The Complications of Diabetes

Hyperglycemia
Metabolic syndrome
(50 million Americans)
1) Obesity (+)Intracellular
(+) Glycolysis GAPDH (+) Intracellular OXPHOS (+) ROS (+) PARP
Hyperglycemia
2) Hypertension ROS produciton @ ETC/OXPHOS
> Nerve Cells+ Kideny Cells + Retinal Cells
3) Dyslipidemia > Cells that don't need insulin for metabolic function
Beta-Ox
> Hyperglycemia >>> (+)Glycolgysis >>> (+) ETC >>> (+)ROS
> limit to how much of a proton gradient you can get
> not fat or muscle cells
-NEFA > electrons leak out of ETC and generate free radicles
> cause DNA damage
-Cholesterol XS Glucose NEFA
4) Insulin resistance is Shunted
The Intracellular Complications of Diabetes
*MS is risk factors for CHD + DM2

(+)Polyol Pathway (+) AGEs (Glycation) (+)Hexosamine (+) PKC >>> DAG + IP3 >>> (+) ic [Ca++]
Polyol Pathway Glycation of Proteins Hexose amine pathway
> We useNADPH to recycle Glutathione > Non-Enzymatic > Amino-group on glucoses (-)eNOS & (+)ET-1 (+)VEGF
> glucosamines are used for GAGs (+) TGF-B (+) PAI-1 (+)NK-kB
> Polyol consumes NADPH >>> cant regenerate Glutathion > Alter enzyme function (+) Collagen
> increase Sorbitol produciton >>> cataracts > Glycate a GBM @ Kidney >>> (microalbuminuria) > Bad effects on gene Transcription (+) Fibronectin
> Aldose Reducase inhibitors have been tried and helps some > Glycation is irreversible, permanent
(+) Blood-Flow (+) Vascular Permiability (+) Pro-Inflammatory
> Conversion of Glucose to Furctose + NADPH -long T1/2 proteins affected most (-)Fibrinolysis
Abnormalities (+) Angiogenesis Gene Expression
> receptors (RAGE) (immunoglobulin-like)
-Receptors of Advanced Glycation End-Products (+) Capillary
-RAGE bind to AGE >>> abnormal cell metabolism Occlusion
(+) Vascular
-Response is inflammatory
Occlusion
-RAGE normally have an immune function

(+) ROS

(+) Polyol Pathway (+) Glycation (+) Hexoseamine (+) PKC

Intracellular Complications
Manifeste as....

The Complications of Diabetes Good News! Proper Control of Diabetes lowers the Risk of Complications

Actue problems
DKA (life threatening)
HONK (life threatening)
CC: Diabetic Foot Hypoglycemia
**lower extremity amputation 12.7x Vascular
a. Diabetic Neuropathy = Sensory+Motor Neuropathy a. Macro
> intrinsic muscles of foot are tonic, Chronic Problems -Accelerated athlersclerotic plaque disease
> interosseus muscles loos support, shape of foot changes total morality 2x RR -stroke
lower extremity amputation 12.7x RR -treating DM2 will not necessarily prevent MI (helps some)
b. Foot Autonomics
> Impaired tempurature control Vasculature b. Micro
> reduced sweating >>> (dry cracked skin) cardiovascular mortality 3x RR -NO, enothelial function, cytokines
Rentinal Cells -treating diabetis delays microvasular complication (very good data)
c. Foot gets Contracted Postion blindness 2x RR
Retinopathy
> Callus buildup (hyerkeretosis)
> Callus does not have normal blood supply Kidney Cells
> Calluses breaks down and get ulceration (#infection prone) kidney failure 2.5x RR -Leading cause of blindness in working-age americans
-12% of all new cases of blindness
d. Surpisingly not that painful due to Neuropathy Nerve Cells -8000 new cases annulally
> Encourage Diabetics to look at your foot Neuropathy -By 20 years after diagnosis of DM1, 99% have retinopathy
> Compromized nerve function, compromised vasculature a. Proliferative = (neovascularization) bleed into vitrous and make cloudy
> Impaired healing, osteomyelitis + gangrene -Hypoxia >>> VEGF >>> Proliferation of vessels in front of retina
> prominance @ metatarsel joint
b. Background not sight threatening: cotton wool spots (small bleeds)
Mechanism: -exudates andf dot hemorrhages
Contractures > Hammer-Toe > Improper Weight Bearing >
> Calluses > Ulcer > Infection > Osteomyelitis > Amputation -Retinopathy frequently diagnosed @ time of DM2 diagnosis
-pre-proliferative changes: an opthamologist can cauterize vessels

Neuropthy Diabetic Nephropathy

(=a mircovascular problem) -32.5% of renal failure largest contributor
1) Peripheral -Due to Poor glycemic control
> Kill nerves: disasthesias -Hypertension (very important)
*manifests as: pain, burning, hypersensitivitry, numbness -Diabetic and familial hypertension + CHF
> Pain: neuropathic, burning, throbing, lancinating, = ALTERED RENAL FLOW
> STOCKING GLOVE DISTRIBUTION -Glycation of GBM (loss of normal barrier)
bc the longest nerves affected most -AGT2 receptor blockers are protective to kidenys
> Worse when go to bed orthostatic *note: ULTIMATE LOSS OF NEPHRONS
(in bed trying to be comfortable)
*CC: Kimmelsteil-Wilson Kidney = Nodular Glomerulosclerosis
2) MonoNeuropathy
CC: Occular Neuropathy of a Diabetic

3) Autonomic (big problem but not as common)

a. Orthostatic Hypotenstion
b. Abnormal Gut Motility (constipation vs diarrhea)
c. Sexual Dysfunction ( genitourinary)
d. Abnormal Sweating
e. Abnormal Cardiac function (arrythmias = sudden death)
f. Loss of normal Epinephrine response to Hypoglycemia