Professional Documents
Culture Documents
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
Acute
Complications of
Diabetes Mellitus
Hyperglycemia
crisis
Diabetic
ketoacidosis
Hyperglycemia
hyperosmolar State
Lactic acidosis
Hypoglycemia
Microvascular
Complications
Advanced
Glycation End-Product
Formation
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
Neovascularitation
Preretinal
haemorrhage
Pericyte
loss
Neovascular
glaucoma
Vitrous
haemorrhage
Blindness
Retinal
detachment
Diabetic retinopathy
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
Hyperfiltration
Microalbuminuria
Overtproteinuria
Declining GFR
End stage renal failure
Diabetic neuropathy
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
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
Treatment of Symmetric
Neuropathy
Glucose control
Pain control
Tricyclic antidepressants
Anticonvulsants
Carbamazepine, gabapentin
Topical creams
Amitriptyline,desipramin, nortriptilin,
trazodone
capsaicin
Foot care
Autonomic Neuropathy
Macrovascular
complications
Macrovascular
complication
Macrophages
bind to and enter
intima wall
Uptake of Lipids by
Macrophages
Macrophages
become foam
cells & fatty
streak formed
Smooth muscle
cells (SMCs)
migrate into the
intima
Result: Atherosclerotic
plaque2
Myocardial
infarction
Angina:
Stable
Unstable
Macrovascular disease in
diabetes mellitus
Glucose intolerance
Hypertension
Dyslipidemia
Coagulopathy
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
Precipitating factors
Definition of HHS
Extreme hyperglycemia
Increased serum osmolality
Severe dehydration without
significant ketosis or acidosis
Laboratory Findings
DKA
HHS
ICF = 28 L
ECF
ICF
H2O
ECF hyperosmolar from ICF autotransfusion
Osmotic Diuresis
H2O
Osmotic Diuresis
Priority in the
Treatment of
Hyperglycemia Crisis
Non-Enzymatic Glycosylation
and Pharmaceutical Intervention
Monica Morgan
What is Non-Enzymatic
Glycosylation?
Exogenous Glycation
Exogenous Glycation
Retinal dysfunction
Cardiovascular diseases
Type II diabetes
Other age-related diseases
http://en.wikipedia.org/wiki/Glycation
Exogenous Glycation
Endogenous Glycation
http://www.b
enbest.com/li
feext/amador
i.gif
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
http://www.liebertonline.com/doi/abs/10.1089/rej.2006.9.264?
AGEs
AGEs
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?
itool=abstractplus&db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=1
1237208
Common AGEs
http://www.cosmobio.co.jp/export_e/products/antibodies/products_kal_2005
0412/fluorescent.gif
Cross-Linking in Long-Lived
Proteins
http://www.benbest.com/lifeext/Glucose
pane.jpg
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
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.
http://www.alteon.com/scientific_publications/intervention/Williams_AGE_inhibitors_an
d_Diabetic_Kidney_Disease.pdf
Alagebrium
Pyridoxamine
cross-link breaker
inhibitor of AGEs resulting from Amadori products
carbonyl trapping and scavenging of metal ions
Pimagedine
http://www.alteon.com/scientific_publications/intervention/Williams
_AGE_inhibitors_and_Diabetic_Kidney_Disease.pdf
Results
Results
Pimagedine
Comparative Results
http://www.alteon.com/scientific_publications/intervention/Williams_AGE_inhibitors_and_Diabetic_Kidne
Pharmaceutical Intervention of
Glycation
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?
cmd=Retrieve&db=PubMed&list_uids=11280026&dopt=Abstract
http://www.alteon.com/cross1.htm
Alagebrium Benefits
http://www.alteon.com/cross1.htm
Pyridoxamine
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?
cmd=Retrieve&db=PubMed&list_uids=15905958&dopt=C
Methods:
Results:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?
db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids
=16974131&query_hl=2&itool=pubmed_docsum
Aminoguanidine Treatment
Study
http://www.pubmedcentral.nih.gov/articlerender.fcgi?
artid=288284
Aminoguanidine Mechanism of
Action
Amino groups
in
aminoguanidi
ne will bind to
keto groups
and prevent
AGE formation
and crosslinking.
http://209.209.34.25/webdocs/Biochemistry/alejandro/glycation%20slides/glycation%20webpage/glycation%20web
Methods
Results
3.1 +/- .2 mg/g body weight vs. 3.5 +/- .4 mg/g body
weight.
http://www.pubmedcentral.nih.gov/picrender.fcgi?
http://www.pubmedcentral.nih.go
v/picrender.fcgi?
artid=288284&blobtype=pdf
http://www.pubmedcentral.nih.gov/p
icrender.fcgi?
artid=288284&blobtype=pdf
http://www.med.k
obeu.ac.jp/journal/co
ntents/48/125.pdf
http://www.med.kobeu.ac.jp/journal/contents/48/125.pdf
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
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11280026&dopt=Abstract
http://www.alteon.com/cross1.htm
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15905958&dopt=Citation
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?
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
http://www.aapspharmaceutica.com/search/view.asp?ID=54959
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
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=288284
http://209.209.34.25/webdocs/Biochemistry/alejandro/glycation%20slides/glycation%20webpage/glycation%20webpage
%20(1)/img013.jpg
PATHOPHYSIOLOGY
OF CARBOHYDRATE
METABOLISM
Prof. J. Hanacek, MD, PhD
A. Physiologic remarks:
- polysaccharides
polysaccharide
Processing of carbohydrates in GIT
Ingested carbohydrates cleaving proces
monosaccharides absorbtion in stomach,
duodenum and proximal jejunum
laktase
maltase
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
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
DIABETES MELLITUS
DIABETES MELLITUS
Definition of DM
Classification of DM
(according to International Expert Committee, 1997
Types of DM
islets
cells of pancreatic
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
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)
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
A. Acute complications
Hypoglycemia
Ketoacidosis
A. Acute complications
B. Chronic complications
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
Characteristic lesion :
- thickening of the capillary basement membrane
- increased accumulation of glycoprotein in wall of small
arteries and capillaries
a)Retinopathy
- diffuse intercapillary
glomerulosclerosis
proteinuria
(more than 0.3g/day)
3. Infection
Causes:
- disturbancies of senses (neuropathy, retinopathy)
decreasing the function of early warning system