Diabetes mellitus II - III First and second type of diabetes mellitus Lecture from pathological physiology Oliver Rácz, 2011-2018 Definition of diabetes mellitus Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels. Type 1 diabetes geographic differences, hot spots and genetic background Peak: 10-25 years In any age Last years very low age INCIDENCE = cases/100 000/y Finnland: 41 USA 15 Germany 7 Greece: 5 Mexico, Japan, Cuba < 5 Sardinia 32 (hot spot) HLA haplotypes and DM 1 DR3/DR3 5.0 DR4/DR4 6.8 DR3/DR4 14.3 DR3/X 0.7 DR4/X 1.0 X/X 0.04 95% of DM 1 patients posses DR3 or 4 but these haplotypes are common in population! 1
Genes of MHC (HLA) system Groove for peptides on MHC glycoproteins Interaction between T lymphocyte, and antigen presenting cells 2
Etiology of type 1 diabetes The genetic background is related to the immune system (HLA glycoproteins are parts of antigen presenting cells*) (Susceptibility to autoimmune destruction of β cells) External trigger viral infections, cow milk protein (Islet cell antibodies, Insulin autoantibodies, antigad present already before the manifestation) Long process, when the number of cells is < 5-10 % acute manifestation of symptoms in some days weeks Without insulin death in coma Etiology of type 1 diabetes The genetic background is related to the immune system (HLA glycoproteins are parts of antigen presenting cells*) (Susceptibility to autoimmune destruction of β cells) External trigger viral infections, cow milk protein The role of other genes The actual constellation of immune system nonderstructive or destructive insulitis (Islet cell antibodies, Insulin autoantibodies, antigad present already before the manifestation) Long process, when the number of cells is < 5-10 % acute manifestation of symptoms in some days weeks Without insulin death in coma Definition of diabetes mellitus Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels. 3
Etiology of type 2 diabetes mellitus Heterogenous group of patients (heterogenous disease!) Mostly obese adults, family background Long period without complains, no ketosis Often hypertension, CHD At the beginning hyperinsulinemic (insulin resistant), later the secretion of insulin decreases T2DM is a progressive disease Diabetes is only the end of the story! 4
INSULIN glucose IR GLUT4 INSULIN glucose IR GLUT4 disorder of secretion and disturbance of function performance of B cells burden - obesity 5
Secretion disorder is the first Genes regulating the intrauterine development of Langerhans islets Lessons from an extreme rare condition transient neonatal diabetes Small babies and DM2 Different burden Different performance HETEROGENITY OF T2DM? HROZBA PRE ŠTUDENTOV: T2DMA, T2DMB...T2DMG OR? 6
COMPONENT ANALYSIS! McCarthy 2017 7
Everything is more complicated Increase of BG secretion of insulin No insulin (T1DM) Disturbed function of signal pathway (T2DM) But our diet does not contain glucose! ENTEROINSULAR AXIS! INCRETINS Glucagon like protein I and its decreased activity in T2DM? 8
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TYPE 2 DIABETES IS THE TIP OF THE ICEBERG 5 % TYPE 2 DIABETES MELLITUS often undiagnosed usual diagnosed too late microvascular complications present atherosclerosis accelerated 12 % IMPAIRED GLUCOSE TOLERANCE* atherosclerosis accelerated cca 25 % INSULIN HYPERSECRETION (INSULIN RESISTANCE, METABOLIC SYNDROME) impaired sympathetic regulation? obesity, hypertension, impaired lipid status atherosclerosis accelerated TYPE 2 DIABETES IS THE TIP OF THE ICEBERG 8 % TYPE 2 DIABETES MELLITUS 15 % IMPAIRED GLUCOSE TOLERANCE* cca 25 % INSULIN HYPERSECRETION WHY??? Nondiagnosed Late diagnosed Obesity Aging of the whole population CVD & DM 2 PREVENTION, 21 st CENTURY NUTRITION energy composition, micronutrients SMOKING & ALCOHOL HUNTING & GATHERING (PHYSICAL ACTIVITY) HEALTH AWARENESS weight control blood lipids, glucose blood pressure inherited and acquired health risks 55% S, 30% F, 15% P 10