Module 4: Mechanisms of insulin resistance

net result of insulin resistance

• increased FFA in blood

• hyperglycemia

• decreased muscle glucose uptake

• increased adipose lipolysis

• increased glucose output

adipocyte hypertrophy

fat cells grow in size

adipocyte hyperplasia

fat cells grow in number

what triggers adipose tissue expansion

increased nutrient influx drives tissue growth trhough hypertrophy and hyperplasia6

what do larger adipocytes secrete that attracts macrophages

macrophage-attracting chemokines

why do insulin-resistant adipocytes release more FFA

insulin fails to shut off lipolysis, more FFAs are released, further activates macrophages

what do increased FFAs do to macrophages

activate them, increasing inflammation

what do activated macrophages do to adipose tissue

• block preadipocyte recruitment

• worsen insulin resistance

• Increase FFA release

blocking preadipocyte recruitment

limits healthy expansion through new small adipocytes (hyperplasia), pushing tissue toward dysfunction

viscious cycle starting with nutrient influx

• expansion (grow and multiply)

• chemokines recurit macrophages

• FFA and cytokines worsen insulin resstance

• more FFA and inflammation follow

ceramides

sphingolipids made from saturated fats that can interfere with insulin signaling, impair insulin signaling and promote insulin resistance and inflammation

macrophages

immune cells that engulf pathogens and debris and release signalling molecules; in adipose M1 macrophages are pro-inflammatory (predominant in obese adipose tissue), M2 are anti-inflammatory (predominant in lean tissue)

chemokines

signaling proteins that attract immune cells to a site, in enlarged adipocytes, they recruti macrophages-increase inflammation; broad subset of cytokines that attract immune cells

cytokines

signaling proteins that regulate immune response and inflammation, specifically attract cells

howe do chemokines, macrophages, and cytokines fit together in obese adipose tissue

chemokines attract macrophages → activated macrophages secrete cytokines that worsen insulin resistance

not all obese adults are

insulin resistant (metabollically healthy obese vs abnormal)

adipose tissue insulin resistance often attributed to

• impaired adipose tissue expandability

• adipose tissue inflammation

• altered adipose tissue adipokines

adipose tissue expandability

aka lipid overflow hypothesis

adipose has limited maximal capacity to increase mass; once limit is reached,

lipid can no longer be stored appropriately - storing fat effectively in subcutaneous is the healthiest place for it to be, very important

The capacity to expand fat mass to store lipid is a more importnat determinant of

obesity than the absolute amount of fat mass

if lipid is not stores in adipose tissue,

it finds a home elsewhere

positive energy balance can be caused by

• increased energy intake

• decreased energy expenditure

  • decrease PA

  • increase sedentariansim

  • decreased vigorous exercise

positive energy balance → lipids overflow because

• saturation of expansion capacity of adipose tissue

• inability of subcutaneous adipose tissue to expand

other places fat can be stored

• visceral

• liver

• epicardial and myocardial

• msucle

• renal sinus

  • all lead to insuline resistance/inflammation

• pancreatic fat - imapired insulin secretion

although this fat does not take up a lot of space, it is extremely metabolically active - wreaks havoc

inability to store FAs resultes in

high FA mobilization from subcutaeous adipose tissue and insulin resistance

a person with higher FA levels has

lower insulin sensitvity

when FAs are mobilized from subcutaneous AT because they can’t be stored, it becomes

ectopic fat (looks for somewhere else to go) - extra fat goes to body organs that do not normally store fat

larger adipocytes

• Release more FAs

• associated with insulin resistance

• problematic because they cause you to reach storage maximum

for the same adipose tissue mass, it is better to have

more small cells

increased cell size also means increase glycolysis

increased stress to cope with stretching, glucose handling becomes abnormal, contribuing to systemic insulin resistance and type 2 risk

obese women with adipocyte hyperplasia have better metabolic health than hypertrophy

• same BMI

• those with more smaller cells had lower FFA, imporved metabolic healtg and lower Insulin resistance

Europeans tend to have higher HDL- healthy cholesterol than

South Asians (cell size is simialr, but Europeans tend to have smaller - note ethnic difference in adipocyte cell size ahve been documented)

South Asians have a lower capacity to store fat in subcutaneous adipocytes compared to

