alterations of lipid metabolism in diabetes mellitus

Alterations of Lipid Metabolism in Diabetes

Mellitus

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

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

LiverSkeletal Muscle

Adipocytes

Intestine & Pancreas

InsulinInsulin

Insulin

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

LPL

Triglyceride

LipolysisGlycerol

Free fatty acids

Free fatty acids

Glucose

Synthesis

Insulin

Insulin

Triglyceride

LPL

Type 1 Diabetes Mellitus

LipolysisGlycerol

Free fatty acids

Free fatty acids

Glucose

Synthesis

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

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

Lysophosphatidic acid

Phosphatidic acid

Diglyceride

Triglyceride

FACoA

FACoA

FACoA

Pi

Antilipolysis

AC

Gs Gi

IRS

ATP cAMP

PKAHSLAMP

PDE

PI3K

PKB

AC

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

FA-CoA

Mitochondrial membranes

outer

inner

CPT-I CPT-II

carnitine

FA-CoA

carnitine

ATP, CO2 HB, AcAc

Malonyl CoA

TG

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

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

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

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

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

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

“Lipotoxicity” hypothesis

Bad Places for Excess Lipid

Liver

Pancreas

Skeletal Muscle

Heart Muscle

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

Insulin

1. Infuse insulin to induce hyperinsulinemia

2. Measure blood glucoseevery 2 min

150 mg/dLGlucose

3. Adjust glucose infusion rate to maintain euglycemia.

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

0

2

4

6

8

10

12

Control Intralipid

Infusion

Glu

cose

Dis

posa

l

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 ResistanceFFA in Liver

• Increased triglyceride synthesis

• Increased oxidation

• Increased gluconeogenesis

• Hepatic glucose output contributes to hyperglycemia

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

Pancreatic Histology

Control Diabetic

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– Reduce caloric intake– Increase exercise

• Purpose– 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