria continues to increase as renal function deteriorates. Therefore, ESRD is preceded by massive, nephrotic-range proteinuria (>4 g/d). The presence of hypertension speeds up this process. Hypertension worsens as renal function deteriorates. Therefore, controlling hypertension is critical in preventing the progression of diabetic nephropathy.

6.2.4 Neuropathy

Occurs in about 60% of both type 1 and type 2 DM patients and is a major cause of morbidity. Diabetic neuropathy can be divided into three major types: (a) a distal, primarily sensory, symmetric polyneuropathy the most common (50% incidence); (b) an autonomic neuropathy, occurring frequently in individuals with distal polyneuropathy (>20% incidence); and (c) much less common, transient asymmetric neuropathies involving specific nerves, nerve roots or plexuses.

1. Symmetric distal polyneuropathy – The demyelination of peripheral nerves, a hallmark of diabetic polyneuropathy, affects distal nerves preferentially and is usually manifested clinically by a symmetric sensory loss in the distal lower extremities (stocking distribution) that is preceded by numbness, tingling and paraesthesias. These symptoms, which begin distally and move proximally, can also occur in the hands (glove distribution). Pathologic features of affected peripheral somatic nerves include the demyelination and loss of nerve fibres with reduced axonal regeneration, accompanied by microvascular lesions, including the thickening of basement membranes. In addition, the microvascular disease that accompanies these neural lesions may also contribute to nerve damage.

2. Mononeuropathy: Vascular occlusion and ischemia are thought to play a central role in the pathogenesis of these asymmetric focal neuropathies, which are usually of limited duration and occur more frequently in type 2 DM. It is characterized by the abrupt, usually painful onset of motor loss in isolated cranial or peripheral nerves (mononeuropathy) or in multiple isolated nerves.

6.3 Macrovascular complications

Accounting for significant morbidity and mortality in both types of diabetes, the effects of large-vessel disease are particularly devastating in type 2 DM and are responsible for approximately 75% of deaths.

6.3.1 Atherosclerosis

Atherosclerotic macrovascular disease commonly occurs in diabetes, resulting in an increased incidence of myocardial infarction, stroke and claudication and gangrene of the lower extremities. The reasons for the increased risk of atherosclerosis in diabetes are threefold: (1) traditional risk factors, hypertension and hyperlipidaemia, (2) diabetes itself is an independent risk factor for atherosclerosis; and (3) diabetes when synergized with other known risk factors increases atherosclerosis. Hence, the elimination of other risk factors, therefore, can greatly reduce the risk of atherosclerosis in diabetes.

6.3.2 Hypertension

Hypertension is associated with increased total body extracellular Na+ content and volume expansion which occurs in type 1 DM and type 2 DM. Insulin resistance is associated with activation of the renin-angiotensin system, which leads to hypertension, while renin-angiotensin system activation, in turn, decreases insulin sensitivity. Insulin resistance is central to the pathogenesis of two obesity-associated syndromes: (1) prediabetes (e.g., FPG 100–125 mg/dL, A1C 5.7–6.4%); and (2) metabolic syndrome (a cluster of metabolic abnormalities, including central obesity [waist ≥102 cm for males or≥88 cm for females], elevated glucose [≥100 mg/dL], elevated blood pressure [≥130/≥85 mm Hg], elevated triglycerides [≥150 mg/dL] and low high-density lipoprotein [HDL] cholesterol [<40 mg/dL]). Both syndromes are associated with increased cardiovascular risk, as well as an increased risk for the later development of diabetes. The Diabetes Prevention Programme has demonstrated that significant risk reductions for the development of type 2 DM occur in response to lifestyle interventions in this population.¹Hypertriglyceridemia, which is associated with an increased risk of cardiovascular disease. The compositions of LDL and HDL are altered by elevated levels of VLDL. It also transfers triglycerides to these particles, depletes them of cholesterol and creates small, dense LDL particles and low HDL cholesterol levels. Eventually, both of these are independent risk factors for cardiovascular disease. Treatment of hyperglycaemia does not normalize lipid profiles in obese, insulin-resistant individuals with type 2 DM unless accompanied by weight reduction treatment.

6.3.3 Diabetic foot ulcers

Symmetric polyneuropathy (present in 75–90% of diabetics with foot ulcers) results in insensate feet among diabetics, which makes them highly susceptible to foot injuries. Once developed, it is less amenable to regular healing, and the wound may get complicated by osteomyelitis and result in amputation in 1%, an event associated with high mortality (50% by 3 years). Other reasons for diabetic foot ulcers are macrovascular disease (present in 30–40% of those with foot ulcers) and microvascular disease; infections caused by alterations in neutrophil function and vascular insufficiency; and faulty wound healing. Unfortunately, about 10% of diabetics develop diabetic foot ulcers.

6.3.4 Infection

Abnormal cell-mediated immunity, defective neutrophil chemotaxis and phagocytosis, reduced blood flow from vascular lesions prevent inflammatory cells reaching wound sites, making them prone to infections which often become severe infection. Candidal infections, periodontal disease, necrotizing papillitis, mucormycosis and malignant otitis externa caused by Pseudomonas aeruginosa are common infections that occur in diabetics.

Skeletal changes in diabetes – Adults with type 2 DM have a 40–70% increased fracture risk, perhaps owing to increased cortical porosity. Bone fragility in diabetes is considered as an additional factor attributable to microvascular disease [17].

