Pathophysiology of Diabetes Complications - Olson Flashcards
What was found in the Diabetes Control and Complications Trial (DCCT)?
Intensive therapy to control blood glucose levels significantly decreased risk of diabetic complications (retinopathy, nephropathy, and neuropathy)
Intensive therapy to control blood glucose levels significantly reduced risk of macrovascular disease
*findings implicate hyperglycemia or other metabolic abnormalities as the overriding pathogenic abnormality
How can chronically elevated glucose levels cause diabetic complications?
directly damage specific critical cellular components in a complications-prone tissue; Ex: peripheral nerve axons or Schwann cells
indirectly damage functional or structural elements; Ex: extracellular matrix or microvasculature
What are the most commonly cited mechanisms for glucose-induced diabetic complications?
What is the protein kinase C hypothesis?
Examples: microvascular complications and diabetic peripheral nephropathy
hyperglycemia -> Gq activation -> increased PKC activity
What do PKC inhibitors do?
Ruboxistaurin (RBX)
in diabetic animal models, ameliorated diabetic microvascular complications including retinopathy, neuropathy, and nephropathy
Phase 1 and 2 clinical trials demonstrated that agent is tolerated in diabetic humans
Phase 3 clinical trials demonstrated moderate delays in progression of advanced nephropathy and late stage retinopathy
What is the Sorbitol Hypotheses?
hyperglycemia -> increased glucose -aldose reductase-> sorbitol -sorbitol dehydrogenase-> fructose
arginine -NOsynthase-> decrease nitric oxide + citrulline
GS-SG -glutathione reductase-> decrease GSH
What are the aldose reductase inhibitors?
Effective for treatment of retinopathy and neuropathy in diabetic rats and dogs
Limited usefulness in human trials due to toxicity associated with delivery of drug through blood-retinal barrier
Clinical trial in diabetic humans failed
What are advanced glycation end products?
Formed non-enzymatically from sugar derived intermediates
Glucose has slowest rate of AGE formation compared to other sugars such as glucose-6P or glyceraldehyde
AGE formation is much more rapid inside the cell than outside (e.g. extracellular matrix)
What are the mechanisms by which Advanced Glycation Endproducts (AGE) formation cause pathological changes?
AGE can directly alter protein function in target tissue
AGE can alter signal transduction pathways by altering matrix-matrix and matrix-cell interactions
AGE can alter the levels of soluble signals such as cytokines, hormones, or free radicals
- this occurs through the binding of AGE to receptor for AGE (RAGE)
What would an AGE inhibitor do?
Aminoguanidine
reacts with dicarbonyl intermediates (one step distal to Amidori product formation)
Improves pathologies of the retina, kidney, nerve, and artery in diabetic animal models
How does oxidative stress and free radicals affect diabetes?
free radicals are highly reactive molecules with unpaired electrons
excessive free radicals or inadequate antioxidant defense mechanisms lead to damage of cellular structures and enzymes
superoxide anion; hydrogen peroxide; hydroxyl radical; nitric oxide
how does hyperglycemia produce free radicals and lipid peroxidation?
Direct autooxidation of glucose
Increased glucose metabolism (mitochondrial respiration)
Activation of glycation pathways
Reduction of antioxidant mechanisms
Induction and activation of lipoxygenase pathways
Increased NADPH oxidase activity (superoxide)
What is the inflammation hypothesis?
Elevated glucose -> increase inflammatory cytokine production (IL-1beta, TNF-alpha) -> increase expression of adhesion molecules (ICAM and VCAM) on endothelial cells -> increase adhesion of leukocytes to endothelial cells
Can occur in:
- astrocytes
- muller cells in the retina
- podocytes in the kidney
- endothelial cells
