complications of diabetes mellitus

Complications of Complications of Diabetes MellitusDiabetes Mellitus

Complications of Diabetes Mellitus

Chronic Complications of Diabetes Mellitus Microvascular

Retinopathy (nonproliferative/proliferative)

Nephropathy Neuropathy Sensory and motor (mono-

and polyneuropathy) Autonomic

Macrovascular Coronary artery disease Peripheral vascular

disease Cerebrovascular disease

Acute Complications of Diabetes Mellitus Hyperglycemia Hyperglycemia

crisiscrisis Diabetic

ketoacidosis Hyperglycemia

hyperosmolar State Lactic acidosis

Hypoglycemia

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

Microvascular Microvascular ComplicationsComplications

Increased Polyol Pathway FluxAldose Reductase Function

Increased Intracellular Advanced

Glycation End-Product Formation

Activation of Protein Kinase C

Increased Hexosamine Pathway

Diabetic retinopathyDiabetic retinopathy

Hyperglycemia

Pericyteloss

Hyperperfusion Capillary/Endothelial

damage

Loss ofautoregulation

Capillaryocclusion

Vasoactivefactors Loss of tight

junction

Retinal ischemia

New vessels -Low resistance

- No pericyte/autoregulation

Growth factors

Macularoedema

Pathophysiology of diabetic Pathophysiology of diabetic retinopathyretinopathy

Advanced diabetic eye Advanced diabetic eye diseasedisease

Retinal ischemia

Pericyteloss

Neovascularitation

Preretinal haemorrhage

Neovascular glaucoma

Vitrous haemorrhage

Retinal detachment

Blindness

Diabetic retinopathyDiabetic 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 nephropathyDiabetic nephropathy

Pathophysiology of diabetic Pathophysiology of diabetic nephropathynephropathy

Hyperglycemia

Renal vasodilatation Increased

intraglomerular capillary pressure

Protein glycation

Increased glomular filtration rate

Hypertension

Increased protein excretion

Microalbuminuria or macroalbuminuria

Nephropathy

Glomurular damage

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 neuropathyDiabetic neuropathy

Mechanism of nerve damage in Mechanism of nerve damage in diabetesdiabetes

METABOLIC VASCULAR

glucose

sorbitol

H2O

nerve oedema

myoinositol

NOproduction

AGEformation

vasoconstriction

Arterial narrowing

Vesselocclusion

Slow nerveconduction

Impairingaxonal transport

Altered membrane potensial

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 Clinical features symmetrical sensorimotor symmetrical sensorimotor

neuropathyneuropathySymptomsSymptoms Loss of sensation ;Loss of sensation ;

Anaesthesia;Anaesthesia;’’numbnessnumbness’’ Loss of pain perceptionLoss of pain perception

Altered sensation:Altered sensation: ParaesthesiaeParaesthesiae DysaesthesiaeDysaesthesiae

PainPain BurningBurning Hyperalgesia/allodyniaHyperalgesia/allodynia Neuralgia – lancinating painNeuralgia – lancinating pain Cramps ; restless legCramps ; restless leg

SignsSigns Sensory lossSensory loss Diminished/absent Diminished/absent

tendon reflexstendon reflexs Muscle wasting and Muscle wasting and

weaknessweakness Autonomic Autonomic

dysfunctiondysfunction Foot ulerationFoot uleration

Burning, feeling like the feet are on fire Freezing, like the feet are on ice, although they feel warm to touch

Stabbing, like sharp knives Lancinating, like electric shocks

Treatment of Symmetric Treatment of Symmetric NeuropathyNeuropathy

Glucose controlGlucose control Pain controlPain control

Tricyclic antidepressants Tricyclic antidepressants Amitriptyline,desipramin, nortriptilin, Amitriptyline,desipramin, nortriptilin,

trazodonetrazodone

AnticonvulsantsAnticonvulsants Carbamazepine, gabapentinCarbamazepine, gabapentin

Topical creamsTopical creams capsaicincapsaicin

Foot careFoot 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 Macrovascular complicationscomplications

Macrovascular Macrovascular complication 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

Initiation:

Accumulation of lipids at vascular junctions

experiencing high shear forces

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

Result: Atherosclerotic plaque2

Macrophages bind to and enter intima wall

Macrophages become foam cells & fatty streak formed

Smooth muscle cells (SMCs) migrate into the intima

Inflammatory cytokines induce expression of adhesion molecules

Uptake of Lipids by Macrophages

Chemo-attractants such as PDGF released from activated macrophages

Pathology of Atherogenesis

Atherothrombosis Has Multiple Manifestations

Adapted from: Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6

Transient ischemic attack

Angina:• Stable• Unstable

Ischemic stroke

Myocardial infarction

Peripheral arterial disease:• Intermittent claudication• Rest pain• Gangrene• Necrosis

Macrovascular disease in Macrovascular disease in diabetes mellitusdiabetes 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 Strategies for reducing macrovascular complicationsmacrovascular complications

Prevention proven intervention trialsPrevention proven intervention trials Hyperglycemia Hyperglycemia DyslipidemiaDyslipidemia HypertensionHypertension Antiplatelet therapiesAntiplatelet therapies

