Lipids Carbohydrate Protein Fatty Acids Glycerol Mono/di-saccarides Fat Liver Muscle Aminoacids Triglycerides Glycogen Protein
Microvascular Macrovascular Diabetes-specific Diabetes-enhanced
HbA1c 5.7(6.0) 6.4% Plasma glucose (mmol/i) Status FPG 2-hour post-ogtt IFG ADA WHO IDF 6.1 and <7.0 6.1 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 <11.1 7.8 but <11.1 7.8 but 11.0
151 million 415 million 642 million 2000 2015 2040 International Diabetes Federation. IDF Diabetes Atlas. Seventh Edition. 2015
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
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
PATHOGENESIS 5-8 % Genetic Epigenetic Up to 25% Run Environmental
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
EVOLUTION 2/1/2017
URBANISATION
2/1/2017
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 1994 2000 No Data <14.0% 14.0-17.9% 18.0-21.9% 22.0-25.9% >26.0% 2000 2009 2009 No Data <4.5% 4.5-5.9% 6.0-7.4% 7.5-8.9% >9.0%
Age-adjusted relative risk of diabetes Increased Risk of T2DM with increasing BMI 100 90 80 70 60 50 40 30 20 10 0 < 22 22-22.9 23-23.9 24-24.9 25-26.9 27-28.9 29-30.9 31-32.9 33-34.9 35 + BMI (kg/m 2 ) Colditz GA et al.ann Intern Med 1995
Reduced/altered insulin secretion Hyperglycemia Inappropriate endogenous glucose production Impaired insulin-mediated glucose disposal
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
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
I n s u l i n s e c r e t i o n ( p m o l / m i n ) 1000 900 800 700 600 500 400 300 200 Obese Lean Polonsky et al., 1988a 100 6 a.m. 2 p.m. 6 p.m. 10 p.m. 2 a.m. 6 a.m.
Beta-cell function (%) 100 80 60 40 20 0 12 10 8 6 4 2 0 2 4 Years from diagnosis Adapted from UKPDS 16. Diabetes 1995;44:1249 58
Insulin (nmol/l) Insulin (nmol/l) Glucose (mmol/l) Glucose (mmol/l) MEAL TOLERANCE TEST : Type 2 Diabetes Mellitus 20 16 12 8 4 Normals Type 2 : Fasting PG < 10 10 mmol/l 8 4 0.6 0 0.4 0.4 0.2 0.2 0 0 1 2 3 4 0 0 1 2 3 4 hrs Owens D, et al 1995
Plasma glucose (mmol/l) Plasma insulin (pmol/l) 12 11 10 9 8 7 6 5 4 0 60 120 180 240 300 TIME (min) 400 350 300 250 200 150 100 50 0 0 60 120 180 240 300 TIME (min)
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
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) 700 20 16 12 8 4 0 240 480 720 960 Time (min) 600 500 400 300 200 100 0 1200 1440 Before weight loss 0 240 480 720 960 Time (min) 1200 1440 After weight loss
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
Leptin Resistin
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
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)
Fat Topography In Metabolic Syndrome Hi TG Hi FFA Intramuscular Fat Intrahepatic Fat Low HDL Cholesterol Subcutaneous Fat Intraabdominal Fat DeFronzo, JCEM, 2014
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
Metformin Sulfonylurea (long and short acting) DPP4 inhibitors Thiazolidinediones SGLT2 Acarbose GLP-1 agonist Insulin ( OD, BID, TID, CSII ) Medication for concomitant diseases
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
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
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
(photocoagulation, vitreous haemorrhage, renal failure) Intensive (SU/Ins) vs. Conventional glucose control HR (95%CI)
(fatal or non-fatal myocardial infarction or sudden death) Intensive (SU/Ins) vs. Conventional glucose control HR (95%CI)
Access to care - Type 2 11.15 N (%) of patients seen regularly at clinic (e.g. 4 times a year) 11.16 N (%) of patients with regular screening for late complications (micro- and/or macro vascular) (e.g. yearly) 11.17 N (%) patients receiving regular glucose test at clinic (HbA1c, BG profile, PPG, FPG, RPG) (each visit) 11.18 N (%) of patients who do regular HMBG (e.g. daily or weekly) 11.19 N (%) of patients within agreed target for glucose control (HbA1c, BG profile, PPG, FPG, RPG, urine glucose) 11.20 N (%) of patients with improvements in metabolic control 11.13 N (%) of patients with reduction in BMI
11.14 N (%) of patients with normal BP (<140/90) 11.15 N (%) of patients with reduction in BP 11.16 N (%) of patients with neuropathy, retinopathy or nephropathy 11.17 N (%) of patients with macro vascular complications 11.18 N (%) of patients with improvements in KAP (Knowledge, Attitude and Practises)