Transcript DIABETES AND LIPID

S-KHALILZADEH
 Lipids are hydrophobic molecules that are insoluble in
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water. They are in cell membranes
as a major form of stored nutrients (triglycerides),
as precursors of adrenal and gonadal steroids and bile
acids
as extracellular and intracellular messengers (e.g.,
prostaglandins, phosphatidylinositol).
Lipoproteins provide a vehicle for transporting the
complex lipids in the blood as water-soluble complexes
and deliver lipids to cells
 Fatty acids vary in length and in the number and
position of double bonds
 Saturated fatty acids lack double bonds
 unsaturated fatty acids have one or more double bonds.
 Monounsaturated fatty acids have one double bond,
and polyunsaturated fatty acids (PUFAs) have two or
more.
 Cholesterol is a four-ring hydrocarbon
with an eight-carbon side chain.
 It is a major component of cell
membranes and as a precursor of
steroid hormones (adrenal and gonadal
hormones) and bile acids
 In the blood, about two thirds of the
cholesterol is esterified
 Triglycerides consist of three fatty acid
molecules esterified to a glycerol
molecule Triglycerides store fatty acids
and form large lipid droplets in adipose
tissue. They are also transported as a
component of certain lipoproteins.
When triglycerides are hydrolyzed in
adipocytes, free fatty acid (FFA) are
released to be used as a source of energy
 Chylomicrons are the largest of the plasma lipoproteins
(>1000 Å in diameter) ,float after ultracentrifugation of
plasma.
 They are composed of 98% to 99% lipid (85%-90%
triglyceride) and 1% to 2% protein
 Chylomicrons are present in postprandial plasma (but
are absent after an overnight fast) and contain apo-B48,
apo-AI, apo-AIV, apo-E, and the C apolipoproteins
VLDLs are particles 300 to 700 Å
They are composed of 85% to 90%
lipid (about 55% triglyceride, 20%
cholesterol, and 15% phospholipid)
and 10% to 15% protein. The
distinctive apolipoprotein is apoB100, the hepatic form of apo-B.
VLDLs also contain apo-E and C
apolipoproteins
IDLs present in low concentrations in 
the plasma and are intermediate in size
and composition between VLDL and
LDL
Their proteins are apo-B100 and apo-E. 
The IDLs are precursors of LDLs and
represent metabolic products of VLDL
catabolism in the plasma by the action
of lipases.
IDLs are often considered to be VLDL 
remnants and to be atherogenic.
 LDLs are about 200 Å in diameter, are
the major cholesterol-carrying
lipoproteins in the plasma; about 70% of
total plasma cholesterol is in LDL. LDLs
are composed of approximately 75%
lipid (about 35% cholesteryl ester, 10%
free cholesterol, 10% triglyceride, and
20% phospholipid) and 25% protein.
Apo-B100 is the principal protein in
these particles, with trace amounts of
apo-E
The clearance of LDL is mediated by
apo-B100. The affinity of apo-B100
for the LDL receptor is lower than
that of apo-E, and clearance of LDL
is much slower (with a half-life of 2
to 3 days).
Compared with apo-B100–
containing LDLs, apo-E–containing
lipoproteins have 20-fold greater
affinity for the LDL receptor
HDLs are small particles (70-120 Å in
diameter)
HDLs contain about 50% lipid (25%
phospholipid, 15% cholesteryl ester,
5% free cholesterol, and 5%
triglyceride) and 50% protein Their
major apolipoproteins are apo-AI
(65%), apo-AII (25%), and smaller
amounts of the C apolipoproteins
and apo-E
Apo-E is a minor component of a
subclass of HDL referred to as
HDL1, but about 50% of total
plasma apo-E is in this HDL
fraction. The major classes of HDLs
lack apo-E and do not interact with
the LDL receptor
Apolipoproteins — Understanding
the major functions of the different
apolipoproteins is important
clinically, because defects in
apolipoprotein metabolism lead to
abnormalities in lipid handling
Apolipoproteins
 A-I — Structural protein for HDL; activator of
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lecithin-cholesterol acyltransferase (LCAT).
