Type 2 diabetes Derek LeRoith. Insulin Resistance: A Core Defect of The Metabolic Syndrome Insulin Resistance Dyslipidemia Obesity Hypertension Dysfibrinolysis.

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Presentation transcript:

Type 2 diabetes Derek LeRoith

Insulin Resistance: A Core Defect of The Metabolic Syndrome Insulin Resistance Dyslipidemia Obesity Hypertension Dysfibrinolysis Hyperglycemia Endothelial Dysfunction Macrovascular Disease Glucose Intolerance Adapted from McFarlane SI, et al. J Clin Endocrinol Metab. 2001;86: ; Reusch JEB. Am J Cardiol. 2002;90(suppl):19G-26G.

Chris Rhodes Ph.D. PNRI, Seattle, WA Fasting Glucose (mM/L) Fasting Insulin (pmol/L) Plasma FFA ( µmol/L) ß-Cell Mass (% change) Amyloid Deposit (% Pancreatic Area) INCREASING AGE AND/0R DEGREE OF OBESITY (increasing peripheral insulin resistance) Fasting Plasma Glucose Fasting Serum Insulin Circulating FFA Pancreatic ß-Cell Mass Islet Amyloid Deposit NormalAdaptation Glucose Intolerant Type-2 Diabetes The Pathogenesis of Obesity-linked Type-2 Diabetes [TIMM (2002) 8: ]

Chris Rhodes Ph.D. PNRI, Seattle, WA. Type-2 Diabetes - A Question of Balance PERIPHERAL INSULIN RESISTANCE ß-CELL MASS & FUNCTION Non-Diabetic State PERIPHERAL INSULIN RESISTANCE ß-CELL MASS & FUNCTION Diabetic State

Regulation of Islet  -Cell Mass and Function

Mechanisms of  cell failure in T2D Christopher J. Nolan

Mechanisms of  cell compensation for insulin resistance Christopher J. Nolan

 Cell Compensation: Christopher J. Nolan 1.Expansion of  cell mass 2.Enhanced insulin biosynthesis 3.Increased responsiveness of nutrient-secretion coupling

Christopher J. Nolan Expansion of  Cell Mass GlucoseFFAGLP-1

Enhanced Insulin Biosynthesis

Increased Responsiveness

Biphasic Insulin Secretion

Glucose Ins/IGF Acetylcholine Kristina M. Utzschneider

Christopher J. Nolan Susceptible  Cells Genetic and acquired defects: Glucolipo-detoxification Mitochondrial function Anaplerosis/cataplerosis AMPK/Mal-CoA TG/FFA cycling Insulin biosynthesis Coupling mechanisms Exocytosis Intrauterine factors

I. E.T. van den Berg Diacylglycerol Triglycerides Fatty Acids Acylated Proteins K ATP -independent Insulin Secretion carnitine palmitoyltransferase-1 (CPT 1)

AMPK/Malonyl-CoA Signaling Network

TG/FFA Cycling in Beta Cells

IntraUterine Growth Retardation (IUGR) REBECCA A. SIMMONS IUGR

Christopher J. Nolan  Cells dysfunction IGT and early T2D T2D: initiation roles Gluolipotoxicity Lipotoxicity Oxidative stress/ROS Dysregulated TG/FFA cycling Altered AMPK/Mal-CoA  Cell exhaustion ER stress

Lipotoxicity

Glucolipotoxicity in Beta Cells Marc Prentki

F.M. Ashcroft Nicotinamide nucleotide transhydrogenase: a link between insulin secretion, glucose metabolism and oxidative stress

Christopher J. Nolan  Cell failure Overt and late T2D T2D: progression roles Gluolipotoxicity Glucotoxicity Oxidative stress/ROS Islet inflammation Protein O-glycosylation AGEs Dedifferentiation Amyloid deposition Apoptosis

Michael Brownlee Four Pathways of Hyperglycaemic Damage

Michael Brownlee Aldose Reductase and The Polyol Pathway Decreased levels of GSHIncreased oxidative stress

Michael Brownlee Production of Advanced Glycation End- Product (AGE) Precursors

Michael Brownlee Consequences of Hyperglycaemia-Induced Activation of Protein Kinase C (PKC)

Michael Brownlee The Hexosamine Pathway