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Mechanisms of Insulin Resistance


INSULIN RESISTANCE = fasting serum insulin level greater than UL (approximately 60 pmol/L)
normal amounts of insulin don't get response from fat, muscle, liver cells
IR = "almost universal finding in diabetic individuals who are obese" (Robbins, Pathol)
IR often detected 10-20 years before onset of DM2
increases hydrolysis of stored TGs-->increases blood lipids
muscle cells can't take inglucose, can't make glycogen-->low energy
liver cells can't take up glucose-->can't make glycogen, still making glucose
IR-->liver makes glucose even though blood levels are high because insulin signal not heard
too much TG's in blood
concept that IR-->DM2 published in Vienna, 1931, Falta
confirmed 1936, London, Himsworth
Yale school of med: IR in skel muscle-->changes in energy storage-->metabolic syndrome
high insulin-->higher cancer risk, diabetes, high chol, HTN, heart dz
insulin phosphorylates, glucagon dephosphorylates

ROBBINS p1195:
downreg of insulin receptor
decreased insulin receptor phosphorylation
decreased tyrosine kinase activity
reduced levels of active intermediates in insulin signalling pathway
impairment of translocation, docking, and fusion of GLUT-4 containing vesicles w/ plasma memb
in humans point mutations of receptor gene is rare (1-5% of pts with IR, see Monogenic)
many polymorphisms are assoc with DM2 phenotype
associations weak, studies not reproducible, population risk seems high

THE VICIOUS CYCLE
HIGH INSULIN-->DECREASED GLUT4 RECEPTORS-->MORE INSULIN NEEDED-->DECR RECEPTORS
Exercise reverses this process in muscle tissue
elevated blood glucose-->incr glycation of proteins with changes in fx

SX
fatigue, sleepiness
brain fog, depression
high blood sug and TGs
incr BP-->hypertension (kidney retains more Na+-->incr BP)
bloating after carb intake
wt gain, fat storage, can't loose weight
fat storage around abodominal organs (central obesity), visceral adiposity (as vs subcu)
atherosclerosis of long arteries (not just at branchpoints) (source: West)

ASSOCIATIONS
increased inflammatory cytokine levels (TNF alpha, IL-1, IL-6)
dyslipidemia: incr TGs, small dense low-density lipoprotein (sdLDL) particles, decr HDL hypercoagulable state (impaired fibrinolysis)
sedentary lifestyle
aging
Haemochromatosis
Polycystic ovarian syndrome (PCOS)
Hypercortisolism (e.g., steroid use or Cushing's disease)
Drugs (rifampicin, isoniazid, olanzapine, risperidone, progestogens, antiretrovirals, alc, methadone)
growth hormone replacement therapy
use of insulin for diabetes
liver dz

THE GUT LINK
some kinds of bariatric surgery-->increased insulin sensitivity, remission of DM2
diabetic/insulin resistant non-obese rats w/ proximal small intestine and duodenum removed
-->increased insulin sensitivity and remission of Type 2 diabetes
effect seems to be same in humans
speculation: some substance from the SI may signal IR

ETIOLOGY

Willet in Eat, Drink and Be Healthy says on p104 that four things contribute to insulin resistance: 1) obesity 2) inactivity 3) dietary fats and 4) genes
Obesity challenges glucose handling
Inactivity-->low fat/muscle ratio-->harder to clear glucose from bloodstream
Diet of trans fat and lacking polyunsaturated fats-->IR
Native Americans, Pacific Islanders and Asians more susceptible than Europeans

GENETICS
genetics, blood type (O), metabolism type (primitive, feast/famine programming)
Insulin receptor mutations (Donohue Syndrome, Rabson-Mendenhall Syndrome)
LMNA mutations (Familial Partial Lipodystrophy)

DIET
high-carbohydrate diet
acidosis
increasing fructose intake: fructose processed only in liver
fructose consumption, HFCS-->changes liver fx (sucrose is 1/2 fructose)

INFLAMMATION
inflam/infx (TNFα)
high FFAs and inflam cytokines-->Protein Kinase c isoform theta activated-->inhibits insulin receptor substract activation and prevents manufacture of receptors