White Caucasions

storing fat ectopically or viscerally can change cardiometabolic factrors like

• increased insulin

• increased glucose

• increased triglycerides

• lower HDL cholesterol

• increased C-reactive protein

• increased blood pressure

independent predictor of CVD adter adjustment for conventioinal and novel risk markers for CVD

social disadvantage

significant variation in social disadvatnge by

age, sex, and ethnic group exist; increases social disadvatnage is associated with increased burden of some CV risk factors

adipose tissue fibrosis impacts adipose tissue expandability

lower fibrosis (ex. collagen) → greater expansion allowed → lower FA mobilization from adipose tissue → less ectopic fat deposition

lipodystrophy

• Subcutaneous adipose tissue storage disease

• inability to store fat as TGs in SAT

• limited SAT and abundance of Visceral fat

• severe insulin resistance

inflammation

• Adipocyte hypertrophy can lead to low pO2 and hypoxia

• M2 macrophage polarization to M1 phenotype results in greater release of inflammatory cytokines ( ex. IL-6 ad TNF-alpha) that cause insulin resistance in adipose tissue

• Cytokines spill over into circulation leading to proinflammatory state that characterizes obesity and insulin resitance in other tissues

in obesity,

adipose tissue becomes inflamed

when FFAs release from adipocytes, they

activate macrophages

pro-inflammatory macrophages infilitrate

adipose tissue

macrophages in adipose tissue release

pro-inflammatory cytokines (TNF-alpha, IL-6) that directly cause insulin resistance (increase lipolysis)

adipocyte inflammation →increased circulation of

cytokines

• TNF-alpha

• IL-6

• MCP-1

decrease IL-10

adipocyte inflammation →increased circulation of cytokines →

• insulin resitance

• pro-inflammatory or pro-atherogenic mediators

• atherosclerosis

tumor necorss factor alpha (TNF-alpha)

• increases secretion of other cytokines (IL-6)

• impairs insulin signaling in adipocyte

• induces insulin resistant in adipocytes by increasing HSL (turn on lipolysis) and decreasing GLUT4 (glucose tranporter helps with uptake)

• FFAs released, increased glycolysis

IL-6: Interleukin-6

• increase lipolysis via increased HSL

• similar role to epinephrine, which increased when you’re stressed (hungry when you exercise

all contribute to increeased lipolysis and release of FFAs

• epinephrine/norepinephrine

• IL-6

• TNF-alpha

adipose tissue is an

endocrine organ

adipokines communitcate with other tissues

adipocytes and other cells within adipose tissue secrete signaling molecules that act locally and systemically

adipokines

bioactive cell-signaling proteins and hormones released by adipose tissue (body fat) that regulate metabolismm inflammation, and immune responses

healthy adipose tisse

support lipid stoarage and endocrine signaling that favor insulin sensitvity

dysfunctional adipose tissue

hypertrophy and cellular stress alter adipokine secretion and inflammatory signalling - can impair insulin action in liverm, skeletal muscle, and adipose tissue

leptin

usually a positive hormone

• signalls efficiceny when full

  • surpresses appetite

leptin typically rises with fat mass

• signals sufficiency to hypothalamus

• normally suppresses appetite and supports energy expenditure

obesity commonly involves leptin resistance

• even though it rises with body mass, you become resistant to it - diluted

adiponectin

• declines with adipose dysfunction

• supports muscle FA oxidation and insulin sensitvity

• suppresses hepatic glucose production

• has anti-inflammatory effects

  • more macrophages, positive effects occur less,

• declines as adiposity increases

increased lipolysis and FFA release is key driver of

whole body insulin resistance - ectopic lipid deposition in other tissues

limited expandability, adipocyte hypertrophy, fibrosis, and inflammation in adipocytes

promote lipolysis and insulin resistance

inflammatory and hormonal profile of adipose tissue is altered in obesity

promotes adipose tissue and whole body insulin resistance - everything is a feeback mechanism

liver insulin resistance WHY

• liver needs to go from a glucose producing organ to a glucose storing organ in response to insulin - always wants to produce and release

• with insulin resistance, liver fails to suppress glucose production

liver insulin resistance leads to

• increased gluconeogenesis (release)

• decreased glycogenesis

many problems with increased hepatic fat

• ectopic liver fat deposition = hepatic fat = fatty liver

• close link with hepatic insulin resistance

• decreased suppression of glucose production in repsonse to insulin

• decreased stimulation of glycogen synthesis in response to insulin

NAFLD: non alcoholic fatty liver disease

• one of the most common medical conditions in NA - 24% of NAs

when insulin sensitive,

insulin promote glycogen synthesis through insulin signaling pathway, which helps to lower hepatic glucose production

healthy insulin signaling pathway in liver (glycogen synthesis)

• insulin circulating in blood

• enters liver through insulin receptor 1 (IRS-1)

• increase PI3K

• increase Akt (and PI3K are central downstream messengers in pathway)

• increase glycoen synthase (rate-limiting enzyme)

