Metabolic Syndrome - Abali 3/17/16 Flashcards
blood glucose levels and stress
stress
→ glucagon (alpha cells of pancreas), norepi/epi (adrenal medulla), cortisol (adrenal cortex)
→ spike in blood glucose via metab of carbs/lipids
effect on glycogenolysis…
+++ epi/norepi
++ glucagon
0 cortisol
effect on gluconeogenesis…
++ glucacon
++ cortisol
0 epi/norepi (will activate HSL to stim beta ox, but not gluconeo)
types of hypoglycemia
insulin-induced hypoglycemia (diabetic patients)
- mild tx* : oral carbs
- severe tx* : admin glucagon subcutaneously/intramuscularly
post-prandial (exaggerated insulin release after meal)
tx : frequent small meals
fasting hypoglycemia
alcohol
liver during starvation (overview)
glycogenolysis: glycogen → glucose for export
- once glycogen stores depleted (~18 hr), gluconeogenesis kicks in through degradation of a.a.s, glycerol, lactate
- once gluconeogenesis starts to target muscle breakdown of essential organs, it levels off and you shift to ketogenesis
liver metabolism in starvation
after first 24 hr
to make up for loss of liver glycogen…
- flux through gluconeogenic pathway increases → more glucose made for brain, RBCs
- FAs become primary fuel → saves glucose for brain, RBCs
- as blood glucose levels off at low bound during extended starvation → FAs also used by liver for increased synth of ketone bodies for the brain
- beta-hydroxybutyrate and aceto acetate can cross blood brain barrier→ acetyl CoA (in brain) → TCA cycle
criteria for metabolic syndrome
1. central obesity : M > 40in, F > 35 in
2. fasting TAG : > 150mg/dl
3. low HDL : M < 40, F < 50
4. bp : > 135/85
5. fasting glucose : > 110
3 or more = metabolic syndrome
types of fat tissue and characteristics
1. brown adipose tissue used for thermogenesis and is insulin sensitive
2. subcutaneous white adipose tissue (hips) is insulin sensitive → able to store glucose
in contrast…
3. visceral white adipose tissue (abd) is insulin-resistant → gives you DM2, metabolic syndrome, risk for mortality
role of visceral fat in metabolic syndrome
visceral intra-abd fat does a lot of stuff that has overall effect of increased cardiometabolic risk
- increase in FFAs
- increase in adipokine secretion (and decrease in adiponectin - antihyperglycemic)
- increase in inflammatory markers (C-reactive protein)
→ dyslipidemia, insulin resistance, inflammation
→ increased cardiometabolic risk
effects of NEFA (non-esterified FAs) on metabolism
adipose-derived non-esterified FAs…
-
pancreas: inhibits insulin secretion
- muscle: decreases glucose uptake (GLUT4 regulated by insulin!)
- fat cells: decreases glucose uptake (GLUT4 regulated by insulin!)
- liver: stimulates gluconeogenesis
collectively, hyperglycemia → DM2
***effects of adipocyte-secreted proteins on metabolism
prohyperglycemic/prodiabetic
- resistin : inhibits AMPK signalling
antihyperglycemic/antidiabetic
- leptin : activates AMPK signalling
- adiponectin : activates AMPK signalling
AMPK signalling…
- increased glucose uptake in muscle
- increased glycolysis in muscle
- increased beta ox
- decreased lipolysis in adipose tissue
- inhibited FA synthesis
normal vs obesity profiles of AMPK regulation
healthy individual
adiponectin and leptin : antihyperglycemic
- activate AMPK pathway → catabolic pathways activated
- glucose uptake by extrahepatic tissues → no hyperglycemia!
resistin : prohyperglycemic
- inhibits AMPK pathway → synthetic pathways activated, gluconeogenesis activated
- obese individual*
adiponectin and leptin : NONE or adiponectin/leptin insensitivity
- AMPK pathway is not activated → catabolic pathways inhibited, glucose uptake by extrahepatic tissues inhibited
resistin : prohyperglycemic : high levels
- inhibits AMPK pathway → synthetic pathways activated, gluconeogenesis activated
leptin
- antihyperglycemic effects on organs
also
- interacts with CNS → alters signalling from hypothal to decrease food intake, increase energy expenditure
3 types of diabetes mellitus
DM1 (5-10%) : formerly insulin-dependent diabetes/juvenile-onsetdiabetes
- autoimmune destruction of pancreatic beta cells
DM2 (90-95%): formerly non-insulin dependent diabetes/adult-, maturity-onset diabetes
- insulin resistance and/or beta cells making insufficient insulin
gestational diabetes: temp condition in some pregnancies (affects 4% of all preg women)
- big babies, increases chances of baby growing up to have diabetes
mechanism of insulin secretion
beta cells in pancreas
- glucose enters through GLUT2 transporter
- glucose metabolized → ATP
- increase in ATP → ATP-sensitive K channels close → intracellular K builds up → cell depolarizes
- depol activates voltage-dependent Ca channels → increase in intracellular Ca → triggers secretion of insulin from secretory granules!
or
- incretins bind to incretin receptor → activate cAMP pathway → triggers secretion of insulin from secretory granules
incretins
GI hormones that lead to “anticipatory” rise in insulin in response to eating (before glucose levels actually become elevated and glucose → ATP can act on the K and Ca channels of pancreatic beta cells)
- CCK (weak response)
- GLP-1 (glucagon-like peptide)
- GIP (gastric inhibitory peptide)
some DM2 drugs target hydrolases that degrade insulin → more incretins = more insulin → better response to insulin!
long term consequences of untreated hyperglycemia
- diabetic retinopathy: blindness
- diabetic neuropathy: occlusive vasc disease/neuropathy → amputation
- diabetic nephropathy
- atherosclerosis, HTN, CVD (stroke, MI)
new level for diabetes diag is fasting glucose > 126 mg/dL
what organs does diabetes affect most?