ENDOCRINE
central obesity-->elevated adipokines-->dysfunctional leptin signalling
central obesity due to long term elevated cortisol? stress???
postmenopausal estrogen supplementation increases IR
"women taking estrogen had a 31 percent lower utilization rate of insulin compared to postmenopausal women not on estrogen replacement therapy"
PCOS (polycystic ovary syndrome)
sub-clinical Cushing's syndrome and hypogonadism

MEDS & SUPPLEMENTS
drugs (glucocorticoids)
glucosamine (one study)

MALNUTRITION
vitamin D deficiency
chromium def

IR IN INSULIN DEPENDENT DIABETICS
dt ABs vs insulin-->glucose doesn't drop because insulin is destroyed before working
happens more with the use of animal insulin, this is rare now

CENTRAL OBESITY
favored by high cortisol levels (stress)
generates more adipokines
changes leptin signalling
strongest assoc with IR, much more than with peripheral (glut/subcu) fat depots
FFAs: inverse correlation btw fasting plasma FFA's and insulin sensitivity (Robbins)
level of intracellular TGs incr in muscle/liver of obese
intracellular TGs and fatty a products-->inhibit insulin signalling-->
acquired insulin resistance state
TWO PROPOSED MECHANISMS
1) visceral adipose cells produce proinflammatory cytokines: TNF-a, IL-1, IL-6
these cytokines disrupt insulin action in fat & muscle
IKK-beta/NF-kappa-B pathway = protein network that enhances transcription of cytokine genes
2) accumulation of fat in the liver = nonalcoholic fatty liver disease (NAFLD)
increased FFAs in blood dt lipolysis, increased hepatic glucose production
-->worsens peripheral insulin resistance-->DM2

MAGNESIUM
concentrations constant in healthy individuals, tightly regulated
insulin is part of magnesium regulation
high insulin helps shift magnesium into cells from extracellular space
intracellular Mg modulates insulin action (mainly oxidative glucose metabolism)
offsets calcium-related excitation-contraction coupling
decreases smooth cell responsiveness to depolarizing stimuli
DM2 and HTN pts have poor intracellular Mg concentrations-->tyrosine kinase not work-->intracellular Ca increases-->another mechanism of insulin impairment
Mg daily as tx for DM2 helps reduce resistance

ADIPOKINES
adipose functions as endocrine organ
variety of prots released, collectively called adipokines, short for adipose cytokines
three main types so far: leptin, adiponectin, resistin
LEPTIN
leptin acts on CNS receptors to reduce food intake and induce satiety (Robbins)
leptin deficient animals show severe IR reversed by administration of leptin
many insulin sensitizing actions mediated by CNS receptors, some exerted directly at level of insulin target tissues
actively being researched at this time
regulates blood sugar
leptin is how your fat talks to your brain to let it know how much energy is available
no known drugs that regulate its activities
only known way to reestablish proper leptin (and insulin) signaling is via diet
pro-inflam, and mediates manufacture of other inflammatory adipokines
influences hypothalamic control of autonomic function incl: body temp, HR, hunger, stress response, fat burning/storage, reprod behavior, bone growth, blood sugar
significant in: heart dz, obesity, DM, osteoporosis, AI dz, reprod disorders, aging
two different brain-body passageways
1) controls appetite and fat storage
2) tells the liver what to do with its stored glucose
NOTES FROM ROBBINS FIG 9-33 p463
leptin made by adipose tissue (only?)
leptin is both stimulatory and inhibitory in the hypothalamas
inhibits NPY/AARP receptor-->no signal to feed
this receptor also inhibited by PYY from intestines, and stimulated by Ghrelin from stomach
activates POMC/CART receptor-->increased TRH and CRH-->higher activity level
nothing else is shown that increases these but there must be....??
MOUSE STUDIES ON LEPTIN
disruptions in both of leptin's pathways-->full-blown diabetes (mice studies)
study mice were genetically disabled: no leptin-STAT3 cell-signaling
mice without leptin, or without receptors, got obese, got diabeties and died
control mice could still make leptin and receptor, and did not become diabetic even when obese
this suggests brain-->liver signalling by leptin to control blood sugar
Cell Metabolism March 2005; Vol 1, 169-178 (Free Full-Text Article)
LEPTIN INFLUENCES MOTIVATION TO EAT: LEPTIN RESISTANCE
new study describes leptin-responsive neurons in the brain's lateral hypothalamic area (LHA)
these feed directly into mesolimbic dopamine system-->controls reward associations
supports idea that leptin appetite regulation does not depend on actual food intake
you can want more food regardless of hunger
Eurekalert August 5, 2009
Cell Metabolism August 2009; 10(2):89-98
Leptin encourages hunger, fat generation, reproduction, body maintenance and repair
"hunkering down"
leptin can "rewire" brain areas that control hunger and metabolism
overweight-->extra leptin-->should tell brain that body is storing too much fat and to burn it
so leptin signals-->don't be hungry, stop eating
if brain hears message, behavior is corrective
if brain doesn't hear message, you keep feeling hungry, eating, and getting fatter
not hearing message = leptin resistance
high leptin long time-->resistance (just like with insulin, receptors are downregulated)
sugar metabolism in cells-->release leptin surges-->resistance
role in heart dz, obesity, DM2, osteoporosis, AI dz, reproductive disorders, aging
to avoid leptin resistant: eat good fats and avoid blood sugar spikes