A-II — Structural protein for HDL; activator of
hepatic lipase.
A-IV — Activator of lipoprotein lipase (LPL) and
LCAT.
B-100 — Structural protein for VLDL, IDL, LDL,
and Lp(a); ligand for the LDL receptor; required
for assembly and secretion of VLDL.
B-48 — Contains 48 percent of B-100; required for
assembly and secretion of chylomicrons; does not
bind to LDL receptor.
C-I — Activator of LCAT.
C-II — Essential cofactor for LPL.
C-III — Interferes with apo-E mediated
clearance of triglyceride-enriched
lipoproteins by cellular receptors ;
inhibits triglyceride hydrolysis by
lipoprotein lipase and hepatic lipase
,interferes with normal endothelial
function .
D — May be a cofactor for
cholesteryl ester transfer protein
(CETP).
E — Ligand for hepatic chylomicron
and VLDL remnant receptor, leading
to clearance of these lipoproteins
from the circulation; ligand for LDL
receptor.
 Human LPL is synthesized by adipocytes, by myocytes in
skeletal and cardiac muscle, and by macrophages but is not
produced by hepatocytes.
 LPL is transported to the capillary endothelial cells where it
interacts with chylomicrons and VLDL in the circulation and
mediates the hydrolysis of their triglycerides to FFAs.
 The fatty acids are stored as triglyceride in adipocytes and in
the formation of hepatic VLDL.
 Hepatic lipase is primarily a phospholipase but also possesses
triglyceride hydrolase activity
 It is synthesized by hepatocytes
 Hepatic lipase is transported from the liver to the capillary
endothelium of the adrenals, ovaries, and testes, where it
functions in the release of lipids from lipoproteins for use in
these organs.
 Its activity is increased by androgens and reduced by estrogens
EXOGENOUS PATHWAY OF LIPID
METABOLISM
 starts with the intestinal absorption of
dietary cholesterol and fatty acids The
mechanisms regulating the amount of
dietary cholesterol that is absorbed are
unknown.
 Sitosterolemia is a rare autosomal recessive
disorder associated with hyperabsorption
of cholesterol and plant sterols from the
intestine .
 Within the intestinal cell, free fatty acids combine with
glycerol to form triglycerides, and cholesterol is esterified by
acyl-coenzyme A:cholesterol acyltransferase (ACAT) to form
cholesterol esters
 Triglycerides and cholesterol are assembled intracellularly as
chylomicrons.
 The main apolipoprotein is B-48, but C-II and E are acquired
as the chylomicrons enter the circulation. Apo B-48 permits
lipid binding to the chylomicron but not to LDL receptor.
 Apo C-II is a cofactor for LPL which makes the chylomicrons
smaller by hydrolyzing the core triglycerides and releasing
free fatty acids. The free fatty acids are then used as an energy
source, converted to triglyceride, or stored in adipose tissue.
The end-products of chylomicron are chylomicron remnants
that are cleared from the circulation by hepatic chylomicron
remnant receptors for which apo E is a high-affinity ligand.
ENDOGENOUS PATHWAY OF LIPID
METABOLISM
 begins with the synthesis of VLDL by the liver
 Microsomal triglyceride transfer protein is essential for
the transfer of the bulk of triglycerides into the
endoplasmic reticulum for VLDL assembly
 They include apo C-II which acts as a cofactor for LPL,
apo C-III which inhibits this enzyme, and apo B-100
and E which serve as ligands for LDL receptor
The triglyceride core of VLDL particles
is hydrolyzed by lipoprotein lipase.
During lipolysis, the core of the VLDL
particle is reduced, generating VLDL
remnant particles (also called IDL) that
are depleted of triglycerides via a
process similar to the generation of
chylomicron remnants.
Some of the excess surface components
in the remnant particle, including
phospholipid, unesterified cholesterol,
and apolipoproteins A, C and E, are
transferred to HDL
VLDL remnants can either be cleared
from the circulation by the apo B/E
(LDL) or the remnant receptors or
remodeled by hepatic lipase to form
LDL particles.
