Chronic Complications of Diabetes Mellitus

Chronic Complications of
Diabetes Mellitus
Du Ying，MD，
Dept of Endo, Sir RunRunShaw Hospital,
Zhejiang University School of Medicine
Contents
– Overview of chronic complications
– Microvascular complications
• Retinopathy
• Nephropathy
• Neuropathy
– Macrovascular complications
– Diabetic foot
http://www.srrsh.com
Contents
• Retinopathy
• Nephropathy
• Neuropathy
– Diabetic foot
Chronic Complications of Diabetes: Overview
Microvascular Complications Macrovascular Complications
Diabetic Retinopathy Stroke

Leading cause of
blindness in working
age adults
Diabetic Nephropathy Heart

Disease
Leading cause of end-
stage renal disease
Diabetic Neuropathy
Leading cause of non- Peripheral
traumatic lower Vascular Disease
extremity amputations
2- to 4-fold increase in
Diabetic foot cardiovascular mortality
Harris MI. Clin Invest Med 1995;18:231-239
and stroke
Nelson RG et al. Adv Nephrol Necker Hosp 1995;24:145-156
World Health Organization, 2002;Fact Sheet N° 138
Chronic Complications of DM
• Microvascular complications clearly increase with

’d duration of hyperglycemia
• However, some diabetics never develop
microvascular complications regardless of
glycemic control implies that genetic
susceptibility plays a role.
• Macrovascular complications appear to increase
even before the onset of frank diabetes
Proposed Mechanisms of Diabetic
Vascular Complications
• Hyperglycemia
results in
production of
intermediaries
that alter cellular
function and
initiate a cascade
of events that
result in cellular
damage.
• These events
lead to micro-
and
macrovascular
complications.
Contents
• Retinopathy
• Nephropathy
• Neuropathy
– Diabetic foot
Diabetic Retinopathy (DR)
Definition
Diabetic retinopathy refers to progressive
pathologic alterations in the retinal
microvasculature, leading to areas of retinal
nonperfusion, increased vascular permeability,
and the pathologic proliferation of retinal vessels
Epidemiology
• Diabetes is the leading cause of blindness among
adults (ages 20-74) in the US.
• Retinopathy in poorly controlled type 1 diabetics
occurs in about 25% of patients 5 years after diagnosis,
60% at 10 years, and more than 95% at 15 years.
• Blindness occurs 25 times more frequently in diabetic
patients than in control subjects and is seen most often
after the disease has been present for at least 15 years,
in the setting of advanced retinopathy.
• Approximately 10 to 15% of type 1 diabetic patients
will become legally blind (visual acuity of 20/200 or worse
in the better eye).
• In type 2 diabetes, although the incidence of blindness is
lower, higher disease prevalence results in an even
larger number of patients affected with severe visual loss.
Pathogenesis
• Thought to result from hyperglycemia, which

causes accumulation of sorbitol in retinal cells,
accumulation of advanced glycosylation end
products in extracellular fluid, and impaired
autoregulation of retinal blood flow.
• This leads to capillary leakage and retinal
ischemia.
Clinical Manifestations
• Nonproliferative DR
– Usually appears late in first decade of disease
– See microaneurysms, blot hemorrhages, cotton wool
spots (soft exudates）, hard exudates
– At this early stage of retinopathy, visual acuity is
generally unaffected, and the risk of progression to
high-risk proliferative diabetic retinopathy is about
15% at 5 years.
– At 5 years, moderate and severe nonproliferative
diabetic retinopathy are associated with a 30% and
60% risk of progression to high-risk proliferative
diabetic retinopathy, respectively.
• Proliferative DR
– Hallmark is appearance of newly formed blood
vessels （neovascularization）in response to
retinal hypoxia new vessels prone to bleed with
resultant retinal fibrosis，contracture and retinal
detachment - blindness
– On occasion, new vessels can invade the iris and
anterior chamber, leading to sight-threatening closed-
angle glaucoma.
• Clinically Significant Macular Edema :
– Results from vascular leakage at the macula
– Suggested by hard macular exudates
– An important contributor to the loss of visual acuity
Treatment
• Medical Therapy
Controlling risk factors (hyperglycemia, hypertension,
hyperlipidemia, nephropathy, and careful follow-up
during pregnancy)
• Surgical Therapy
scatter (panretinal) photocoagulation
a complete examination including a dilated funduscopic
examination, tonometry, and slit-lamp biomicroscopy
• Follow-up at least on a yearly basis
Guidelines for treatment and
Follow-up of Diabetic Retinopathy
CSME = clinically significant macular edema; NPDR = nonproliferative diabetic retinopathy;

