Diabetic Complications

Diabetic Complications

Diabetic complications
• Neuropathy
• Retinopathy
• Nephropathy
• Atherosclerosis
• Diabetic cardiomyopathy
• Charcot foot
Case presentation
70 yo WM presents to your office for a
consultation from a diabetes expert. He has
had diabetes for 25 years, with a probable
average HgA1C value of 8-9%. He is not a
smoker, and does not have a Hx of CAD.

What is the likelihood that he has DM
neuropathy?
Epidemiology of DM Neuropathy
• Neuropathy, defined as decreased
sensation in the feet and depressed or
absent ankle reflexes.
• The onset of neuropathy correlates
positively with the duration of diabetes
and, by 25 years, 50 percent of patients
have neuropathy
• Autonomic neuropathy
• Somatic neuropathy
Autonomic neuropathy
• Sweating
• Cardiac denervation
• Postural hypertension
• Resting tachycardia
• Gastroparesis
• Atonic bladder
• Erectile dysfunction

Somatic neuropathy
• Ocular palsies
• CTS
• Small muscle wasting
• Amyotrophy
• Painful neuropathy
• Neuropathic foot
Neuropathic Foot Ulcer
• Warm, with intact
pulses
• Diminished
sensation, callus
• Ulceration
• Local necrosis
• Edema
• Sepsis
• Charcot’s joints
Watkins, BMJ 2003
Glycemic control affects neuropathy
DCCT 1993 NEJM
What causes the nerve damage?
Metabolic Stress
Ischemia
Inflammation
Loss of Regeneration Genetic Susceptibility
Neuron Death
Diabetic complications
• Neuropathy
• Retinopathy
• Nephropathy
• Atherosclerosis
• Diabetic cardiomyopathy
• Charcot foot
Diabetic eye disease
• The lens: blurred vision, cataracts
• Rubeosis iridis: new vessel formation in
the iris – glaucoma
• External ocular palsy – VI
(mononeuritis)
• Maculopathy – hard exudates, loss of
acuity
• Diabetic retinopathy
Diabetic retionpathy
• Non-proliferative
(background):
Microaneurysms
(dot hemorrhages)
Blot hemorrhages
Hard exudates
• Pre-proliferative:
Multiple cotton wool
spots (infarcts)
Venous bleeding


• Proliferative:
Neovascularization
Preretinal
hemorrhage
Vitreous
hemorrhage
• Advanced
retinopathy:
Retinal fibrosis
Traction retinal
detachment
Diabetic retinopathy
Mechanisms
•impaired autoregulation
of retinal blood flow
•retinal microthrombosis
•vasoactive substances
•genetic factors
Diabetic retinopathy
Pathophysiology
•loss of retinal pericytes
due to cellular damage
•capillary microaneurysms
•leakage of lipid and
protein ―hard exudate‖
•macular edema

Repeated cycles lead to
next stage of retinopathy
Diabetic retinopathy
Pathophysiology
•intralumenal proliferation
of cells
•RBC aggregation
•flame hemorrhages
•intraretinal infarcts ―soft
exudates‖

Repeated cycles lead to
next stage of retinopathy
Diabetic retinopathy
Pathophysiology
•intralumenal proliferation
of cells
•RBC aggregation
•flame hemorrhages
•intraretinal infarcts ―soft
exudates‖

Repeated cycles lead to
next stage of retinopathy
Diabetic retinopathy
Pathophysiology
•proliferation of endothielial
cells of retinal veins
•formation of tortuous loops
•severe ischemia results in
neovascularization


Repeated cycles lead to
next stage of retinopathy
Diabetic retinopathy
Pathophysiology
•proliferation of endothielial
cells of retinal veins
•formation of tortuous loops
•severe ischemia results in
neovascularization


Repeated cycles lead to
blindness
Diabetic complications
• Neuropathy
• Retinopathy
• Nephropathy
• Atherosclerosis
• Diabetic cardiomyopathy
• Charcot foot

Diabetic nephropathy
Incidence in T1DM
•20-30% have microalbuminuria after 15 years
•ESRD occurs in 16% at 30 years

In T2DM
At 10 years from diagnosis:
• 25% had microalbuminuria
• 5% had macroalbuminuria
• 0.8% had ESRD
Diabetic nephropathy
• Glomerular change
• Ischemia resulting from hypertrophy of
afferent and efferent arterioles
• Ascending infection



Diabetic nephropathy
Mechanisms
•impaired autoregulation
of retinal blood flow
•retinal microthrombosis
•vasoactive substances
•genetic factors
Hyperglycemia induces mesangial expansion by increased matrix
production and glycosylation (AGE)
Diabetic nephropathy
Activation of cytokines, profibrotic elements, inflammation, VEGF lead to
matrix accumulation. Decreased nephrin expression affects podocytes
Diabetic complications
• Neuropathy
• Retinopathy
• Nephropathy
• Atherosclerosis
• Diabetic cardiomyopathy
• Charcot foot

Diabetic cardiac disease
Pathophysiology
•autonomic
neuropathy leads to
ventricular
dysfunction
•altered substrate
utilization makes
heart less efficient
•impaired
vasoregulation

Diabetic cardiovascular disease
DCCT 2005 NEJM
Diabetic complications
• Neuropathy
• Retinopathy
• Nephropathy
• Atherosclerosis
• Diabetic cardiomyopathy
• Charcot foot

Charcot’s foot
Progressive
degenerative bone
deformity
Occurs in ~0.5% of
diabetic patients
Painless, hot,
swollen foot

Charcot’s foot
46 yo woman with Type 1
DM tripped while walking.
Three days later she
could not get her shoe on.

Dysregulation of bone
turnover
Occurs typically after
trauma
Remodeling of bone can
occur in days
Charcot’s foot
46 yo woman with Type 1
DM tripped while walking.
Three days later she
could not get her shoe on.

Dysregulation of bone
turnover
Occurs typically after
trauma
Remodeling of bone can
occur in days
Proposed mechanisms of toxicity
Brownlee, Nature 2001
Sorbitol pathway
Aldose reductase inhibitors
• Sorbinol Retinopathy Trial: 497 IDDM pts randomized to drug or
placebo. After 41 mo f/u, no difference seen (1990 Arch
Ophthalmol)
• Tolrestat Withdrawal Study: 392 IDDM pts treated for 4.1 yrs,
then randomized to placebo or continued drug for one year.
Placebo group had deterioration of motor nerve conduction
velocities, whereas drug-treated group did not. (1993 J Diab
Complications)
• Fidarestat Neuropathy Trial: 279 pts c DM neuropathy treated
for one year. Nerve electrophysiology studies demonstrated
improvement in drug-treated group versus worsening in control
group (2001 Diabetes Care)
1998--Tolrestat and Sorbinol withdrawn from market
due to liver toxicity and overall lack of efficacy
Proposed mechanisms of toxicity
Brownlee, Nature 2001
Hexosamine pathway
O-linked sugars regulate insulin sensitivity
OGT has homology to
Protein Phosphatase 5

OGT found on to bind to
PIP species

Activation of PI-3 Kinase
by serum recruits OGT
(and AKT) to the
membrane

Made a mutant form that
could not bind PIP—did
not translocate

Yang, et al
Nature 2008
O-linked sugars regulate insulin sensitivity
When at the plasma membrane, OGT modifies AKT to repress activity
and IRS1 to prevent inactivation
Demonstrated in mouse models that OGT overexpression induced
insulin resistance
Yang, et al
Nature 2008
Proposed mechanisms of toxicity
Brownlee, Nature 2001
Hyperglycemia and PKC activation
Evcimen and King, Pharm Res 2007