Chapter 5 Type 2 diabetes

Chapter overview Introduction Aetiology Prevalence Obesity as a risk factor Physical inactivity as a risk factor Low physical fitness as a risk factor Mechanisms Exercise as therapy Summary

Introduction Diabetes is characterized by hyperglycaemia and high NEFA concentration. Life expectancy is impaired by 5–10 years, mainly because of high incidence of CVD in diabetics. Type 1 diabetes involves autoimmune destruction of pancreatic ß-cells in islets of Langerhans, thus inability to produce insulin. Type 2 diabetes involves insensitivity to insulin, with some impairment of insulin secretion. Comprises 85–95% of diabetes, usually found in obese or overweight adults.

Defining type 2 diabetes Venous plasma glucose mmol l-1 (mg dl-1) Fasting 120 minutes after 75 mg glucose load Normal < 6.1 (110) < 7.8 (140) Impaired fasting glucose ≥ 6.1 (110)–< 7.0 (126) – Impaired glucose tolerance ≥ 7.8 (140)–< 11.1 (200) Diabetes mellitus ≥ 7.0 (126) ≥ 11.1 (200)

Normal response to insulin Normal responses to insulin and the influence of insulin resistance on these Normal response to insulin Insulin resistance Liver Glucose uptake Glycogen synthesis Suppressed glycogenolysis and gluconeogenesis Glucose release due to the lack of suppression of glycogenolysis and gluconeogenesis Triglyceride and ketone synthesis and release due to high NEFA concentrations Muscle Glucose oxidation Impaired glucose uptake, oxidation and storage Adipocytes Glucose uptake and utilization Triglyceride synthesis Suppression of NEFA release Impaired glucose uptake and utilization Inappropriate triglyceride catabolism due to lack of suppression via insulin Release of glycerol and NEFAs Brain Appetite suppression Possible suppression of hepatic glucose output Increased appetite Possible increase in hepatic glucose output Outcome Normal blood glucose and NEFA concentrations Elevated blood glucose and NEFA concentrations

Major complications of diabetes Site Complication Brain and cerebral circulation Eyes Heart and coronary circulation Kidney Lower limbs Peripheral nervous system Diabetic foot Cerebrovascular disease Retinopathy Coronary heart disease Nephropathy Peripheral vascular disease Neuropathy Ulceration and amputation

Prevalence of type 2 diabetes Prevalence tends to be higher in developed countries, but the largest increases in prevalence are predicted to occur in developing countries. Each year approximately seven million people develop diabetes, and 6% of total global mortality is attributable to this disease. Prevalence increases with age. In the UK, since 1991, prevalence has more than doubled for men and increased by 80% for women.

Type 2 diabetes is associated with obesity, particularly abdominal obesity

Relative risk of developing diabetes, according to indices of fatness at baseline

Prevalence of obesity and diabetes in US adults, 1991 and 2001

Relative risk of diabetes during a 13-year follow-up in overweight men and women who intentionally lost weight Note: For every 9 kg of weight lost, there was an 11% lower risk for diabetes in men and a 17% lower risk in women.

Elevated NEFAs ... impair glucose uptake in adipocytes and muscle; enhance hepatic glucose production; lead to accumulation of intracellular fatty acid metabolites; reduce β-cell insulin secretion.

Obesity ... is associated with elevated concentrations of cytokines (markers for inflammation); causes inflammation which may be associated with endothelial dysfunction (compromising vasodilation and blood flow) through suppression of nitric oxide production; causes visceral adipocytes which are particularly resistant to the antilipolytic effects of insulin, with concomitant effects on hepatic fat metabolism.

Environmental influences Migrant studies show strong effect of lifestyle on diabetes prevalence. Strong temporal changes in prevalence occur within one society when there is rapid economic development, which shows importance of environmental factors, e.g. Singapore.

Changing prevalence of diabetes in the adult population of Singapore between 1975 and 1998

Physical activity associated with low risk for type 2 diabetes Overall, epidemiological evidence suggests that physically active individuals have a 30–50% lower risk of developing type 2 diabetes than their sedentary counterparts.

Relative risk for developing diabetes according to level of physical activity Note: Quintile 1, lowest level of activity; quintile 5, highest level.

Relative risk for diabetes in women, according to energy expenditure (left) and BMI (right) Note: Scales for relative risk differ in these two figures.

Diet and exercise intervention in overweight people with impaired glucose tolerance Notes: Randomly-controlled trial; n = 522.

Lifestyle intervention versus pharmacological treatment in overweight people with impaired glucose tolerance Notes: Randomly-controlled trial; n = 3,234; ‘Lifestyle’ = weight loss and exercise.

Fitness and risk of developing type 2 diabetes in women Note: 17-year follow-up; n = 6,249.

Indices of glucose/insulin dynamics in rats bred for low or high exercise capacity Note: RG, random glucose; FG, fasting glucose; TG, triglycerides.

Mechanisms Glucose tolerance is maintained through improved insulin sensitivity; glucose transport into muscle is improved, as is glycogen synthesis; improved capillarization; more mitochondria; increased activity of oxidative enzymes. Remember that skeletal muscle is the body’s largest insulin-sensitive tissue.

Improved glucose transport into muscle and glycogen synthesis after one exercise session and after six weeks of training Note: Subjects were offspring of diabetic parents.

Exercise as therapy in people with type 2 diabetes Cohort studies report that higher levels of activity or fitness are associated with lower risk for CV or all-cause mortality in follow-up. Regular walking (amount or pace) is associated with fewer CVD events and with reduced CV or all-cause mortality. No RCTs of exercise alone, but a combination of exercise, diet and pharmacological treatment does reduce CV events in diabetics. Glycosylated haemoglobin is reduced by exercise training (indicating improved glucose control and reduced risk for complications).

Summary I Type 2 diabetes is characterized by insulin resistance and defective insulin secretion, leading to hyperglycaemia and elevated NEFA concentrations. Type 2 diabetes increases the risk of CVD, which is a major cause of premature mortality. The prevalence of type 2 diabetes is increasing in many countries, and this appears to be linked to increases in the prevalence of obesity, a major risk factor. Prospective observational studies demonstrate an association between low levels of physical activity or physical fitness and increased risk of type 2 diabetes.

Summary II Lifestyle intervention programmes are effective in prevention, but the relative contributions of diet and exercise remain to be determined. Exercise promotes a variety of metabolic responses and adaptations which collectively improve glucose tolerance and insulin sensitivity. Among type 2 diabetics, high levels of physical activity and physical fitness are associated with a reduced risk of CVD and all-cause mortality. Exercise training improves glycaemic control, confirming the importance of exercise as therapy in type 2 diabetes.