PC = photocoagulation; PDR = proliferative diabetic retinopathy
*If retinopathy and CSME coexist, focal PC for CSME should always precede panretinal PC.
† In these patients, follow-up is recommended in just 2 to 4 months if CSME is also present.
Modified from Aiello LP, Gardner TW, King GL, et al: Diabetic
http://www.srrsh.com retinopathy [technical review]. Diabetes Care 1998;21:143.
Contents
• Retinopathy
• Nephropathy
• Neuropathy
– Diabetic foot
Epidemiology
• End-stage renal disease (ESRD) from diabetic
nephropathy is a major cause of morbidity and mortality,
particularly in patients with type 1 diabetes, of whom 30
to 35% are susceptible to this complication.
• In type 2 diabetics ∼ 20%
• Diabetes is the leading cause of ESRD in the United
States, accounting for more than one third of cases.
Risk Factors
• Duration of disease
• Elevated glycohemoglobin levels
• Hypertension
• Hyperlipidemia
• Tobacco use
• Race (African American, Hispanic, and Native American )
• Family history
• Others: a deletion polymorphism of the ACE gene,
increased sodium-lithium countertransport, and degree of
insulin resistance.
Pathogenesis of Diabetic Nephropathy
• Related to chronic hyperglycemia
• Leads to end stage renal disease due to effects of:
– Soluble factors
• growth factors
• angiotensin II
• endothelins
• AGEs
– Hemodynamic alterations in the renal microcirculation
• glomerular hyperfiltration or hyperperfusion
• increased glomerular capillary pressure
– Structural changes in the glomerulus
• increased extracellular matrix
• basement membrane thickening
• mesangial expansion
• fibrosis
• Smoking accelerates the decline in renal function
• Natural history of diabetic
nephropathy in type 1 diabetes
Pathogenesis of diabetic nephropathy. CR = creatinine; ESRD = end-stage renal