LDL can be internalized by hepatic and
nonhepatic tissues. Hepatic LDL
cholesterol can be converted to bile
acids and secreted into the intestinal
lumen.
LDL cholesterol internalized by
nonhepatic tissues can be used for
hormone production, cell membrane
synthesis, or stored in the esterified
form
Circulating LDL can also enter
macrophages and some other tissues
through the unregulated scavenger
receptor. This pathway can result in
excess accumulation of intracellular
cholesterol and the formation of foam
cells which contribute to the formation
of atheromatous plaques
 These cholesterol-enriched cells can
rupture, releasing oxidized LDL,
intracellular enzymes, and oxygen free
radicals that can further damage the vessel
wall. Oxidized LDL induces apoptosis of
vascular smooth muscle and human
endothelial cells via activation of a protease
which suggests a mechanism for the
response to injury hypothesis of
atherosclerosis
anti-atherogenic effect of HDL
 Apolipoprotein A-I on the surface of HDL serves as a
signal to mobilize cholesterol esters from intracellular
pools. After diffusion of cholesterol onto HDL, the
cholesterol is esterified to cholesterol esters by LCAT, a
plasma enzyme that is activated primarily by
apolipoprotein A-I.
 HDL can act as an acceptor for cholesterol released
during lipolysis of triglyceride-containing lipoproteins
Diabetes mellitus
 insulin deficiency and poor glycemic control lead to
increases in the plasma levels of triglycerides and apoB–containing lipoproteins insulin deficiency results in
impaired LPL activity and diminished clearance of
triglyceride-rich particles.
 Insulin deficiency also enhances lipolysis, which
increases FFA flux to the liver, increased FFA flux
drives triglyceride and VLDL synthesis and secretion.
 Plasma levels of LDL are increased in some but not all
subjects. the hyperlipidemia in type 2 diabetes is often
characterized by an increase in small, dense LDLs which are
particularly atherogenic
 a portion of the plasma LDL undergoes glycosylation, which
can increase binding to arterial wall proteoglycans and
susceptibility to oxidation.
 (CHD) are common in industrialized societies
 There is a direct relation between the plasma levels of
total and LDL cholesterol and the risk of CHD and
mortality
 LDL cholesterol lowering in moderate to high-risk
patients leads to a reduction in cardiovascular events
 Abnormalities of plasma lipids (dyslipidemia) other than
LDL cholesterol are common in patients with early onset
CHD
 HDL cholesterol levels are related to absolute CHD event
rates in treated hypercholesterolemic subjects with and
without baseline clinical CHD
 Screening tests for dyslipidemia are widely available
Guidelines developed by the NCEP
in 2001 recommend that a complete
plasma lipid profile (total
cholesterol, LDL-C, HDL-C, and
triglycerides) be measured in all
adults 20 years of age and older at
least once every 5 years
 The ATP III recommendations for the
treatment of hypercholesterolemia are
based on the LDL-cholesterol (LDL-C)and
are influenced by the coexistence of CHD
and the number of cardiac risk factors.
 There are five major steps to determining
an individual's risk category, which serves
as the basis for the treatment guidelines
Step 1 — The first step in
determining patient risk is to
obtain a fasting lipid profile
 Step 2 — CHD equivalents, that is, risk factors that place the
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patient at similar risk for CHD events as a history of CHD
itself, are identified :
Diabetes mellitus
Symptomatic carotid artery disease
Peripheral arterial disease
Abdominal aortic aneurysm
Multiple risk factors that confer a 10-year risk of CHD >20
percent
 Step 3 — Major CHD factors other than LDL are
identified:
 Cigarette smoking
 Hypertension (BP ≥140/90 or antihypertensive
medication)
 Low HDL-C (<40 mg/dL)
 Family history of premature CHD (in male first degree
relatives <55 years, in female first degree relative <65
years)
 Age (men ≥45 years, women ≥55 years)
 HDL-C ≥60 mg/dL counts as a "negative" risk factor; its
presence removes one risk factor from the total count
STEP-4
 If two or more risk factors other than LDL (as defined
in step 3) are present in a patient without CHD or a
CHD equivalent (as defined in step 2), the 10-year risk
of CHD is assessed using the ATP III modification of
the Framingham risk tables
 Step 5 — The last step in risk
assessment is to determine the risk
category that establishes the LDL goal,
when to initiate therapeutic lifestyle
changes, and when to consider drug
therapy
Total-to-HDL-cholesterol ratio
 Among men, a ratio of 6.4 or more
identified a group at 2 to 14 percent
greater risk than predicted from serum
total or LDL-C
 Among women, a ratio of 5.6 or more
identified a group at 25 to 45 percent
greater risk than predicted from serum
total or LDL-C
Non-HDL-cholesterol
 Non-HDL-C is defined as the difference
between the total cholesterol and HDL-C.
