Complications of

Diabetes Mellitus

Complications of Diabetes
Mellitus

Chronic
Complications of
Diabetes Mellitus

Microvascular

Retinopathy
(nonproliferative/proliferat
ive)
Nephropathy
Neuropathy
Sensory and motor (monoand polyneuropathy)
Autonomic

Macrovascular

Coronary artery disease

Peripheral vascular disease
Cerebrovascular disease

Acute
Complications of
Diabetes Mellitus

Hyperglycemia
crisis

Diabetic
ketoacidosis
Hyperglycemia
hyperosmolar State
Lactic acidosis

Hypoglycemia

Figure 6 Potential mechanism by which hyperglycaemia-induced mitochondrial superoxide

overproduction activates four pathways of hyperglycaemic damage. Excess superoxide
partially inhibits the glycolytic enzyme GAPDH, thereby diverting upstream metabolites from
glycolysis into pathways of glucose overutilization. This results in increased flux of
dihydroxyacetone phosphate (DHAP) to DAG, an activator of PKC, and of triose phosphates to
methylglyoxal, the main intracellular AGE precursor. Increased flux of fructose-6-phosphate to
UDP-N-acetylglucosamine increases modification of proteins by O-linked N-acetylglucosamine
(GlcNAc) and increased glucose flux through the polyol pathway consumes NADPH and
depletes GSH.

Microvascular
Complications

Increased Polyol Pathway Flux

Aldose Reductase Function

Advanced
Glycation End-Product
Formation

Activation of Protein Kinase

C

Increased Hexosamine Pathway

Diabetic retinopathy

Pathophysiology of diabetic
retinopathy
Hyperglycemia
Pericyte
loss

Hyperperfusion

Capillary/
Endothelial
damage
Capillary
occlusion

Loss of
autoregulation
Vasoactive
factors

Loss of tight
junction

Retinal
ischemia
Growth
factors
New vessels
-Low resistance
- No pericyte/autoregulation

Macular
oedema

Advanced diabetic eye

disease
Retinal ischemia

Neovascularitation

Preretinal
haemorrhage

Pericyte
loss

Neovascular
glaucoma

Vitrous
haemorrhage

Blindness

Retinal
detachment

Diabetic retinopathy

Blindness is primarily the result of progressive diabetic

retinopathy and clinically significant macular edema.
Diabetic retinopathy is classified into two stages:
nonproliferative and proliferative.
Nonproliferative diabetic retinopathy : marked by retinal
vascular microaneurysms, blot hemorrhages, and cotton
wool spots
The appearance of neovascularization in response to retinal
hypoxia is the hallmark of proliferative diabetic
retinopathy.
Duration of DM and degree of glycemic control are the best
predictors of the development of retinopathy; hypertension
is also a risk factor
The most effective therapy for diabetic retinopathy is
prevention.

Diabetic nephropathy

Pathophysiology of diabetic
nephropathy
Hyperglycemia

Renal
vasodilatation
Increased glomular
filtration rate

Protein glycation

Increased
intraglomerular
capillary pressure
Hypertension
Increased
protein excretion

Microalbuminuria or
macroalbuminuria

Glomurular
damage

Nephropathy

Diabetic nephropathy

Diabetic nephropathy is the leading cause of ESRD in the US.

Individuals with diabetic nephropathy almost always have diabetic
retinopathy.
The stages of diabetic nephropathy are :

Hyperfiltration
Microalbuminuria
Overtproteinuria
Declining GFR
End stage renal failure

Microalbuminuria is defined as 30 to 300 mg/d in a 24-h collection or

30 to 300 g/mg creatinine in a spot collection (preferred method).
The appearance of microalbuminuria (incipient nephropathy) in type
1 DM is an important predictor of progression to overt proteinuria
(300 mg/d) or overt nephropathy.
Hypertension more commonly accompanies microalbuminuria or
overt nephropathy in type 2 DM

Diabetic nephropathy treatment

The optimal therapy for diabetic nephropathy is

prevention.
Interventions effective in slowing progression from
microalbuminuria to overt nephropathy include:

near normalization of glycemia,

strict blood pressure control, and
administration of ACE inhibitors or ARBs, and
treatment of dyslipidemia.

Blood pressure should be maintained at 130/80 mmHg

in diabetic individuals without proteinuria.
A slightly lower blood pressure (125/75) should be
considered for individuals with microalbuminuria or
overt nephropathy
A consensus panel of the ADA suggests modest
restriction of protein intake in diabetic individuals with
microalbuminuria (0.8 g/kg per day) or overt
nephropathy (<0.8 g/kg per day)

Diabetic neuropathy

Mechanism of nerve damage in

diabetes
METABOLIC

myoinositol

VASCULAR

glucose

Altered membrane
potensial

Slow nerve
conduction

sorbitol

nerve
oedema

AGE
formation

Arterial
narrowing
vasoconstriction

NO
production

Impairing
axonal transport

Vessel
occlusion

H2O

Diabetic neuropathy

Diabetic neuropathy occurs in approximately 50% of

individuals with long-standing type 1 and type 2 DM.
The development of neuropathy correlates with the
duration of diabetes and glycemic control; both
myelinated and unmyelinated nerve fibers are lost.
Several stage :
Intraneural biochemical abnormalities; sorbitol
accumulation, myoinositol depletion
Impairement of electrophysiological measurement;
decreased nerve conduction velocity; asymptomatic
Clinical neuropathy; detectable using clinical
methods; maybe symptomatic. Histological changes
evident
End stage complications. Exp are ulceration and
Charcot neuroarthropathy; major derangements of
neural structure and function.

