lipid metab in diabetes mellitus lecture 04.ppt
TRANSCRIPT
![Page 2: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/2.jpg)
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
![Page 3: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/3.jpg)
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
![Page 4: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/4.jpg)
Type 1 Diabetes Mellitus:Background
• Affects ~1 million people
• Juvenile onset
• Genetic component
• Autoimmune/environmental etiology
![Page 5: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/5.jpg)
Type 1 Diabetes:Hallmarks
• Progressive destruction of beta cells
• Decreased or no endogenous insulin secretion
• Dependence on exogenous insulin for life
![Page 6: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/6.jpg)
Diabetes: General Information
• Juvenile Diabetes Research Foundation– www.jdf.org
• American Diabetes Association– www.diabetes.org
![Page 7: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/7.jpg)
Type 1 Diabetes:Presenting Symptoms
• Polyuria• Polydipsia• Hyperphagia• Growth retardation• Wasting
![Page 8: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/8.jpg)
Insulin Stimulates Cellular Glucose Uptake
LiverSkeletal Muscle
Adipocytes
Intestine & Pancreas
InsulinInsulin
Insulin
![Page 9: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/9.jpg)
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
![Page 10: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/10.jpg)
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
![Page 11: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/11.jpg)
Growth Retardation
• Insulin required for normal growth
• Necessary for normal amino acid and protein metabolism
• Stimulates synthesis, inhibits degradation
![Page 12: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/12.jpg)
Wasting
• Calories are inefficiently stored as fat
• Adipose stores are depleted
![Page 13: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/13.jpg)
Normal
LPL
Triglyceride
LipolysisGlycerol
Free fatty acids
Free fatty acids
Glucose
Synthesis
Insulin
Insulin
![Page 14: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/14.jpg)
Triglyceride
LPL
Type 1 Diabetes Mellitus
LipolysisGlycerol
Free fatty acids
Free fatty acids
Glucose
Synthesis
![Page 15: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/15.jpg)
Clinical Chemistry
• Normal– 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
![Page 16: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/16.jpg)
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
![Page 17: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/17.jpg)
Adipocyte Triglyceride Synthesis Decreased
Glycerol-3-P
Lysophosphatidic acid
Phosphatidic acid
Diglyceride
Triglyceride
FACoA
FACoA
FACoA
Pi
![Page 18: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/18.jpg)
Antilipolysis
AC
Gs Gi
IRS
ATP cAMP
PKAHSLAMP
PDE
PI3K
PKB
AC
![Page 19: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/19.jpg)
Enhanced Lipolysis: Consequences in Liver
• Liver partitions fatty acids:
– Triglyceride synthesis (VLDL)
– Oxidation
– Ketogenesis
![Page 20: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/20.jpg)
Insulin Regulation of Hepatic Fatty Acid Partitioning
FA-CoA
TG ATP, CO2 -hydroxybutyrate
acetoacetate
Mitochondrion
![Page 21: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/21.jpg)
In Liver:FFA Entry into Mitochondria is Regulated by
Insulin/Glucacon
FA-CoA
Mitochondrial membranes
outer
inner
CPT-I CPT-II
carnitine
FA-CoA
carnitine
ATP, CO2 HB, AcAc
Malonyl CoA
TG
![Page 22: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/22.jpg)
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
![Page 23: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/23.jpg)
Ketone Bodies
• Hydroxybutyrate, acetoacetate• Fuel for brain• Excreted in urine
• At 12-14 mM reduce pH of blood• Can cause coma (diabetic
ketoacidosis)
![Page 24: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/24.jpg)
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
![Page 25: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/25.jpg)
Type 2 Diabetes Mellitus
• 16 million estimated affected• Genetic component• Associated with obesity• Previously maturity-onset• Progressive
![Page 26: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/26.jpg)
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
![Page 27: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/27.jpg)
Oral Glucose Tolerance Test
0
100
200
300
0 30 60 90 120
Time Post Glucose Load (min)
Blood
Glucos
e (mg
/dL)
Normal • Normal– Low basal glucose– Small, transient
rise in glucose
– Low basal insulin, two-phase, transient increase in insulin
![Page 28: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/28.jpg)
Oral Glucose Tolerance Test
0
100
200
300
0 30 60 90 120
Time Post Glucose Load (min)
Blood
Glucos
e (mg
/dL)
I nsulin Resistant • Insulin Resistant– Tissues unresponsive
to insulin
– Basal hyperinsulinemia
– First phase insulin release blunted
– Blood glucose curve looks normal
![Page 29: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/29.jpg)
Oral Glucose Tolerance Test
0
100
200
300
0 30 60 90 120
Time Post Glucose Load (min)
Blood
Glucos
e (mg
/dL)
Normal IGT • 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
![Page 30: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/30.jpg)
Oral Glucose Tolerance Test
0
100
200
300
0 30 60 90 120
Time Post Glucose Load (min)
Blood
Glucos
e (mg
/dL)
Normal IGT T2DM • Diabetes Mellitus– Hyperinsulinemia can’t
compensate for insulin resistance
– Fasting blood glucose >126 mg/dL
– 2 hr glucose >200 mg/dL
– Insulin resistance increases
![Page 31: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/31.jpg)
Ectopic deposition of lipid contributes to the etiology and progression of T2DM.
