NST 160 Final
Acute diabetic complications - ANS-1) DIABETIC KETOACIDOSIS (T1DM)
- absolute decrease in insulin increases lipolysis --> FFA + glycerol
- FFA + glycerol shuttled into ketogenesis --> hyperketonemia
- hyperketonemia caused acidosis, fruity kussmall respiration
- arises because blood is unable to buffer pH
characterized by: hyperglycemia (increased GNG), low pH, high ketone bodies
cause: insulin deficiency and excess counterregulatory hormones
leads to: deep sigh (expel CO2), fruity breath, protein denaturation, organ failure, high
blood glucose and ketone levels lead to high serum osmolarity --> severe dehydration
along with excessive urination + glucose in urine + excessive thirst
treatment: IV fluid replacement and insulin therapy
2) hyperglycemic hyperosmolar state (T2DM)
- insulin deficiency and inadequate fluid intake cause hyperosmolarity, hyperglycemia,
osmotic diuresis but no ketoacidosis
- muscle releases GNG precursors like AA that increase GNG and glycogenolysis
- hyperglycemia causes osmotic diuresis that leads to dehydration. this coupled with
inadequate fluid intake creates hyperosmolarity that can cause hypertension and mental
stress
cause: relative decrease in insulin, inadequate fluid intake
leads to: dehydration, hyperosmolarity, hypotension, tachycardia
Adipokines - ANS-1. Leptin
- product of ob gene
- ob/ob and db/db lack leptin or receptor and are hyperphagic, hyperinsulinemic, and
obese
- downregulates NPY, MCH, orexin and AgRP
- upregulates alpha-MSH and CART
- levels reflect adipose mass
- efficacy decreases but amount increases in obesity leading to leptin resistance
- mechanisms of resistance: decreased transport across BBB, hypothalamic
inflammation, ER stress, defects in autophagy
Alzheimer's disease - ANS-- a progressive and irreversible brain disorder characterized
by gradual deterioration of memory, reasoning, language, and physical functioning
,- apoE4 isoform is the strongest genetic link associated with Alzheimers (apoE2
associated with decreased risk)
- strongest risk factor is aging
1) linking insulin resistance with AD
a) insulin and amyloid-beta compete for insulin-degrading enzyme under
hyperinsulinemia/insulin resistance
- leads to build-up of amyloid-beta plaques (not degraded) which are a hallmark of AD
b) amyloid-beta (and JNK) decreases INSR signaling
- low Akt, removes block on GSK3B which causes tau phosphorylation and NFTs which
are a hallmark of AD
- INSR linked to memory formation
c) hyperglycemia leads to oxidative stress and neuronal toxicity
- increased glucose causes mitochondrial dysfunction --> ROS, inflammation and
oxidative stress
- increased glucose leads to formation of AGEs through polyol pathway and NEG
- neuronal toxicity causes AD
2) how alzheimers could be considered type 3 diabetes
- linked with insulin resistance
- patients have impaired glucose tolerance
- associated with oxidative stress and AGEs
- abnormal brain defects found due to JNK and serine kinase phosphorylation of IRS1
- IGF and its receptor are found in patients with AD even in the absence of
T2DM/obesity
BUT: AD doesn't show symptoms like increased urine, glucose in urine
3) lifestyle changes
- increase exercise to reduce obesity
- eat more PUFAs instead of saturated/trans fatty acids
- increased vitamin D, folate, vit. B, anti-oxidants, Mediterranean diet
- increase cognitive engagement
4) new treatments
- cholesterol lowering statins
- PPAR agonists (PPAR delta particularly)
,- insulin and GLP-1 receptor agonists can reduce beta amyloid induced insulin
resistance and improved cognitive function
- intra nasal in
AMPK - ANS-- promotes glucose uptake, fatty acid oxidation, and mitochondrial
biogenesis
- active in the fasted (low energy) state
- inhibits mTOR
main activators: AMP, metformin, berberine, EGCG, low glucose and ghrelin
(hypothalamus), leptin, and adiponectin (adipocytes)
main inhibitors: ATP, leptin (hypothalamus)
downstream outcomes: increase catabolism, decreased anabolism, increased
autophagy
Anorexigenic signals - ANS-- governed by POMC/CART in the arcuate nucleus
1. CART
- expression is decreased by fasting
- reduces feeding and blocks NPY signaling
- peptides found outside CNS regulate islet cell function in pancreas
- mutations linked to obesity, depression, alcoholism
2. POMC
- precursor to melanocortins
- in the ARC, generates alpha-MSH
- alpha-MSH signals through MC4 receptor
3. GLP-1, CRF, serotonin
atherosclerosis - ANS-condition in which fatty deposits called plaque build up on the
inner walls of the arteries
- caused by increased adiposity and insulin resistance
- high TG lead to increased VLDL, IDL, small LDL which converted to modified LDL in
artery wall and stimulate conversion of macrophages to foam cells
- foam cells lead to fatty streak, lesions, rupture and cause blood clots
, can be fixed by increasing HDL:
1. inhibit conversion of LDL --> modified LDL
2. inhibit conversion of foam cells to macrophages
3. inhibit adhesion molecules from grabbing monocytes
autophagy - ANS-- lysosomes break down damaged organelles
- activated by starvation, inhibited by insulin
BAT (brown adipose tissue) - ANS-1. constitutive
color: brown
function: thermogenesis, increases the metabolism of lipoproteins carrying TG, secretes
neuregulin (reduces lipogenesis and consequences of insulin resistance) and FGF21
(induces recruitable BAT) = "batokines"
morphology: multilocular LD
mitochondria: many
activation: cold, B-agonist, T3, DIT
high UCP1
links appetite inversely with temperature
impaired by diabetes, anorexia, malnutrition
inverse relationship with BMi
2. brite/beige (recruitable)
color: brownish
function: adaptive thermogenesis
morphology: multilocular LD
mitochondria: many
activation: cold, b-agonist, T3, DIT
high UCP1
exercise stimulates valine conversion to BAIBA, which induces BAT and FAO via
activating PPARalpha in liver and UCP1 in beige tissue
--> agents that activate BAT also cause
- cachexia
- hepatic steatosis
- bone loss
- immune suppression
Calcium - ANS-muscle contraction, neurotransmission, blood clotting, cell adhesion -->
bone structure
