CHRONIC COMPLICATIONS OF

DIABETES MELLITUS

Microvascular

complications:

• Diabetic retinopathy

• Diabetic nephropathy

• Diabetic neuropathy

Macrovascular

complications

Systemic atheroscerosis

Mixted: diabetic foot

Pathogeny of chronic complications

in diabetes mellitus

Main factors:

• Genetic factors

• Duration of diabetes

• Metabolic control

Pathogenic mechanisms:

• Glycosilation of proteins

• Poliol pathway activation

• Increased production of oxidative stress

• Haemorrheological disturbancies

Post-prandial hyperglycaemia

Post-prandial hyperglycaemia contributes HbA1c ~1%

B=breakfast; L=lunch; D=dinner.

Adapted from Riddle MC. Diabetes Care. 1990;13:676-686.

Pla

sm

a g

luco

se

(m

g/d

L)

300

200

100

0

Time of day (h)

6 12 18 24 6

Uncontrolled Diabetes HbA1c 8%

Fasting hyperglycaemia

Basal hyperglycaemia contributes ~2%

B

L

D

Normal HbA1c ~5%

CONTRIBUTIONS OF FASTING AND POST-

PRANDIAL GLYCEMIA IN INCREASING HbA1c

Classification of diabetic

retinopathy Non-proliferative DR:microaneurisms, “hard” exudates,microhaemorrhagies

- Oftalmologic control in 1 year

Diabetic maculopathy:macular oedema or ischaemical disorders

-ophtalmologic control in 3-4 months

Preproliferative DR:”soft” exudates,haemorrhagies

Ophtalmologic cntrol in 2-3 months

Proliferative retinopathy:capillary new vessels

Ophtalmologic control in 2-3 months.

Advanced eye disease:detached retina, rubeosis iridis,neovascular glaucoma

SCREENING OF DIABETIC

RETINOPATHY

TYPE OF

DIABETES

FIRST EYE

FUNDOSCOPY

USUAL

EXAMINATION

TYPE 1 3-5YEARS

AFTER

DIAGNOSIS

EVERY YEAR

TYPE 2 AT FIRST

DIAGNOSIS

EVERY YEAR

PREGNANCY Preconception

al and during

pregnancy

Main mechanisms of atherogenesis in

diabetes

Disturbancies in concentration,composition and lipoproteins

Glycosilation end-products in plasma and arterial wall

Oxidisation and glycosilatin of LDL

Procoagulant status

Insulinresistance and hyperinsulinism

Muscle cell proliferation and “foam’cells in vascular wall

Mechanisms Contributing to

Arterial Disease in Metabolic Syndrome and

Type 2 Diabetes

Adapted from Libby et al. Circulation. 2002;106:2760-2763.

Cardiac disturbancies in diabetes

Hyperglycemia

Macroangiopathy Autonomic cadiac neuropathy

Microangiopathy

Diabetic cardiomiopathy

Genetic factor

Age,sex

Family history

Endothelial

dysfunction

Oxidative

stress Procoagulant

status

Protein

glycosilation

insulinresistence

dyslipidemia

Arterial

hypertension

Abdominal

obesity

DIABETIC NEPHROPATHY

The evolution of glomerular filtrate and urinary

albumin excretion

STAGE I –RENAL HYPERFILTRATION AND

HYPERTROPHY

• AT FIRST DIAGNOSIS OF DIABETES

• reversible

• 20-50 % of GFR (>150 ml/min/1,73 m2)

• After decreasing glycemia: 50% - GFR is normalising

50% - hiperfiltration

microalbuminuria

• Intermitent microalbuminuria:increasing the glomeruli

and kidneys

• Normal blood pressure

STAGE II –SILENT, NORMOALBUMINURIC

STAGE

• In first five years of diabetes

• Renal biopsy:thickening of basal membrane and

mesangium

• GFR is increased ( 20-50 %)

• UAER is normal

• normal BP

STAGE III – EARLY NEPHROPATHY

• After 6-15years of diabetes

• The progression is stopped by a good metabolic

control

• Persistent microalbuminuria (30-300 mg/24 h) –

• GFR is increased, but is decreasing with 3-5

ml/min/year

• Normal or little increased blood pressure ( with 3

mm Hg/year)

• Much more histological abnormalities +glomerular

obstructions

STAGE IV –CLINIC DIABETIC

NEPHROPATHY

• After 15-25 years of diabetes

• Clinic proteinuria (albuminuria > 300 mg/24 ore)

• GF progressivelly( 8-12 ml/min/year)

• 3 substages: - early(GF > 130 ml/min)

- intermmediary (GF < 100 ml/min)

- advanced (GF < 70 ml/min)

• BP ( with 5 mm Hg/year)

• Morphopatology:progressive glomerular sclerosis

distruction of renal mass

•Good glycemic and BP control is delaying the

progression of renal disease.