WHY?
eyes, kidneys, nerves, heart/vessels
- these organs do not have insulin-dep transporters
- insulin insensitivity → glucose is not picked up by insulin-dep transporters on sk muscle/adipose tissue → stays in blood → accumulates in the tissues with insulin-indep transporters (like the ones above)
effects/changes occuring due to chronic elevated glucose
- non-enzymatic glycosylation
- glycation of Hb → elevated HbA1c, used to get an idea of longer-range glucose level
- glycosylation of proteins can affect half-life, activity, binding
- stimulation of polyol pathway in specific tissues
* glucose → sorbitol (kidneys, nerve, lens) [aldose reductase]
Type 1 DM
autoimmune destruction of pancreatic beta cells → reduced capacity to secrete insulin
- relatively modest genetic component
abrupt appearance of symptoms due to hyperglycemia
- 3Ps: polyphagia, polydipsia, polyuria
- weight loss despite constant hunger
explanation for symptoms of DM1
- symptoms of DM1
- major diff between DM1, DM2
- explanation of 3Ps
- can’t pick glucose up from blood (sk muscle, adipose transporters; liver glucokinase are insulin-sensitive) → hyperglycemia and hyperuricemia
-
absence of insulin/overproduction of glucagon
- glucagon stimulates gluconeogenesis → further elevates blood glucose
- low insulin → low LPL synthesis → VLDL accumulation = hypertryglyceridemia
- glucagon/epi stimulate HSL → mobilization of FA from adipose tissue, rise in hepatic beta ox, rise in ketogenesis → ketoacidosis
major diff between DM1 and DM2
- much greater ketone body production in DM1
explaining the 3Ps
increase in glucose/ketones in blood → polyuria
increased lipolysis/protein degradation → polyphagia
volume depletion → polydipsia
tradeoff between standard and intensive insulin therapy
intensive has better control of blood sugar, lower HbA1c but 3x likelihood of hypoglycemia
- can treat with glucose (mild) or glucagon (severe)
intensive not appropriate for children and elderly
- brain devpt in children
- stroke/MI in elderly
Type 2 DM
- symptoms, onset, genetics
- specific symptoms
- distinguishing symptom
- tx
milder symptoms than DM1, more gradual onset, prob a greater genetic component
- hyperglycemia without ketoacidosis
- less triglyceridemia (SOME insulin → more LPL action → better processing of VLDL, so less buildup)
LINK BETWEEN INSULIN RESISTANCE AND OBESITY! (VISC FAT)
- desensitization of insulin receptor signaling → insulin tx prob wont give you a correction of symptoms
tx: diet/weight loss (insulin rare)
how does obesity → insulin resistance
how does insulin resistance → hyperglycemia?
obesity via more visceral fat → increase in resistin; decrease in adiponectin, leptin secreted → insulin resistance
- adipose tissue: less beta ox, more lipolysis → elevated FFA
- liver: more gluconeogen → hyperglycemia
- extrahep insulin-sensitive tissues: lower glucose uptake → hyperglycemia
why is ketosis minimal in DM2?
insulin downregulates hepatic ketogenesis (even in case of insulin-resistance)
treatment of DM2
- diet
- weight reduction
- exercise
- drugs (sulfonylureas, etc)
- insulin (maybe 1/3 of DM2 pts)
acarbose
inhibition of alpha-glucosidases (breakdown of starch, sucrose)
- slows absorption of carbs → reduces postprandial elevation in glucose
sulfonylureas (gliburide)
binds to ATP-sensitive K channel → longer depol/Ca/secretory vesicle action → more insulin secreted into circ
- insulin secretagogue
- reduction of serum glucagon
- augmentation of insulin signaling
biguanides (metformin)
current understanding: acts by inhibiting oxphos Complex I → ATP production lower, AMPK production higher
- higher AMP → less phosphorylation of adenylate cyclase by glucagon → lower cAMP → lower PKA signalling → less gluconeogen, more glycolysis
inhibition of gluconeogenesis
DPP4 inhibitors (Januvia)
inhibits hydrolase that degrades incretins → more incretins → stimulate beta cell insulin secretion
SGLT2 inhibitors
reduce reabs of glucose by kidneys (more excretion)
- increased risk of UTIs because more glucose in urinary tract = nutrition for bacteria
thiazolidinedione (Avandia)
activates PPARgamma → increases insulin sensitivity of adipose tissue
comparison of DM1 and DM2