Prevention suggested by epidemiologic Prevention suggested by epidemiologic analysisanalysis Disorders of thrombolysisDisorders of thrombolysis Endothelial disordersEndothelial disorders

The diabetic footThe diabetic foot

Diabetic foot diseaseDiabetic 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 Pathophysiology of diabetic foot foot

Neuropathy

Motor dysfunction

Neuropathy Neuropathy

Abnormal Foot posture

Cheiroarthropathy

Reduced painSensation and proprioception

Increased foot prssure

Callus

Microvascular disease

Poor tissue nutrition and oxygenation

Ulcer

Macrovascular diseaseIschemia

Dry, cracked skin

Arteriovenous shunting

TraumaMechanical,

thermal, chemical

Acute Complication of Acute Complication of Diabetes MellitusDiabetes Mellitus

Hyperglycemia crisisHyperglycemia crisis Diabetic ketoacidosis (DKA)Diabetic ketoacidosis (DKA) Hyperglycemic Hyperosmolar State (HHS)

HypoglycemiaHypoglycemia

Diabetic ketoacidosis Diabetic ketoacidosis (DKA)(DKA)

Hyperglycemic Hyperosmolar State (HHS)

Pathophysiolgy of Pathophysiolgy of hyperglycemia crisis hyperglycemia crisis

Diabetic ketoacidosis (DKA)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 DKAHHS: Differences from DKA

Patients usually older- typically 60 or morePatients usually older- typically 60 or more Major pathophysiologic differencesMajor pathophysiologic differences

longer uncompensated osmotic diuresislonger uncompensated osmotic diuresisgreater volume depletiongreater volume depletion

Acidemia (pH > 7.3) and ketosis are mildAcidemia (pH > 7.3) and ketosis are mild Higher mortality -Higher mortality -

often 30-50%often 30-50%primarily due to underlying vascular or infectious primarily due to underlying vascular or infectious

eventevent Occurs in Type 2 diabetics, often mild or Occurs in Type 2 diabetics, often mild or

unrecognizedunrecognized

Definition of HHSDefinition of HHS

Extreme hyperglycemiaExtreme hyperglycemia Increased serum osmolalityIncreased serum osmolality Severe dehydration without Severe dehydration without

significant ketosis or acidosissignificant ketosis or acidosis

Joslin’s Diabetes Mellitus, 13th ed

Clinical Findings of HHSClinical Findings of HHS

HHS should be suspect : elderly patient with or HHS should be suspect : elderly patient with or without the preexisting diagnosis of diabetes who without the preexisting diagnosis of diabetes who exhibits acute or subacute deterioration of CNS exhibits acute or subacute deterioration of CNS function and severely dehydratedfunction and severely dehydrated

Tachycardia Tachycardia Low grade feverLow grade fever Low or normal blood pressureLow or normal blood pressure Dehydration – dry mucous membrane, absent axillary Dehydration – dry mucous membrane, absent axillary

sweat, poor skin turgor.sweat, poor skin turgor. Nausea, vomiting, distension, and pain-gastroparesis is Nausea, vomiting, distension, and pain-gastroparesis is

due to hypertonicitydue to hypertonicity Lethargy, hallucinations, and psychosisLethargy, hallucinations, and psychosis

Laboratory FindingsLaboratory Findings DKA HHS

Fluid Balance in DiabeticFluid Balance in DiabeticHyperosmolarityHyperosmolarity

ECF = 14 L ICF = 28 L

H2O

ECF ICF

H2O

Osmotic Diuresis

Osmotic Diuresis ECF hyperosmolar from ICF autotransfusion

ECF and ICF both hyperosmolar

Priority in the Priority in the Treatment of Treatment of

Hyperglycemia CrisisHyperglycemia Crisis Replacing volume deficitsReplacing volume deficits –– normal normal

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

Correcting hyperosmolarityCorrecting hyperosmolarity to 300 to 300 milliosmoles/Lmilliosmoles/L

Managing any underlying illnessesManaging any underlying illnesses Insulin ; Insulin ; RI 0.15u/kg bolus then 0.1/kg/hr RI 0.15u/kg bolus then 0.1/kg/hr

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

Thank your for your Thank your for your attentionattention

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

http://www.sciencemag.org/cgi/content/abstract/211/4481/491

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.

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

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


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


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)


Glycation Theory of Aging:

http://www.benbest.com/lifeext/amadori.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

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

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


AGEs AGE formation in vascular wall collagen

causes loss of elasticity and leads to cardiovascular disease.

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

http://www.cardioprim.com/Jpeg/open_heartgif.gif

Common AGEs

http://www.cosmobio.co.jp/export_e/products/antibodies/products_kal_20050412/fluorescent.gif

Cross-Linking in Long-Lived Proteins

http://www.benbest.com/lifeext/Glucosepane.jpg

How Are AGEs important? “interfere with molecular and cellular functionin

g” 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 Alzheimer’s 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


AGEs in the Body Diabetes, which increases blood sugar level, reduces the

kidney’s 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.

