OMA Review Couse Flashcards
Where is Ghrelin secreted from?
Primarily from stomach body and fundus and smaller amts from proximal small intestine(duodenum)
What does Ghrelin stand for?
Growth hormone release inducing peptide
What is the function of Ghrelin?
To stimulate appetite
What type of hormone is Ghrelin?
Orexigenic
What triggers Ghrelin to be secreted?
When stomach is empty. It will surge and peak right before meals. Initiates eating and decreases energy expenditure.
Fasting will also increase levels of Ghrelin.
What inhibits Ghrelin?
When stomach is stretched, so after eating or nutrient ingestion. Levels will drop after eating. (If obese, you will have less of a drop in Ghrelin). A vagotomy can also inhibit Ghrelin as it disrupts the gut brain axis.
How does Ghrelin impact the CNS?
Via the orexigenic pathway. It stimulates NPY/AgRP in the arcuate nucleus in the hypothalmus. It also can reach brain to the NTS via the vagus nerve.
What is foraging?
Seeking out and looking for food
What hormone plays a role in spatial learning and memory ?
Ghrelin
What enzyme activates Ghrelin?
Ghrelin O-acyltransferase(GOAT). It acylates Ghrelin into active form.
Which genetic condition has the highest amount of Ghrelin?
Prader-Willi Syndrome- so have hyperphagia and severe obesity. In adults and children.
What happens to levels of Ghrelin as we lose weight?
Levels of Ghrelin increase and increase and once we start to gain weight, this increase slows down until we are back to our baseline weight.
What is the relationship between Ghrelin and Insulin?
Inverse relationship. So when you eat, insulin increases and ghrelin decreases.
How does insulin resistance affect Ghrelin?
Insulin’s ability to regulate Ghrelin is impaired. Therefore, you can get increase Ghrelin even after eating.
How does weight gain affect ghrelin?
decreases to reduce hunger to more easily lose weight
What is relationship between leptin and ghrelin?
Leptin tells brain when body has enough energy. Higher after eating and higher fat stores. Supposed to prevent overeating, unless leptin resistance, obesity and IR.
What affect do stress and sleep have on Ghreling?
High stress and lack of sleep increase Ghrelin
Why does sleeve gastrectomy decrease ghrelin?
Because it removes most of the body and fundus of the stomach.(removes 80%)
What is the most powerful way to lower ghrelin?
Sleeve gastrectomy
What are factors that increase Ghrelin?
Fasting, sleep deprivation, stress, weight loss, Genetics/Prader Willi
What are factors that decrease Ghrelin?
Meals, Weight Gain, Leptin, Gastric Sleeve Surgery,
What macronutrient suppresses Ghrelin the fastest?
CHO
What macronutrient causes rebound Ghrelin secretion?
CHO
What macronutrient suppresses Ghrelin the longest?
Protein
What are the 5 appetite regulating hormones that are secreted in the small and large intestine?
CCK(Cholecystokinin), GLP-1(glucagon like peptide 1), GIP(Glucose dependant insulinotropic polypeptide), OXM(Oxytomodulin), PYY(Peptide YY)
What cells in the intestine secrete CCK?
I-cells in duodenum and jejunum
What cells in the intestine secrete GLP-1?
L-cells in the distal small bowel and colon
What cells in the intestine secrete GIP?
K-cells in the duodenum and proximal jejunum
What cells in the intestine secrete OXM?
L-cells in distal small bowel and colon
What cells in the intestine secrete PYY?
L-cells in distal small bowel, colon and rectum
What stimulates CCK to be released?
Fat and protein ingestion
Gastric distension
How long does CCK last after meal initiation?
15-30 minutes
What are the actions of CCK?
Stimulates GB contraction
Slows gastric emptying
Reduces appetite
Where are the CCK receptors? What types are there?
Located in gut and brain. CCK-1(GI tract - slows gastric emptying) and CCK-2(Brain - decreases appetite)
What macronutrients triggers GLP-1 to be released?
Carbs, proteins and fats, but primarily Carbs
What macronutrients triggers CCK to be released?
Fat and protein, but primarily fat
What is purpose of incretin effect?
To regulate blood sugar after meals
What are the 4 actions of the incretin effect?
- Glucose dependent insulin secretion - gives a quick burst of insulin after meals to control BS
- Reduced hepatic gluconeogenesis(suppresses glucagon)
- Delays gastric emptying(increases satiety)
- Reduces appetite(weight loss) by affecting GLP1 receptors in the brain
What is the the 1/2 life of our natural GLP-1?