Clinical features
symmetrical sensorimotor
neuropathy
Symptoms
Loss of sensation ;

Altered sensation:

Anaesthesia;numbness
Loss of pain perception
Paraesthesiae
Dysaesthesiae

Pain

Signs
Sensory loss
Diminished/absent
tendon reflexs
Muscle wasting and
weakness
Autonomic
dysfunction
Foot uleration

Burning
Hyperalgesia/allodynia
Neuralgia lancinating pain
Cramps ; restless leg

Burning, feeling like the feet are on fire

Stabbing, like sharp knives

Freezing, like the feet are on ice,

although they feel warm to touch

Lancinating, like electric shocks

Treatment of Symmetric
Neuropathy

Glucose control
Pain control

Tricyclic antidepressants

Anticonvulsants

Carbamazepine, gabapentin

Topical creams

Amitriptyline,desipramin, nortriptilin,
trazodone

capsaicin

Foot care

Autonomic Neuropathy

DM-related autonomic neuropathy can involve multiple

systems, including the cardiovascular, gastrointestinal,
genitourinary, sudomotor, and metabolic systems.
Autonomic neuropathies affecting the cardiovascular
system cause a resting tachycardia and orthostatic
hypotension.
Gastroparesis and bladderemptying abnormalities are
often caused by the autonomic neuropathy seen in DM
(discussed below).
Hyperhidrosis of the upper extremities and anhidrosis of
the lower extremities result from sympathetic nervous
system dysfunction.
Anhidrosis of the feet can promote dry skin with cracking,
which increases the risk of foot ulcers.
Autonomic neuropathy may reduce counterregulatory
hormone release, leading to an inability to sense
hypoglycemia appropriately ((hypoglycemia unawareness)

Macrovascular
complications

Macrovascular
complication

Macrovascular complications of diabetes mellitus are

condition characterized by atherosclerotic occlusive
disease of cerebral, myocard and lower extremities.
Atherothrombosis is the most common cause of
macrovascular complications
Atherothrombosis is characterized by a sudden
(unpredictable) atherosclerotic plaque disruption
(rupture or erosion) leading to platelet activation and
thrombus formation
Atherothrombosis is the underlying condition that
results in events leading to myocardial infarction,
ischemic stroke, amputation and vascular death

Atherogenesis A Complex And Progressive

Process1
Pathology of Atherogenesis
Initiation:
Accumulation of lipids at
vascular junctions
experiencing high shear
forces

Inflammatory cytokines induce

expression of adhesion molecules

Macrophages
bind to and enter
intima wall

Uptake of Lipids by
Macrophages

Macrophages
become foam
cells & fatty
streak formed

Chemo-attractants such as PDGF

released from activated macrophages

Smooth muscle
cells (SMCs)
migrate into the
intima

Result: Atherosclerotic
plaque2

Adapted from: P Libby, The Vascular Biology of Atherosclerosis, in: Braunwald

E, Zipes DP & Libby P 6th Edition, Heart Disease: a Textbook of Cardiovascular
Medicine 2001: London: WB Saunders. 2. Davies MJ. Heart 2000;83:361-66, with permission from the BMJ Publishing Group

Atherothrombosis Has Multiple

Manifestations
Ischemic stroke

Myocardial
infarction

Transient ischemic attack

Angina:
Stable
Unstable

Peripheral arterial disease:

Intermittent claudication
Rest pain
Gangrene
Necrosis
Adapted from: Drouet L. Cerebrovasc Dis 2002;13(suppl 1):16

Macrovascular disease in
diabetes mellitus

Cardiovascular and cerebrovascular disease account for

up 70% of death in patients with type 2 DM
All patients with type 2 diabetes have greater
predipostition to macrovascular disease, often having a
constellation of risk factors, which have been term
insulin resistance.
It has been hypotethesized that insulin resistance and
hyperinsulinemia (environmental and genetic factors),
are central to development :

Glucose intolerance
Hypertension
Dyslipidemia
Coagulopathy

These factors promote accelerated atherosclerosis,

explaining the increased risk of macrovascular disease.

Diabetes and Macrovascular

Disease

Libby and Plutsky. Circulation. 2002.

Strategies for reducing

macrovascular complications

Prevention proven intervention trials

Hyperglycemia
Dyslipidemia
Hypertension
Antiplatelet therapies

Prevention suggested by epidemiologic

analysis
Disorders of thrombolysis
Endothelial disorders

The diabetic foot

Diabetic foot disease

Approximately 15% of individuals with DM develop a

foot ulcer, and a significant subset will ultimately
undergo amputation (14 to 24%risk with that ulcer or
subsequent ulceration).
Syndrome of diabetic foot disease
Peripheral neuropathy, peripheral vascular disease
and tissue infection
Risk factors for foot ulcers or amputation include:
male sex, diabetes 10 years duration, peripheral
neuropathy, abnormal structure of foot (bony
abnormalities,callus, thickened nails), peripheral
arterial disease, smoking, history of previous ulcer or
amputation, and poor glycemic control.
The plantar surface of the foot is the most common
site of ulceration.
Ulcers may be primarily neuropathic (no
accompanying infection) or may have surrounding
cellulitis or osteomyelitis.