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

Effects of Glycation and AGEs

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=/images%3Fq%3Dglycation%26svnum%3D10%26hl%3Den

“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.”

http://www.alteon.com/scientific_publications/intervention/Williams_AGE_inhibitors_and_Diabetic_Kidney_Disease.pdf

AGE Inhibitors Tested (pro-pharmaceuticals) Alagebrium

cross-link breaker

Pyridoxamine inhibitor of AGEs resulting from Amadori products carbonyl trapping and scavenging of metal ions

Pimagedine competitive inhibitor of AGE pathway reacts with dicarbonyl compounds


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


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


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.


Comparative Results


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

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?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

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


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 patient’s 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


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

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15905958&dopt=Citation

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

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16974131&query_hl=2&itool=pubmed_docsum

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


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.”


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 Lévy of University Hospital Maastricht, Netherlands

Aminoguanidine inhibits formation of AGEs through reaction with Amadori product.

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=288284

Aminoguanidine Mechanism of Action

http://209.209.34.25/webdocs/Biochemistry/alejandro/glycation%20slides/glycation%20webpage/glycation%20webpage%20(1)/img013.jpg

Amino groups in aminoguanidine will bind to keto groups and prevent AGE formation and cross-linking.

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.

http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=288284&blobtype=pdf

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.


Fluid Filtration Rate Increased vascular

permeability is a well-established feature of diabetic angiopathy

and has been shown in both experimental (21, 22) and

clinical (23, 24) studies.


Carotid Artery Compliance


Aortic Input Impedance


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.

http://www.med.kobe-u.ac.jp/journal/contents/48/125.pdf

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.

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


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.

http://www.aapspharmaceutica.com/search/view.asp?ID=54959

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.gifhttp://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=/images%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.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15905958&dopt=Citation



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=288284http://209.209.34.25/webdocs/Biochemistry/alejandro/glycation%20slides/glycation%20webpage/glycation%20webpage

%20(1)/img013.jpg

PATHOPHYSIOLOGY PATHOPHYSIOLOGY OF CARBOHYDRATE OF CARBOHYDRATE

METABOLISMMETABOLISM

Prof. J. HanProf. J. Hanacacekek, MD, PhD , MD, PhD

Technical co-operative: L.Technical co-operative: L.ŠŠurinovurinováá

A. Physiologic remarks:A. Physiologic remarks: Carbohydrates are present Carbohydrates are present in in food in food in various formsvarious forms::

1. 1. simple sugarssimple sugars - monosaccharides- monosaccharides

2. 2. complex chemical unitscomplex chemical units - disaccharides- disaccharides

- polysaccharides- polysaccharides

Processing of carbohydrates in GIT Ingested carbohydrates Ingested carbohydrates cleaving procescleaving proces monosaccharides monosaccharides absorbtion in absorbtion in stomach, stomach, duodenum and proximal jejunumduodenum and proximal jejunum

B. B. Disturbancies in Carbohydrate ResorbtionDisturbancies in Carbohydrate Resorbtion

1.1. Disaccharidase deficiency syndromeDisaccharidase deficiency syndrome

saccharasesaccharase = = enzyme which hydrolyenzyme which hydrolysesses disaccharide disaccharide saccharosesaccharose (to fructose and glucose(to fructose and glucose))

laktase laktase = = enzyme which splits disaccharide lactose enzyme which splits disaccharide lactose

((to to glucoseglucose and and galactose) galactose)

maltase maltase = = enzyme which splits disaccharide maltoseenzyme which splits disaccharide maltose

(to two molecule of glucose)(to two molecule of glucose)

PathomechanismPathomechanismss a)a) Activity of disaccharidase is decreasedActivity of disaccharidase is decreased decreaseddecreased

hydrolysishydrolysis o of disaccharidef disaccharide decreased resorbtion of decreased resorbtion of

substratesubstrate increased concentration of disaccharide in increased concentration of disaccharide in

small intestinesmall intestine

lumen lumen increased osmotic activity of the lumenincreased osmotic activity of the lumen fluidfluid

diarrhea diarrhea

b)b) Activity of disaccharidase is decreasedActivity of disaccharidase is decreased increased increased

concentration of disaccharide in small intestine lumenconcentration of disaccharide in small intestine lumen

increased concentration of disaccharide in large intestineincreased concentration of disaccharide in large intestine

disaccharide disaccharide fermentation fermentation by bacteriaby bacteria increased increased

concentration of lactic acid and fatty acids concentration of lactic acid and fatty acids

stimulation of intestine wallstimulation of intestine wall abdominal cramps, abdominal cramps,

bloating, diarrhea, acidic stools, explosive diarrheabloating, diarrhea, acidic stools, explosive diarrhea

Lactase deficiency syndromeLactase deficiency syndrome Causes of lactase deficiencyCauses of lactase deficiency::

- genetic defect- genetic defect (primary) (primary)

- secondary to a wide variety of gastrointesti- secondary to a wide variety of gastrointestinal nal

diseases diseases

that damage the mucosa of the that damage the mucosa of the smallsmall intestineintestine

(secondary)(secondary)

Disaccharide lactoseDisaccharide lactose is the principal carbohydrateis the principal carbohydrate in milkin milk..