7. Measures to maintain Cardiorespiratory fitness (CRF)

Enhanced Physical Activity (PA) was and continues to be a cornerstone of diabetes prevention and management. Regular aerobic exercise at modest levels (<6METs) can lessen HbA1c by almost 0.7% and improve insulin sensitivity while keeping weight unchanged [18]. In other words, 1-week aerobic exercise can improve your body’s sensitivity to insulin in peripheral tissues irrespective of insulin usage. Optimally, subjects with diabetes should engage in regular PA on a daily basis, and the shorter the exposure to PA, the higher the effort is needed to get the same effect on insulin sensitivity for lasting effect [19].

Physical activity or exercise can be classified broadly as aerobic or anaerobic. Physical activity refers to energy expenditure above resting stage while exercises is a type of planned, structured and repetitive bodily activity aimed at improving physical fitness. Physical activity or exercise can be classified broadly as aerobic or anaerobic. Aerobic activity refers to repetitive, low-intensity, long-duration movements that apply large muscle groups utilizing aerobic energy pathways using fatty acids as substrate. Specifically, chronic exposure to aerobic exercises of adequate intensity and duration leads to increased aerobic capacity or cardiorespiratory fitness (CRF). CRF is typically reported as metabolic equivalents (METs), with one MET defined as the amount of oxygen consumption at rest (3.5 ml O2/kg/min).

Today’s lifestyle marked by prosperous socioeconomic status, sedentariness and obesity have made significant contributions as independent risk factors for T2DM. Encouraging reasonable dynamic physical activity for 150 min/week can typically reduce health risks associated with numerous chronic illnesses and their prevention.

Irrespective of sedentary lifestyle and duration of the disease, individuals with diabetes exhibit exercise intolerance with subnormal cardiorespiratory fitness, owing to certain vascular abnormalities and slowed kinetics for oxygen uptake.

Older adults with DM2 have greater muscle mass loss, reduced upper and lower body strength, increased visceral adiposity and increased disability [20, 21, 22]. Poorly controlled DM2 patients have, in addition, poor capillary recruitment during skeletal contraction [23]. Resistance Training (RT) has largest effect on the musculoskeletal measurements such as muscle strength [24], can significantly improve insulin sensitivity, glycaemic control including HbA1c, increase fat-free mass, reduce the requirement for diabetes medications, reduce abdominal adiposity and improve cardiovascular risk markers [25, 26, 27].

Resistance exercise training (RT) is a promising strategy to promote overall metabolic health in individuals with T2DM, with improvements in muscle mitochondrial performance, increase in muscle mass, positive impact insulin responsiveness and glucose control [28]. Current guidelines for DM2 prevention and management recommend at least 150 min per week of MVPA and an additional two (ideally three) resistance sessions per week (at least 60 min). Besides, breaking up of prolonged sedentary time with light walking promises with improved glycaemic parameters. The duration of DM2 is associated with response to exercise. Resistance training may benefit patients with long-standing DM2, having more extreme exercise intolerance, muscle weakness and sarcopenia.

8. Conclusion

Poor Cardiorespiratory Fitness (CRF) is a well-established independent predictor of Cardiovascular Disease and overall mortality among subjects with prediabetes, DM1 and DM2. Increased Physical Activity (PA) and higher CRF offer metabolic health benefits for DM2 patients in proportion to the level of fitness independent of BMI. Increases in Physical Activity patterns have emerged as an integral part of the prevention and management supported by a multitude of reproducible randomized studies confirming the strong link to enhanced CRF. Significant implementation challenges are, however, the bottom being adherence, therapeutic regimens should be designed to improve CRF in a society where a profound lifestyle shift has taken place dominated by non-exercise PA and sedentary behaviours. Being a modifiable risk factor, a healthcare provider prescription for enhanced fitness is perhaps using CRF as a vital sign. Involvement of progressive societal and political encounter via education and support for alternatives to transportation, creating more appropriate indoor and outdoor architecture harm from emerging exposure risks from pollution is an indispensable component of promoting physical activity for better CRF in the population particularly for those who are at risk of noncommunicable diseases such as DM and hypertension. This will bring significant reduction in excessive economic burden of diabetes and reduce premature mortality and morbidity among existing diabetics and prediabetics. Prevention is better than cure.

9. A word of caution: preventive measures to save the budding generation

India, being a developing country, has over 253 million adolescents who need to be protected from premature morbidity and mortality through health education and creating a favourable environment to adopt an active healthy lifestyle. They should be motivated to exercise, avoid high calorie food habits and maintain a healthy BMI. Government should develop policies to allow provision for healthy meals and snacks in hotels and restaurants, cancellation of license for junk food sale at all types of food outlets, providing warning signs about unhealthy food consumption, etc. Also, promotion policies such as reduced insurance premium for people with normal BMI, healthy food habits and regular health check-ups. Provision for exercise and healthy food habits should be provided mandatorily at all working places in order to facilitate 150 minutes of physical exercise a week. The same should be mandatorily implemented at all schools and colleges. The recognition and licences should be tagged with these requirements to create public awareness on the importance of controlling and preventing diabetes mellitus.

Ensure availability of healthy groceries, vegetables and fruits at markets, healthy food items at shopping malls and restaurants, canteens and hostels to promote healthy eating habits among the public. At present, all restaurants and bakeries as well as small food outlets provide high-calorie sweetened and oily foods, highly processed foods that are attractive to the population, particularly the youngsters. Strong awareness about dangers of obesity and NCDs such as DM, HT and cancer along with provision for healthy meal will encourage more than 50% of population to adopt healthy eating habits.

“An ounce of prevention is worth a pound of cure!”

Benjamin Franklin

Conflict of interest

Nil.