Etiopathology of Diabetes Dr Shahjada Selim Assistant Professor Department of Endocrinology Bangabandhu Sheikh Mujib Medical University, Dhaka Email: selimshahjada@gmail.com, info@shahjadaselim.com

Diabetes: A global emergency

Diabetes around the world

Diabetes around the world

Diabetes around the world

South-East Asia At a glance 2015 2040 Adult population (20-79 years) 926 million 1.31 billion Diabetes (20-79 years) Regional prevalence 8.5% (6.8-10.8%‡) 10.7% (8.5-13.7%‡) Age-adjusted comparative prevalence 9.1% (7.3-11.6%‡) 9.9% (7.9-12.8%‡) Number of people with diabetes 78 million (63-100 million‡) 140 million (112-180 million‡) Number of deaths due to diabetes 1.2 million - Health expenditure due to diabetes (20-79 years) Total health expenditure, R=2*, USD 7.3 billion 12.9 billion Impaired glucose tolerance (20-79 years) Regional prevalence 4.6% (2.2-6.5%‡) 5.6% (2.7-7.4%‡) Age-adjusted comparative prevalence 4.7% (2.4-6.7%‡) 5.4% (2.5-7.2%‡) Number of people with impaired glucose tolerance 42.2 million (20.7-60.2 million‡) 73.9 million (35.0-96.9 million‡) Type 1 diabetes (0-14 years) Number of children with type 1 diabetes 81,400 - Number of newly diagnosed children each year 13,100 - * See Glossar y ‡ Uncertainty inter val IDF Diabetes Atlas · Seventh Edition

Health expenditure Data sources Mortality Mauritius has one of the highest adult diabetes prevalence rates in the world (22.3% age- adjusted comparative prevalence, 24.3% raw prevalence). The Maldives (9.2% age-adjusted, 7.5% raw) has the second-highest prevalence rate in the region. India is home to the second largest number of adults living with diabetes worldwide, after China. People with diabetes in India, Bangladesh, and Sri Lanka make up 99.0% of the region’s total adult diabetes population. Health expenditure A total of USD7.3 billion (R=2*) to USD12.4 billion (R=3*) (ID24.9 billion to ID42.4 billion) was spent on the 78 million people living with diabetes in 2015, 12% of the health budget of the region. This accounts for 1% of the global health spending on diabetes. Compared to the other IDF regions, the South-East Asia Region had the lowest health expenditure per person with diabetes (USD93 to USD158, ID319 to ID542). A further 42.2 million people have impaired glucose tolerance and are at increased risk of developing type 2 diabetes in the future. The number of people with diabetes in the region is predicted to be 140 million by 2040 – 10.7% of the adult population aged 20-79. This increase is largely a consequence of ongoing urbanisation and increasing life expectancy. Data sources All countries except Bhutan had primary data sources that were used to generate estimates for diabetes in adults in the region. A total of 13 data sources from six countries were used. Diabetes prevalence estimates for India, Nepal, Sri Lanka and Bhutan were based, in part, on data sources that were more than five years old and may be underestimates. There are an estimated 81,400 children under the age of 15 living with type 1 diabetes in the South- East Asia Region. Approximately 13,100 children developed type 1 diabetes in the region during 2015. Estimates for type 1 diabetes in children were largely based on data from India, the Maldives and Mauritius. 91 India is home to the second largest number of children with type 1 diabetes in the world (70,200), after the USA, and accounts for the majority of the children with type 1 diabetes in the region. The incidence rate for type 1 diabetes in India was used to extrapolate figures for other similar countries, and therefore plays a pivotal role in the regional and global estimates. Mortality With 1.2 million deaths in 2015, the region had the second highest number of deaths attributable to diabetes of any of the seven IDF regions, after the Western Pacific Region. More than half (53.2%) of these deaths occurred in people under 60 years of age. India was the largest contributor to regional mortality, with one million deaths attributable to diabetes. Chapter 4 – Diabetes by region

Map 4.6 Prevalence* (%) estimates of diabetes (20-79 years), 2015 Pr di (2 20 15 10 5 Pr evalence (%) estimates of Male Female diabetes by age (20-79 years) and sex < 7 7 - 8 8 - 8.5 8.5 - 9 9 - 10 > 10 20-29 30-39 40-49 50-59 60-69 70-79 * comparative prevalence Figure 4.6 Mortality due to diabetes, South-East Asia Region, 2015 93 Percentage of all-cause mortality due to diabetes by age (20-79 years) and sex Male Female 35 30 25 20 15 10 5 20-29 30-39 40-49 50-59 60-69 70-79 Death due to diabetes by age 3% 8% 15% 27% 25% 22% 50-59 years 60-69 years 70-79 years 20-29 years 30-39 years 40-49 years 53% under the age of 60 1,188,465 total deaths due to diabetes (664,071 women, 524,394 men) Chapter 4 – Diabetes by region