- - Many persons showing milk intolerance prove to be Many persons showing milk intolerance prove to be

lactaselactase – – deficientdeficient - - Primary lactase deficiency incidence is as high as 80 % Primary lactase deficiency incidence is as high as 80 % to 90 % to 90 % amongamong African - AmericanAfrican - Americanss, Asians, and Bantus , Asians, and Bantus populationpopulation - - Milk intolerance may not become clinically apparent until Milk intolerance may not become clinically apparent until adolescenceadolescence

Causes of secondary lactase deficiencyCauses of secondary lactase deficiency::

- - nontropical nontropical (celiac disease)(celiac disease)and tropicaland tropical sprue,sprue,

-- regional enteritis, regional enteritis,

- - viral and bacterial infections of the intestinaviral and bacterial infections of the intestinal l

tract,tract,

-- giardiasis, cystic fibrosis, ulcerative colitis, giardiasis, cystic fibrosis, ulcerative colitis,

- - kwashiorkor, coeliac disease kwashiorkor, coeliac disease

Symptoms and signs - are mentioned atSymptoms and signs - are mentioned at previous page previous page

Monosaccharides malabsorbtionMonosaccharides malabsorbtion

Small intestine ability to resorb glucose and galactose isSmall intestine ability to resorb glucose and galactose is

decreaseddecreased Cause:Cause: Specific transport system for galactose and glucoseSpecific transport system for galactose and glucose

absorbtion in cells of small intestine is insufficientabsorbtion in cells of small intestine is insufficient Results:Results: Symptoms and signs similar to disaccharidaseSymptoms and signs similar to disaccharidase

deficiency syndromedeficiency syndrome

Glycogenosis (glycogen storage disease)Glycogenosis (glycogen storage disease)

Autosomal recessive diseaseAutosomal recessive disease (inborn errors of (inborn errors of metabolism,metabolism,

emzymopathy)emzymopathy) There are defects in degradationThere are defects in degradation of glycogen. of glycogen.

The disturbances result in storage of abnormalThe disturbances result in storage of abnormal

glycogen, glycogen, or storage of abnormal amount of glycogen in various or storage of abnormal amount of glycogen in various organs of the bodyorgans of the body

Example:Example: Hepatorenal glycogenosis (Morbus Hepatorenal glycogenosis (Morbus von von

Gierke)Gierke)

Cause:Cause: Deficit of glucose-6-fosfatase in liver and Deficit of glucose-6-fosfatase in liver and

kidneykidney

Results:Results: Hypoglycemia in fasting individuals, Hypoglycemia in fasting individuals, hyperlipemia, ketonemiahyperlipemia, ketonemia There are There are 9 9 other types of glycogenosisother types of glycogenosis

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 manifestationof diabetic symptoms and signs

Regulation of the blood glucose level depends on liver:Regulation of the blood glucose level depends on liver:

1. extracting glucose1. extracting glucose from blood from blood

2. synthesizing glycogen2. synthesizing glycogen

3. performing glycogenolysis3. performing glycogenolysis

4. performing gluconeogenesis4. performing gluconeogenesis

To a lesser extent To a lesser extent peripheral tissuesperipheral tissues (muscle and adipocytes) use (muscle and adipocytes) use

glucose for their energy needs, thus contributing to maintinance glucose for their energy needs, thus contributing to maintinance

of normal blood glucose levelof normal blood glucose level

The liverThe livers uptake and output of glucose and the use of s uptake and output of glucose and the use of

gglucoselucose by peripheral tissues depend on the physiologic by peripheral tissues depend on the physiologic

balance of several hormones that:balance of several hormones that:

1. lower blood glucose level1. lower blood glucose level - insulin - insulin

2. rise blood glucose level2. rise blood glucose level - glucagon, epinephrine, - glucagon, epinephrine, GH, GH,

glucocorticoids...glucocorticoids...

DM is a chronicDM is a chronic complex syndromecomplex syndrome induced by induced by absolute or or

relative deficit of insuline which is characterized by which is characterized by

metabolic disorders of carbohydrates, lipids and proteins.metabolic disorders of carbohydrates, lipids and proteins.

The metabolic disturbances are accompanied by The metabolic disturbances are accompanied by loss of loss of

carbohydrate tolerance, fasting hyperglycemia, carbohydrate tolerance, fasting hyperglycemia,

ketoacidosis, decreased lipogenesis, increased lipolysis, ketoacidosis, decreased lipogenesis, increased lipolysis,

increased proteolysisincreased proteolysis and some other metabolic and some other metabolic

disordersdisorders

Definition of DMDefinition of DM

CClassification of DMlassification of DM(according to International Expert Committee, 1997)(according to International Expert Committee, 1997)

Base for the classification are Base for the classification are etiopathogenetic mechanismsetiopathogenetic mechanismsinvolved in onset and development of DMinvolved in onset and development of DM

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

cellcellss of pancreatic of pancreatic isletsislets

Consequence:Consequence: absolute deficit of insulinabsolute deficit of insulin

A. A. subtype:subtype: induced by autoimmunity processesinduced by autoimmunity processes

B. B. subtype: subtype: idiopathic mechanismidiopathic mechanism

Types of DMTypes of DM

II.II.Diabetes mellitus -type 2:Diabetes mellitus -type 2: at the beginningat the beginning--predominancepredominance

of insulinof insulin resistance resistance and and relative deficit of insulinrelative deficit of insulin(normo- or (normo- or

hyper -insulinemia), later onhyper -insulinemia), later on - - combination of combination of impaimpaiired insulin red insulin

secretion and simultaneous insulin resistancesecretion and simultaneous insulin resistance (hypoinsulinemia(hypoinsulinemia, ,

insulin resistanceinsulin resistance))