Non-HDL-C includes all cholesterol
present in lipoprotein particles that is
considered atherogenic, including
LDL,lp(a),IDL and VLDL .
 It has been suggested that the non-HDL-C
fraction may be a better tool for risk
assessment than LDL-C
ATP III identifies the non-HDL-C
concentration as a secondary target of
therapy in people who have high
triglycerides ≥200 mg/dl.
The goal for non-HDL-C in this
circumstance is a concentration that is
30 mg/dL (0.78 mmol/L) higher than
that for LDL-C
 A standard serum lipid profile consists of
total cholesterol, triglycerides, and HDLcholesterol. Lipoprotein analysis should be
performed after 9 to 12 hours of fasting to
minimize the influence of postprandial
hyperlipidemia. Either a plasma or serum
specimen can be used; the serum
cholesterol is approximately 3 percent lower
than the plasma value
HMG-CoA Reductase Inhibitors
 Inhibition of cholesterol
biosynthesis up-regulates cellular
LDL receptors and enhances
clearance of LDL from the plasma
into cells.
Statins
 Competitive inhibitors of 3-hydroxy-3-methylglutaryl
coenzyme
 A (HMG-CoA) reductase, which catalyzes an early,
ratelimiting step in cholesterol biosynthesis
Chemistry
 The statins possess a side group that is structurally
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similar to HMG-CoA
Mevastatin, lovastatin, simvastatin, and pravaslatin are
fungal metabolites
fluvastatin, atorvastatin, and rosuvastatin are entirely
synthetic
Lovastatin and simvastatin are lactone prodrugs that
are modified in the liver to active hydroxy acid forms
Since they are lactones, they are less soluble in water
than are the other statins
Mechanism of Action
 Statins exert their major effectreduction of LDL levels-
through a mevalonic acid-like moiety that
competitively inhibits HMG-CoA reductase.
 By reducing the conversion of HMG-CoA to
mevalonate, statins inhibit an early and rate-limiting
step in cholesterol biosynthesis
 Inhibition of hepatic cholesterol synthesis, results in
increased expression of the LDL receptor gene
 Degradation of LDL receptors also is reduced
 The greater number of LDL receptors on the surface of
hepatocytes results in increased removal of LDL from
the blood,
 statins also can reduce LDL levels by enhancing the
removal of LDL precursors (VLDL and IDL) and by
decreasing hepatic VLDL production
Triglyceride Reduction by Statins.
 Triglyceride levels >250 mgldl are reduced
substantially by statins,
 If baseline triglyceride levels are below 250 mg/dl.
Reductions in triglycerides do not exceed 25%
irrespective of the dose or statin used
 simvastatin and atorvastatin, 80,mg/day; rosuvastatin,
40 mg/day experience a 35% to 45% reduction in
fasting triglyceride levels
Effect of Statins on HDL-C Levels
 patients with elevated LDL-C levels and gender-
appropriate HDL-C levels (40 to 50 mgldl for men; 50
to 60 mg/dl for women). an increase in HDL-C of 5%
to 10% was observed, irrespective of the dose or statin
employed
 In patients with reduced HDL-C levels (35 mg/dl)
statins may differ in their effects on HDL-C levels
(Simvastatin >Atorvastatin)
Effects of Slatins on LDL-C Levels
 Statins lower LDL-C by 20% to 55% depending on the dose
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and statin used
Maximal effects on plasma cholesterol levels are achieved
within 7 to 10 days.