disease; GBM = glomerular basement membrane; GFR = glomerular filtration
rate; GS = glomerulosclerosis; K-W = Kimmelstiel-Wilson.
Algorithm for Screening for
Diabetic Nephropathy
Treatment
• Early Stage Treatment
Strict glycemic control is of the utmost importance.
DCCT and UKPDS
SGLT-2 inhibitors lower incident or worsening of nephropathy
Use ACE inhibitors and angiotensin II receptor blockers
Systolic blood pressure should be maintained at 120-130 mm Hg or less if
possible
• Later Stage Treatment
Strict glycemic control, reducing hypertension and glomerular pressure
become the mainstay of therapy.
Dietary protein restriction may add limited benefit.
Aggressive lipid management is useful in preventing both renal and
extrarenal vascular complications.
Current options for ESRD patients include hemodialysis, peritoneal dialysis,
kidney transplantation, and combined kidney-pancreas transplantation.
• Avoid nephrotoxic agents, i.e., NSAIDs, dye studies
• Management of Complications
Asymptomatic bacteriuria and pyelonephritis
autonomic bladder dysfunction
Papillary necrosis
Renal artery stenosis
Hyperkalemia
Syndrome of hyporeninemic hypoaldosteronism
…
Contents
• Retinopathy
• Nephropathy
• Neuropathy
– Diabetic foot
Epidemiology and risk factors of
Diabetic Neuropathy
• Symptomatic, potentially disabling neuropathy affects
about 50% of diabetic patients.
• It is usually symmetrical but can be focal and frequently
involves the autonomic nervous system as well.
• Diabetes is the most common cause of neuropathy in
developed nations and the leading cause of nonhealing
skin ulcers and limb amputation.
• Duration of diabetes and degree of glycemic control are
the best predictors of development of neuropathy.
• Other risk factors include:
– Dyslipidemia – Smoking – Hypertension
Pathogenesis of Diabetic Neuropathy
• Related to chronic hyperglycemia as well as
vascular insults  increase oxidative stress.
• Mechanism by which causes nerve damage is
incompletely understood, but probably includes:
– Accumulation of advanced glycosylation end products
•  collagen crosslinking
•  vascular permeability
•  procoagulant activity
– Accumulation of sorbitol
• Results in ’d cellular myoinositol
• Interferes with normal cell metabolism
– Increased oxidative stress  ’d ROS {Reactive Oxygen
Species} with resultant nerve cell damage and death
http://www.srrsh.com Vincent et al. Endocrine Reviews 25:612-28, 2004
• Diffuse neuropathy
– Acute sensory neuropathy
– Distal symmetric sensorimotor polyneuropathy (most common)
– Autonomic neuropathy
• Genitourinary autonomic neuropathy
– Bladder dysfunction
– Sexual dysfunction
• Gastrointestinal autonomic neuropathy
– Gastric atony
– Diabetic diarrhea, constipation
• Cardiovascular autonomic neuropathy
– Postural hypotension
– Tachycardia, sudden death
• Hypoglycemic unawareness, Sudomotor Dysfunction
• Focal neuropathy
– Mononeuropathy (any cranial or peripheral nerve including
oculomotor, median, radial, and lateral popliteal nerves)
– Polyradiculopathy (w/ weakness and atrophy of affected area)
Signs and Symptoms of
Diabetic Peripheral Neuropathy
Symptoms Signs
• Numbness or loss of • Diminished vibratory perception
sensation (asleep or • Decreased knee and ankle
“bunched up sock under reflexes
toes” sensation) Reduced protective sensation
•
• Prickling/Tingling such as pressure, hot and
• Pain (aching, burning, cold, pain
lancinating) • Diminished ability to sense
• Unusual sensitivity or position of toes and feet
tenderness when feet are
touched (allodynia)
Peripheral and Symmetric