IV. IV. Gestational DMGestational DM - -

III. Other specific types of DMIII. Other specific types of DM

DM due to DM due to genetic defectsgenetic defects of beta cellsof beta cells of pancreas islets and due of pancreas islets and due to to genetic defect of insulin functiongenetic defect of insulin function

DM due to DM due to diseases influencing exocrine functions of pancreasdiseases influencing exocrine functions of pancreas – – - - secondary is damaged endocrine function,secondary is damaged endocrine function, too.too.

DM due to DM due to endocrinopathies, drugs, chemicals,endocrinopathies, drugs, chemicals, infections, infections, metabolic and genetic disturbancesmetabolic and genetic disturbances

glucose intolerance which onsetglucose intolerance which onsetss

fofor r thethe first time during pregnancyfirst time during pregnancy

Main differences between Main differences between ““oldold”” and and ““newnew”” classification classificationof diabetes mellitusof diabetes mellitus In new classification of DMIn new classification of DM::

-- terms IDDM and NIDDM are not usedterms IDDM and NIDDM are not used

-- term DM due to malnutrition is not usedterm DM due to malnutrition is not used

- terms - primary and secondary DM are not usedterms - primary and secondary DM are not used New termNew termss w wereere introduced introduced ininto new classification of DM:to new classification of DM: ** impaired fasting impaired fasting plasma plasma glucoseglucose((FPG)FPG)

** impaired glucose tolerance(IGT) impaired glucose tolerance(IGT) WhyWhy??

Normal fasting value of plasmatic glucose concentration:Normal fasting value of plasmatic glucose concentration: 6.1 mmol/l6.1 mmol/l

●● Normal value of PGTT – Normal value of PGTT – blood glucose concentration blood glucose concentration 2 h2 hss after beginningafter beginning of test of test 7.8 mmol/l 7.8 mmol/l

New criteria for diagnose of DMNew criteria for diagnose of DM

11stst: : classic symptoms and signs of DM are presentclassic symptoms and signs of DM are present (polyuria, (polyuria, polydipsia, wpolydipsia, weeight loss), ight loss), and and increased day-timeincreased day-time blood glucose blood glucose concentration toconcentration to 11.1 mmol/l11.1 mmol/l and moreand more oror

22ndnd: : fasting glucose levelfasting glucose level isis 7.0 mmol/l7.0 mmol/l and moreand more oror

33rdrd: : 2 hours glucose level in2 hours glucose level in PGTT is PGTT is 11.1 mmol/l11.1 mmol/l and and moremore

For confirmation of diagnosis DMFor confirmation of diagnosis DM p poossitivity each of the mentioned itivity each of the mentioned parameters have to be parameters have to be cconfirmedonfirmed next day by ponext day by possitivity any of itivity any of

the mentioned paramthe mentioned parametereter

Impaired fastingImpaired fasting plasma plasma glucose: glucose:

6.1 but 6.1 but 7.0 mmol/l 7.0 mmol/l

Impaired glucose toleranceImpaired glucose tolerance (IGT) (IGT)::

Glucose tolerance test shows abnormal values but these Glucose tolerance test shows abnormal values but these

patients are asymptomaticpatients are asymptomatic and they do not meet the and they do not meet the

criteria criteria

for diagnosis of DM.for diagnosis of DM.

IGT criteria:IGT criteria: - fasting plasma glucose level can be normal- fasting plasma glucose level can be normal - 2 hours after - 2 hours after intake intake glucose is plasma glucoseglucose is plasma glucose level level higher higher than normal (from than normal (from 7.87.8mmol/l mmol/l to 11.1to 11.1mmol/l)mmol/l)

The individuals The individuals with IGT with IGT are recognized as being at are recognized as being at higher higher

risk than the general popurisk than the general popullation for the development of ation for the development of

DM (about 1.5 DM (about 1.5 -- 4.0 % of patients with IGT 4.0 % of patients with IGT DM). DM).

Syndrome X (metabolic X syndrome)Syndrome X (metabolic X syndrome)

- - frequently occurs in people suffering formfrequently occurs in people suffering form visceral visceral obesityobesity

Characteristic featuresCharacteristic features::

insuline resistanceinsuline resistance

compensatory hyperinsulinemiacompensatory hyperinsulinemia

visceral obesityvisceral obesity

dyslipidemia (dyslipidemia ( LDL, LDL, TG, TG, HDL) HDL)

systemic hypertensionsystemic hypertension

Increased probability of DM-type2 developmentIncreased probability of DM-type2 development

Insuline ResistanceInsuline Resistance (IR) (IR) IR is one of the IR is one of the mechanisms mechanisms involved in involved in pathogenesis pathogenesis of IGT of IGT

and DM,and DM, especially in DM especially in DM type 2 type 2

Causes of insuline resistance:Causes of insuline resistance:

