Complications of

diabetes mellitus

Nóra Hosszúfalusi
2011.03.29.
 Acute and chronic complications
Acute Chronic
- Diabetic ketoacidosis - nephropathy
(DKA) - retinopathy
- Hyperglycemic - neuropathy
hyperosmolaris - Macrovascular diseases
syndrome (HHS) (CHD, peripheral
- hypoglycemia vascular disease,
- metformin associated stroke)
lactic acidosis, MALT
Chronic complications
Associations between HbA1c and MI
and microvascular complications
80

MI
Microvascularis végpontok
60
1000 betegévre (%)
Incidencia

40

20

0
5 6 7 8 9 10 11
Átlagos HbA1c koncentráció (%)

Stratton IM, et al. UKPDS 35. BMJ 2000; 321:405–

321:405–412
 Good glycemic control decreases
the diabetic complications
DCCT Kumamoto UKPDS
HbA1c 9 → 7% 9 → 7% 7,9 → 7%

Retinopathy 76% 69% 17-21%

Nephropathy 54% 70% 24-33%
Neuropathy 60% - -
Macrovascular 41%* - 16%*
disease
* not statistically significant
DCCT Study Group. N Engl J Med 329:977-86, 1993
Ohkubo Y. Diabetes Res Clin Prac 28:103-17, 1995
UKPDS Study Group. Lancet 352:837-53, 1998
 genetic background

repeated acute,
reversible changes

hyperglycemia functional structural

changes changes

cumulative, irreversible
changes in
stable macromolecules
other risk factors
 Hyperglycemia causes
acute reversible and
cumulative irreversible changes

• Acute, reversible intracellular metabolic

changes

• Cumulative, irreversible effects on

stabile macromolecules
Metabolic changes caused by
hyperglycemia
 Acute, reversible intracellular
metabolic changes

• Increased activity of polyol pathway

• Modified protein kinase C activity
• Early glycation products
• Increased production of free radicals
 Consequences of increased
protein kinase C (PKC) activity
 Development of advanced glycation
end products (AGE)
Early → Intermedier → Advenced (AGE)

fehérje + Amadori Késői glikációs termékek

redukáló cukor Schiff bázis (AGE) keresztkötései
termékek

FFI AFPG Pentozidin Pirralin CML

(2-(2-furoil)-4(5)-(2-furanil)- (1-alkil-2-formil-3,4- (Nεε-karboximetil
1H-imidazol) diglűkozil-pirrol) lizin)
 Effects of advanced glycation
end products (AGE)

• Crosslinking of extracellular proteins

• Interactions with specific AGE receptors
• Crosslinking with intracellular DNA
 Cells having AGE-receptors

• Monocyta, macrophage
• Endothel
• Pericyta
• Podocyta
• Astrocyta
• Microglia
Interactions with specific AGE receptors
 Hemodynamic disturbances
in diabetes
• Increased blood flow
• Increased permeability
• Hemorrheological and coagulation
abnormalities
- increased plasma viscosity
- decreased red-cell deformability
- increased platelet aggregability
 Structural abnormalities
in diabetes
• Leakage of glycated plasma proteins
• Extracellular matrix is increased
- BM is thickened
- mesangial matrix is expanded
- collagen is increased
• Hypertrophy and hyperplasia of
endothelial, mesangial and arterial
smooth muscle cells
Nephropathia
 Stages of nephropathy in T1DM
Stages GFR PU RR Histology
I. hypertrophy ↑ No Normal Glomerular
hyperfiltration hypertrophy
II. glomerular ↑/→ No, Normal GBM
tissue changes transient thickening,
mesangium ↑
III. „beginning” ↑/→ MAU + ↑ within the Severe > st. II.
nephropathy persist. normal
IV. manifest ↓ macro- ↑ glomeruloscl.,
nephropathy albumin- arterioscler.,
uria tubulointerst.
V. insuff. renalis ↓↓ ↓ ↑ Severe > st. IV.
 Diagnosis and treatment of
microalbuminuria
• Screening once a year in T1DM (at least), at
diagnosis in T2DM
• Urinary albumin excretion 30-300 (299) mg / 24 h
• 2 positive out of 3 samples (collected urine)
(fever, urinary tract infection, heart failure etc.)
• ACE-inhibitors (ARB), good metabolic control
• DM + albuminuria increases the CVD mortality
with 20 x
 NOT characteristic for diabetic
nephropathy

