Diabetes Mellitus Flashcards
What is the function of insulin?
Increase glucose uptake by certain cells (via insulin dependent GLUT 4)
Cells = striated muscle and fat cells
What type of hormone is insulin?
Anabolic hormone - promotes synthesis and decreases degradation of glycogen, lipid and protein in target tissues
What mitogenic functions does insulin have on target cells?
DNA synthesis and stimulation of growth and differentiation
What are the two hallmark metabolic defects in Type 2 diabetes?
Insulin resistance - decreased response of target tissues to insulin
Beta cell dysfunction - inadequate insulin secretion in the face of insulin resistance and hyperglycaemia
What occurs with insulin resistance before frank diabetes?
B-cell hyperfunction and hyperinsulinemia - this mechanism is exhausted and hyperglycaemia ensures.
What plays a major role in insulin resistance?
Obesity
Risk for diabetes increases as BMI increases
Central obesity is more linked with insulin resistance than gluteal obesity
What 3 components of obesity contributes to insulin resistance?
Free fatty acids
Adipokines
Inflammation
State the function of FFAs in obesity and insulin resistance.
Excess intracellular FFAs in obese individuals overwhelm oxidative pathways
Generation of toxic intermediates that inhibit intracellular insulin signaling
Describe why adipokines are a factor in obesity related insulin resistance.
Adipose tissue secretes pro and anti-hyperglycaemic cytokines.
Leptin and adiponectin are anti-hyperglycaemic cytokines that increase insulin sensitivity.
Adiponectin levels are decreased in obesity.
How is inflammation involved in obesity related insulin resistance?
Excess FFAs in macrophages stimulates secretion of pro-inflammatory cytokines IL-1B which stimulates secretion of other cytokines that impede insulin signaling in target tissues.
What causes beta cell dysfunction in diabetes type 2?
Excess FFAs that compromise B cell function and insulin release = lipotoxicity
Impact of chronic hyperglycaemia - glucotoxicity
Reduced levels of hormones secreted by gut cells (incretins). These normally promote insulin release following food intake (e.g. GIP)
Amyloid deposition within pancreatic islets
Genetic factors
List the long term complications of diabetes.
Macrovascular disease (macroangiopathy) - retinopathy, nephropathy, neuropathy Microvascular disease (mircoangiopathy) - retinopathy, nephropathy, neuropathy Susceptibility to infections - skin infections, TB, pneumonia, pyelonephritis
Why are diabetic patients susceptible to infections?
Impaired leukocytic functions and vascular compromise
Name the mechanisms implicated in changes seen in tissues (mainly in blood vessels = angiopathy).
Formation of advanced glycation end products (AGEs)
Activation of Protein Kinase C (PKC)
Disturbance in Polyol Pathways
** All due to increased glucose delivery to various intracellular metabolic pathways, generating harmful substrates.
Where do the effects of intracellular hyperglycaemia occur?
In tissues where glucose transport is insulin independent
E.g. nerves, kidneys, blood vessels, eyes, brain
How are AGEs formed?
Advanced Glycation End Products
Formed by binding of glucose derivatives to the amino groups of intra and extracellular proteins
Rate of formation is proportional to the degree of hyperglycaemia
Describe how AGEs lead to the crosslinking of ECM proteins.
Crosslinking of collagen type I in large vessels - decreases their elasticity predisposing to endothelial injury.
Crosslinking of collagen type IV in vascular basement membrane leads to:
- Protein synthesis and deposition exceeding degradation = BM thickening
- Decreased endothelial activation = vascular leakage and extravasation of fluid
Glycated ECM proteins trap other proteins
- In large vessels, LDL is trapped = enhanced atherosclerosis
- In capillaries, albumin binds to BM = further BM thickening
Describe AGE-RAGE interactions.
AGEs bind to a specific receptor (RAGE) expressed on inflammatory, endothelial and vascular smooth muscle cells.
Describe the effect of AGE-RAGE signaling in blood vessels.
Inhibition of neutrophil functions
Release of pro-inflammatory cytokines and growth factors
- Transforming growth factor B implicated in BM thickening
- Vascular Endothelial Growth Factor (VEGF) leading to angiogenesis implicated in neovascularization in the retina
Production of reactive oxygen species by endothelial cells
- Increased procoagulant activity of endothelial cells
- Vascular smooth muscle cell proliferation and synthesis of ECM
Describe the effect of hyperglycaemia on PKC.
Intracellular hyperglycaemia stimulates synthesis of diacyl glycerol (DAG) which activates PKC.
List the effects PKC activation has.
Production of VEGF = angiogenesis (neovascularization in retina)
Increased production of Endothelin-1 = vasoconstriction
Decreased production of the vasodilator NO
Production of Transforming Growth Factor B (TGF-B) = fibroblastic proliferation and ECM/BM deposition
Production of pro-inflammatory cytokines and procoagulant plasminogen activator inhibitor-1 (PAI-1) by vascular endothelium
Explain the disturbances in Polyol Pathways.
Excess intracellular glucose in tissues that do no require insulin is metabolized to sorbitol (a polyol) and fructose.
This reaction uses up NADPH.
NADPH is also required to generate reduced glutathione (GSH); a major cellular antioxidant mechanism.
Decreased NADPH and GSH makes cells more susceptible to oxidative stress and damage.
= seen in inulin-independent tissues like nerves and eye lenses (sorbitol accumulation in eye lenses leads to cataract)
List some examples of diabetic macrovascular disease.
Accelerated atherosclerosis = MI, Peripheral vascular disease and gangrene of lower limbs, retinal arteries are also affected
Hyaline atherosclerosis
What is hyaline atherosclerosis?
Arterioles show a homogenously pink, markedly thickened wall due to plasma protein leakage and ECM deposition leading to narrowing of their lumens
Not specific to diabetes, also caused by HTN