1. autoimmune reactions1. autoimmune reactions

- development of anti-insulin antibodies- development of anti-insulin antibodies

- development of anti-insulin receptor antibodies- development of anti-insulin receptor antibodies 2. defects in the insulin receptor at the cell surface2. defects in the insulin receptor at the cell surface

a) defect in receptor processinga) defect in receptor processing

b) b) decrease in receptor numberdecrease in receptor number

3. defective signal transduction 3. defective signal transduction

(from the receptor to the plasma of cell)(from the receptor to the plasma of cell)

4. postreceptor defect4. postreceptor defect

5. increased concentration of anti5. increased concentration of anti--insulininsulinicic hormones hormones

Etiopathogenesis of DMEtiopathogenesis of DM

Type 1 DM - characteristicsType 1 DM - characteristics

- it is most typical in individuals - it is most typical in individuals under 30 yearsunder 30 years of age of age

(juvenile DM)(juvenile DM) - - 80 % - 90 % of beta cells in the islets of Langerhans 80 % - 90 % of beta cells in the islets of Langerhans areare destroyeddestroyed Possible mechanisms of beta cells destruction:Possible mechanisms of beta cells destruction: a) by islet cell antibodies of the IgG classa) by islet cell antibodies of the IgG class b) by non-immune mechanism (idiopathic up to b) by non-immune mechanism (idiopathic up to now)now)

Evidence suggest that type Evidence suggest that type 11 DM is caused by a gradual DM is caused by a gradual pprocessrocess

ooff autoimmune destruction of beta cells in genetically susceptive

individuals

TThe result of beta cells destruction:he result of beta cells destruction:

- - almost no or absolute no functional insulin almost no or absolute no functional insulin is producedis produced -- glucagon is present in relative excessglucagon is present in relative excess

- - individuals are prone to ketoacidosis - - insulin resistance is rareinsulin resistance is rare

- - patients arepatients are insulininsulin dependen dependentt

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 -characteristicsType 2 DM -characteristics

- is rare in populations not affected by urban - is rare in populations not affected by urban

modernizationmodernization

- adult onset (mostly after 40 years of age, slow, - adult onset (mostly after 40 years of age, slow,

insidious insidious

onset)onset)

- results from the action of several - results from the action of several abnormal abnormal genesgenes ; - ; -

inherited inherited susceptibility, familial tendency stronger than for type susceptibility, familial tendency stronger than for type 1 DM1 DM

- associated with long - duration obesity- associated with long - duration obesity (mainly (mainly

visceral)visceral)

- islet of Langerhans cells antibodies - islet of Langerhans cells antibodies are are rarerare

- increased insulin resistance- increased insulin resistance

- nonspecific changes- nonspecific changes (damage) (damage) of islet cells of islet cells

- usually not insulin dependent- usually not insulin dependent

- individuals are not ketosis prone (but they may form - individuals are not ketosis prone (but they may form

ketonketon bodies bodies under stress)under stress)

Main symptomes and signs of DM and mechanisms Main symptomes and signs of DM and mechanisms of their onsetof their onset

Hyperglycemia:Hyperglycemia:

relative or absolute deficiency of insulin effect relative or absolute deficiency of insulin effect transport of transport of glucose to muscle and fat cells glucose to muscle and fat cells glycemia glycemia

insulin effect insulin effect gluconeogenesis in liver gluconeogenesis in liver blood level of blood level of glucoseglucose

glycogenolysisglycogenolysis (?) (?)

Glycosuria:Glycosuria: hyperglycemia (8-15 mmol/l) hyperglycemia (8-15 mmol/l) glycosuria glycosuria

Polyuria:Polyuria: high blood level of glucose high blood level of glucose increased amount of glucose increased amount of glucose

filtered by the glomeruli of the kidney filtered by the glomeruli of the kidney absorbtion capacityabsorbtion capacity

of renal tubules for glucose is exceededof renal tubules for glucose is exceeded glycosuria resultsglycosuria results,,

accompanied by largeaccompanied by large amounts of water lost in the urine amounts of water lost in the urine

(osmotic effect of glucose)(osmotic effect of glucose)

Polydipsia :Polydipsia : high blood level of glucose high blood level of glucose hyperosmolality hyperosmolality of of plasma plasma water moves from cellswater moves from cells to ECF (IVF) to ECF (IVF) intracellular dehydratationintracellular dehydratation

creation creation of thirstof thirst feeling feeling ((inin hypothalamushypothalamus) )

intake of fluidsintake of fluids

Polyphagia:Polyphagia: depletion of cellular stores of carbohydrates, depletion of cellular stores of carbohydrates, fats, fats,

and proteins results in and proteins results in cellular starvationcellular starvation and and

a a

corresponding corresponding increase in hungerincrease in hunger

Weight loss :Weight loss : fluid lossfluid loss in in osmotic diuresisosmotic diuresis, , loss of body loss of body tissuetissue

as fats and proteins are used for energyas fats and proteins are used for energy

creationcreation

Fatigue :Fatigue : metabolic changes result in metabolic changes result in poor use of food poor use of food

products products lethargy and fatique lethargy and fatique

Complications of Diabetes MellitusComplications of Diabetes Mellitus

A.A. Acute complicationsAcute complications

•• HypoglycemiaHypoglycemia

•• KetoacidosisKetoacidosis

•• Hyperosmolar hyperglycemic nonketotic comaHyperosmolar hyperglycemic nonketotic coma