Pathophysiology of diabetic
foot
Neuropathy

Motor
dysfunction

Abnormal
Foot posture

Microvascular
disease

Neuropathy Neuropathy
Reduced pain
Sensation and
proprioception

Increased foot
prssure

Dry, cracked
skin

Poor tissue
nutrition and
oxygenation

Cheiroarthropathy
Arteriovenous
shunting

Callus

Trauma

Mechanical,
thermal,
chemical

Ulcer
Ischemia

Macrovascular
disease

Acute Complication of
Diabetes Mellitus

Hyperglycemia crisis
Diabetic

ketoacidosis (DKA)
Hyperglycemic Hyperosmolar State (HHS)

Hypoglycemia

Diabetic ketoacidosis
(DKA)
Hyperglycemic
Hyperosmolar State (HHS)

Pathophysiolgy of
hyperglycemia crisis

Diabetic ketoacidosis (DKA)

DKA was formerly considered a hallmark of

type 1 DM
The symptoms and physical signs of DKA

Symptoms : Nausea/vomiting, Thirst/polyuria,

Abdominal pain, Shortness of breath
Physical findings : Tachycardia, Dry mucous
membranes/reduced skin turgor, Dehydration /
hypotension, Tachypnea / Kussmaul,
respirations/respiratory distress, Abdominal
tenderness (may resemble acute pancreatitis or
surgical abdomen), Lethargy /obtundation /
cerebral edema / possibly coma

Precipitating factors

Inadequate insulin administration

Infection (pneumonia/UTI/
Gastroenteritis/sepsis
Infarction (cerebral, coronary,
mesenteric, peripheral)
Drugs (cocaine)
Pregnancy

HHS: Differences from DKA

Patients usually older- typically 60 or more
Major pathophysiologic differences
longer uncompensated osmotic diuresis
greater volume depletion
Acidemia (pH > 7.3) and ketosis are mild
Higher mortality often 30-50%
primarily due to underlying vascular or infectious
event
Occurs in Type 2 diabetics, often mild or unrecognized

Definition of HHS

Extreme hyperglycemia
Increased serum osmolality
Severe dehydration without
significant ketosis or acidosis

Joslins Diabetes Mellitus, 13th ed

Clinical Findings of HHS

HHS should be suspect : elderly patient with or without

the preexisting diagnosis of diabetes who exhibits acute
or subacute deterioration of CNS function and severely
dehydrated
Tachycardia
Low grade fever
Low or normal blood pressure
Dehydration dry mucous membrane, absent axillary
sweat, poor skin turgor.
Nausea, vomiting, distension, and pain-gastroparesis is
due to hypertonicity
Lethargy, hallucinations, and psychosis

Laboratory Findings
DKA

HHS

Fluid Balance in Diabetic

Hyperosmolarity
ECF = 14 L

ICF = 28 L

ECF

ICF
H2O
ECF hyperosmolar from ICF autotransfusion

Osmotic Diuresis
H2O

Osmotic Diuresis

ECF and ICF both hyperosmolar

Priority in the
Treatment of
Hyperglycemia Crisis

Replacing volume deficits normal saline

according to BP, urine output and CVP value
for old age, total deficits around 6-9 liters.

Correcting hyperosmolarity to 300

milliosmoles/L

Managing any underlying illnesses

Insulin ; RI 0.15u/kg bolus then 0.1/kg/hr

infusion until blood sugar about 250mg/dl or
osmo about 315

Thank your for your

attention

Non-Enzymatic Glycosylation
and Pharmaceutical Intervention
Monica Morgan

What is Non-Enzymatic
Glycosylation?

also called glycation

the result of a sugar molecule (fructose or glucose)
bonding to a protein or lipid molecule without the
action of an enzyme
Sugars combine with free amino group of proteins,
then rearrange and dehydrate which results in the
formation of pigment and cross-linked proteins.
chaotic process that damages the function of
biomolecules
Slow process
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abstract/211/4481/491
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Exogenous Glycation

Dietary or pre-formed glycation

Exogenous glycations are normally created
when sugars are cooked with proteins or
fats.
Temperatures over 120 degrees F speed up
glycation reactions, but extended cooking
increases formation of AGEs.
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Exogenous Glycation

Previously thought to be important solely to those

suffering with type II diabetes
However, exogenous glycation reactions and their
endproducts have been found to be important to all
people as they contribute to a variety of diseases:

Retinal dysfunction
Cardiovascular diseases
Type II diabetes
Other age-related diseases
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Exogenous Glycation

Food producers have added AGEs to everyday foods to

improve appearance and taste.
Foods with significant browning, caramelization, or with
directly added AGEs can be exceptionally high in these
proinflammatory and disease initiating compounds.
Watch out for these types of foods:
Donuts
BBQ meats
Cake
Dark colored sodas
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Endogenous Glycation

the beginning stages of metabolic reactions

in which the sugar molecules are converted
to usable forms
complex reactions follow glycation:
Amadori, Schiff base, and Maillard
(Browning) reactions
products of the these reactions are called
advanced glycation endproducts (AGEs)
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Glycation Theory of Aging:

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enbest.com/li
feext/amador
i.gif

Long-Lived Proteins

Tissues containing long-lived proteins :

Lens crystalline
Skin collagen
Arteries
Tendons
Lungs
Cartilage

Basement membrane
Have you ever heard of people becoming stiff in their old age?
These tissues containing long-lived proteins lose flexibility through
glycation.
Accumulate cross-linkage from AGEs over time

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AGEs

some are benign

some are more reactive than the sugar products
they themselves formed
these more reactive molecules lead to age related
diseases: type II diabetes mellitus, cardiovascular
diseases, cancer, peripheral neuropathy, deafness,
and blindness
accumulate with age
irreversible, cross-linked proteins
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AGEs

AGE formation in vascular wall collagen

causes loss of elasticity and leads to
cardiovascular disease.

