Lipids Carbohydrate Protein. Fatty Acids Glycerol. Mono/di-saccarides. Aminoacids. Fat Liver Muscle. Triglycerides Glycogen Protein

Transcription

1

2 Lipids Carbohydrate Protein Fatty Acids Glycerol Mono/di-saccarides Fat Liver Muscle Aminoacids Triglycerides Glycogen Protein

3 Microvascular Macrovascular Diabetes-specific Diabetes-enhanced

4

5 HbA1c 5.7(6.0) 6.4% Plasma glucose (mmol/i) Status FPG 2-hour post-ogtt IFG ADA WHO IDF 6.1 and < and <7.0 >6.0 and <7.0 IGT ADA WHO IDF If measured IFG = impaired fasting glucose IGT = impaired glucose tolerance OGTT = oral glucose tolerance test 7.8 but < but < but 11.0

6

7

8 151 million 415 million 642 million International Diabetes Federation. IDF Diabetes Atlas. Seventh Edition. 2015

9 Epidemiology - the rule of halves Slide no 9 1% reduction in BMI = 2.4 million cases of diabetes prevented in the US 1% reduction in HbA1c = 20% reduction in diabetes-related deaths

10

11 Type 1 Type2 Age young elderly Onset abrupt slowly Plasma insulin low high Ketosis yes no Weight thin obese Genetic weak (HLA) strong Treatment insulin Diet,OHA,Insulin Complications micro/macro macro/micro

12 PATHOGENESIS 5-8 % Genetic Epigenetic Up to 25% Run Environmental

13 EPIGENETIC?? Foetal programming? Differentiated RNAreading of DNA Off springs of GDM pregnancy have several fold higher risk Off springs of mothers with malnutrition have higher risk

14 EVOLUTION 2/1/2017

15 URBANISATION

16 2/1/2017

17 Age-adjusted Percentage of U.S. Adults with Obesity or Diagnosed Diabetes Obesity (BMI 30 kg/m 2 ) 1994 O B E S I T Y Diabetes D I A B E T E S No Data <14.0% % % % >26.0% No Data <4.5% % % % >9.0%

18

19 Age-adjusted relative risk of diabetes Increased Risk of T2DM with increasing BMI < BMI (kg/m 2 ) Colditz GA et al.ann Intern Med 1995

20 Reduced/altered insulin secretion Hyperglycemia Inappropriate endogenous glucose production Impaired insulin-mediated glucose disposal

21 Main Pathophysiological Defects in T2DM incretin effect Relative pancreatic insulin secretion gut carbohydrate delivery & absorption - pancreatic glucagon secretion HYPERGLYCEMIA? + - peripheral glucose uptake hepatic glucose production

22 The common denominator in the most common forms of diabetes is relative insufficient beta cell mass Type 2 diabetes Normal / normoglycaemia Obese normoglycaemia Type 1 diabetes

23 I n s u l i n s e c r e t i o n ( p m o l / m i n ) Obese Lean Polonsky et al., 1988a a.m. 2 p.m. 6 p.m. 10 p.m. 2 a.m. 6 a.m.

24 Beta-cell function (%) Years from diagnosis Adapted from UKPDS 16. Diabetes 1995;44:

25 Insulin (nmol/l) Insulin (nmol/l) Glucose (mmol/l) Glucose (mmol/l) MEAL TOLERANCE TEST : Type 2 Diabetes Mellitus Normals Type 2 : Fasting PG < mmol/l hrs Owens D, et al 1995

26 Plasma glucose (mmol/l) Plasma insulin (pmol/l) TIME (min) TIME (min)

27 Inappropriate hepatic glucose production Glucose Glucose-6- Phosphatase Glucokinase PEPCK Glucose-6-Phosphate Fructose 1-6-bisphosphatase Gluconeogenesis Glycerol Lactate Amino acids fructose Glycogenolysis Glycogen Synthase Glycogen phosphorylase Glycogen X Glucagon camp

28 Plasma glucose levels and insulin secretion rates in obese people with Type 2 diabetes Plasma glucose (mmol/l) 24 Insulin secretion rate (pmol/m 2 /min) Time (min) Before weight loss Time (min) After weight loss

29 Figure 1. A simplified model of the insulin signalling pathway that regulates glucose transport in skeletal muscle Insulin Stimulation of glucose transport Insulin receptor α α Cell-surface membrane Glucose Glucose GLUT4 β β ATP PI 3,4-P3 PI 3,4,5-P3 Tyrosine phosphorylation IRS SH2 domains p85 p110 PDK 1/2 Phosphoinositidedependent kinase Phosphoinositide (PI) 3-kinase Protein Kinase B (Akt)? PKCζ PKCλ Atypical protein kinase C? Translocation to cell membrane Cytoplasm GLUT4- containing vesicle