B.B. Chronic complicationsChronic complications

•• Diabetic micro- and macroDiabetic micro- and macrovascularvascular changes changes

•• Diabetic neuropathyDiabetic neuropathy

•• Diabetic retinopathyDiabetic retinopathy

•• Diabetic nephropathyDiabetic nephropathy

•• Other complicationsOther complications

A.A. Acute complicationsAcute complications

1. Hypoglycemia1. Hypoglycemia ( ( 3.33.3mmol/l of blood glucosemmol/l of blood glucose) - results from:) - results from:

a) exogenous causesa) exogenous causes - overdose of insuline plus inadequate - overdose of insuline plus inadequate food intake, increasefood intake, increasedd exercise exercise

- overdose of oral hypoglycemi- overdose of oral hypoglycemicc agents agents - alcohol- alcohol - other agents (e.g. salicylates)- other agents (e.g. salicylates)

b) endogenous causesb) endogenous causes - insulinoma (neoplasm of beta cells - insulinoma (neoplasm of beta cells of islet of Langerhans) of islet of Langerhans) - extrapancreatic neoplasm - extrapancreatic neoplasm

(hepatomas,(hepatomas, tumor of GIT)tumor of GIT) - inborn errors of metabolism (fructose - inborn errors of metabolism (fructose

intolerance)intolerance)

Symptoms and signs of hypoglycemia are caused bSymptoms and signs of hypoglycemia are caused by y

epinephrine release epinephrine release (sweating, shakiness, headache, (sweating, shakiness, headache,

palpitation)palpitation) and by and by lacklack of glucose in the brainof glucose in the brain (bizarre (bizarre

behaviobehaviouur, dullnessr, dullness, , coma).coma).

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

coma

death

2.2. Diabetic ketoacidosisDiabetic ketoacidosis - - the most serious metabolic the most serious metabolic

complication of DMcomplication of DM

– – It develops when there is It develops when there is severe insulin insufficiencysevere insulin insufficiency

– – Insulin insufficiency triggers a Insulin insufficiency triggers a complex metabolic reactionscomplex metabolic reactions

which involve:which involve: - decreased glucose utilisation- decreased glucose utilisation hyperglycemia and hyperglycemia and

glycosuriaglycosuria

-- acceleration of gluconeogenesisacceleration of gluconeogenesis hyperglycemia hyperglycemia

- decreased lipogenesis and increased lipolysis- decreased lipogenesis and increased lipolysis increaseincrease

oxidation ofoxidation of free fatty acids free fatty acids production of ketoneproduction of ketone

bodiesbodies

(aceto(aceto--acetate, hydroxyacetate, hydroxy--butyrate, and acetonebutyrate, and acetone) )

hyperketonemiahyperketonemia

metabolic acidosismetabolic acidosis comacoma

3.3. Hyperosmolar hyperglycemic nonketotic Hyperosmolar hyperglycemic nonketotic comacoma(HHNC)(HHNC)

(hyperosmolar hyperglycemic syndrome)(hyperosmolar hyperglycemic syndrome)

a)a) - insulin is present to some degree- insulin is present to some degree it inhibits it inhibits fat fat

breakdownbreakdown lack of ketosislack of ketosis

b)b) - insulin is present to some degree- insulin is present to some degree its its effectivity is effectivity is

less than needed for effective glucose less than needed for effective glucose

transport transport

hyperglycemiahyperglycemia glycosuria and polyuria glycosuria and polyuria

body fluids body fluids

depletion depletion intracellular dehydration intracellular dehydration

neurologic neurologic

disturbancies (stupordisturbancies (stupor, coma, coma))

B.B. Chronic complications Chronic complications Today, long-term survival of patient suffering from DM is the Today, long-term survival of patient suffering from DM is the

rule. As a result, the problems ofrule. As a result, the problems of neuropathy, microvascularneuropathy, microvascular

disease, and macrovascular diseasedisease, and macrovascular disease have become importanthave become important 1.1. Diabetic neuropathiesDiabetic neuropathies(DN)(DN) - - probably the most common probably the most common

complication in DMcomplication in DM

Pathogenesis:Pathogenesis: a) vascular damagea) vascular damage of vasa nervorum of vasa nervorum

b) metabolic damageb) metabolic damage of nerve cels of nerve cels

c) non-enzymatic glycation of proteinsc) non-enzymatic glycation of proteins

The The very firstvery first morphologic morphologic and functional and functional change changess: :

- - axonal degeneration preferentially involved unmyelinated fibersaxonal degeneration preferentially involved unmyelinated fibers

(in spinal cord, the posterior root ganglia, peripheral nerves(in spinal cord, the posterior root ganglia, peripheral nerves))

Functional consequences:Functional consequences:

- abnormalities in motor nerve function - abnormalities in motor nerve function

(in advanced stages of DM)(in advanced stages of DM)