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itool=abstractplus&db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=1
1237208

Common AGEs

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0412/fluorescent.gif

Cross-Linking in Long-Lived
Proteins

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pane.jpg

How Are AGEs important?

interfere with molecular and cellular

functioning

Diabetes mellitus beta cell damage, increased blood sugar

increases rates of production of AGEs and cross-linking
Heart disease endothelium, fibrinogen, and collagen fibers are
destroyed
Alzheimers disease amyloid proteins are side products of the
Amadori, Schiff, and Maillard reactions
Cancer acrylamide and other side products are released
Peripheral neuropathy the myelin is attacked
Deafness demyelination
Blindness microvascular damage in the retina
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AGEs in the Body

Diabetes, which increases blood sugar level, reduces the

kidneys ability to excrete AGEs.

forms a positive feedback loop, which only enhances the

damaging effects of AGEs.
Aging effects are accelerated in diabetic patients because of the
increased levels of blood sugar.

Damage in the body due to AGE accumulation is

proportional to the amount of endogenous AGEs formed.

Consumption of high glycation sugars, such as fructose and

galactose, contribute to great amounts of AGEs found in the
body.
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ndproduct

Effects of Glycation and AGEs

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Clinical Studies of AGE Inhibitors and

Diabetic Kidney Disease

Mark E. Williams, MD
tested the effects of 3 AGE inhibitors
Glycated proteins injected into mice result in glomeruler
basement membrane thickening, which is a precursor to
diabetic neuropathy.
In diabetic mice, AGEs accumulate in mesangial matrix
and nodular glomerular lesions.
AGE compounds accumulate in the kidney due to
mesangial trapping of circulating AGEs through tubular
reabsorption of AGE peptides or by AGEs formed
intrinsically in the kidney.

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d_Diabetic_Kidney_Disease.pdf

AGE Inhibitors Tested (propharmaceuticals)

Alagebrium

Pyridoxamine

cross-link breaker
inhibitor of AGEs resulting from Amadori products
carbonyl trapping and scavenging of metal ions

Pimagedine

competitive inhibitor of AGE pathway

reacts with dicarbonyl compounds
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ntion/Williams_AGE_inhibitors_and_Diabetic_Kidney_

AGE Formation Pathways

Figure 2. Simplified advanced
glycation end product (AGE)
formation pathways and
inhibitory actions of candidate
therapeutic AGE inhibitors.

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_AGE_inhibitors_and_Diabetic_Kidney_Disease.pdf

Results

Alagebrium restored left ventricular collagen stability.

Alagebrium increased large vessel compliance.
Pyridoxamine resulted in decreased urinary transforming
growth factor beta associated with glomerulosclerosis .
Pyridoxamine also showed statistically significant
reductions in serum creatinine levels.
Patients with placebo 22% showed rise in
creatinine leves
Patients receiving pyridoxamine 12% showed rise
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Williams_AGE_inhibitors_and_Diabetic_Kidney_Disease.pdf

Results

Pimagedine

made it to phase III trials, where it was halted because

of complications in patients.
No significant difference in doubled creatinine levels
in those receiving placebo vs. those receiving drug
(26% vs. 20% respectively)
appeared to limit progression of diabetic retinopathy
Complications included flu-like syndrome, anemia,
and introduction of antinuclear and antineutrophil
cytoplasmic antibodies.
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s_AGE_inhibitors_and_Diabetic_Kidney_Disease.pdf

Comparative Results

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Pharmaceutical Intervention of
Glycation

focused on inhibiting formation of AGEs

dimethyl-3-phenacylthiazolium chloride

Targets alpha dicarbonyl structures present in AGE

protein-protein crosslinks

drugs also focus on breaking the glucose derived

cross-links by cleavage on certain sites
could possibly hinder age-related changes of
tissues

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cmd=Retrieve&db=PubMed&list_uids=11280026&dopt=Abstract

Alteon Pharmaceutical Inc.

Focused on Alagebrium (Alt-711) first

in-class AGE cross-link breaker

Restores normal function to damaged tissues

and organs; restores flexibility to tissues
Reverses age-related and diabetes-related
conditions by cleaving the bonds of AGEs
that cause stiffness and loss of function in
various organs and tissues
Inhibits one of the central aspects of aging
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http://www.alteon.com/cross1.htm

Alagebrium Benefits

shows promising results in phase 2 human clinical trials

initial use for cardiovascular and diabetic associated renal
diseases
may be a novel therapy for conditions resulting from
myocardial or vascular damage
Preliminary evidence shows that the drug can modify the
left ventricle of the heart, which is most affected by AGE
products.
proven to improve function of the arterial system
modifies the underlying disease pathology rather than
treating the symptoms of disease

Alagebrium Mechanism of Action

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Alagebrium DIAMOND Study

23 patients over 60 years of age with isolated DHF

Patients received 210 mg of Alagebrium two times per day for 16
weeks.
Alagebrium was given in conjunction with the patients current
medications.
Patients exhibited an improved quality of life as well has high
tolerance for the drug.
Those who received Alagebrium for 16 weeks showed very rapid
reconstruction of the heart.

