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1 Copyright Notice You are authorized to photograph these slides subject to the following terms and conditions: They are to be used solely for personal, noncommercial, informational, and educational purposes They must not be modified in any way They must not be distributed in any way Copyright information or other proprietary notices may not be removed, changed, or altered

2 Pathophysiology of diabetes Department of Pathophysiology Poznan University of Medical Sciences

3 Diabetes mellitus Greek siphon Aretus the Cappadotian 159 Latin sweet like honey Thomas Willis 1675 polyuria glucosuria

4 Diabetes the scale of the problem Diabetes affects 370 million people worldwide, of which 187 million remain undiagnosed Diabetes affects 7.8% of the U.S. population (23.6 million people) including 5.7 million who do not realize they have diabetes Only within a subpopulation of U.S. citizens above 60, the number of people with diabetes is expected to reach 44.1 million people by 2034 Diabetes cuts 8.5 years off the life span of the average 50-year-old compared to an individual of the same age without diabetes 1/3 of the population born in 2000 will develop diabetes, with up to 30% reduction in life expectancy Annual economic costs of diabetes in the U.S. = 116 billion $ in direct medical cosxts and 58 billion $ in reduced productivity Diabetes-related spending expected to reach 336 billion in 2034

5 Diabetes A disorder of multiple etiology: 1. leading to abnormalities in metabolism 2. resulting from defects in insulin activity 3. characterized by chronic hyperglycaemia

6 Insulin Promotes fuel storage = ANABOLISM Prevents fuel breakdown = CATABOLISM Hormone Insulin Glucocorticoids Glucagon Growth hormone Epinephrine Blood glucose

7 Diagnosis of diabetes Blood glucose Fasting: > 7 mmol/l (126 mg/dl) 2 h after oral glucose load: > 11.1 mmol/l (200 mg/dl) Random: > 11.1 mmol/l (200 mg/dl) + overt clinical symptoms Expert Committee on the Diagnosis and Classification of Diabetes (1997) American Diabetes Association (2004)

8 Classification of diabetes DIABETES Primary (95%) (unrelated to other diseases) Secondary (5%) (caused by another disease) Type 1 = Insulin-dependent Type 2 = Non-insulin dependent MODY Gestational diabetes Destruction of the pancreas pancreatitis, hemochromatosis Endocrine diseases acromegaly, Cushing syndrome, pheochromocytoma, glucagonoma

9 Type I diabetes GENES AUTOIMMUNE REACTION ENVIRONMENT 30-70% concordance in twins HLA antigens DR3 HLA-DQA1*0501/DQB1*0201 DR4 HLA-DQA1*0301/DQB1*0302 Viruses: Rubella, Coxsackie B4 Cow s milk proteins? Others?? Insulin gene

10 Type I diabetes GENES AUTOIMMUNE REACTION ENVIRONMENT Jun et al, Diabetes Rev 2003, 19: 8 Insulitis

11 Type I diabetes GENES AUTOIMMUNE REACTION ENVIRONMENT BETA-CELL DESTRUCTION INSULIN DEFICIENCY TYPE I DIABETES

12 Type I diabetes

13 Type II diabetes GENES OBESITY INSULIN RESISTANCE HYPERINSULINEMIA 70-90% concordance in twins Race (non-white Americans, Pacific islands inhabitants) Visceral obesity Adipocytes secrete mediators, that may interfere with insulin action: leptin, adiponectin TNFa, IL-6, CXCL5, resistin, RBP-4

14 Adipose tissue and inflammation Rosen et al, Cell 2014; 156: 20

15 Insulin signalling Van den Berghe, J Clin Invest 2004; 114, 1187

16 OBESITY Insulin resistance Lipid stress: fatty acids long-chain-acyl-coa ketone bodies Inflammatory stress: NF-kB TNFa IL-6 Adipocrine stress: resistin RBP-4 adiponectin Insulin receptor dysfunction MUSCLES: glucose uptake glycogenolysis protein synthesis protein degradation Aminokwasy acids LIVER: gluconeogenesis Hyperglycaemia Muscle atrophy

17 OBESITY Insulin resistance Lipid stress: fatty acids long-chain-acyl-coa ketone bodies Inflammatory stress: NF-kB TNFa IL-6 Adipocrine stress: resistin RBP-4 adiponectin PANCREAS Genetic predisposition? Normal beta cells: insulin secretion Sensitive beta cells: protein synthesis control amyloid synthesis (IAPP) cell apoptosis insulin secretion Compensatory hypersinsulinemia Relative insulin deficiency

