2.5% of all deaths globally each year. 7th leading cause of death by % of people with diabetes live in low and middle income countries

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1 Lipid Disorders in Diabetes (Diabetic Dyslipidemia) Khosrow Adeli PhD, FCACB, DABCC Head and Professor, Clinical Biochemistry, The Hospital for Sick Children, University it of Toronto

2 Diabetes A Global Epidemic 2.5% of all deaths globally each year 7th leading cause of death by % of people with diabetes live in low and middle income countries Most diabetics are middle-aged (45-64) T2DM accounts for 90% of diabetes worldwide 50-80% of deaths in diabetics due to cardiovascular disease Diabetes deaths likely to double in the next 10 years without urgent action World Health Organisation, Top 10 Causes of Death Worldwide

3 Worldwide Incidence of Diabetes over the Last Decade 2013: 347 million 2013: 347 million Atkins and Zimmet, NDT 2010

5 Global Statistic s

6 JAMA 2003 Jan 1;289(1):76-9 Prevalence of obesity, diabetes, and obesity-related health risk factors, Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, Marks JS

7 Obesity and Diabetes Are Strongly Linked to Insulin Resistance and Metabolic Complications Metabolic Syndrome Hypertension Dyslipidemia (Metabolic bli or Diabetic) ib i) Inflammation Obesity Insulin Resistance Coagulation and fibrinolytic abnormalities Glucose Intolerance I dri k ft 2 dibt Increased Risk of Type 2 diabetes and Cardiovascular Disease

8 MRFIT: Cholesterol and CVD Mortality in Men With Type 2 Diabetes per deaths p -years ted CVD 0 person- e-adjust 10,000 Age Controls Type 2 diabetes < Plasma cholesterol (mg/dl) Stamler et al. Diabetes Care. 16:

9 Relation Between Insulin Resistance and Hypertriglyceridemia Established in 1970s a TG (m mg/dl) Plasm r = 0.73 P < Insulin Response to Oral Glucose* * Total area under 3-hour response curve (mean of 2 tests). Olefsky JM et al. Am J Med. 1974;57:

10 Common Proatherogenic Features of the Lipid Profile in Diabetic Dyslipidemia Elevated TG levels (fasting and post-prandial) - Chylos, VLDL, VLDL remnants Dense LDL profile Elevated ApoB levels Low HDL-C levels; Small Dense HDL ; Glycation of apo-b (LDL, Lp(a)) and apo-ai. Elevated Lp(a) levels

and decreased HDL (decreased large alpha 1 HDL) 5 10 20 40 60 80 1000 Particle Size - Diameter, nm Genest et al Circulation 1992;85:2025

11 Lipoprotein Profile 0.95 VLDL Remnants VLDL VLDL VLDL Chylomicron IDL Particle Density, g/ml HDL 3 HDL 2 LDL Lp(a) Chylomicron Remnants Insulin resistant patients often have elevated remnants, LDL (increased small dense LDL), and and decreased HDL (decreased large alpha 1 HDL) Particle Size - Diameter, nm Genest et al Circulation 1992;85:2025 Campos et al, ATVB 1992; 12:187, Schaefer et al JAMA 1994;59:32, McNamara et al Atherosclerosis 2001;154:229, Asztalos et al ATVB 2004;24:2181, Ai et al Clin Chem 2010; 56:

12 Diabetic Dyslipidemia involves a disequilibrium characterised by an excess of atherogenic apob-containing lipoproteins p relative to low concentrations of anti-atherogenic HDL whose functional properties are defective Dysfunctional Small Dense HDL DIABETIC DYSLIPIDEMIA VLDL VLDL Remnants IDL LDL ; Dense LDL Enhanced Arterial Cholesterol Deposition Attenuated Reverse Cholesterol Transport Accelerated Atherogenesis

13 Characteristic dyslipidemia of insulin resistant states (Obesity, Type 2 diabetes, Metabolic Syndrome) Low HDL cholesterol Hypertriglyceridemia Elevated VLDL Postprandial hyperlipidemia Elevated remnant particles Qualitative LDL particle changes Insulin sensitive TG HDL-C Normal LDL-C Insulin resistant TG HDL-C Normal LDL-C Dense LDL Risk of coronary heart disease

14 Dysfunctional HDL in Type II Diabetes HDL Particle number Small HDL ; Plasma residence time Transport of antioxidative enzymes Reverse Cholesterol Transport Antioxidative protection of LDL A ti i fl t ti it Anti-inflammatory activity Atherosclerotic Disease

15 Pathophysiology and Underlying Mechanisms Tissue and Whole-Body Insulin Resistance

16 Insulin Resistance & Type 2 Diabetes Genetic Predisposition iti & Overnutrition/Lack of Physical Activity Overweight/Obesity Prediabetes/Insulin Resistance Insulin Pancreas Increased insulin action in more sensitive i tissues or biochemical pathways Tissue Insulin Resistance

17 Insulin Resistance and Diabetes are Disorders of Dysregulated Lipid Homeostasis

18 Lipid Overflow / Ectopic Fat Model - Triglyceride surplus deposited in liver, heart, skeletal muscle, & VAT in susceptible subjects (IR, dysfunctional adipose tissue) Despres and Lemieux, Nature 2006

19 Fatty Liver/Hepatic Steatosis in Insulin Resistant States Strongly Associated with: Obesity Insulin Resistance, Type 2 Diabetes,

Fasting dyslipidemia Diabetic ib i dyslipidemia id

sdldl formation Elevated chylomicrons Elevated

LPL Competition for clearance Chylomicrons HDL C

20 Fasting dyslipidemia Diabetic ib i dyslipidemia id i Hypertriglyceridemia Reduced HDL C Elevated VLDL sdldl formation Elevated chylomicrons Elevated chylomicron remnants Postprandial dyslipidemia VLDL LPL Competition for clearance Chylomicrons HDL C sdldl Chylomicron remnants Increased risk of atherosclerosis

21 Mechanisms Relating Insulin Resistance and Dyslipidemia Fat Cells FFA X Insulin resistance FFA CE VLDL CETP Liver CE CETP TG TG IDL HDL TG ApoB HDLc LDLc Hepatic lipase ApoA-I Kidney Insulin Ginsberg HN LDL Lipoprotein lipase or hepatic lipase Small, dense LDL Liver While LDLc is similar, particle burden is heavier

22 Pathophysiology of Dyslipidemia in Type 2 Diabetes TG pool High Low Smaller VLDL LPL IDL LPL Large LDL LDLR LPL LPL/HL Larger Small S ll Remnants VLDL LDL CETP TG HDL HL Smaller LDL Smaller HDL Krauss RM. Diabetes Care. 2004;27 27:

23 Diabetic Dyslipidemia: Treatment Lipoprotein pattern: atherogenic dyslipidemia (high TG, low HDL, small LDL particles) Therapeutic Management: LDL-cholesterol goal: <100 mg/dl Baseline LDL-cholesterol 130 mg/dl Most patients require LDL-lowering drugs Baseline LDL-cholesterol mg/dl Consider therapeutic options Baseline triglycerides: 200 mg/dl Non-HDL cholesterol: secondary target of therapy

24 Conclusions Diabetic Dyslipidemia is a common component of the metabolic syndrome and type 2 diabetes Lipid Abnormalities are critical underlying factors in insulin resistance and type 2 diabetes

25 Thank YOU!

Pathophysiology of Lipid Disorders

Pathophysiology of Lipid Disorders Henry Ginsberg, M.D. Division of Preventive Medicine and Nutrition CHD in the United States CHD is the single largest killer of men and women 12 million have history