• Rapid progression (rapid development of

nephrotic syndrome)
• Considerable hematuria, red-cell casts
• Absence of retinopathy
• Short disease duration (T1DM)
Diabetic Eye Disease
Retinopathy
 Stages of diabetic retinopathy
Non-proliferative retinopathy
• mild non-proliferative (background):
microaneurysms, scattered exsudates,
haemorrhages (no complains)
macular oedema
macular ischaemia
• severe non-proliferative (preproliferative):
multiple previous abnormalities, cotton-wool
spots, intraretinal microvascular abnormalities (
IRMA) through the whole retina
 Stages of diabetic retinopathy
Proliferative retinopathy
• Impaired vision, blindness
• New vessels, fibrous proliferation,
hemorrhages (preretinal vitreous), retinal
detachment
 Screening!
• Screening at least once a year
• DR no + good metabolic control 1x a year
mild DR + good metabolic control 6 months
RD no + bad metabolic control 3-6 months
dilated pupil!!
cataract
glaucoma
Visus, pressure, fundus!
• Laser photocoagulation!! (FLAG, OCT)
OCT (optical coherence tomographic)
image, healthy retina
 OCT
macular oedema
Diabetic Neuropathies
 Classification of diabetic neuropathy
• Diffuse neuropathy
- somatic np.: sensorimotor
- autonomic np.: cardiovascular, gastrointestinal,
genitourinary, pupil
• Focal syndromes
- focal np.: mononeuritis, entrapment syndr.
- multifocal np.: proximal neuropathies
• Subclinical neuropathy
- abnormal electrodiagnostic tests
- abnormal quantitative sensory tests
- abnormal autonomic function tests
Type Large fiber Small fiber Proximal Acute Pressure
motor mononeu. palsies
Sensory 0 → +++ 0→+ 0→+ 0→+ + → +++
loss touch, thermal,
vibration allodynia
Pain + → +++ + → +++ + → +++ + → +++ + → +++

Tendon N → ↓↓↓ N→↓ ↓↓ N N

reflex
Motor 0 → +++ 0 Proximal + → +++ + → +++
deficit + → +++
Diabetic foot syndrome
 Contractures → Hammer toe →
Improper weight-bearing → Ulcer →
Infection → Osteomyelitis → Amputation

Hammer toe

Ulcer
 Quantitative sensory tests

• Tuning fork (vibration perception)

• Monofilament (touch sensation, predict foot
ulceration)
• Pain and thermal sensation
• Tendon reflexes (Achilles)

• Neurometer (áramérzet küszöb)

 Classification of diabetic foot ulcer
(Meggitt-Wagner Ulcer Classification

• Grade 0: No ulcer, but high-risk foot (bony

prominences, callus, deformities, previous
ulcer)
• Grade 1: Superficial, full-thickness ulcer
• Grade 2: Deep ulcer, may involve tendons,
but without bone involvement
• Grade 3: Deep ulcer with osteomyelitis
• Grade 4: Local gangrene
• Grade 5: Gangrene of whole foot
 University Texas Wound Classification
System
• Grade 0: Pre- or postulcerative lesion, completely
epithelialized
• Grade 1: Superficial wound not involving tendon,
capsule or bone
• Grade 2: Wound penetrating to tendon or capsule
• Grade 3: Wound penetrating to bone or joint
• Stage A: without infection or ischemia
• Stage B: with infection
• Stage C: with ischemia
• Stage D: with infection and ischemia
 Treatment of diabetic foot ulcer

• Removing necrotic tissue

• Removing the pressure (casts, total contact
casts)
• Antibiotic treatment (1-12 weeks):
clidamycin, ciprofloxacin, cephalexin,
amoxicillin-clavulanate, impenem,
• Revascularisation
Charcot’s neuropathic arthropathy
Progressive, relatively painless, destructive
 Cardiovascular tests
Quantitative autonomic function tests
Parasympathic Sympathic function
function, heart rate (RR):
Variability:
• Orthostatic
• Valsalva’s maneuver hypotension
• Deep breathing
• Supine vs. standing
Autonomic neuropathy increases
the five-year mortality with 3 times!
Macrovascular
complications
 Cardiovascular risk in diabetes

