Alterations of Lipid Metabolism in Diabetes Mellitus

Lecture Outline Type 1 diabetes Type 2 diabetes Changes in lipid metabolism are a CONSEQUENCE of diabetes Type 2 diabetes Changes in lipid metabolism may be a CAUSE of diabetes AND

Normal Pancreatic Function Exocrine pancreas aids digestion Bicarbonate Lipase Amylase Proteases Endocrine pancreas (islets of Langerhans) Beta cells secrete insulin Alpha cells secrete glucagon Other hormones

Type 1 Diabetes Mellitus: Background Affects ~1 million people Juvenile onset Genetic component Autoimmune/environmental etiology

Type 1 Diabetes: Hallmarks Progressive destruction of beta cells Decreased or no endogenous insulin secretion Dependence on exogenous insulin for life

Diabetes: General Information Juvenile Diabetes Research Foundation www.jdf.org American Diabetes Association www.diabetes.org

Type 1 Diabetes: Presenting Symptoms Polyuria Polydipsia Hyperphagia Growth retardation Wasting

Insulin Stimulates Cellular Glucose Uptake Adipocytes Skeletal Muscle Liver Insulin Intestine & Pancreas

Absence of Insulin Glucose cannot be utilized by cells Glucose concentration in the blood rises Blood glucose concentrations can exceed renal threshold Glucose is excreted in urine

Presenting Symptoms of Type 1 Diabetes Polyuria: Glucose excretion in urine increases urine volume Polydipsia: Excessive urination leads to increased thirst Hyperphagia: “Cellular starvation” increases appetite

Growth Retardation Insulin required for normal growth Necessary for normal amino acid and protein metabolism Stimulates synthesis, inhibits degradation

Wasting Calories are inefficiently stored as fat Adipose stores are depleted

Normal Insulin Glycerol Lipolysis Free fatty acids Triglyceride LPL Triglyceride Lipolysis Glycerol Free fatty acids Free fatty acids Glucose Synthesis Insulin

Type 1 Diabetes Mellitus Triglyceride LPL Glycerol Lipolysis Free fatty acids Synthesis Free fatty acids Glucose

Clinical Chemistry Normal Uncontrolled Type 1 Fasting blood glucose < 100 mg/dL Serum free fatty acids ~ 0.30 mM Serum triglyceride ~100 mg/dL Uncontrolled Type 1 Fasting blood glucose up to 500 mg/dL Serum free fatty acids up to 2 mM Serum triglyceride > 1000 mg/dL

Adipocyte Fatty Acid Uptake Decreased Lipoprotein lipase Synthesized by adipocytes Secreted to capillary endothelium Hydrolyzes circulating triglyceride Fatty acid transporter CD36, FABPpm Facilitates movement of free fatty acids from extracellular to intracellular space

Adipocyte Triglyceride Synthesis Decreased Glycerol-3-P FACoA Lysophosphatidic acid FACoA Phosphatidic acid Pi Diglyceride FACoA Triglyceride

Antilipolysis a b AC ATP cAMP PKA HSL Perilipin PKB AMP PDE PI3K IRS Gs Gi AC AC PDE ATP cAMP PKA HSL Perilipin PI3K PKB Might have to make this one AMP

Enhanced Lipolysis: Consequences in Liver Liver partitions fatty acids: Triglyceride synthesis (VLDL) Oxidation Ketogenesis

Insulin Regulation of Hepatic Fatty Acid Partitioning FA-CoA TG ATP, CO2 -hydroxybutyrate acetoacetate Mitochondrion

In Liver: FFA Entry into Mitochondria is Regulated by Insulin/Glucacon Malonyl CoA carnitine carnitine FA-CoA CPT-II FA-CoA CPT-I ATP, CO2 HB, AcAc inner outer TG Mitochondrial membranes

Malonyl CoA is a Regulatory Molecule Condensation of CO2 with acetyl CoA forms malonyl CoA First step in fatty acid synthesis Catalyzed by acetyl CoA carboxylase Enzyme activity increased by insulin

Ketone Bodies Hydroxybutyrate, acetoacetate Fuel for brain Excreted in urine At 12-14 mM reduce pH of blood Can cause coma (diabetic ketoacidosis)

Type 1 Diabetes Summary Lack of insulin prevents storage of lipid in adipose tissue Unstored lipid circulates as lipoproteins and free fatty acids Free fatty acids are oxidized by liver to form ketone bodies

Type 2 Diabetes Mellitus 16 million estimated affected Genetic component Associated with obesity Previously maturity-onset Progressive

How is Glucose Tolerance Measured? Oral Glucose Tolerance Test (OGTT) Fasting state 75 gm oral glucose load Blood sampled before and at intervals for 2-4 hr. Serum glucose measured clinically Serum insulin measured experimentally

