Alterations of Lipid Metabolism

in Diabetes Mellitus
Neile Edens, Ph.D.
neile.edens@abbott.com

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

Adipocytes
Liver

Insulin
Insulin

Intestine & Pancreas

Skeletal Muscle

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
Insulin
Glycerol

Lipolysis

Free fatty acids

Synthesis
Free fatty acids
LPL

Glucose
Insulin

Triglyceride

Type 1 Diabetes Mellitus

Glycerol

Lipolysis

Free fatty acids

Synthesis
Free fatty acids

LPL

Glucose

Triglyceride

Clinical Chemistry
Normal

Uncontrolled Type 1

Fasting blood glucose <

100 mg/dL

Fasting blood glucose up

to 500 mg/dL

Serum free fatty acids

~ 0.30 mM

Serum free fatty acids

up to 2 mM

Serum triglyceride
~100 mg/dL

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

FACoA

Lysophosphatidic acid
FACoA
Phosphatidic acid
Pi
Diglyceride
FACoA
Triglyceride

Antilipolysis

Gs

AC
AC

Gi

PDE

ATP
HSL

cAMP
PKA

IRS

PKB
AMP

PI3K

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

Malonyl CoA
carnitine

carnitine
FA-CoA

CPT-I

CPT-II
ATP, CO2

TG

inner

outer
Mitochondrial
membranes

FA-CoA

HB, AcAc

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

Normal

Normal
Low basal glucose
Small, transient
rise in glucose

300

B
lo
odG
luc
o
se(m
g
/
d
L
)

200
100
0
0

30

60

90

Time Post Glucose Load (min)

120

Low basal insulin,

two-phase,
transient increase
in insulin

Oral Glucose Tolerance Test

Insulin Resistant

Insulin Resistant
Tissues unresponsive to
insulin

300

B
lo
odG
luc
o
se(m
g
/
d
L
)

200

Basal hyperinsulinemia

100

First phase insulin

release blunted

0
0

30

60

90

Time Post Glucose Load (min)

120
Blood glucose curve
looks normal

Oral Glucose Tolerance Test

Normal

IGT

Impaired Glucose
Tolerance

300

Deterioration in ability to
handle glucose

B
lo
odG
luc
o
se(m
g
/
d
L
)

200

Basal and stimulated

hyperinsulinemia

100
0
0

30

60

90

Time Post Glucose Load (min)

120

Fasting plasma glucose

>100, <126 mg/dL
2 hr glucose >140, <200
mg/dL

Oral Glucose Tolerance Test

Normal

IGT

T2DM

Diabetes Mellitus
Hyperinsulinemia cant
compensate for insulin
resistance

300

B
lo
odG
luc
o
se(m
g
/
d
L
)

200

Fasting blood glucose >126

mg/dL

100
0

2 hr glucose >200 mg/dL

30

60

90

Time Post Glucose Load (min)

120
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

3. Adjust glucose infusion rate to maintain euglycemia.

Glucose

1. Infuse insulin to induce

Insulin hyperinsulinemia

150 mg/dL

2. Measure blood glucose

every 2 min

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 serinephosphorylates 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
Glucose Disposal

12
10
8
6
4
2
0

Control

Intralipid
Infusion

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 Resistance

FFA in Liver
Increased triglyceride synthesis
Increased oxidation
Increased gluconeogenesis
Hepatic glucose output contributes to
hyperglycemia

Consequences of Insulin Resistance

FFA 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

Environmental
insult

Genetic
predisposition

Increased
lipolysis

Insulin
resistance

Compromised

Beta cell

pancreatic function

failure

Ectopic fat
deposition

Fasting
Hyperglycemia

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