5 minutes
What enzyme degrades GLP-1?
DDP-IV
What conditions cause GLP-1 levels to be reduced?
DM(sugars), Prediabetes and obesity
Why does Insulin Resistance, Diabetes and Obesity reduce GLP-1?
When you eat food and it gets broken down into small parts it goes to the proximal small intestine. In patients who are insulin resistant, diabetic and obese, it causes an inhibitory signal to be released which suppresses the release of GLP 1.
How does gastric bypass help you lose weight?
It bypasses the proximal small intestine so you lose the inhibition signal that suppresses GLP-1, therefore, it increases GLP-1 to high levels.
What are the 2 incretin hormones?
GLP-1 and GIP
What triggers GIP to be released?
Glucose load
What percent of the postprandial insulin response is GLP-1 and GIP responsible for?
70%
What 2 hormones are responsible for 70% of the postprandial insulin response?
GLP-1 and GIP
How is GIP different than GLP-1?
It reduces nausea and stimulates Glucagon secretion. It also may improve insulin secretion in white adipose tissue(indepenednt of weight loss and body fat).
Does GLP-1 stimulate or suppress glucagon?
Suppresses
Does GIP stimulate or suppress glucagon?
Stimulates
Which hormone improves insulin sensitivity in the white adipose tissue independent of weight loss or body fat?
GIP - directly on adipose tissue(unlike GLP-1, which improves insulin resistance thru weight loss and reducing body fat).
What hormone is made by the same precursor as GLP-1?
OXM
What hormone is secreted with GLP-1?
OXM
What receptors do OXM bind to?
GLP-1 receptor and Glucagon receptor
How does OXM increase energy expenditure?
By binding to Glucagon receptor
What are the effects of OXM?
Decreased appetite/feeding
Weight loss
Increased energy expenditure
When is PYY secreted?
Within 1 hour of post feeding
What receptor does PYY bind to?
Y2 receptor
What are the functions of PYY?
Potent appetite suppressant
Delays gastric emptying(food stays in stomach longer) and intestinal transit time(slows down how fast food moves thru the small intestine)
What 2 hormones contribute to the ileal brake?
PYY and GLP-1
What is the ileal brake?
Slowing of food thru the small intestine. PYY and GLP-1 cause this.
Which hormone slows food thru the small intestine?
PYY
What hormones are secreted by the small intestine?
GLP-1, GIP, CCK, OXM, PYY
What hormones are secreted in the large intestine?
GLP-1, OXM, PYY
What hormones are secreted by the pancreas?
Pancreatic polypeptide, insulin, amylin and glucagon
Which cells of pancreas secrete pancreatic polypeptide?
F Cells
What cells of pancreas secrete insulin?
Beta cells
What cells of pancreas secrete amylin?
Beta cells
What cells of pancreas secrete glucagon?
Alpha cells
What triggers pancreatic polypeptide to be released?
Caloric load
When is pancreatic polypeptide low?
In fasting state.
Which receptors does pancreatic polypeptide(PP) bind to and what does this cause?
Y4 receptor, reduces gastric emptying in the gut
In brain, there are Y4 receptors in the hypothalamus which causes reduced hunger
Is obesity associated with high or low levels of PP?
low
Which genetic syndrome has lowest PP?
Prader Willi
What genetic syndrome has highest Ghrelin and lowest PP?
Prader Willi
What are the 2 long term adiposity signaling hormones?
Insulin and Leptin
Is insulin supposed to cause weight loss or gain centrally?
Weight loss as it inhibits the AgRP/NPY neurons, but in pts with obesity or IR, this is less efficient
What inhibits glucagon?
High glucose, amylin, GLP-1
What hormone is secreted with insulin?
Amylin
How does amylin work?
Reduces food intake
Slows gastric emptying
Suppress glucagon production(hepatic gluconeogenesis)
Which hormone makes insulin work better?
Amylin
Which medication is an amylin analogue?
Pramlintide
What are the functions of Leptin?
Weight loss, fullness, satiety
What are the functions of Adiponectin?
Insulin sensitizer
What hormones are secreted by adipose tissue that affects weight?
Leptin and adiponectin
Does leptin go up or down with weight loss?
Goes down so appetite increases and energy expenditure decreases
What is relationship between leptin and body fat mass?
When body fat mass goes up, leptin goes up
What pathways does leptin affect and how?
Stimulates the anorexigenic pathway and inhibits the orexigenic pathway
What is the anorexigenic pathway?