ADIPONECTIN
from memory, this is the "good" adipokine
fat people have too much and become resistant to it
RESISTIN
elevated in people with insulin resistance

CONVENTIONAL TREATMENTS
metformin, thiazolidinediones mitigate insulin resistance, but only approved for DM2
newer drug: exenatide (marketed as Byetta), only approved in DM but helps IR, wt loss
(used when folks are on antidepressants)

PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA and THIAZOLIDINEDIONES
PPARgammas and TZDs
TZDs are a class of antidiabetic compounds developed in the 1980's as antiox
best-known PPAR ligands are the thiazolidinediones
target receptor is PPARgamma, a nuclear receptor and transcription factor
PPARgamma is most highly expressed in adipose tissue
activation of receptor by TZDs-->modulation of gene expression in adipocytes-->decr IR
targets of PPARgamma activation incl several adipokines
PPARgamma also decr FFA levels
PPAR OVERVIEW
3 types identified: alpha, gamma, and delta (beta)
from 3 different genes: 22, 6, 3 in order
expression locations::
α (alpha) - liver, kidney, heart, muscle, adipose, etc, targeted by fibrates
β/δ (beta/delta) - in many tissues but esp brain, adipose and skin
γ (gamma) - the expressions from one gene dt alternative splicing:
γ1 - virtually all tissues, incl heart, muscle, colon, kidney, pancreas and spleen
γ2 - mainly in adipose tissue (30 aa's longer)
γ3 - on macrophages, large intestine, white adipose tissue
targeted by thiazolidinediones
perfluorooctanoic acid activates PPARα
perfluorononanoic acid activates both PPARα and PPARγ

MORE TREATMENTS THAT INCREASE INSULIN SENSITIVITY
exercise & wt loss are 2x more effective than metformin
low glycemic diet
magnesium daily
alpha lipoic acid (read Berkson book on ala breakthrough, 1998, tx for hep c)
cinnamon (Cinnamom aromaticum aka cassia may incr bleeding, no bleed prob w/ sp. zeylanicum or verum)
polyunsaturated fatty acids (omega 3)
vanadium (vanadyl sulfate)
chromium (chromium picolinate)
bitter melon (Momordica, use with caution)
Gymnema sylvestre

SOURCES
http://en.wikipedia.org/wiki/Insulin_resistance
Holistic Primary Care Summer '09, August West article:
Digital Pulse Wave Analysis Offers Non-Invasive Early Heart Risk Assessment
http://articles.mercola.com/sites/articles/archive/2009/05/16/This-Antioxidant-Can-Smash-Insulin-Resistance-and-Autoimmune-Disease.aspx
http://articles.mercola.com/sites/articles/archive/2002/02/13/estrogen-part-four.aspx
Eat, Drink and Be Healthy by Walter C Willett, MD p104
http://articles.mercola.com/sites/articles/archive/2009/08/29/Fat-Hormone-Influences-Your-Motivation-to-Eat.aspx

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