Reduced mass of left ventricle

Improved diastolic filling in left ventricle

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1.htm

Pyridoxamine

inhibit glycation reactions and formation of AGEs

prospective drug for the treatment of diabetes
mechanism of action includes 3 steps:

Inhibition of AGE formation through inhibition of

oxidative degradation of Amadori intermediate in
Maillard reaction
Locating toxic carbonyl products of glucose and lipid
degradation
Capture of reactive oxidative species

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Pyridoxamine Research Study

S. Padival and R. H. Nagaraj, Department of

Opthomology, Case Western Reserve University
School of Medicine, Cleveland Ohio
AGEs are partially responsible for the formation
of cataracts
Discovered the effect of PM on AGEs and AGE
precursor metabolizing enzymes in diabetic rat
lenses and organ cultured rat lenses
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Pyridoxamine Research Study

Methods:

Introduced diabetes in rats through injection

of streptozotocin
Diabetic and control rats (with no diabetes)
were treated with PM orally for 20 weeks
Rat lenses were cultured with normal or high
glucose levels
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ist_uids=16974131&query_hl=2&itool=pubmed_d
ocsum

Pyriodoxamine Research Study

Results:

Rats treated with 250 microM of PM and

glucose showed inhibition of AGE formation
in organ cultured lenses
PM can inhibit AGE formation in the
diabetic lens by enhancing the activity of
aldose reductase and reacting with precursors
of AGEs.

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Aminoguanidine Treatment
Study

Aminoguanidine treatment increases

elasticity and decreases fluid filtration of
large arteries from diabetic rats

M S Huijberts, B H Wolffenbuttel, H A Boudier,

F R Crijns, A C Kruseman, P Poitevin, and B I
Lvy of University Hospital Maastricht,
Netherlands
Aminoguanidine inhibits formation of AGEs
through reaction with Amadori product.

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artid=288284

Aminoguanidine Mechanism of
Action
Amino groups
in
aminoguanidi
ne will bind to
keto groups
and prevent
AGE formation
and crosslinking.

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Methods

Diabetes was introduced to rats through

injection of streptozotocin
The experimental group of rats were given
daily injections with 50 mg/kg
aminoguanidine hemisulphate
Rats were studied for 10-12 weeks after
induction of diabetes.
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Results

Aminoguanidine treatment resulted in a 40% lower

characteristic aortic input impedance in diabetic
rats.
Pulse pressure, a measurement of arterial elasticity,
was 15% lower in rats treated with aminoguanidine.
Left ventricular weight/body weight ratio was
significantly lower in rats treated with
aminoguanidine as compared to control rats.

3.1 +/- .2 mg/g body weight vs. 3.5 +/- .4 mg/g body
weight.

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Fluid Filtration Rate

Increased
vascular
permeabilityisa
wellestablished
featureof
diabetic
angiopathy
andhasbeen
showninboth
experimental(21,
22)and
clinical(23,24)
studies.
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Carotid Artery Compliance

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Aortic Input Impedance

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Experimental Studies on the Role of Fructose in the

Development of Diabetic Complications

M. Sakai, M. Oimomi, and M. Kasuga

Found that fructose resulted in the production of
greater amounts of AGEs than glucose.
Fructose is not only important in glycation but
also in the formation of free radicals:

Fructose accelerated oxygen radical generation and

the breakdown of lipids and proteins.

Thus, fructose was found to play a key role in the

progression of diabetic complications.
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Hydroperoxide Formation with

Fructose, Glucose, and Neither
FIG. 3. LDL peroxidation was accelerated by
incubation of LDL with glucose or fructose. In
particular, more rapid and marked LDL
peroxidation was observed in case of fructose.

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obeu.ac.jp/journal/co
ntents/48/125.pdf

What Does This Mean?

It suggests that fructose results in a greater

amount of dicarbonyl compounds (found in
AGEs) in glycation.
Fructose results in increased rates of
protein degredation and lipid peroxidation.

inhibits cellular functioning

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Possible Targets for Future

Drugs?

target receptors for advanced glycation end

products (RAGE)
Accumulation AGEs and RAGEs contribute to
cellular dysfunction and vascular disease:

Vascular blockage and loss of elasticity

Inhibiting AGE receptors could prevent vascular disease,

especially in diabetic patients.
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Works Cited

http://en.wikipedia.org/wiki/Glycation

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?
itool=abstractplus&db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=11237208

http://www.benbest.com/lifeext/amadori.gif
http://www.cosmobio.co.jp/export_e/products/antibodies/products_kal_20050412/fluorescent.gif
http://images.google.com/imgres?imgurl=http://209.209.34.25/webdocs/Biochemistry/alejandro/glycation
%2520slides/glycation%2520webpage/glycation%2520webpage
%2520(1)/img012.jpg&imgrefurl=http://209.209.34.25/webdocs/Glycation%2520Page/Glycation
%2520Page.htm&h=300&w=400&sz=32&hl=en&start=1&tbnid=ri2AVDLmqCO3vM:&tbnh=93&tbnw=124&prev=/i
mages%3Fq%3Dglycation%26svnum%3D10%26hl%3Den
http://en.wikipedia.org/wiki/Advanced_glycation_endproduct
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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15905958&dopt=Citation
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db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16974131&query_hl=2&itool=pubmed_docsum
http://www.med.kobe-u.ac.jp/journal/contents/48/125.pdf
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http://www.sciencemag.org/cgi/content/abstract/211/4481/491