POMC neuron system
What is the orexigenic pathway?
NPY/AgRP neuron system
Why does leptin resistance happen?
2 proposed theories:
1. Impaired crossing thru the BBB
2. High levels of leptin lead to decreased leptin signaling downstream
Which hormone activates the Sympathetic nervous system?
Leptin
Which hormone can stimulate the TRH neurons?
Leptin
Why does high levels of leptin cause high BP?
Stimulates the sympathetic nervous system
What are other functions of Leptin?
Regulates immune function, angiogenesis and hematopoiesis.
Controls TRH
Activates SNS
Interacts with gonadotropin pulse generators in men/women so can get secondary hypogonadism if not enough leptin
Where is adiponectin exclusively synthesized?
White adipose tissue
What is relationship of adiponectin with body fat mass?
Inverse relationship
What helps improve adiponectin levels?
Insulin sensitivity thru weight loss or insulin sensitizers
What is relationship of adiponectin and insulin resistance?
Inverse
What is the most abundantly secreted adipose hormone?
Adiponectin
What is the role of adiponectin in the liver?
Enhances insulin sensitivity
decreases non esterified fatty acids
increases fatty acid oxidation
reduces hepatic glucose output
What is the role of adiponectin in the muscle?
stimulates glucose use and fatty acid oxidation
What is the role of adiponectin in the vascular endotheliuim?
inhibits monocyte adhesion
inhibits macrophages(foam cells)
decreases smooth muscle proliferation
increases nitric oxide production
What are the functions of adiponectin?
Improves insulin sensitivity in liver, muscle
Improves vascular function
What is the part of the hypothalamus that has a permeable barrier so that it can take in peripheral signals and relay them to the CNS?
Arcuate nucleus(this is where hormones and nutrients get into the brain)
Where are the first order neurons found?
Arcuate neurons
What is the role of Arcuate nucleus?
To receive signals from periphery(nutrients, gut hormones, adipose hormones) and relay to CNS
What are the 2 first order neuron systems of the arcuate neurons?
Weight gaining(NPY/AgRP)
Weight losing(POMC/CART)
What are second order neurons?
Neurons deeper in the hypothalamus that receive signals from first order neurons and relay signals to other parts of the brain
What is the second order neurons of Orexigenic pathway?
NPY goes to Y1 and Y5 receptors
AgRP blocks MC4R
What is the second order neurons of Anorexigenic pathway?
POMC to alpha-MSH to MC4R
What are the signals of the second order orexigenic pathway?
MCH
Orexin A
Orexin B
What are the signals of the second order anorexigenic pathway?
MC3R
MC4R
BDNF
What are some Orexigens?
NPY
AgRP
MCH
Orexin A
Orexin B
What are some Anorexigens?
POMC
CART
alpha-MSH
BDNF
Serotonin
Where are the second order neurons?
Paraventricular nucleus
Lateral hypothalamus
Where are the first order neurons?
Arcuate nucleus
What is the most abundant and potent orexigen?
Neuropeptide Y(NPY)
What inhibits NPY?
Insulin, Leptin, PP, PPY and serotonin
How does NPY stimulate hunger?
It binds to Y1 and Y5 receptors of second order neurons to stimulate MCH release
How does AgRP keep hunger going?
acts on MC3R and MC4r receptors on second order neurons to block effects of POMC/CART(alpha-MSH)
What inhibits AgRP?
Insulin, Leptin, PYY and serotonin
What are functions of AgRP?
Decreases energy expenditure
Oxygen consumption and
TRH
At what percent of weight reduction is termed clinically meaningful for medically supervised weight loss?What is weight loss goal?
5%
5-10%
What improvements can be seen clinically at 2.5% weight reduction?
Improved glucose metabolism
Decreased TGL
Improvement in PCOS/fertility
What improvements can be seen clinically at 5% weight reduction?
Improvement in Impact on Weight on Quality of Life score
Improvement in depression
Improvement in mobility
Improvement in knee function, walking speed, distance and pain with knee OA
Reduction in hepatic steatosis
Improved urinary incontinence
Improved sexual function
Increase in HDL
Improvement in health care costs
What improvements can be seen clinically at 10% weight reduction?
Improvement in Sleep Apnea
Improvement in NASH
What improvements can be seen clinically at 16% weight reduction?
Potential reduction in overall mortality
At what percent of weight reduction do you have a reduction in overall mortality?
16%
At what percent of weight reduction do you have a reduction in health care costs?