Stocking Glove Distribution
Symptoms and signs progress from
http://www.srrsh.com distal to proximal over time
Screening and Diagnosis for
Diabetic Peripheral Neuropathy
Screening:
• All patients with diabetes should be screened
annually for DPN.
• Examination should include:
- Pinprick
- Temperature
- Vibration perception (with tuning fork)
- Pressure sensation (w/ 10-g monofilament)
- Ankle reflexes
• Symptoms (numbness, tingling, pain)
• Loss of 10-g monofilament perception and
vibration perception predict foot ulcers
• Nerve conduction velocity studies
Diagnosis:
• Clinical evaluation
Nerve Conduction Studies
• Confirmation of DPN after considering
differential diagnoses (rule out B12 defic,
Photograph: Boulton et al, 2001
hypothyroidism, uremia)
Boulton et al. Diabetes Care 28:956-62, 2005
American Diabetes Association. Diabetes Care 29(Suppl 1): S4-42, 2006.
Treatment
Tight glycemic control
ACE inhibitors, the antioxidant α-lipoic
acid, and γ-linoleic acid (an important
constituent of neuronal membrane
phospholipids) are still mainly in
investigational stages.
Contents
• Retinopathy
• Nephropathy
• Neuropathy
– Diabetic foot
Macrovascular Complications of
Diabetes
• Macrovascular complications appear to increase even
before the onset of frank diabetes
• Correlates with elevation of both fasting and postprandial
blood glucose
• Patients with DM are at 2-4 fold increased risk of
myocardial infarction (MI)
– Other factors (dyslipidemia, hypertension) play role as well.
– Prognosis for diabetic with coronary disease (CAD) or MI is worse
than for nondiabetics
– CAD tends to involve multiple vessels in diabetics
• 3-fold increased risk of stroke
• 8-fold increased risk of heart failure
• 40-fold increased risk of amputation
Acute Hyperglycemia and
Macrovascular Complications
• Acute hyperglycemia:
– Impairs endothelial NO-mediated function
– Induces a pro-coagulative state
– Increases adhension proteins
– Induces oxidative stress
http://www.srrsh.com Ceriello A: Diabetic Medicine 15:188-93, 1998
Diabetes and other risk factors
• When diabetes accompanied by other risk
factors such as hypertension, dyslipidemia, and
smoking, it markedly increases the incidence of
macrovascular complications.
• For example, the observed 2- to 3-fold greater
risk of myocardial infarction with diabetes rises
to 8-fold in the presence of hypertension and to
nearly 20-fold if both hypertension and
dyslipidemia are present; smoking increases
these risks even further.
Symptoms and Signs of
Macrovascular Disease
Patients may present with:
– Anginal equivalent or myocardial infarction
• Chest pain, shortness of breath or fatigue with exertion
• Silent ischemia may be more common in patients with
autonomic neuropathy
– Claudication
– Acute neurologic changes (stroke)
Atherosclerosis involving the coronary, cerebral,
and peripheral (lower extremity) arteries is the
predominant cause of diabetes-related mortality,
responsible for up to 70% of all deaths in
patients with this disease.
Screening for Coronary Artery Disease
• Diagnostic cardiac stress testing should be done
in patients with:
– Typical or atypical chest pain.
– Resting EKG suggestive of ischemia or infarct.
• Stress test for risk stratification is warranted in
pts with:
– Hx of CV event or peripheral or carotid vascular
disease.
– Pts > 35 yo with sedentary lifestyle planning to
embark on vigorous exercise regimen.
– Do not recommend routine stress testing in patients
with no symptom and normal EKG.
American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care. 29:S4-42, 2006
Macrovascular Disease in Diabetes:
Prevention and Management
• Cardiovascular disease (CVD) is the major cause of
mortality in patients with DM
• Decreasing risk factors prevents/ slows CVD.
• Hence, these patients should be treated as secondary
intervention, with all macrovascular risk factors aggressively
treated as one would do in a patient with known
cardiovascular disease.
– Achieve tight glycemic control
– All diabetics should have LDL of <100 mg/dl, for patients with CAD
or stroke, LDL-c should be <70 mg/dl.
– Attain tight blood pressure control, Bp <130/80mmHg
• Consider use of beta blockers and ACE inhibitors
– Push for smoking cessation.
– Consider daily aspirin for all diabetics over age 40.
American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care. 29:S4-42, 2006
Good Glycemic Control (Lower A1c)
Reduces Complications
DCCT/EDIC Kumamoto UKPDS
(Type 1 DM) (Type 2 DM) (Type 2 DM)
HbA1c 9  7% 9  7% 8  7%
Retinopathy 76% 69% 17-21%
Nephropathy 54% 70% 24-33%
Neuropathy 60% - -
Macrovascular 57%* - 16%**
disease
*Includes all macrovascular events in the EDIC study. ’d risk of CV events by 42%.
Of note, events ’d by 41% in the DCCT but this was not statistically significant.
**Not statistically significant
DCCT Study Group N Engl J Med 329:977-86, 1993
Nathan et al. N Engl J Med 353:2643-53, 2005
http://www.srrsh.com Ohkubo et al. Diabetes Res Clin Pract 28:103-17, 1995
UKPDS Study Group Lancet 352:837-53, 1998
Effects of Tight Blood Pressure Control in
the UKPDS
0
% Risk Reduction
-25
-24 *
†
-32 -34
§
‡
-37
-50 -44 ll
-47¶
-56 **
Any Diabetes- Diabetes- Micro-

-75 Related Related and vascular Retinopathy Vision Heart
Endpoint All-Cause Disease Progression Deterioration Stroke Failure
Mortality
*P=0.0046; †P=0.019; ‡P=0.0092; §P=0.0038; ¶P=0.0036; llP=0.013; **P=0.0043
UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713.
4S: CAD Event Reduction with Simvastatin in
Subgroup of Patients With Diabetes
1.0
0.9
Proportion without
major CHD event
0.8
32%
0.7 Diabetic, simvastatin