Works Cited

http://www.liebertonline.com/doi/abs/10.1089/rej.2006.9.264?cookieSet=1&journalCode=rej

http://www.benbest.com/lifeext/Glucosepane.jpg
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%20(1)/img013.jpg

PATHOPHYSIOLOGY
OF CARBOHYDRATE
METABOLISM
Prof. J. Hanacek, MD, PhD

Technical co-operative: L.urinov

A. Physiologic remarks:

Carbohydrates are present in food in various for

1. simple sugars - monosaccharides
2. complex chemical units - disaccharides

- polysaccharides
polysaccharide
Processing of carbohydrates in GIT
Ingested carbohydrates cleaving proces
monosaccharides absorbtion in stomach,
duodenum and proximal jejunum

B. Disturbancies in Carbohydrate Resorbtion

1. Disaccharidase deficiency syndrome

saccharase = enzyme which hydrolyses disaccharide

saccharose (to fructose and glucose)

laktase

= enzyme which splits disaccharide lact

maltase

= enzyme which splits disaccharide mal

(to glucose and galactose)

(to two molecule of glucose)

Pathomechanisms
a) Activity of disaccharidase is decreased decreased
hydrolysis of disaccharide decreased resorbtion of
substrate increased concentration of disaccharide in
small intestine
lumen increased osmotic activity of the lumen fluid
diarrhea
b) Activity of disaccharidase is decreased increased
concentration of disaccharide in small intestine lumen

increased concentration of disaccharide in large intestine

disaccharide fermentation by bacteria increased
concentration of lactic acid and fatty acids
stimulation of intestine wall abdominal cramps,
bloating, diarrhea, acidic stools, explosive diarrhea

Lactase deficiency syndrome

Causes of lactase deficiency:
- genetic defect (primary)
- secondary to a wide variety of gastrointesti nal
diseases
that damage the mucosa of the small intestine
(secondary)
Disaccharide lactose is the principal carbohydrate in milk.
- Many persons showing milk intolerance prove to be
lactase
deficient
- Primary lactase deficiency incidence is as high as 80 %
to 90 %
among African - Americans, Asians, and Bantus

Causes of secondary lactase deficiency:

- nontropical (celiac disease)and tropical sprue,
- regional enteritis,
- viral and bacterial infections of the intestina l
tract,
- giardiasis, cystic fibrosis, ulcerative colitis,
- kwashiorkor, coeliac disease
Symptoms and signs - are mentioned at previous page

Monosaccharides malabsorbtion
Small intestine ability to resorb glucose and galactose is
decreased
Cause: Specific transport system for galactose and glucose
absorbtion in cells of small intestine is insufficient
Results: Symptoms and signs similar to disaccharidase
deficiency syndrome

Glycogenosis (glycogen storage disease)

Autosomal recessive disease (inborn errors of
metabolism,
emzymopathy)
There are defects in degradation of glycogen.
The disturbances result in storage of abnormal
glycogen,
or storage of abnormal amount of glycogen in various
organs of the body
Example: Hepatorenal glycogenosis (Morbus von
Gierke)
Cause: Deficit of glucose-6-fosfatase in liver and
kidney

DIABETES MELLITUS

DIABETES MELLITUS

DM complex chronic metabolic disorder leading

to multiorgan complications
Main pathophysiological questions related to DM

Why and how the DM develops?

Why and how develop the complications of DM?

What are the mechanisms involved in manifestatio

of diabetic symptoms and signs

Regulation of the blood glucose level depends on liver:

1. extracting glucose from blood
2. synthesizing glycogen
3. performing glycogenolysis
4. performing gluconeogenesis
To a lesser extent peripheral tissues (muscle and adipocytes) use
glucose for their energy needs, thus contributing to maintinance
of normal blood glucose level
The liver s uptake and output of glucose and the use of
glucose by peripheral tissues depend on the physiologic
balance of several hormones that:
1. lower blood glucose level - insulin
2. rise blood glucose level - glucagon, epinephrine, GH,
glucocorticoids...

Definition of DM

DM is a chronic complex syndrome induced by absolute or

relative deficit of insuline which is characterized by
metabolic disorders of carbohydrates, lipids and proteins.
The metabolic disturbances are accompanied by loss of
carbohydrate tolerance, fasting hyperglycemia,
ketoacidosis, decreased lipogenesis, increased lipolysis,
increased proteolysis and some other metabolic
disorders

Classification of DM
(according to International Expert Committee, 1997

Base for the classification are etiopathogenetic mecha

involved in onset and development of DM

Types of DM

I. Diabetes mellitus - type 1: due to destruction of

beta

islets

cells of pancreatic

Consequence: absolute deficit of insulin

A. subtype: induced by autoimmunity processes

B. subtype: idiopathic mechanism

II.Diabetes mellitus -type 2: at the beginning-predominan
of insulin resistance and relative deficit of insulin(normo- or
hyper -insulinemia), later on - combination of impaired insulin

secretion and simultaneous insulin resistance (hypoinsulinem

insulin resistance)

III. Other specific types of DM

DM due to genetic defects of beta cells of pancreas islets an

to genetic defect of insulin function

DM due to diseases influencing exocrine functions of panc

- secondary is damaged endocrine function, too.