Pathogenesis of Type 1 diabetes. Autoimmune Type 1 Diabetes Beta cells destroyed via autoimmune mechanism. Genetically predisposed people:triggering factor = production of islet cell Ab. Islet cell Ab destroy Beta cells. Insulin production decreases. 3 August 2018 Etiopathogenesis of diabetes by Dr Shahjada Selim

Pathogenesis of Type 1 diabetes. Autoimmune Type 1 Diabetes Viruses + other environmental agents have been shown to be triggering factors. Viruses can damage beta cells by: 1.Direct invasion. 2.Triggering an auto immune response. 3 August 2018 Etiopathogenesis of diabetes by Dr Shahjada Selim

Pathogenesis of Type 1 diabetes. Autoimmune Type 1 Diabetes Implicated viruses: mumps, intrauterine rubella, coxsackie B virus, echo virus, gytomegalo virus and herpes virus. Chemical substances that reduce diabetes: alloxan, streptozotosin and dietary nitroamides. 3 August 2018 Etiopathogenesis of diabetes by Dr Shahjada Selim

Pathogenesis of Type 1 diabetes. Idiopathic Type 1 Diabetes No known aetiology. Permanent insulinopaenia. This form is strongly inherited. Not HLA associated. 3 August 2018 Etiopathogenesis of diabetes by Dr Shahjada Selim

Clinical features of Type 1 diabetes. Presents acutely. Symptoms due to hyperglycaemia (thirst, polyuria, tiredness,weight loss). Ketone production - abdominal pain, nausea and vomiting. Other symptoms: blurred vision, repeated infections. No chronic complications at diagnosis, may only be apparent 5-10 years post diagnosis. 3 August 2018 Etiopathogenesis of diabetes by Dr Shahjada Selim

Incidence of Type 1 diabetes. Incidence peaks at 11-13 years. Seasonal variation: lowest rates in spring and summer. Geographical variation: Japan has a very low incidence. 10% of Type 1 diabetics are over 65 years of age. 3 August 2018 Etiopathogenesis of diabetes by Dr Shahjada Selim

Etiopathogenesis of diabetes by Dr Shahjada Selim 3 August 2018 Etiopathogenesis of diabetes by Dr Shahjada Selim

Etiopathogenesis of diabetes by Dr Shahjada Selim 3 August 2018 Etiopathogenesis of diabetes by Dr Shahjada Selim

Etiopathogenesis of diabetes by Dr Shahjada Selim 3 August 2018 Etiopathogenesis of diabetes by Dr Shahjada Selim

Etiopathogenesis of diabetes by Dr Shahjada Selim Natural history of patients with type 2 diabetes...Problems before you see them Content Points: People with type 2 diabetes are at high risk for atherosclerosis and consequent CVD. Part of this risk is thought to be due to insulin resistance and resultant hyperinsulinemia as the pancreas secretes extra insulin to overcome the resistance of muscle and fat to insulin. There is evidence that hyperglycemia is one factor that may cause oxidation of compounds and contribute to endothelial dysfunction and, subsequently, CVD.36 Many individuals who are insulin resistant or who have type 2 diabetes are not diagnosed until they have sustained cardiovascular damage from hyperglycemia and hyperinsulinemia. Prediabetics (people with impaired glucose tolerance or IGT), without chronic hyperglycemia, have a 2-fold increase in risk of coronary artery disease compared with normal subjects. By the time a person has developed full-blown type 2 diabetes, their risk has increased to 3-fold greater than normal.37 In an effort to decrease the high level of morbidity and mortality and to facilitate early diagnosis, the American Diabetes Association has recently revised their guidelines by lowering the fasting plasma glucose level at which diabetes is diagnosed from 140 mg/L to 126 mg/L.38 Physicians need to be aggressive in diagnosing and treating type 2 diabetes to reduce risk of cardiovascular events. 3 August 2018 Etiopathogenesis of diabetes by Dr Shahjada Selim

Pathophysiology of type 2 diabetes Skeletal Muscle GI tract Pancreas Adipocyte Muscle α cells  cells Incretin deficiency Altered fat metabolism Hyperglucagonaemia ↑ hepatic sensitivity to glucagon INSULIN RESISTANCE INADEQUATE INSULIN SECRETION ↑ HEPATIC GLUCOSE PRODUCTION CNS Kidney ↑ BLOOD GLUCOSE Enhanced glucose reabsorption CNS, central nervous system; GI, gastrointestinal; T2DM, type 2 diabetes mellitus Cernea S & Raz I. Diabetes Care 2011;34(suppl 2):S264–S271

Etiopathogenesis of diabetes by Dr Shahjada Selim 3 August 2018 Etiopathogenesis of diabetes by Dr Shahjada Selim

Etiopathogenesis of diabetes by Dr Shahjada Selim Type 2 diabetes Patients frequently undiagnosed for many years. May present with hyperglycemia symptoms. Coma is rare in type 2 diabetes. May progress to an absolute state of insulin deficiency. 3 August 2018 Etiopathogenesis of diabetes by Dr Shahjada Selim

