Alterations of Lipid Metabolism in Diabetes Mellitus

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Alterations of Lipid Metabolism in Diabetes
Mellitus

• Neile Edens, Ph.D.
• neile.edens_at_abbott.com

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Lecture Outline

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

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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

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Type 1 Diabetes MellitusBackground

• Affects 1 million people
• Juvenile onset
• Genetic component
• Autoimmune/environmental etiology

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Type 1 DiabetesHallmarks

• Progressive destruction of beta cells
• Decreased or no endogenous insulin secretion
• Dependence on exogenous insulin for life

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Diabetes General Information

• Juvenile Diabetes Research Foundation
• www.jdf.org
• American Diabetes Association
• www.diabetes.org

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Type 1 DiabetesPresenting Symptoms

• Polyuria
• Polydipsia
• Hyperphagia
• Growth retardation
• Wasting

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Insulin Stimulates Cellular Glucose Uptake
Adipocytes
Skeletal Muscle
Liver
Intestine Pancreas
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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

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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

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Growth Retardation

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

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Wasting

• Calories are inefficiently stored as fat
• Adipose stores are depleted

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Normal
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Type 1 Diabetes Mellitus
Glycerol
Lipolysis
Free fatty acids
Synthesis
Free fatty acids
Glucose
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Clinical Chemistry

• Normal
• Fasting blood glucose lt 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
• gt 1000 mg/dL

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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

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Adipocyte Triglyceride Synthesis Decreased
Glycerol-3-P
FACoA
Lysophosphatidic acid
FACoA
Phosphatidic acid
Pi
Diglyceride
FACoA
Triglyceride
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Antilipolysis
a
b
Gs
Gi
AC
AC
PDE
AMP
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Enhanced Lipolysis Consequences in Liver

• Liver partitions fatty acids
• Triglyceride synthesis (VLDL)
• Oxidation
• Ketogenesis

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

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Ketone Bodies

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

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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

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Type 2 Diabetes Mellitus

• 16 million estimated affected
• Genetic component
• Associated with obesity
• Previously maturity-onset
• Progressive

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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

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Oral Glucose Tolerance Test

• Normal
• Low basal glucose
• Small, transient rise in glucose
• Low basal insulin, two-phase, transient increase
  in insulin

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Oral Glucose Tolerance Test

• Insulin Resistant
• Tissues unresponsive to insulin
• Basal hyperinsulinemia
• First phase insulin release blunted
• Blood glucose curve looks normal

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Oral Glucose Tolerance Test

• Impaired Glucose Tolerance
• Deterioration in ability to handle glucose
• Basal and stimulated hyperinsulinemia
• Fasting plasma glucose gt100, lt126 mg/dL
• 2 hr glucose gt140, lt200 mg/dL

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Oral Glucose Tolerance Test

• Diabetes Mellitus
• Hyperinsulinemia cant compensate for insulin
  resistance
• Fasting blood glucose gt126 mg/dL
• 2 hr glucose gt200 mg/dL
• Insulin resistance increases

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Ectopic deposition of lipid contributes to the
etiology and progression of T2DM.

• Lipotoxicity hypothesis

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Bad Places for Excess Lipid
Liver
Skeletal Muscle
Heart Muscle
Pancreas
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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

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(No Transcript)
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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
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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.

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Why is Glucose Transport Reduced?

• Mitochondrial phosphorylation decreased 30
• Intramyocellular lipid is increased 80
• Ectopic fat may hinder insulin-stimulation of
  glucose transport.

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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
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What is consequence of muscle insulin resistance?

• Pancreas compensates gt hyperinsulinemia
• Hyperinsulinemia exacerbates insulin resistance
  in adipose tissue.

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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

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Effect of excess free fatty acids on insulin
sensitivity
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Consequences of Insulin Resistance FFA in Muscle

• Increased intramyocellular lipid
• Hypothetical inhibition of insulin signaling by
  diglyceride
• Reduction in glucose uptake by muscle

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Consequences of Insulin ResistanceFFA in Liver

• Increased triglyceride synthesis
• Increased oxidation
• Increased gluconeogenesis
• Hepatic glucose output contributes to
  hyperglycemia

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Consequences of Insulin ResistanceFFA in Pancreas

• Animal models of diabetes
• Lipid droplets accumulate in beta cells
• Beta cells undergo apoptosis
• Reduced beta cell mass
• Decreased circulating insulin

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Pancreatic Histology
Diabetic
Control
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Timeline Development of Type 2
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Diet and Exercise

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

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Insulin-releasing Drugs

• Goal
• Stimulate pancreas to produce more endogenous
  insulin
• Purpose
• Overcomes insulin resistance
• Plasma glucose is taken up and oxidized
  appropriately

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Hepatic Insulin Sensitizers

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

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Thiazolidinediones new class of drugs

• Goal
• Peripheral insulin sensitizers
• Enhance muscle insulin sensitivity
• Purpose
• Reduce blood glucose, insulin

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Thiazolidinediones new class of drugs

• Unintended consequences
• Increase lipid storage in adipose tissue
• Reduce lipid storage in muscle, pancreas
• Preserve beta cell mass

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Summary

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

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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