“Lipotoxicity” hypothesis
![Page 32: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/32.jpg)
Bad Places for Excess Lipid
Liver
Pancreas
Skeletal Muscle
Heart Muscle
![Page 33: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/33.jpg)
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
![Page 34: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/34.jpg)
Insulin
1. Infuse insulin to induce hyperinsulinemia
2. Measure blood glucoseevery 2 min
150 mg/dLGlucose
3. Adjust glucose infusion rate to maintain euglycemia.
![Page 35: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/35.jpg)
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
![Page 36: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/36.jpg)
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.
![Page 37: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/37.jpg)
Why is Glucose Transport Reduced?
• Mitochondrial phosphorylation decreased 30%
• Intramyocellular lipid is increased 80%
• Ectopic fat may hinder insulin-stimulation of glucose transport.
![Page 38: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/38.jpg)
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
![Page 39: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/39.jpg)
What is consequence of muscle insulin resistance?
• Pancreas compensates > hyperinsulinemia
• Hyperinsulinemia exacerbates insulin resistance in adipose tissue.
![Page 40: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/40.jpg)
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
![Page 41: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/41.jpg)
Effect of excess free fatty acids on insulin sensitivity
0
2
4
6
8
10
12
Control Intralipid
Infusion
Glu
cose
Dis
posa
l
![Page 42: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/42.jpg)
Consequences of Insulin Resistance FFA in Muscle
• Increased intramyocellular lipid
• Hypothetical: inhibition of insulin signaling by diglyceride
• Reduction in glucose uptake by muscle
![Page 43: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/43.jpg)
Consequences of Insulin ResistanceFFA in Liver
• Increased triglyceride synthesis
• Increased oxidation
• Increased gluconeogenesis
• Hepatic glucose output contributes to hyperglycemia
![Page 44: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/44.jpg)
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
![Page 45: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/45.jpg)
Pancreatic Histology
Control Diabetic
![Page 46: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/46.jpg)
Timeline: Development of Type 2
Genetic
predisposition
Environmental
insult
Insulin
resistance
Increased
lipolysis
Ectopic fat
deposition
Compromised
pancreatic function
Fasting
Hyperglycemia
Beta cell
failure
![Page 47: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/47.jpg)
Diet and Exercise
• Goal– Reduce caloric intake– Increase exercise
• Purpose– Reduce size of adipose stores– Improve insulin sensitivity– Increase lean body mass
![Page 48: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/48.jpg)
Insulin-releasing Drugs
• Goal– Stimulate pancreas to produce more
endogenous insulin
• Purpose– Overcomes insulin resistance
– Plasma glucose is taken up and oxidized appropriately
![Page 49: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/49.jpg)
Hepatic Insulin Sensitizers
• Goal– Work selectively on the liver
– Inhibit glycogenolysis and gluconeogenesis
• Purpose– Reduce hepatic glucose output
– Reduce blood glucose concentration
![Page 50: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/50.jpg)
Thiazolidinediones: new class of drugs
• Goal– Peripheral insulin sensitizers– Enhance muscle insulin
sensitivity
• Purpose– Reduce blood glucose, insulin
![Page 51: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/51.jpg)
Thiazolidinediones: new class of drugs
• Unintended consequences
– Increase lipid storage in adipose tissue
– Reduce lipid storage in muscle, pancreas
– Preserve beta cell mass
![Page 52: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/52.jpg)
Summary
• Insulin deficiency perturbs lipid metabolism in type 1 diabetes.
• Prevention– Under investigation
• Treatment – Insulin replacement– Management of carbohydrate intake
![Page 53: Lipid Metab in Diabetes Mellitus lecture 04.ppt](https://reader036.vdocuments.us/reader036/viewer/2022062407/55cf905f550346703ba54f64/html5/thumbnails/53.jpg)
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