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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 Normal Pancreatic Function Exocrine pancreas aids digestion Bicarbonate ... – PowerPoint PPT presentation

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Title: Alterations in Lipid Metabolism in Diabetes Mellitus


1
Alterations in Lipid Metabolism in Diabetes
Mellitus
  • Neile Edens, Ph.D.
  • neile.edens_at_abbott.com

2
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

3
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

4
T1 DM SymptomsWHY?
  • Growth retardation
  • Wasting
  • Polydypsia
  • Polyuria
  • Hyperphagia

5
Adipose Tissue Lipid Storage/Mobilization
Glycerol
Lipolysis
Free fatty acids
Triglyceride
Synthesis
Free fatty acids
Glucose
LPL
6
Adipose Tissue Absence of Insulin
  • Reduced anabolism
  • Glucose uptake by cells
  • Fatty acid uptake by cells
  • Lipid synthesis decreased
  • Enhanced catabolism
  • Lipolysis

7
Adipocyte Glucose Uptake Decreased
  • GLUT1
  • GLUT4
  • Glycolysis Glycerol-3-phosphate

8
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

9
Adipocyte Triglyceride Synthesis Decreased
Glycerol-3-P
FACoA
Lysophosphatidic acid
FACoA
Phosphatidic acid
Pi
Diglyceride
FACoA
Triglyceride
10
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)

11
Enhanced Lipolysis Mechanism-2
  • PI3K activates protein kinase B (PKB)
  • PKB phosphorylates and acivates phosphodiesterase
    3B (PDE3B)
  • PDE3B hydrolyzes cAMP

12
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

13
Lipolysis Schematic
14
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

15
Enhanced Lipolysis Consequences in Liver
  • Liver partitions fatty acids
  • Triglyceride synthesis (VLDL)
  • Oxidation
  • Ketogenesis

16
Insulin Regulation of Hepatic Fatty Acid
Partitioning
FA-CoA
TG
?-hydroxybutyrate acetoacetate
ATP, CO2
Mitochondrion
17
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
18
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

19
Ketone Bodies
  • Hydroxybutyrate, acetoacetate
  • Fuel for brain
  • Excreted in urine
  • At 12-14 mM reduce pH of blood
  • Can cause coma (diabetic ketoacidosis)

20
Type 2 Diabetes Mellitus
  • 16 million estimated affected
  • Genetic component
  • Associated with obesity
  • Previously maturity-onset
  • Treatment modalities
  • Diet, exercise
  • Oral hypoglycemic agents
  • Insulin

21
Oral Glucose Tolerance Test
22
T2DM is Progressive
  • Insulin resistance
  • Tissues unresponsive to insulin
  • First phase insulin release blunted
  • Hyperinsulinemia
  • Normoglycemia

23
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

24
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

25
T2DM is Progressive
  • Late Stage Diabetes Mellitus
  • Pancreatic failure
  • Plasma insulin decreases
  • Oral hypoglycemic agents no longer effective
  • Insulin replacement necessary

26
Ectopic deposition of lipid contributes to the
etiology and progression of T2DM.
  • Lipotoxicity hypothesis

27
Bad Places for Excess Lipid
  • Muscle
  • Pancreas
  • Liver
  • Blood

28
Role of Adipose Tissue
  • Adipocyte size is increased in obesity
  • Visceral vs. subcutaneous
  • Portal drainage of FFA
  • FFA reduce hepatic extraction of insulin

29
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.

30
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

31
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

32
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

33
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

34
Consequences of Insulin ResistanceFFA in Liver
  • Increased TG synthesis
  • Increased oxidation
  • Increased gluconeogenesis
  • Hepatic glucose output contributes to
    hyperglycemia

35
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

36
Diet and Exercise
  • Goal
  • Reduce caloric intake
  • Increase exercise
  • Purpose
  • Reduce size of adipose stores
  • Improve insulin sensitivity
  • Increase lean body mass

37
Insulin-releasing Drugs
  • Goal
  • Stimulate pancreas to produce more endogenous
    insulin
  • Purpose
  • Overcomes insulin resistance
  • Plasma glucose is taken up and oxidized
    appropriately

38
Hepatic Insulin Sensitizers
  • Goal
  • Work selectively on the liver
  • Inhibit glycogenolysis and gluconeogenesis
  • Purpose
  • Reduce hepatic glucose output
  • Reduce blood glucose concentration

39
Thiazolidinediones new class of drugs
  • Goal
  • Peripheral insulin sensitizers
  • Enhance muscle insulin sensitivity
  • Purpose
  • Reduce blood glucose, insulin

40
Thiazolidinediones new class of drugs
  • Unintended consequences
  • Increase lipid storage in adipose tissue
  • Reduce lipid storage in muscle, pancreas
  • Preserve beta cell mass

41
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--
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