Pathogenesis of Type 2 diabetes. Cause: insulin secretory failure on the background of insulin resistance. Impaired insulin secretion due to beta cell malfunction can be associated with: Incorrect secretion pattern. Ratio of proinsulin to insulin. Amyloid deposits. Slow destruction of beta cells 3 August 2018 Etiopathogenesis of diabetes by Dr Shahjada Selim

Mechanisms for insulin resistance. Receptor numbers are decreased. (Often seen in obese and aged patients.) Receptor structure is abnormal. Insulin resistance at post receptor events. 3 August 2018 Etiopathogenesis of diabetes by Dr Shahjada Selim

Clinical features of Type 2 diabetes. Diagnosis due to presence of complications. (At least 30% patients have complications at diagnosis). Symptoms are mild, gradual onset : classic diabetic symptoms may be present. Type 2 diabetics are usually: usually occurs in young or elderly, in fat (“apple obesity”). 3 August 2018 Etiopathogenesis of diabetes by Dr Shahjada Selim

Etiopathogenesis of diabetes by Dr Shahjada Selim 3 August 2018 Etiopathogenesis of diabetes by Dr Shahjada Selim

Etiopathogenesis of diabetes by Dr Shahjada Selim 3 August 2018 Etiopathogenesis of diabetes by Dr Shahjada Selim

Insulin Secretion in Non-Diabetics and Type 2 Diabetics Clock Time (Hours) 06:00 Normal Type 2 DM 10:00 14:00 18:00 22:00 02:00 800 700 600 500 400 300 200 100 Insulin Secretion (pmol/min) O'MEARA et al. Am. J. Medicine, 1990;89 3 August 2018 Etiopathogenesis of diabetes by Dr Shahjada Selim

Glucose Contributions to HbA1c + Postprandial Glucose, Influenced by: Preprandial glucose Glucose load from meal Insulin secretion Insulin sensitivity in peripheral tissues and liver Fasting Glucose, Hepatic glucose production Hepatic sensitivity to insulin HbA1c = 3 August 2018 Etiopathogenesis of diabetes by Dr Shahjada Selim

Etiopathogenesis of diabetes by Dr Shahjada Selim Postprandial glucose Most of the day may be postprandial HbA1c = FPG + PPG Postprandial from the time glucose starts to rise until it comes down again Time period up to 2.5 h after a meal – normal individuals 1.5 h Testing of PPG recommended 2h after the start of a meal 3 August 2018 Etiopathogenesis of diabetes by Dr Shahjada Selim

Possible Pathogenesis of Diabetic Complications Overall Glycemic Control (HbA1c) Hyperglycemic "Peaks" Fasting/Preprandial glucose elevations Acute toxicity Chronic toxicity Tissue lesion Complications 3 August 2018 Etiopathogenesis of diabetes by Dr Shahjada Selim

Which glucose variable? Fasting plasma glucose (FPG), postprandial plasma glucose (PPG) and HbA1c all have pros and cons Where feasible, HbA1c should be the standard measurement by which to gauge risk and treatment efficacy FPG and PPG are useful to adjust daily treatment to monitor for hypoglycaemia for confirmation as haemoglobin metabolism problems may mask true HbA1c levels if there is a lack of resources for HbA1c measurement 3 August 2018 Etiopathogenesis of diabetes by Dr Shahjada Selim

Link Between Obesity and Type 2 Diabetes: Nurses’ Health Study Colditz GA, et al. Ann Intern Med. 1995;122:481-486. 3 August 2018 Etiopathogenesis of diabetes by Dr Shahjada Selim

Lessons from UKPDS: Better control means fewer complications EVERY 1% reduction in HBA1C REDUCED RISK* 1% -21% Deaths from diabetes -14% Heart attacks Lessons from UKPDS: better control means fewer complications The UKPDS has proven beyond doubt that intensive glycaemic control is strongly associated with significant clinical benefits for patients with type 2 diabetes. In an epidemiological analysis of the UKPDS cohort every 1% decrease in HbA1C was associated with clinically important reductions in the incidence of diabetes-related death ( 21%) myocardial infarction ( 14%) microvascular complications ( 37%) peripheral vascular disease ( 43%) There is no lower limit beyond which reductions in HbA1C cease to be of benefit. Taking diabetes-related death as an example, this means that:  HbA1C of 2% delivers a 42% reduction in risk  HbA1C of 3% delivers a 63% reduction in risk, and so on. Therefore, the greater the reduction in HbA1C, the greater the protection against complications. Stratton MI Adler AI, Neil AW, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405-12. -37% Microvascular complications -43% Peripheral vascular disorders *p<0.0001 UKPDS 35. BMJ 2000; 321: 405-12 3 August 2018 Etiopathogenesis of diabetes by Dr Shahjada Selim