•

STAGE V –CHRONIC RENAL FAILURE

• After 25-30 years of diabetes

• Proteinuria

• Urinary ureea<10g/24h

• GF < 10 ml/min

• BP

• Morphopatology: severe glomerular occlusions and lesion

V. SCREENING FOR MICROALBUMINURIA

Every year :

• At puberty or 5 years of type 1 diabetes

• At first diagnosis of type 2 diabetes

ADA. Diabetes Care. 2005;28(suppl 1):S1-79.

• Diet

• Physical exercise

• Smoking cessation

• Weight control

• HbA1c <7%

• Glucose (mg/dL):

Preprandial 90–130

Postprandial <180

• Dyslipidemia: Statines

• Hypertension : ≥2 classes

of drugs

• Microalbuminuria:

ACE or ARB

• Aspirin

• CHD: ACE, -blockers

• CVD/risc: ACE

Optimising lifestyle Intensive glycemic

control

Intensive treatment

to decrease

cadiovascular

risk

Optimal treatment of arterial hypertension in

diabetic patient

Hyperglycemia

polyol pathway

Intracellular hyperosmolarity

Decreasing intracellular

myoinositol

Decreasing activity decreasing axonal flow decreased phosphoinositol Na+/K+ ATP-ase

Axonal demyelinisation

CLASSIFICATION AND STAGING of DIABETIC

NEUROPATHY ADA: Consensus San Antonio

Subclinical neuropathy

• Abnormal Electrodiagnostic Tests

1.decreased nerve conduction velocity

2.decreased amplitude of evoked muscle or nerve action potential

• Abnormal Quantitative Sensory Testing

1.vibratory/tactile

2.thermal

3.others

• Abnormal Autonomic Function Tests

1.Diminished sinus arrhythmia

2.Diminished sudomotor function

3.Increased pupillary latency

Clinical neuropathy

Diffuse neuropathy

1.distal symmetric sensorimotor polyneuropathy

-primarly small-fiber neuropathy

-primarly large fiber neuropathy

- mixed

2.autonomic neuropathy

a.abnormal pupillary function

b.sudomotor dysfunction

c.genito-urinary autonomic neuropathy

-bladder dysfunction

-sexual dysfunction

d.gastro-intestinal autonomic neuropathy

-gastric atony

-gallbladder atony

-diabetic diarrhea

-hypoglycemia unawareness

Clinical neuropathy

e.Cardiovascular autonomic neuropathy

f.Hypoglycemia unawareness

Focal Neuropathy 1.Mononeuropathy

2.Mononeuripathy multiplex

3.Plexopathy

4.Radiculopathy

5.Cranial neuropathy

AUTONOMIC NEUROPATHY

• Cardiovascular -tachycardia, exercise

intolerance

-cardiac denervation

-orthostatic hypotension

• Gastrointestinal -esophageal dysfunction

-gastroparesis

-diarrhea

-constipation

-fecal incontinence

• Genitourinary

- erectile dysfunction

- retrograde ejaculation

-cystopathy

-neurogenic bladder

• Neurovascular -heat intolerance

-gustatory sweating

-dry skin

-impaired skin blood flow

• Pupillary • Decreased diameter of dark

adapted pupil

Clinical manifestations of cardiac

autonomic neuropathy

Exercise intolerance • Impairment of exercise tolerance

• Reduced response to heart rate and blood pressure

• Decreased cardiac output

• Decreased ejection fraction

• Systolic dysfunction

• Decrease in diastolic filling

Intraoperative cardiovascular lability

Increased necessity for vasopresor support

Excessive vasodilation with anesthesia due to loss of normal vasoconstrictor response and tachycardia

Orthostatic hypotension • Dizziness

• Weakness

• Fatigue

• Visual blurring

• Neck pain

Sylent myocardial ischemia • Decreased perception of anginal

pain, often accompanied by unexplained fatigue, confusion, tiredness, edema, hemoptysis, nausea, vomiting, diaphoresis, arrhytmias, cough or dyspnea