Biochemistry And Pathology Of Uncontrolled Diabetes Flashcards
Maturity onset diabetes of the young
Mutations in either pancreatic glucokinase or specific nuclear transcription factors
Type 2 MODY-> enzyme has reduced activity -> release insulin at higher glucose levels
Increased Km for glucose or reduced Vmax
Normal insulin release stages
1) glucose enters via GLUT-2 (beta cell specific)
threshold for inulin release-> 80mg glucose/dL, rerelease is proportional to glucose conc up to 300
2) glucose is phosphorylated to glucose-6-phosphate by glucokinase
3) glucose6phosphate is metabolise causing increased ATP
4) increased ATP:APP ratio-> ATP dependent K+ channels close -> membrane depolarisation
5) membrane depolarisation leads to activation of voltages gated Ca2+ channels-> Ca enters
6) increased Ca stimulates fusion of insulin containing exocytotic vesicles to plasma membrane -> insulin secretion
Insulin receptor stimulation
1) insulin binds alpha subunits on receptor
2) beta subunits autophosphorylate each other and also phosphorylate cytosolic enzymes
3) IRS-1 is phosphorylated -> binds to various signal transduction molecules on the SH2 domains
4) physiological responses initiated-> GLUT-4 transporters bind to membrane-> glucose enters cell
Effects of phosphorylation cascade
Increased TAG synthesis, decreased lipolyisis
Increased glucose uptake in muscles and adipose tissue
Increased glucagon synthesis in muscle and liver
Increased protein synthesis
Decreased hepatic glucose
Type 1 diabetes gene
Susceptibility caused by defect in HLA region of B cells that codes MHCII-> presents an intracellular antigen to the cell surface for self recognition by immune cells
Varying degrees of beta cell destruction
Defective insulin biosynthesis and secretion
Abnormal levels of insulin antibodies
Over production of glucagon-> glucagonoma
Type 2 diabete
Defective insulin receptors Genetically defective substrate Decreased glucose transporters Complex metabolic disorders Insulin resistance and dysfunctional beta cells
Metabolic syndrome
Group of conditions that put you at risk of type 2 and heart disease Abdo obesity High blood glucose High blood TAG Lowe HDL High blood pressure Insulin resistance syndrome
Lipid metabolite insulin resistance hypothesis
Increased plasma FFA-> accumulation of triglycerides and metabolites of the re esterification pathway -> acyl-coAs, DAG
DAG activates PKC-> PKC decreases tyrosine phosphorylase activity of insulin receptors-> on for longer
-> impaired IRS/PI3P-K pathway
Insulin resistance
Inflammation insulin resistance hypothesis
Obesity is an inflammatory state associated with increased levels of pro inflammatory cytokines and Chemokines
FFAs activate conical pro inflammatory NF-Kb pathway-> increased expression of TNF-a, IL-b and IL-6, increased MCP levels
MCP regulates macrophage recruitment -> macrophages secrete cytokines
-> TNF-a and IL-6 considered important inhibitors of insulin
-> activation of JNK by cytokines
-> induction of suppressors of cytokine signalling which interfere with binding of IRS1/2 to insulin receptor
Oxidative and ER stress insulin resistance hypothesis
Converting excess amounts of FFAs in to fat-> oxidative and ER stress
-> FFAs activate NADPH oxidase-> induces reactive O2 species
Oxidative stress results in dysregulated inflammatory response -> cytokines
ER stress activates JNK
FFA release also causes competitive inhibition of glycolysis-> decreased ATP -> decreased insulin release
Beta cell dysfunction
Caused by chronic over nutrition
-> increased demand for insulin-> increased beta cell activity
-> increased amyloid production(cell gets confused and produces useless proteins)-> accumulation around islet cells-> amp hours deposited-> cell death -> increased blood glucose
and -> increased insulin synthesis-> ER stress> loss of ER required to produce insulin-> increased blood glucose
Also
-> increased FFA-> inhibition of glycolysis-> decrease ATP -> decreased insulin secretion-> glycolipotoxic effect -> loss of beta cell secretory function
Pathophysiology of type 2
Ageing, genetic, obesity-> insulin resistance
- > fatty acids
- > bad diet, sedentary life style -> environmental factors
- > beta cell compensation-> hyperinsulinemia
- > increased gluconeogensis
- > beta cell decompensation
- > decreased insulin
- > impaired glucose tollerance
- > T2DM
Pathology of diabetes
Glucose -> increases vascular permeability-> Microvascular circulation effected first
Advanced glycation end products-> bind to receptors on blood vessels-> proinflammatory mediator release-> increased NADH and O2 free radicals -> oxidative stress
Increased sorbitol conversion as excess glucose enters the sorbitol/aldose reductase pathway-> increased NADH-> O2 free radicals-> stress-> inflammation
Activation of PKC-> increased intracellular diacylglyceol activates PKC -> vasoconstriction, platlet aggregation-> plaques-> thrombosis
Endothelial cells are insulin independent-> constantly take up glucose-> increased cell osmolality-> increased water in-> cell damage
Clinical manifestations
Retinopathy-> vessel wall changes lead to haemorrhage and vascular proliferation
Neuropathy-> loose injury reflex in hands and feet-> repeated small injury goes unnoticed -> trophic ulcers
Nephropathy-> basement membrane thickening associated high leaky capillaries-> increased GFR-> protienuria-> glomeruloscerlosis
Hypertension-> faster, more severe atherosclerosis in smaller vessels
Coronary artery disease
Peripheral vascular disease
Diabetic foot ulcers
Infections-> decreased healing through poor micro circulation
Clinical symptoms
Fatigue Polyuria Polydipsia Polyphagia with weight loss Poor wound healing and infections Blurred vision Altered mental state Diabetic ketoacidosis or hyperosmolar non ketotic acidosis
