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Diabetes, Physiology - Coggle Diagram
Diabetes
Diabetes type 1 = absolute deficiency of insulin- usually as a result of T cell mediated autoimmune destruction of beta islet cells (10% of diabetes). In T1, there is high blood glucose and low cell uptake of glucose, so catabolic hormones e.g glucagon are unoppose=weight loss, ketoacidosis, hypertriglyceremia (as insulin stimulates LPL on endothelial capillary cells, so no chylomicrons/VLDLs broken into free FA)
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Pathophys
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Genetic predistposition:
INS (mutation means lack of INS expression in the thymus, which allows autoreactive T cells to escape)
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Phases of development:
Phase 1: beta cell death + APC activation. Viral infection of beta cells e.g MUMPs, rubella etc. can directly lyse cells or induce upregulation of MHC and secretion of inflammatory cytokines. Viral antigens released from cell lysis/death are taken up by resident dendritic cells and migrate to local LN
Phase 2: Activated dendritic cells in the local LN present beta cell antigens to CD4+ T cells. Self reactive T cells that have escaped from the Thymus are activated to activate other immune cells e.g B cells and CD8 which causes antibody production. Remeber, usually central tolerance would have detected all autoreactive T cells which would prevent most individuals from developing type 1, but because of mutations e.g INS, self recative T cells have escpaed from the thymus
Phase 3: immune cell crosstalk occurs, alla ctivated cells and autoantibodies traffic to beta islet cells and cause destruction e.g CD8+ cells kill them using perforin and granulozymes
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Secondary Diabetes
Chronic pancreatitis, pancreatic surgery
Drugs and chemicals: glucocorticoids, diurectics, antipsychotics, BB
Endocrine disease: acromegaly (GH supresses insulin) cushings syndrome, phaeochromocytoma
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Diabetes type 2: heterogenous disorder that results from an interaction between genetic predisposition and enviormental factors , which leads to insulin deficiency AND insulin resistance. Initially, insulin secretion increases, but due to the impaired sensitivity of cells, the ins receptors are downregulated and so the actions of the hormone are lost
Pharma
Sulphonylureas
Example: Glimepiride, Gliclazide
MoA: binds to SUR1 receptor (KATP channel) which inhibits K+ efflux (just as physiologically this happens when ATP/ADP ratio rises to close this channel. This depolarises and causes ca2+ efflux = insulin exocytosis. So increases the amount of insulin released from beta islets
ADE: hypoglycemia esepcially in elderly, weight gain
Biguanides
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MoA: increases glucose uptake, increases glycogen storage in skeletal muscle and adipose, supresses hepatic glucose output, decreases absorbtion of glucose from small intestine— lowers HbA1c by 11-22 mol/mol (1st line in all T2DM gudielines)
ADE: lactic acidosis especially in pt who are unable to excrete lactate or bignaides such as low GFR, liver disease. Also cause GI upset
Thiazolidinedione
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MoA: activate PPAR gamma receptor (nuclear R)= transcription factor for insulin sensitive genes. This increases glucose uptake into cells and utilisation. Lowers HbA1c by 6-16 mmol/mol
ADE: weight gain, fluid retention- causing HF, oedema
Lifestyle: drop BMI, reduce total dietary and saturated fats, moderate exercise for 150 min/week= all imporve insulin sensitivity
GLP-1 R agonists
MoA: binds to GLP1 R on beta islets, GI, to cause incretins release produced in L cells of the ileum. Incretins cause overall increased insulin, decreased glucagon
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ADE: pancreatitis, GI upset
Example: liraglutide, semaglutide
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DPP4 inhibitors
MoA: DPP4 degrades GLP1, so inhibiting increases endogenous GLP1 half life. Lowers HbA1c by 8-11 mol/mol
ADE: nausea, but DONT cause hypoglycemia or weight gain which is a slay
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SGLT2 inhibitors
MoA: prevents glucose reabsorbtion in the PCT in the kidney (blocks the sodium/AA/Glucose cotransporter, so increases glucose excretion in the kidney
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Pathophys
- Obseity, etc causes insulin resistance
- Initially, plasma glucose normal despite the insulin resistance, because beta islets will compensate by increasing insulin production
- Later, beta islets become exhausted, so postprandial glucose will start elevating without dropping as less insulin released.
This insulin resistance + exhausted islets= failure to supress gluconeogenisis, which causes fasting hyperglycemia as hepatic glucose output is always high (there is no insulin to supress this)
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Complex metabolic disorder charachterised by persistent hyperglycemia, due to relative or absolute deficicney insulin
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Physiology
Effects of hormones/NT
Glucagon effects
LIVER: promotes glycogenolysis + exports the freed glucose, promotes conversion of AA to glucose via gluconeogenisis, lipolysis of TG when insulin is low
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GH
Catabolic effects: lipolysis, glycogenolysis
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Anabolic effects: protein synthesis, AA uptake
Inulin effects
Lipid metabolism:
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LIVER + ADIPOSE: increases TG synthesis from excess glucose and FA to lower plasma FA, decreases lipolysis by inhibiting HSL
Overall, insulin increases synthesis of fats and directs it into adipose, and it reduces fat mobboilisation
CHO metabolism:
Increases rate of glucose uptake into all insulin sensitive tissues by stimulating GLUT4 transporters to translocate to the membrane
Decreases hepatic glucose production ( indirectly inhibits gluconeogenisis via inhibiting FA mobilisation from adipose, stimulates glycogenisis and glycolysis)
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IGF
Anabolic effects: growth, cell division, protein synth, glucose utlilisation
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Major control: GH and insulin both stimulate IGF 1 production in the liver (IGF2 is only in fetal life)
Cortisol effects
Catabolic: proteolysis, gluconeogenisis, inhibits glucose utilisation
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Steps of insluin release
Glucose converted into ATP via glycolysis= raises the ATP: ADP ratio within the cell -> closes the K+ ATP channel preventing K+ efflux
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Depolarisation causes VGIC Ca2+ channels to open= calcium dependant exocytosis of insulin vesicle occurs
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Catabolic hormones: glucagon, cortisol, GH, catecholamins, high thyroid
Anabolic hormones: insluin, GH, low thyroid hormone
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