Alterations in Lipid Metabolism in Diabetes Mellitus

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Alterations in Lipid Metabolism in Diabetes
Mellitus

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

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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 Mellitus

• Affects 1 million people
• Genetic component
• Juvenile onset
• Autoimmune/environmental etiology
• Progressive destruction of beta cells
• Decreased or no endogenous insulin, C-peptide
• Dependence on insulin for life

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T1 DM SymptomsWHY?

• Growth retardation
• Wasting
• Polydypsia
• Polyuria
• Hyperphagia

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Adipose Tissue Lipid Storage/Mobilization
Glycerol
Lipolysis
Free fatty acids
Triglyceride
Synthesis
Free fatty acids
Glucose
LPL
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Adipose Tissue Absence of Insulin

• Reduced anabolism
• Glucose uptake by cells
• Fatty acid uptake by cells
• Lipid synthesis decreased
• Enhanced catabolism
• Lipolysis

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Adipocyte Glucose Uptake Decreased

• GLUT1
• GLUT4
• Glycolysis Glycerol-3-phosphate

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Adipocyte Fatty Acid Uptake Decreased

• Lipoprotein lipase
• Synthesized by adipocytes
• Secreted to capillary endothelium
• Hydrolyzes circulating TG
• Fatty acid transporter
• CD36, FABPpm
• Facilitates movement of FFA 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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Enhanced Lipolysis--Mechanism

• Insulin binds to cell surface receptor
• Binding leads to tyrosine phosphorylation of
  receptor and insulin receptor substrates (IRS-1)
• IRS-1-P activates phosphatidylinositol-3-phosphate
  kinase (PI3K)

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Enhanced Lipolysis Mechanism-2

• PI3K activates protein kinase B (PKB)
• PKB phosphorylates and acivates phosphodiesterase
  3B (PDE3B)
• PDE3B hydrolyzes cAMP

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Enhanced Lipolysis Mechanism-3

• Decreased cAMP decreases activation of protein
  kinase A (PKA)
• Decreased PKA activity reduces phosphorylation/act
  ivity of hormone sensitive lipase (HSL)
• Reduced activity of HSL means less triglyceride
  hydrolysis

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Lipolysis Schematic
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Enhanced Lipolysis Consequences

• Free fatty acid (FFA) and glycerol release from
  adipose tissue
• Plasma levels from 0.25 to 1.0 mM
• Oxidation of FFA by muscle

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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
?-hydroxybutyrate acetoacetate
ATP, CO2
Mitochondrion
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In LiverFFA Entry into Mitochondria is
Regulated by Insulin/Glucacon
Malonyl CoA
carnitine
carnitine
CPT-I
FFA-CoA
CPT-II
FFA-CoA
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 carbolylase
• 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 2 Diabetes Mellitus

• 16 million estimated affected
• Genetic component
• Associated with obesity
• Previously maturity-onset
• Treatment modalities
• Diet, exercise
• Oral hypoglycemic agents
• Insulin

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Oral Glucose Tolerance Test
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T2DM is Progressive

• Insulin resistance
• Tissues unresponsive to insulin
• First phase insulin release blunted
• Hyperinsulinemia
• Normoglycemia

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T2DM is Progressive

• Impaired glucose tolerance
• Deterioration in ability to handle glucose
• Hyperinsulinemia
• Fasting plasma glucose gt 110 lt 126 mg/dL
• 2 hr glucose gt 140 mg/dL lt 200 mg/dL

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T2DM is Progressive

• Diagnosed diabetes mellitus
• Hyperinsulinemia cannot compensate for insulin
  resistance
• Fasting blood glucose gt 126 mg/dL
• 2 hr glucose gt 200 mg/dL
• Insulin resistance increases

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T2DM is Progressive

• Late Stage Diabetes Mellitus
• Pancreatic failure
• Plasma insulin decreases
• Oral hypoglycemic agents no longer effective
• Insulin replacement necessary

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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

• Muscle
• Pancreas
• Liver
• Blood

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Role of Adipose Tissue

• Adipocyte size is increased in obesity
• Visceral vs. subcutaneous
• Portal drainage of FFA
• FFA reduce hepatic extraction of insulin

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Adiposity vs. Insulin Sensitivity

• As adiposity increases, insulin sensitivity
  decreases
• A reduction in insulin sensitivity may limit the
  amount of fat stored in adipose tissue
• This may contribute to ectopic deposition of
  lipid in cells where it is harmful.

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Homeostasis Works Both Ways

• As adiposity decreases, insulin sensitivity
  increases
• An increase in insulin sensitivity may predispose
  toward increased fat storage
• Increased insulin sensitivity predicts weight
  gain in the reduced-obese

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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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Consequences of Insulin Resistance FFA in Muscle

• Increased FA storage (IMCL)
• Increased FFA oxidation
• Reduced glucose uptake, oxidation, glycogen
  storage
• Reduced glucose utilization contributes to
  hyperglycemia

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Clamp Methodology

• Infuse insulin to predetermined level
• Frequent measurement of blood glucose
• Infuse glucose to maintain euglycemia
• Glucose is clamped
• Measure the amount of glucose infusion necessary
  to maintain euglycemia

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Consequences of Insulin ResistanceFFA in Liver

• Increased TG 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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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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T2DM Results in Part from Ectopic Body Lipid

• Diet/exercise reduce total body lipid
• Thiazolidinediones move body lipid to adipose
  tissue where can do less harm--