DM due to endocrinopathies, drugs, chemicals, infections,

metabolic and genetic disturbances

intolerance which onsets

IV. Gestational DM glucose
for the first time during pregnancy

Main differences between old and new classification

of diabetes mellitus

In new classification of DM:

- terms IDDM and NIDDM are not used
- term DM due to malnutrition is not used
-terms - primary and secondary DM are not used

New terms were introduced into new classification of DM:

* impaired fasting plasma glucose(FPG)
* impaired glucose tolerance(IGT)
Why?

 Normal fasting value of plasmatic glucose concentration:

6.1 mmol/l

Normal value of PGTT blood glucose concentration 2 hs

after beginning of test 7.8 mmol/l

New criteria for diagnose of DM

1st: classic symptoms and signs of DM are present (polyuria,

polydipsia, weight loss), and increased day-time blood gluco
gluc
concentration to 11.1 mmol/l and more
or

2nd: fasting glucose level is 7.0 mmol/l and more

or
3rd: 2 hours glucose level in PGTT is 11.1 mmol/l and mor

For confirmation of diagnosis DM positivity each of the mentio

parameters have to be confirmed next day by positivity any of
the mentioned parameter

 Impaired fasting plasma glucose:

6.1 but 7.0 mmol/l

Impaired glucose tolerance (IGT):

Glucose tolerance test shows abnormal values but these
patients are asymptomatic and they do not meet the
criteria
for diagnosis of DM.
IGT criteria:
- fasting plasma glucose level can be normal
- 2 hours after intake glucose is plasma glucose level
higher
than normal (from 7.8mmol/l to 11.1mmol/l)
The individuals with IGT are recognized as being at higher
risk than the general population for the development of

Syndrome X (metabolic X syndrome)

- frequently occurs in people suffering form visceral
obesity
Characteristic features:
insuline resistance
compensatory hyperinsulinemia
visceral obesity
dyslipidemia ( LDL, TG, HDL)
systemic hypertension
Increased probability of DM-type2 development

Insuline Resistance (IR)

IR is one of the mechanisms involved in pathogenesis
of IGT
and DM, especially in DM type 2
Causes of insuline resistance:

1. autoimmune reactions
- development of anti-insulin antibodies
- development of anti-insulin receptor antibodies
2. defects in the insulin receptor at the cell surface
a) defect in receptor processing
b) decrease in receptor number

3. defective signal transduction

(from the receptor to the plasma of cell)
4. postreceptor defect
5. increased concentration of anti-insulinic hormones

Etiopathogenesis of DM

Type 1 DM - characteristics
- it is most typical in individuals under 30 years of age
(juvenile DM)
- 80 % - 90 % of beta cells in the islets of Langerhans
are destroyed
Possible mechanisms of beta cells destruction:
a) by islet cell antibodies of the IgG class
b) by non-immune mechanism (idiopathic up to
now)

Evidence suggest that type 1 DM is caused by a gradual proce

of autoimmune destruction of beta cells in genetically suscep

individuals

The result of beta cells destruction:

- almost no or absolute no functional insulin
- glucagon is present in relative excess
- individuals are prone to ketoacidosis
- insulin resistance is rare
- patients are insulin dependent

is produced

Type 2 DM - characteristics

1. Primary disturbance:
- biological activity of insuline
2. Compensatory hyperinsulinemia
- due to concentration of blood glucose
3. Insulinoresistentia:
- ability of insuline to inhibit production of
glucose in
liver glucose production

Type 2 DM -characteristics
- is rare in populations not affected by urban
modernization
- adult onset (mostly after 40 years of age, slow,
insidious
onset)
- results from the action of several abnormal genes ; inherited
susceptibility, familial tendency stronger than for type
1 DM
- associated with long - duration obesity (mainly
visceral)
- islet of Langerhans cells antibodies are rare

Main symptomes and signs of DM and mechanisms

of their onset
Hyperglycemia:
relative or absolute deficiency of insulin effect transport
glucose to muscle and fat cells glycemia
insulin effect gluconeogenesis in liver blood level of
glucose
glycogenolysis (?)
Glycosuria: hyperglycemia (8-15 mmol/l) glycosuria

Polyuria: high blood level of glucose increased amount of glu

gl

filtered by the glomeruli of the kidney absorbtion c

of renal tubules for glucose is exceeded glycosuria

accompanied by large amounts of water lost in the u

(osmotic effect of glucose)

Polydipsia : high blood level of glucose hyperosmolality

of
plasma water moves from cells to ECF (IVF)
intracellular dehydratation
creation of thirst feeling (in hypothalamus)
intake of fluids
Polyphagia: depletion of cellular stores of carbohydrates,
fats,
and proteins results in cellular starvation and
a
corresponding increase in hunger
Weight loss : fluid loss in osmotic diuresis, loss of body
tissue
as fats and proteins are used for energy

Complications of Diabetes Mellitus

A. Acute complications
Hypoglycemia
Ketoacidosis

Hyperosmolar hyperglycemic nonketotic coma

B. Chronic complications
Diabetic micro- and macrovascular changes
Diabetic neuropathy
Diabetic retinopathy
Diabetic nephropathy
Other complications