30 Leptin Resistin

31 Adverse cardiometabolic effects of products of adipocytes Inflammation TNFα IL-6 Adipsin (Complement D) Atherosclerosis Adiponectin Lipoprotein lipase Adipose tissue Agiotensinogen FFA Resistin Leptin Lactate Plasminogen activator inhibitor-1 (PAI-1) Thrombosis Lyon 2003; Trayhurn et al 2004; Eckel et al 2005 Hypertension Insulin Atherogenic dyslipidaemia Type 2 diabetes

32 Elevated lipid levels are detrimental in type 2 diabetes Increased hepatic glucose output (hyperglycaemia) MUSCLE TG accumulation Insulin resistance FFA TG Hormones LIVER Increased VLDL Decreased HDL Increased small dense LDL Atherosclerosis B CELLS TG accumulation Disturbed insulin secretion (hyperinsulinaemia)

33 Fat Topography In Metabolic Syndrome Hi TG Hi FFA Intramuscular Fat Intrahepatic Fat Low HDL Cholesterol Subcutaneous Fat Intraabdominal Fat DeFronzo, JCEM, 2014

34

35 Central Obesity WHR > 0.9 men > 0.8 women or BMI > 30 kg/m² Microalbuminuria UAE 20 µg min IGT/IFG or type 2 diabetes METABOLIC SYNDROME Triglycerides 150 mg/dl & HDL-Ch < 35/39 mg/dll Insulin resistance (glucose uptake below lowest quartile) Blood pressure 140/90 mmhg

36

37

38

39

40

41

42

43

44

45

46

47 Metformin Sulfonylurea (long and short acting) DPP4 inhibitors Thiazolidinediones SGLT2 Acarbose GLP-1 agonist Insulin ( OD, BID, TID, CSII ) Medication for concomitant diseases

48

49

50 Figure 1. A simplified model of the insulin signalling pathway that regulates glucose transport in skeletal muscle Insulin Stimulation of glucose transport Insulin receptor α α Cell-surface membrane Glucose Glucose GLUT4 β β ATP PI 3,4-P3 PI 3,4,5-P3 Tyrosine phosphorylation IRS SH2 domains p85 p110 PDK 1/2 Phosphoinositidedependent kinase Phosphoinositide (PI) 3-kinase Protein Kinase B (Akt)? PKCζ PKCλ Atypical protein kinase C? Translocation to cell membrane Cytoplasm GLUT4- containing vesicle

51 Adipose tissue: Lipolysis (indirect) Liver: Glucose production (?) Glucose uptake (?) Glycogen synthesis (?) Brain: Effects of GLP-1 Hypothalamus: appetite, satiety food intake Heart: Glucose uptake Ejection fraction Stomach: Gastric emptying Acid secretion Muscle Ileum: Synthesis (from proglucagon), Secretion (after meals, glucose, fat) Endocrine pancreas: Secretion: β-cells: insulin secretion α-cells: glucagon secretion δ-cells: somatostatin secretion Biosynthesis: (Pro-)insulin β-cell mass: Neogenesis, replication apoptosis

52

53

54

55 TYPE 2 DIABETES : Treatment Targets Good Poor Bl.Glucose (mm) HbA 1c (%) <7.0 >8.5 Lipids (mm) Cholesterol <5.2 >6.5 HDL-C >1.1 <0.9 fasting triglycerides <1.7 >2.3 BMI (kg.m 2 ) <25 >27 <24 >26 BP (mmhg) <135/85 >160/95 STOP SMOKING

56

57 (photocoagulation, vitreous haemorrhage, renal failure) Intensive (SU/Ins) vs. Conventional glucose control HR (95%CI)

58 (fatal or non-fatal myocardial infarction or sudden death) Intensive (SU/Ins) vs. Conventional glucose control HR (95%CI)

59

60 Access to care - Type N (%) of patients seen regularly at clinic (e.g. 4 times a year) N (%) of patients with regular screening for late complications (micro- and/or macro vascular) (e.g. yearly) N (%) patients receiving regular glucose test at clinic (HbA1c, BG profile, PPG, FPG, RPG) (each visit) N (%) of patients who do regular HMBG (e.g. daily or weekly) N (%) of patients within agreed target for glucose control (HbA1c, BG profile, PPG, FPG, RPG, urine glucose) N (%) of patients with improvements in metabolic control N (%) of patients with reduction in BMI

61 11.14 N (%) of patients with normal BP (<140/90) N (%) of patients with reduction in BP N (%) of patients with neuropathy, retinopathy or nephropathy N (%) of patients with macro vascular complications N (%) of patients with improvements in KAP (Knowledge, Attitude and Practises)