- P=0.002
Diabetic, placebo 55%
0.6 Nondiabetic, simvastatin
- P=0.0001
Nondiabetic, placebo
0.0
0 1 2 3 4 5 6
Years since randomization
http://www.srrsh.com Pyörälä K et al. Diabetes Care 20:614-620, 1997.
Contents
• Retinopathy
• Nephropathy
• Neuropathy
– Diabetic foot
Definition
• The diabetic foot is characterized by slowly healing
plantar ulcers that result from apparently insignificant
trauma. Left untreated, superficial ulcers may penetrate
to underlying tissues, leading to complications including
cellulitis, abscess formation, joint sepsis, and
osteomyelitis. Gangrene may occur, and amputation may
be required in severe cases.
Epidemiology
• Overall, about 15% of diabetic patients
experience clinically significant foot
ulceration. Many affected diabetic patients
will eventually require amputation, with
diabetes accounting for more than half of
nontraumatic lower extremity amputations
in the United States.
• To varying degrees, the diabetic foot is
characterized by the combination of chronic
sensorimotor neuropathy, vascular disease,
autonomic neuropathy, and impaired immune
function.
• Sensory neuropathy prevents the detection of
minor traumatic events without signaling pain.
Pedal neuropathy alters weight distribution on
the metatarsal heads and leading to “clawing” of
the metatarsophalangeal joints.
• In advanced cases, abnormal loading of the foot
can result in repeated painless fractures and the
displacement of normal joint surfaces, producing
the so-called Charcot foot or Charcot joint.
• Aortic and peripheral vascular disease often
coexist. Diminished cardiac output or disturbed
autoregulatory mechanisms of the
microcirculation may further contribute to
impaired blood flow and delay ulcer healing.
• Finally, abnormal immune function (secondary to
hyperglycemia) can predispose to prolonged
inflammation and infection, further slowing
wound closure and increasing the likelihood of
ulcer complications.
Impact of Diabetic Peripheral
Neuropathy
Clawing toes, callus,

superficial ulceration
Plantar ulcer, callus

Prevention
• Prevention of the diabetic foot parallels general diabetes
care:
Proper nutrition
Tight glycemic control
Medical risk factor modification, including smoking cessation.
In affected patients, examination by a specialist at least
once per year.
In cases of deformed feet, pressure relief (offloading) is
essential and may include the use of orthotics, specialty
shoes, assistive devices, or a total contact cast to direct
pressure away from a high-risk area.
Treatment 1
• Antibiotics, appropriate local wound care,
and debridement of necrotic tissue.
• local application of recombinant human
platelet–derived growth factor
• Bioengineered tissue therapies, containing
human dermal-epidermal components,
• Surgical amputation for extensive cases of
gangrene or deep tissue infections
• Revascularization for severe PAD
Treatment 2
• Maintain the euglycemic range
• Reduce risk of hypoglycemia.
• Treat other cardiovascular risk factors
• Prevention of microvascular complication
early.
• Preventive care
Regular medical screening examinations
Regular screening for microalbuminuria
Regular ophthalmologic examinations
Regular podiatric examinations (and self-examinations)
Regular dental check-ups
Yearly influenza vaccinations
Pneumococcus vaccination
Thanks for your attention

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Chronic Complications of Diabetes Mellitus

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Chronic Complications of

Microvascular Complications Macrovascular Complications

Diabetic Retinopathy Stroke

Diabetic Nephropathy Heart

• Microvascular complications clearly increase with

• Thought to result from hyperglycemia, which

CSME = clinically significant macular edema; NPDR = nonproliferative diabetic retinopathy;

Pathogenesis of diabetic nephropathy. CR = creatinine; ESRD = end-stage renal

Peripheral and Symmetric

Any Diabetes- Diabetes- Micro-

*P=0.0046; †P=0.019; ‡P=0.0092; §P=0.0038; ¶P=0.0036; llP=0.013; **P=0.0043

0.7 Diabetic, simvastatin

Clawing toes, callus,

Plantar ulcer, callus

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