- sensory nerve conduction is impaired- sensory nerve conduction is impaired

- autonomic neuropathy (diabetic diarrhea, orthostatic - autonomic neuropathy (diabetic diarrhea, orthostatic hypotensionhypotension........)) Possible mechanismsPossible mechanisms involved in development involved in development ofof DN DN

- blood supply to nerves is decreased because of - blood supply to nerves is decreased because of

microvascular damagemicrovascular damage

(vasa nervorum may be damaged)(vasa nervorum may be damaged)

- energy source for normal rest membrane potential maintain - energy source for normal rest membrane potential maintain

is is

insufficientinsufficient

- increased accumulation of sorbitol and fructose, decreased - increased accumulation of sorbitol and fructose, decreased concentration of myoinositol concentration of myoinositol

- non-enzymatic glycation of protein- non-enzymatic glycation of proteins s

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

2. Diabetic micro- and macroangiopathies

A)A) Microvascular diseaseMicrovascular disease - - specific lesion of DM that affectspecific lesion of DM that affect capillariescapillaries and arterioles of the retina, renal glomeruli,and arterioles of the retina, renal glomeruli, peripheral nerves, musclesperipheral nerves, muscles and skinand skin

Characteristic lesion :Characteristic lesion : - - thickening thickening of the capillaryof the capillary basement membrane basement membrane

- - increased accumulation of glycoprotein in wall of small increased accumulation of glycoprotein in wall of small arteries and capillaries arteries and capillaries

a)a)RetinopathyRetinopathy - - it is the result of retinal ischemia caused by it is the result of retinal ischemia caused by microangiopathymicroangiopathy

Pathomechanisms Pathomechanisms involved in retinopathy occurenceinvolved in retinopathy occurence::

- increased retinal capillary permeability, vein dilation- increased retinal capillary permeability, vein dilation

- microaneurism formation and hemorrhages- microaneurism formation and hemorrhages

- narrowing of small arteries lumen- narrowing of small arteries lumen

- neovasculari- neovascularissation and fibrous tissue formation within ation and fibrous tissue formation within the retina the retina

- retinal scars formation - retinal scars formation blindness blindness

Vessels in retina in healthy man

Diabetic retinopathy – hard exudates, dot-and-blot hemorrhages,hard exudates attacks the fovea, cotton-wool patches,microaneurysms

Diabetic retinopathy – neovascularisation of neural target

b) Nephropathyb) Nephropathy - - it is the result of glomerular changesit is the result of glomerular changes causedcaused by DMby DM Pathologic processes involved in Pathologic processes involved in diabetic diabetic nephropathy:nephropathy: - glomerular enlargement - glomerular enlargement - - diffuse intercapillary diffuse intercapillary

- glomerular basement membrane- glomerular basement membrane glomerulosclerosisglomerulosclerosis thickeningthickening proteinuriaproteinuria - - systemic systemic hypertension often occurshypertension often occurs (more than 0.3g/day (more than 0.3g/day)) - neuropathy - see at B1.- neuropathy - see at B1.

Diabetic nephropathy - nodular glomerulosclerosis and hyalinic atherosclerosis of small artery

Diabeti changes of glomerulus – advanced changes of the glomerulus

B)B) Macrovascular disease Macrovascular disease -- atherosclerotic lesionatherosclerotic lesion of larger arteriesof larger arteries (coronary arteries, brain arteries, (coronary arteries, brain arteries, peripheralperipheral arteries)arteries) Main biochemical disturbancies leading to macrovascularMain biochemical disturbancies leading to macrovascular

diseasedisease::

- accumulation of sorbitol in the vascular intima- accumulation of sorbitol in the vascular intima

- hyperlipoproteinemia - hyperlipoproteinemia vascular abnormality in blood vascular abnormality in blood

coagulationcoagulation,, occlusion occlusion by by

thrombus,thrombus,

accelerated atherosclerosisaccelerated atherosclerosis

a)a) Coronary artery diseaseCoronary artery disease acute or chronicacute or chronic myocardialmyocardial ischemia and/orischemia and/or infarctioninfarction

b)b) StrokeStroke acute or chronicacute or chronic cerebral ischemiacerebral ischemia

c)c) Peripheral vascular diseasePeripheral vascular disease gangrene and gangrene and

amputationamputation (diabetic foot)(diabetic foot)

3. 3. InfectionInfection

Persons Persons with DM with DM are are at increased risk for infection at increased risk for infection

throughout the body. throughout the body.

Causes:Causes: - - disturbanciesdisturbancies of of senses (neuropathy, retinopathy) senses (neuropathy, retinopathy)

decreasing the function of early warning system decreasing the function of early warning system

breaks in skin integritybreaks in skin integrity - tissue hypoxia (macro- and microangiopathy)- tissue hypoxia (macro- and microangiopathy) - increased level glucose in body fluids - increased level glucose in body fluids pathogens pathogens

areare ableable to multiply rapidlyto multiply rapidly - white blood cells supply to the tissue is decreased- white blood cells supply to the tissue is decreased - function of white blood cells is impaired- function of white blood cells is impaired

Diabetic nephropathy- infection present in renal pelvis

complications of diabetes mellitus

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