The statins are effective in almost all patients with high
LDL-C levels.
The exception is patients with homozygous familial
hypercholesterolemia,
the partial response in these patients is due to a reduction
in hepatic VLDL synthesis associated with the inhibition of
HMG-CoA reductase-mediated cholesterol synthesis
potency
rosuvastatin > atorvastatin > simvastatin > pravastatin 
= lovastatin > fluvastatin
Nonlipid roles of statins
 Endothelial Function
 Plaque Stability
 Inflammation
 Lipoprotein Oxidation
 Coagulation
Statins and Endothelial Function
 Statin therapy enhances endothelial production of the
vasodilator nitric oxide, leading to improved
endothelial function after a month of therapy
Statins and Plaque Stability.
 They reportedly inhibit monocyte infiltration into the
artery wall in a rabbit model
 Inhibit macrophage secretion of matrix
metalloproteinases in vitro modulate the cellularity of
the artery wall by inhibiting proliferation of smooth
muscle cells and enhancing apoptotic cell death
Statins and Inflammation
 Statins decreased the risk of CHD and levels of C-
reactive protein (CRP, an independent marker for
inflammation and high CHD risk) independently of
cholesterol lowering
Coagulation
 Statins reduce platelet aggregation
 reduce the deposition of platelet thrombi in the
porcine aorta model
 the different statins have variable effects on fibrinogen
levels
SECONDARY BENEFITS
 Bone metabolism
 Hypertension
 Heart failure
 Dementia
 Cancer prevention
 Renal function
 Sepsis and infections
Hepatotoxicity
 Elevation in hepatic transaminase to values greater
than three times the upper limit of normal
 Incidence as great as 1%
 The incidence appeared to be dose related
 liver failure one case per million person-years of use
 measure alanine aminotransferase (ALT) at baseline
and thereafter when clinically indicated.
 Patients taking 80-mg doses (or 40 mg of
rosuvastatin) should have their ALT checked after 3
months. If the ALT values are normal, it is not
necessary to repeal the ALT test unless clinically
indicated
Myopathy
 myopathy as any muscle disease
 myalgia as muscle ache or weakness without increased
serum CK levels
 myositis as muscle symptoms with elevated CK levels
 rhabdomyolysis as muscle symptoms with marked CK
elevations (>10 times upper limit of normal [ULN])
plus an elevated serum creatinine.
 (FDA) defines rhabdomyolysis as organ damage,
typically renal insufficiency, with a CK level greater
than 10,000 IU/L
Myopathy
 major adverse effect
 The incidence of myopathy is quite low (~0.0 1%). but
the risk of myopathy and rhabdomyolysis increases in
proportion to plasma statin concentrations
 Factors inhibiting statin catabolism are associated
with increased myopathy risk, including advanced age
(especially >80 years of age), hepatic or renal
dysfunction. perioperative periods. multisystem
disease (especially in association with diabetes
mellitus), small body size, and untreated
hypothyroidism
RISK FACTORS FOR STATIN MYOPATHY
 conditions that increase statin serum and muscle
concentration
 factors that increase muscle susceptibility to injury
Asymptomatic patients
 Routine surveillance of CK levels is not required except
in high-risk patients
 If CK measured
 CK < 5× ULN: reassurance
 CK ≥5 - <10× ULN: monitor for symptoms and periodical
CK determination
 CK ≥10× ULN: stop statin and reconsider risks and
benefits of statin treatment
Factors related to an increase in statin
serum level
 Statin dose
 Small body frame
 Decreased statin metabolism and excretion
 Drug–drug interactions
 Grapefruit juice (possibly also pomegranate & starfruit)
 Hypothyroidism and diabetes mellitus
 Advanced age
 Liver disease
 Renal disease
Factors related to muscle predisposition
 Alcohol consumption
 Drug abuse (cocaine, amphetamines, heroin)
 Heavy exercise
 Baseline muscular disease:
 Multisystemic diseases: diabetes mellitus,
hypothyroidism
 Inflammatory or inherited metabolic muscle defects
Bile acid sequestrants
 The bound bile acids are excreted in the feces.The
increased excretion of bile acids causes increased
oxidation of cholesterol to form bile acids in
hepatocytes, and the resultant up-regulation of
hepatic LDL receptors in turn lowers plasma LDL
concentrations.