• increase glycogen synthesis

• decreased glucose production - promote storage, prevent release

when lipids accumulate in the liver,

they impair the insulin signaling pathway. The liver becomes resistant to the effects of insulin, therefore resulting in lower glycogen synthesis

impaired insulin signaling pathway because of FAs (glycogen synthesis)

• FA enters liver as fatty-acyl CoA

• increases ceramides (fat accumulation)

• increase diaglycerides (DAG) and trialgycerides (DAG) - types of fat

• increased DAG activates PKC (protein kinase C)

• PKC induces phosphorylation and puts a brake on pathway

• decreases glycogen synthesis

• increased glucose production

not all fat is equal - diaglycerides DAG

• formed via incompete TG synthesis

• activates protein kinase C (PKC) → impairs insulin signaling in liver

high blood glucose concentrations can stimulate

de novo lipogenesis (liver starts making more fat) = further insulin resistance because there is extra glucose → problem because accumulation of fat

when insulin sensitive, insulin promotes the down-regulation of gluconeogenesis through

insulin signaling pathway by increasing FOXO, helps lower hepatic glucose production

FOXO

key downstream targets and regulators of the inslin/PI3K/Akt singaling pathway, acting as a molecular swtich between feeding and fasting states

healthy insulin signaling pathway in liver (gluconeogenesis)

• insulin enters liver through IRS-1

• increase in PI3-K

• increase in Akt

• increase in FOXO - protein that acts like a switch for fed/fasted state

• decreases gluconeogenesis

• decreases glucose production

When lipids accumulate in liver, they impair the insulin signaling pathway. The liver becomes resistant tot he effects of insulin,

results in higher gluconeogenesis

impaired insulin signaling pathway (gluconeogenesis)

• FAs enter liver, accumulate

• DAGS increase

• PKC increases

• IRS-1 blocks

• PI3K, Akt, and FOXO decrease

• gluconeogenesis increases

• glucose production increases

increased glycerol (FAs + glycerol) from systemic circulation provides a

substrate for increased gluconeogenesis and glucose production

decreased mitochondria content and function results in

lower fat oxidation and limited removal of fat

reduced mitochondira results in

increased deilvery and decreased oxidation which results in accumuatlion of lipid in liver (limtied removal of fat); high influx of fat going to the liver

increased FA deliver to liver →

ectopic lipid deposition

lipid species, specifically DAGS

impair insulin-dependent increase in glycogen synthesis = increase blood glucose

hyperglycemia further stimulates

de novo lipogenesis in liver

gluconeogensis incnreased due to

impaired signaling pathway

glycerol from elevated adipose tissue lipolysis provides

substrate for gluconeogenesis

insulin resistance is associated with

lower hepatic mitochondrial content and function = decreased fat oxidation = increased fat storage

hepatic glycogen synthesis in response to insulin is ________ correlated with hepatic lipid content

negatively

hepatic glycogen synthase activity after eating carbs is likely _____ if HOMA-IR is high

low

adipocyte hyperplasia is associated with having more _______ adipocytes, which is associated with _____ glycerol production from adipose tissue

small, lower

TNF-alpha is a ______-inflammatory which can _____ rates of lipolysis by increasing the hormone ______

pro, increase, HSL

during a hyperinsulinemic-euglycemic clamp, FFA mobilization from adipose tissue would be _______ if insulin sensitive

low

which glucoe transporter is regulated by insulin in muscle and fat

GLUT4 -found mainly in skeletal muscle and adipose tissue

how does insulin increase glucose euptake into muscle and fat cells

triggers GLUT4 vesicles to move to the cell membrane (translocation)

what does insulin bind to at cell surface

insulin receptor, a receptor tyrosine kinase - starts siganling cascade

main order of insulin signaling pathway leading to GLUT4 translocation

• insulin

• IRS

• PI3K

• Akt

• GLUT4 translocation - glycogen synthase

IRS

insulin receptor substrate - docking proteins phosphorylated by the insulin receptor that activate PI3K

insulin resistance on GLUT4 translocation

insulin siganling is impaired, less GLUT 4 translocates, glucose uptake falls

without insulin, GLUT 4 can be translocated through

muscle contraction - con trigger GLUT4 translocation indpendent of insulin (AMPK)

which transport lets glcuose move into and out of the liver

GLUT2, not regulated by insulin like GLUT4, high capacity transporter in the liver and pancreatic beta cells

what happens to glucose once it enters the cell

hexokinase phosphorylates it to G6-P, trapping it for glycolysis or storage

people with type 2 diabetes have

decrease insulin stimulate muscle glucose uptake

when body is at rest (basal), the muscle is

not responsible for glucose uptake, can’t detect any because no insulin is present