• Peripheral arterial disease 2-4x ↑ (risk of

amputation 16x ↑)
• CHD: risk of AMI 2-3x ↑, heart failure 5x ↑
• Stroke 2-4 x ↑
• Protection of female gender is disappeared
• The macrovascular risk is 10 x ↑ in the
presence of microvascular complication
Survival (9-
(9-years follow-
follow-up): Hoorn Study
in the 50-
50-75 year old population
DM (WHO-
(WHO-criteria): 8 %
1,0

,9 NGT
Cum Survival

IGT
,8
NDM

,7

,6
KDM
,5
0 2 4 6 8 10
follow-up (years)
De Vegt et al: Diabetes Care.2000;23:40
 Survival rate with DM and/or AMI

100
90
80
(%)
ival (%)

70
60
Survival

50 Nondiabetic without prior MI

Diabetic without prior MI
Surv

40
30 Nondiabetic with prior MI
20 Diabetic with prior MI
10
0
0 1 2 3 4 5 6 7 8
Year
 Results of OGTT after AMI

100 n = 181
90
80 IGT Newly diagnosed DM
% of Patients

70
60
50 35% 40% 31% 25%
40
30
20
10
0
At Discharge 3 mo later At Discharge 3 mo later
Norhammar A, et al. Lancet 2002;359:2140-44.
Hypertension/blood pressure control

• Should be measured at every visit

• Repeat RR ≥ 130/80 Hgmm confirms the
diagnosis of hypertension
• Therapeutic goal: RR < 130/80 Hgmm
• 130-139/80-89 Hgmm lifestyle for 3 months
• RR ≥ 140/90 Hgmm drug therapy
• ACE-I or ARB
 Dyslipidemia/lipid management
• At least annually measurement (low risk 2 years)
• Therapeutic goal:
LDL-chol. < 2.6 mmol/l (no CVD)
LDL-chol. < 1.8 mmol/l (with CVD)
TG < 1.7 mmol/l
HDL-chol. > 1.0 (male); > 1.3 mmol/l (female)
 Dyslipidemia/lipid management
• Lifestyle modification
• Statin regardless of basal lipid levels!!!! If
- DM + overt CVD
> 40 years of age, + risk faktor(s) for CVD
• < 40 years of age, LDL > 2.6 mmol/l or
multiple CVD risk factors
• Contraindicated in pregnancy
 Antiplatelet therapy
(low dose aspirin)
• Primary prevention (T1, T2)
CV 10-year risk >10 %; male > 50 years, female >
60 years + at least one major CVD risk factor
• Major risk factors: family history of CVD,
hypertension, smoking, dyslipidemia, albuminuria
• No aspirin if the 10-year CVD risk < 5 %
• Clinical judgment between 5-10 %
• Secondary prevention
• CVD + aspirin allergy → clopidogrel
• Combination up to one year after ACS
 CHD screening in diabetes
(ESC and EASD guideline 2007)

• Resting ECG (1x a year)

• Echocardiographia
• Exercise testing ECG
 ADA recommendation 2011
• In asymptomatic patients, routine screening
for CHD is not recommended, as it does not
improve outcomes as long as CVD risk
factors are treated (A).
STENO-2 vizsgálat eredménye
HbA1c< 6,5%
TC< 4,5 mmol/l
TG< 1,7 mmol/l
RR< 130/80
aspirin

CV halál,
AMI,
Stroke,
Amputáció
> 50 %-kal ↓
 Diabetes and infections
• Infections are more frequent: pneumonia, urinary
tract, skin and mucosal infections 1.5-2 x ↑
• Infections are more severe, mortality rate is
increased 2-3x ↑.
• Provokes hyperglycemic crisis.
• Rare, life threatening infections.
• Immunization: annually influenza vaccine,
pneumococcal polysaccharid vaccine > 2 years
(repeat > 64 years of age, renal disease,
transplantation)
 Rare, life threatening infections.
in diabetes
• Mucormycosis (rhinocerebralis)
• Malign otitis externa (Ps. aeruginosa)
• Psoas abscessus (St. aureus)
• Emphysematosus cholecystitis (E. coli, Cl.
Perfringens)
• Emphysematosus urocystitis, pyelonephritis
(E. coli, K. pneumoniae)
• Fasciitis necrotisans (polymicrobe)