 side effects are limited to local effects in the
gastrointestinal system (e.g., bloating, gas,
constipation)
these agents can lower plasma
cholesterol levels by 15% to 25%.
they can increase plasma
triglyceride levels and must be
used with caution in patients
predisposed to
hypertriglyceridemia.
 because they bind negatively charged molecules in the
intestine, these agents can interfere with the
absorption of other medications, including
levothyroxine, digoxin, warfarin, and thiazide diuretics.
Therefore, resins are given at least 4 hours before or 1
hour after other medications. Colesevelam does not
bind other drugs to the same extent as the resins
cholestyramine and colestipol.
niacin
 typically 2.0 to 6.0 g/day lower both total and
LDL cholesterol by 15% to 30%, lower
triglyceride levels by 30% to 40%, and raise
HDL-C levels by 15% to 25%. Maximum HDL
increases usually occur with therapeutic doses
of 1.5 to 2.0 g/day. Niacin also lowers plasma
Lp(a) concentrations by up to 40%.
 The mechanism whereby niacin affects plasma
lipids is unclear, but it seems to be associated
with decreased hepatic VLDL production.
 The most troublesome side effect of niacin is a flushing
syndrome that occurs shortly after taking the medicine.
Flushing can be minimized by initiating therapy with
small doses (e.g., 100 mg) and gradually increasing the
dosage to the therapeutic range over weeks to months.
 taking an aspirin about 1 hour before the niacin can
diminish the flushing, possibly by inhibiting
prostaglandin-mediated side effects.
 The most serious complication of niacin therapy is
hepatotoxicity, and therapy should be accompanied
by monitoring of serum liver function tests
 therapy should be discontinued if transaminases
reach >3 times normal. Because hepatotoxicity
appears to be more common with sustained-release
preparations of niacin, the immediate-release form
is preferred.
 Other side effects of niacin therapy include
impairment or worsening of glucose tolerance and
hyperuricemia.
The fibric acid derivatives
 clofibrate, gemfibrozil, and fenofibrate—
lower plasma triglycerides by about 40% and
increase HDL-C levels by about 10% but have
only minor effects on LDL-C. These agents act
by activating the (PPAR) a, a nuclear hormone
receptor that is expressed in the liver and
other tissues. This results in increased fatty
acid oxidation, increased LPL synthesis, and
reduced expression of apo-CIII, all of which
contribute to lowering plasma triglycerides.
 Side effects include gastrointestinal discomfort and
possibly an increased incidence of cholesterol
gallstones (documented for clofibrate). Fibric acid
derivatives should be used with great caution in the
setting of renal insufficiency
 Fenofibrate, which does not interfere with statin
metabolism and has a much lower risk of causing
myopathy, is the preferred fibrate to use in combination
with a statin.
 Omacor is prepared in capsule form containing a
gram of oil, which includes a total of 840 mg of EPA
plus DHA. At the recommended dosage of four
capsules daily given to patients who have
triglycerides of 500-2000 mg/dL, Omacor lowers
triglycerides by about 50%, raises HDL-C by about
10%, lowers VLDL-C by about 40%, and raises LDL-C
by about 50%. Overall the total cholesterol-to-HDLC ratio is reduced by about 20% and the non-HDL-C
is lowered by about 10%
Chylomicronemia Syndrome
 Patients with the chylomicronemia syndrome often present with
acute pancreatitis and severe hypertriglyceridemia (triglycerides
>22.6 mm/L [2000 mg/dL]).
 These patients should be treated with total fat restriction until
the triglyceride level falls to a safe range
 The goal is to maintain the triglyceride level at less than 11.3
mm/L (1000 mg/dL) and preferably less than 4.5 mm/L (400
mg/dL).
 such patients often require a triglyceride-lowering drug, such as a
fibrate or niacin, to maintain the plasma triglyceride level in a
range that prevents subsequent episodes of pancreatitis