9539954 diabetic complications

8/2/2019 9539954 Diabetic Complications

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Diabetic Complications


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Diabetic complications

Neuropathy

Retinopathy

Nephropathy Atherosclerosis

Diabetic cardiomyopathy

Charcot foot


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Case presentation

70 yo WM presents to your office for aconsultation from a diabetes expert. He hashad diabetes for 25 years, with a probableaverage 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 DMneuropathy?


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Epidemiology of DM Neuropathy

Neuropathy, defined as decreasedsensation in the feet and depressed orabsent ankle reflexes.

The onset of neuropathy correlatespositively with the duration of diabetesand, by 25 years, 50 percent of patients

have neuropathy Autonomic neuropathy

Somatic neuropathy


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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


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Neuropathic Foot Ulcer

Warm, with intactpulses

Diminishedsensation, callus

Ulceration

Local necrosis

Edema

Sepsis

Charcots joints

Watkins, BMJ2003


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Glycemic control affects neuropathy

DCCT 1993 NEJM


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What causes the nerve damage?

Metabolic Stress

IschemiaInflammation

Loss of RegenerationGenetic Susceptibility

Neuron Death


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Neuropathy

Retinopathy



Charcot foot


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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


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Diabetic retionpathy

Non-proliferative(background):

Microaneurysms(dot hemorrhages)

Blot hemorrhagesHard exudates

Pre-proliferative:

Multiple cotton woolspots (infarcts)

Venous bleeding

Proliferative:Neovascularization

Preretinalhemorrhage

Vitreoushemorrhage

Advancedretinopathy:

Retinal fibrosis

Traction retinaldetachment


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Diabetic retinopathy

Mechanisms

impaired autoregulationof retinal blood flow

retinal microthrombosis

vasoactive substances

genetic factors


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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


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Pathophysiology

intralumenal proliferation

of cells

RBC aggregation

flame hemorrhages

intraretinal infarcts soft

exudates




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Pathophysiology

intralumenal proliferation

of cells

RBC aggregation

flame hemorrhages

intraretinal infarcts soft

exudates




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Pathophysiology

proliferation of endothielial

cells of retinal veins

formation of tortuous loops

severe ischemia results in

neovascularization

Repeated cycles lead tonext stage of retinopathy


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Pathophysiology

proliferation of endothielial

cells of retinal veins

formation of tortuous loops

severe ischemia results in

neovascularization

Repeated cycles lead toblindness


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Neuropathy

Retinopathy



Charcot foot


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Diabetic nephropathy

Incidence in T1DM20-30% 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


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Glomerular change Ischemia resulting from hypertrophy of

afferent and efferent arterioles

Ascending infection


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Mechanisms

impaired autoregulationof retinal blood flow

retinal microthrombosis

vasoactive substances

genetic factors

Hyperglycemia induces mesangial expansion by increased matrixproduction and glycosylation (AGE)


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Activation of cytokines, profibrotic elements, inflammation, VEGF lead tomatrix accumulation. Decreased nephrin expression affects podocytes


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Neuropathy

Retinopathy



Charcot foot


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Diabetic cardiac disease

Pathophysiology

autonomic

neuropathy leads to

ventriculardysfunction

altered substrate

utilization makes

heart less efficient

impaired

vasoregulation


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Diabetic cardiovascular disease

DCCT 2005 NEJM


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Neuropathy

Retinopathy



Charcot foot


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Charcots foot

Progressivedegenerative bonedeformity

Occurs in ~0.5% ofdiabetic patients

Painless, hot,swollen foot


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Charcots foot

46 yo woman with Type 1DM tripped while walking.Three days later shecould not get her shoe on.

Dysregulation of boneturnover

Occurs typically aftertrauma

Remodeling of bone canoccur in days


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Charcots foot

46 yo woman with Type 1DM tripped while walking.Three days later shecould not get her shoe on.

Dysregulation of boneturnover

Occurs typically aftertrauma

Remodeling of bone canoccur in days


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Proposed mechanisms of toxicity

Brownlee, Nature2001


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Sorbitol pathway


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Aldose reductase inhibitors

Sorbinol Retinopathy Trial: 497 IDDM pts randomized to drug orplacebo. After 41 mo f/u, no difference seen (1990 ArchOphthalmol)

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 conductionvelocities, whereas drug-treated group did not. (1993 J DiabComplications)

Fidarestat Neuropathy Trial: 279 pts c DM neuropathy treatedfor one year. Nerve electrophysiology studies demonstratedimprovement in drug-treated group versus worsening in control

group (2001 Diabetes Care)

1998--Tolrestat and Sorbinol withdrawn from marketdue to liver toxicity and overall lack of efficacy


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Hexosamine pathway


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O-linked sugars regulate insulin sensitivity

OGT has homology to

Protein Phosphatase 5

OGT found on to bind toPIP species

Activation of PI-3 Kinaseby serum recruits OGT(and AKT) to themembrane

Made a mutant form that

could not bind PIPdidnot translocate

Yang, et alNature2008


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O-linked sugars regulate insulin sensitivity

When at the plasma membrane, OGT modifies AKT to repress activity

and IRS1 to prevent inactivationDemonstrated in mouse models that OGT overexpression inducedinsulin resistance

Yang, et alNature2008


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Hyperglycemia and PKC activation

E i d Ki R

9539954 diabetic complications

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