18 Natural course of type II diabetes Henry M, Am J Med. 1998; 105, 20S

19 Type II diabetes GENES OBESITY INSULIN RESISTANCE HYPERINSULINEMIA BETA-CELL EXHAUSTION RELATIVE INSULIN DEFICIENCY TYPE II DIABETES

20 Type I vs. type II diabetes Type 1 Type 2 Prevalence 10% 90% Age at onset < 30 > 40 Clinical course Rapid Slow Ketosis Common Rare Obesity Rare Common HLA association Yes No Concordance in twins 40% 80% Autoimmune reaction Yes No Islet antibodies Yes No Beta cells Massive destruction Dysfunction Insulin release Severe deficiency Hyperinsulinaemia Relative deficiency Insulin resistance No Yes Treatment with insulin Always Usually not

21 Acute complications of diabetes Hyperglycaemia Hyperosmolality Glucosuria Ketogenesis Cellular dehydration Urinary tract infections Polyuria Acidosis Kussmaul breathing Coma Polydipsia Hyperkaliemia Loss of potassium Renal hypoperfusion Dehydration Vomiting

22 Chronic complications of diabetes Microvascular Retinopathy Nephropathy Neuropathy Macrovascular Ischaemic heart disease Stroke Peripheral vascular disease Diabetic angiopathy is the primary cause of all diabetic pathies

23 Molecular mechanisms underlying diabetic angiopathy Generation of reactive oxygen species Polyol pathway Hexosamine pathway Kinase C pathway Non-enzymatic protein glycation

24 Pathogenesis of diabetic angiopathy 1. Long-term exposure to high glucose 2. Endothelial cell dysfunction 3. Basement membrane alterations 4. Thick and leaky blood vessels 5. Ischaemia and exudation 6. Organ damage

25 Cardiovascular complications in DM Malmberg et al. Circulation 2000; 102: 1014

26 Diabetic macroangiopathy DIABETES Endothelial dysfunction: Impaired vasodilation nitric oxide endothelin Inflammation Procoagulant activity prostacyclin PAI-1 Autonomic imbalance parasympathetic activity sympathetic activity predisposition to hypertension Hyperlipidaemia: VLDL oxldl ATHEROSCLEROSIS

27 Diabetic retinopathy Background retinopathy with small blot haemorrhages Cotton wool spots Donnelly et al, Br Med J 2000; 320, 1062

28 Coronary heart disease in diabetes Higher incidence of multi-vessel diffusive disease Plaque rupture more common Superimposed thrombosis more likely Mortality double Complications more common Re-occlusion and re-infarction rates higher Survival after angioplasty or bypass lower Donnelly et al, Br Med J 2000; 320, 1062

29 Diabetic nephropathy Thickening of glomerular basement membrane 2. Mesangial expansion: matrix accumulation, vascular distortion, podocyte injury, decreased filtration surface area 3. Nodular sclerosis (Kimmelstiel-Wilson lesions): focal mesangiolysis, endothelial cell detachment, hyalin masses Normal Diabetes 4. Advanced glomerular sclerosis 5. Interstitial fibrosis and tubular atrophy 6. Vascular hyalinosis (the efferent arteriole)

30 Diabetic neuropathy Normal Segmental demyelination and axonal degeneration Remyelination with shorter internodes and regeneration by sprouting Said G. Nature Rev Neurol 2007; 3: 331

31 Diabetic neuropathy Polyneuropathy Mononeuropathy Autonomic neuropathy: Cardiovascular Resting tachycardia Orthostatic hypotension Silent myocardial infarction Gastrointestinal Gastroparesis Esophageal dysfunction Diarrhea, constipation Genitourinary Bladder dysfunction Impotence Peripheral Decreased catecholamine response to hypoglycemia Gustatory sweating

32 Diabetic foot

33 Diabetic gastropathy Apoptosis of neurons in mesenteric plexus Delayed gastric emptying Rayner et al. J Clin Invest 2006; 116: 299 Rapid intestinal transit

34 Infections in diabetes Impaired phagocyte function Tissue ischaemia Increased microorganism proliferation in high glucose Candidiasis The commonest infections in diabetes: Genito-urinary tract infections Pneumonia Skin and soft tissue infections

35 Dental problems in diabetes Periodontitis and gingivitis Impaired saliva secretion Alterations in oral bacterial microflora Caries? Stomatitis (Candidiasis) Glossitis Dysgeusia