A. Acute complications

1. Hypoglycemia ( 3.3mmol/l of blood glucose) - results from:

a) exogenous causes - overdose of insuline plus inadequate
food intake, increased exercise
- overdose of oral hypoglycemic agents
- alcohol
- other agents (e.g. salicylates)
b) endogenous causes - insulinoma (neoplasm of beta cells
of islet of Langerhans)
- extrapancreatic neoplasm
(hepatomas,
tumor of GIT)
- inborn errors of metabolism (fructose
intolerance)
Symptoms and signs of hypoglycemia are caused b y
epinephrine release (sweating, shakiness, headache,

Hypoglycemia unawareness (HU)

Cause: antihypoglycemic mechanisms are insufficient
Result: hypoglycemia develops without warning
symptoms and signs
Pathomechanism involved in HU development:
Primary defect is localised to the CNS
- or loss of neurotransmiter production on
hypoglycemic stimulus
- reactivity of peripheral tissues
counterregulatory
hormones
Consequences: Deep hypoglycemia hypoglycemic

2. Diabetic ketoacidosis - the most serious metabolic

complication of DM
It develops when there is severe insulin insufficiency
Insulin insufficiencytriggers a complex metabolic reactions
which involve:
- decreased glucose utilisation hyperglycemia and
glycosuria
- acceleration of gluconeogenesis hyperglycemia
- decreased lipogenesis and increased lipolysis
increase
oxidation of free fatty acids production of ketone
bodies
(aceto-acetate, hydroxy-butyrate, and acetone)
hyperketonemia

3. Hyperosmolar hyperglycemic nonketotic

coma(HHNC)
(hyperosmolar hyperglycemic syndrome)
a) - insulin is present to some degree it inhibits fat
breakdown lack of ketosis
is

b) - insulin is present to some degree its effectivity

less than needed for effective glucose transport

hyperglycemia glycosuria and polyuria body

fluids
depletion intracellular dehydration

B. Chronic complications

Today, long-term survival of patient suffering from DM is the

rule. As a result, the problems of neuropathy, microvascula

disease, and macrovascular disease have become important

1. Diabetic neuropathies(DN) - probably the most common
complication in DM
Pathogenesis:
a) vascular damage of vasa nervorum
b) metabolic damage of nerve cels
c) non-enzymatic glycation of proteins
The very first morphologic and functional changes:
- axonal degeneration preferentially involved unmyelinated fibers
(in spinal cord, the posterior root ganglia, peripheral nerves )

Functional consequences:
- abnormalities in motor nerve function
(in advanced stages of DM)
- sensory nerve conduction is impaired
- autonomic neuropathy (diabetic diarrhea, orthostatic
hypotension....)
Possible mechanisms involved in development of DN
- blood supply to nerves is decreased because of microvascular
damage
(vasa nervorum may be damaged)
- energy source for normal rest membrane potential maintain
is
insufficient

2. Diabetic micro- and macroangiopathies

Main functions of vascular endotelium
regulates vascular tone and permeability
regulates the balance between coagulation and fibrinolysis
regulation of subendothelial matrix composition
influences extravasation of leucocytes
influences the proliferation of vascular smooth muscle
and renal mesangial cells
To curry out these functions, the endothelium produces
components of extracellular matrix and variety of
regulatory mediators

A) Microvascular disease - specific lesion of DM that affect capilla

and arterioles of the retina, renal glomeruli, peripheral nerves, m

and skin

Characteristic lesion :
- thickening of the capillary basement membrane
- increased accumulation of glycoprotein in wall of small
arteries and capillaries

a)Retinopathy

- it is the result of retinal ischemia caused by

microangiopathy

Pathomechanisms involved in retinopathy occurence:

- increased retinal capillary permeability, vein dilation
- microaneurism formation and hemorrhages
- narrowing of small arteries lumen
- neovascularisation and fibrous tissue formation within
the retina

Vessels in retina in healthy man

Diabetic retinopathy hard exudates, dot-and-blot hemorrhages,

hard exudates attacks the fovea, cotton-wool patches,microaneurys

Diabetic retinopathy neovascularisation of neural targ

b) Nephropathy - it is the result of glomerular changes

caused by DM

Pathologic processes involved in diabetic nephropathy:

- glomerular enlargement

- diffuse intercapillary

- glomerular basement membrane

thickening
- systemic hypertension often occurs
- neuropathy - see at B1.

glomerulosclerosis

proteinuria
(more than 0.3g/day)

Diabetic nephropathy - nodular glomerulosclerosis

and hyalinic atherosclerosis of small artery

Diabeti changes of glomerulus advanced changes

of the glomerulus

B) Macrovascular disease - atherosclerotic lesion

of larger arteries (coronary arteries, brain arteries, peripheral
arteries)
Main biochemical disturbancies leading to macrovascular
disease:
- accumulation of sorbitol in the vascular intima
- hyperlipoproteinemia vascular abnormality in blood
coagulation, occlusion by
thrombus,
accelerated atherosclerosis

a) Coronary artery disease acute or chronic

myocardial
ischemia and/or
infarction
b) Stroke acute or chronic cerebral ischemia

3. Infection

Persons with DM are at increased risk for infection

throughout the body.

Causes:
- disturbancies of senses (neuropathy, retinopathy)
decreasing the function of early warning system

breaks in skin integrity

- tissue hypoxia (macro- and microangiopathy)
- increased level glucose in body fluids pathogens
are able to multiply rapidly
- white blood cells supply to the tissue is decreased

Diabetic nephropathy- infection present in renal pelvis