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Diabetes and Insulin Resistance

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imissyou419's version from 2017-04-01 18:27

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Diabetes MellitusCharacterized by: Hyperglycemia (due to impaired insulin receptor response), polyphagia (eating with weight loss) - starving itself cuz can't see high glucose, polyuria (high urine volume), glycourina (glucose in urine), water and electrolyte loss;
In severe cases: ketosis, acidosis, coma and death;
Long term complications: retinopathy (lose sight in eye), nephropathy (kidney failure), angiopathy (blood clots), and increased susceptibility to infection
Type I Diabetes MellitusInsulin-dependent, autoimmune destruction of pancreatic beta-cell (killer T cells from thymus destroys beta cells), early onset, ~10% of diabetics,
early symptoms: high glucose, dehydration, low energy
Type II Diabetes MellitusInsulin-resistant (insulin receptor does not respond to it)/ impaired insulin secretion, lifestyle (overweight - obesity, sedentary), onset in mid-life, 90% of diabetics
What happens without Insulin?inability to transport glucose into cells - alternative energy source used:
(PROTEIN - increase gluconeogenesis - muscles broken down into a.a, a.a. converted to glucose in liver, results in muscle wasting and weight loss,
FAT - increase lipolysis (mobilization of TG and FFA from stores to generate ATP via TCA cycle), byproduct includes ketones, high ketones are marker of diabetes, ketoacidosis can lead to death)
Fate of high serum glucose1. ↑ glucose filtration - ↑ water excretion -> dehydration;
2. conversion of glucose to sorbitol (the "polyol pathway) -> damage to lens, nerve, capillaries.
3. Increased glycosylation (i.e. addition of cellulose, a glycan) of proteins (the "glyoxal pathway") Glycation end-products -> protein damage and misfolding;
4. De novo synthesis of DAG leading to ↑PKC activation -> nephropathy
Insulin resistance related to obesityDiet, lifestyles, genes (to small extent) -> obesity which overlaps with insulin resistance (insulin resistance can lead to Polycystic ovarian syndrome - infertility b/c of high level of androgen output in females, and type II DM)
Insulin resistance summarydecreased glucose transport function (Glut4)
decreased InsR number and activity
Increased FFA metabolism
Decreased PPARgamma function
Genetic predisposition (inherited, acquired - in utero exposure)
Mechanism of insulin resistance - impairing insulin receptor activation1. adipocytes from obese patients have fewer InsR than those of lean controls - increased translocation of XBP-1 decrease InSR transcription (destroy the mRNAs)
2. inappropriate serine phosphorylation (STOP) - increased secretion of TNF alpha
3. weaker tyrosine auto-phosphorylation (receptor activation)
Mechanism of insulin resistance - altered insulin receptor signalling1. IRS proteins (species specific - for humans, impairment of IRS-1 leads to decreased insulin receptor signalling and ultimately decreased translocation of glut4), - IRE-1 -> JNK -> inactivate IRS-1 (ER Stress Pathway); increased secretion of TNF alpha increase serine phosphorylation inactivates IRS-1
2. decreased phosphorylation of PI3 kinase and AKT in T2DM cells (decreased insulin signalling),
3. Decreased translocation of glut4 to cell membranes (decreased PI3k activity? decreased pool of Glut4?)
Mechanism of insulin resistance - obesitythe overloaded fat cell responds by inducing 'ER Stress Pathway' ->
1. activation of IRE1 (inositol-requiring enzyme 1) activates JNK which inactivates IRS-1 = decreased InsR signalling;
2. increased translocation of XBP-1 (nonspecific negative transcriptional regulator) translocates from ER to nucleus -> decrease all mRNA destined for the ER including that of InSR = decreased InsR transcription
3. increased secretion of cytokines (TNF-alpha) which increases serine phosphorylation leading to inactivation of InsR and IRS
4. decreases in adiponectin secretion (an adiokine) leads to increased gluconeogenesis and triglycerides (alternative form of ATP) -> increasing plasma FFA and glycero (ketone acidosis)l; Increased FFA availability switches cellular metabolism away from glucose as the energy source in muscle and liver
- increased acetylcoA levels for ATP results in decreased glucose oxidation
- decreased glucose uptake in muscle
- increased gluconeogenesis in muscle and liver
=> contribute to systemic insulin resistance
Mechanism of insulin resistance - impairment of PPARgammatranscription factor expressed in adipocytes, intestine, macrophages, it is decreased in insulin resistance.
Lowers blood glucose levels by positively regulate genes involved in glucose metabolism (InsR, IRS, Glut 4,etc), reduce triglyceride content of beta-cells, increases insulin response to glucose and improves beta-cell integrity and hyperplasia (growth)
PPARgamma agonistimprove insulin resistance and beta-cell function by positively regulating genes involved in glucose metabolism and reducing triglyceride content of beta-cell, improve its integrity and hyperplasia (growth)
Mutation in InsRrare and usually lethal so there is no direct genetic effect on insulin receptor (genetic mutations leading to obesity and indirectly to type II diabetes)
Barker hypothesisintrauterine insult can have long lasting effect on offspring (children exposed to famine in utero showed symptoms of glucose intolerance and CVD later in later), developing in undernourished conditions affect pancreas, adipose, liver tissue => increased risk of type II diabetes and insulin resistance (babies born smaller and had rapid post-natal catch up growth were at an even greater risk)
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