5%
What are indications for use of AOM?
BMI 27-29 with comorbidities or
BMI >30
What are indications for bariatric surgery?
BMI > 35 with or w/o comorbidities
BMI >30 - 34.9 with metabolic disease
For asians, BMI >= 27.5
What are the AOMs indicated for long term use?
Orlistat, Qsymia, Contrave, Saxenda(Liraglutide), Semaglutide, Tirzepatide, Setmelanotide(Imcivree)
What percent weight loss is considered to be a highly effective AOM?
15%
Which medication is indicated for use in pediatric >= age 12?
Semaglutide up to 2.4mg
Did studies show a higher risk of suicidal ideations with GLP1 compared with nonGLP1 AOM or antidiabetic med?
No
What is the dose of Orilistat
120 mg tid with meals(OTC is 60mg)
What is mechanism of action for Orlistat
GI lipase inhibitor - prevents absorption of 30% ingested fat
What are contraindications to orlistat?
Chronic malabsorption syndrome
Cholestasis
What are adverse effects of Orlistat?
Diarrhea, oily stools, incontinence
Rare hepatoxicity and pancreatitis, fat soluble vitamin deficiency, increased urinary oxalate and kidney stones. More likely to have side effects with high fat diet
What is the pharmacokinetics or Orlistat?
Metabolism of orlistat occurs within the GI wall, systemic exposure is minimal
Which AOM should be used with caution with pts on coumadin?
Orlistat as vitamin k levels tend to decline
What type of vitamins are not absorbed with orlistat?
Fat soluble vitamins and MVI should be taken 2 hours before or after orlistat
What medication should orlistat be taken 4 hours apart from?
Levothyroxine
How many hours should there be between taking orlistat and levothyroxine?
4 hours
What nutrients are decreased when taken together with Orlistat and by what percentage?
Vitamin E by 60% and Beta Carotene by 30%
What is titration regimen of Qsymia?
3.75-23 mg x 2 weeks, then 7.5-46mg
If <3% wt loss by 12 weeks, then increase to 11.5-69 and then to 15/92mg. If <5% loss in 12 weeks at max dose, then stop med
What is mechanism of action for Qsymia?
Phentermine - Sympathomimetic amine
Topamax - augments Gaba activity and inhibits carbonic anhydrase
What are contraindications of Qsymia?
Secondary angle glaucoma
Hyperthyroidism
Taking or within 14 days of stopping MAOI
Risk of cleft palate d/t topamax so women of CBA should be on ocp
What are adverse effects of Qsymia in adults?
Dizziness, insomnia, dysguesia(altered taste), constipation, dry mouth
What are adverse effects of Qsymia in peds?
Depression, dizziness, arthralgia, pyrexia, influenza and ligament sprain
What is the 1/2 life of Qsymia?
Phentermine - 20 hours
Topamax - 65 hours
Do you need to renally/hepatically dose Qysmia?
Yes, if mod/severe renal or hepatic impairment - max dose is 7.5-46mg
How is Qsymia metabolized?
Phentermine metabolized by Liver but excreted by kidney. Topamax excreted mainly by kidney.
What drug interactions with Qsymia?
OCPs - causes spotting but not decreased effectiveness of birth control
Non-potassium sparing diuretics - may cause hypokalemia
CNS depressants including etoh - may potentiate effect
What are increased risks of Qsymia?
Hyperthermia, hypokalemia, oligohidrosis(no sweat), kidney stones
Which AOM should you do a pregnancy test on women of CBA on?
Qsymia
Which med can cause low BS in diabetes?
Qsymia
How does Contrave work?
Buproprion - aminoketone antidepressant that may weakly inhibit neuronal uptake of Norepi and Dopamine that may affect the hypothalmus/hunger
Naltrexone - opioid antagonist that may affect hypothalmus and mesolimbic /dopamine circuit to decrease hunger and may help mitigate reward response
What are contraindications to Contrave?
Uncontrolled HTN
Seizure
Anorexia or bulimia
Abrupt stopping of etoh/benzox/barbituates/antisz meds
Use with other buproprion meds
Chronic opioid use
During or within 14 days of MAOI
What are adverse effects of Contrave?
Nausea/constipation, ha, vomitting, dizziness, insomnia, dry mouth and diarreha
What is 1/2 life of naltrexone?
5 hours
What is 1/2 life of buproprion?
21 hours
How is Contrave metabolized?
Thru kidneys and excreted in kidneys so use with caution if renal impairment