Oral Glucose Tolerance Test Normal Low basal glucose Small, transient rise in glucose Low basal insulin, two-phase, transient increase in insulin

Oral Glucose Tolerance Test Insulin Resistant Tissues unresponsive to insulin Basal hyperinsulinemia First phase insulin release blunted Blood glucose curve looks normal

Oral Glucose Tolerance Test Impaired Glucose Tolerance Deterioration in ability to handle glucose Basal and stimulated hyperinsulinemia Fasting plasma glucose >100, <126 mg/dL 2 hr glucose >140, <200 mg/dL

Oral Glucose Tolerance Test Diabetes Mellitus Hyperinsulinemia can’t compensate for insulin resistance Fasting blood glucose >126 mg/dL 2 hr glucose >200 mg/dL Insulin resistance increases

“Lipotoxicity” hypothesis Ectopic deposition of lipid contributes to the etiology and progression of T2DM. “Lipotoxicity” hypothesis

Bad Places for Excess Lipid Liver Skeletal Muscle Heart Muscle Pancreas

Primary Defect in Type 2 Study healthy 1st degree relatives of patients with type 2 Measure ability of body to use glucose Find defects in muscle glucose uptake before any symptoms develop

150 mg/dL 3. Adjust glucose infusion rate to maintain euglycemia. Insulin 1. Infuse insulin to induce hyperinsulinemia 2. Measure blood glucose every 2 min 150 mg/dL

Clamp Data The amount of glucose infused is a measure of insulin sensitivity. More glucose = more sensitive Less glucose = less sensitive McGarry 2002, Fig 2B

Findings from Clamp Studies Glucose disposal is decreased 60% in some healthy young people with family history of type 2. Defect is in ability of insulin to stimulate glucose transport into the cell.

Why is Glucose Transport Reduced? Mitochondrial phosphorylation decreased 30% Intramyocellular lipid is increased 80% Ectopic fat may hinder insulin-stimulation of glucose transport.

Lipids as Signaling Molecules Fatty acyl CoA esterified to diglyceride Diglyceride activates protein kinase C theta Protein kinase C theta serine- phosphorylates and inactivates insulin receptor substrate 1

What is consequence of muscle insulin resistance? Pancreas compensates > hyperinsulinemia Hyperinsulinemia exacerbates insulin resistance in adipose tissue.

Consequences of Insulin Resistance in Adipose Tissue Similar to insulin deficiency Reduced TG synthesis Enhanced lipolysis Net increase in FA availability to non-adipose tissues

Effect of excess free fatty acids on insulin sensitivity

Consequences of Insulin Resistance FFA in Muscle Increased intramyocellular lipid Hypothetical: inhibition of insulin signaling by diglyceride Reduction in glucose uptake by muscle

Consequences of Insulin Resistance FFA in Liver Increased triglyceride synthesis Increased oxidation Increased gluconeogenesis Hepatic glucose output contributes to hyperglycemia

Consequences of Insulin Resistance FFA in Pancreas Animal models of diabetes Lipid droplets accumulate in beta cells Beta cells undergo apoptosis Reduced beta cell mass Decreased circulating insulin

Pancreatic Histology Diabetic Control

Timeline: Development of Type 2 Genetic predisposition Environmental insult Insulin resistance Increased lipolysis Ectopic fat deposition Compromised pancreatic function Fasting Hyperglycemia Beta cell failure

Diet and Exercise Goal Purpose Reduce caloric intake Increase exercise Reduce size of adipose stores Improve insulin sensitivity Increase lean body mass

Insulin-releasing Drugs Goal Stimulate pancreas to produce more endogenous insulin Purpose Overcomes insulin resistance Plasma glucose is taken up and oxidized appropriately

Hepatic Insulin Sensitizers Goal Work selectively on the liver Inhibit glycogenolysis and gluconeogenesis Purpose Reduce hepatic glucose output Reduce blood glucose concentration

Thiazolidinediones: new class of drugs Goal Peripheral insulin sensitizers Enhance muscle insulin sensitivity Purpose Reduce blood glucose, insulin

Thiazolidinediones: new class of drugs Unintended consequences Increase lipid storage in adipose tissue Reduce lipid storage in muscle, pancreas Preserve beta cell mass

Summary Insulin deficiency perturbs lipid metabolism in type 1 diabetes. Prevention Under investigation Treatment Insulin replacement Management of carbohydrate intake

Summary, cont. Dysregulated lipid metabolism may contribute to the development of type 2 diabetes. Prevention Eat less, exercise more really works Treatment Depends on stage of disease