Endocrinology 11- Metabolic homeostasis

Question 1

What are some causes of prolonged wasting states?

Answer 1

starvation, cancer, burns, trauma, severe infection, psychological effects, drug abuse

Question 2

What are some outcomes of prolonged wasting states

Answer 2

pro inflammatory cytokins, activation of HPA axis, dysregulation of growth hormone and IGF-I

Question 3

Metabolically speaking is starvation entering a state of catabolism or anabolism

Answer 3

catabolism

Question 4

Where does most fuel come from in starvation?

Answer 4

fat and glycogen breakdown – you will also break down protein in initial sages which will release amino acids which can be used for gluconeogenesis. As you go on you will eventually get ketones.

As long as insulin is not present, FFA’s will be used to make ketones so brain does not die

GH prevents huge loss of muscle

Question 5

Direct actions of GH in wasting state:

Answer 5

block glucose uptake

protect muscle from being broken down too much

Question 6

Metabolic syndrome – what does it mean to have this?

Answer 6

Must have 3 or 4 of the following things at the same time
Visceral obesity around waist
insulin resistance as determined by fasting blood glucose
dyslipidemia (High TGs, but low HDL)
Hypertension

Question 7

Is diabetes a requirement to have metabolic syndrome

Answer 7

no – you can have metabolic syndrome for other reasons (ex. cushing syndrome) and not have diabetes.

Question 8

Important transcription factors in white adipose tissue

Answer 8

SREBP-1C and PPARy

Question 9

Important hormone produced in white adipose tissue

Answer 9

leptin

Question 10

SREBP-1C actions in white adipose tissue

Answer 10

important transcription factor for promoting TG storage and synthesis.

When insulin wants to store FFAs as TGs it needs this transcription factor - this is one that is activated by insulin (on same diagram activated by AKT pathway) -

helps increase activity of glucokinase to trap glucose in cells,.

Question 11

PPARy

Answer 11

Nuclear steroid hormone receptor (transcription factor!)
Regulates TG storage and adipocyte differentiation
typically you do’t make new adipocytes as an adult - usually adipocytes just get bigger (hypertrophic) – in some cases you can induce them to multiply but generally speaking they just get bigger

Question 12

PPARy agonists - what are they, what are they used for?

Answer 12

Thiazolidinediones (TZD) - used to treat insulin resistance and type 2 diabetes mellitus (Avandia). If you target this, you make more adipocytes. So this isn’t an ideal medication for everyone, but this can make white adipose tissue with brand new receptors so increase the actions of insulin in adipocytes. Weight gain however is a significant side effect

Question 13

Leptin - relationship of release and total fat content in a region

Answer 13

more fat content –> more leptin

Question 14

Hypothalamic hormone regulators of appetite - stimulators

Answer 14

Neuropeptide Y, agouti-related peptide (AGRP)

Question 15

Leptin interaction with appetite stimulating cells

Answer 15

inhibits them, causing decreased food intake

Question 16

Hypothalamic hormone regulators of appetite - inhibitors of appetite

Answer 16

a-MSH (cleaved from PONC)
Cocaine-amphetamine regulated transcript (CART)

Leptin will stimulate inhibitors of appetite, and decrease overall food intake

Question 17

What does insulin resistance mean

Answer 17

Inability of insulin to move glucose from blood - it does NOT mean every single tissue that has insulin receptors is no longer responsive (ex. in PCOS, we have insulin hypersensitivity).

Question 18

Is prediabetes reversible

Answer 18

yes with diet and exercise and lifestyle changes

Question 19

is DIABETES reversible

Answer 19

no

Question 20

Why is diabetes not reversible

Answer 20

you have cmplete dysfunction and destruction of beta cells

Question 21

What characterizes type 2 diabetes mellitus?

Answer 21

Impaired beta cell function and insulin resistance, as well as polyphagia, polyuria, polydipsia.

Question 22

Why are people with T2 diabeteis mellitus polyphagic?

Answer 22

Excessive hunger is due to glucose not getting into adipose tissue or muscle, so body is telling brain it is starving.

Question 23

What is the goal of T2 Diabetes mellitus treatment

Answer 23

tight glycemic control

Question 24

What do sulfonylureas do?

Answer 24

They close ATP dependent K channels in beta cells (leads to depolarization and insulin release) - so as soon as a vesicle is made it is released - cheap, low side effects, second line treatment

Question 25

What do biguanides like metformin do for treatment of T2DM?

Answer 25

Inhibits hepatic gluconeogenesis - increases insulin receptor activity making cells more sensitive to insulin (gold standard treatment) - helps body work to clear glucose from blood

Question 26

What do alpha-glucosidase inhibitors such as precose and glyset do for T2DM treatment

Answer 26

delay intestinal absorption of carbohydrates - if first phase secretion is impaired and you just need to let insulin catch up to what is there, this can be a good txt method

Question 27

What do sodium-glucose transport protein 2 (SGLT2) inhibitors such as jardiance and farxiga do for T2DM treatment

Answer 27

Try to clear glucose from blood by shunting it into urine (prevents glucose uptake in proximal convoluted tubule) -- normally you don't want glucose in urine, but this is going to be an advantage here. However, you can get genitourinary tract infections

Question 28

What do DPP4 inhibitors such as Januvia do for T2DM treatment

Answer 28

Inhibit degradation of GLP1 to keep it going, which will potentiate insulin release

Question 29

What is the proposed mechanism of beta cell dysfunction in TYPE 2 diabetes mellitus?

Answer 29

Lots of glucose --> insulin remains high to keep up with this. As insulin keeps being poduced, this puts a huge strain on mechanisms in cell that transport proteins, such as ER stress. Processing of glucose coming in via TCA pathway is stressed as well since beta cells are not dependent on insulin for glucose transport (use GLUT2/GLUT1). This results with a litany of consequences, including build up of amyloid plaques due to amylin being made and packaged into insulin secreting vesicles and aggregating together, ER stress, lipotoxicity because there will be increased lipids coming in and causing toxxicity esp because many T2DM patietns have obesity as a comorbidity, oxidative stress from processing glucose coming in, and glucose toxicity from glucose comig in. There may also bea genetic component = beta cells normally proliferate and differentiate in embryogenesis and you have a critical mass at birth, but some genes may reduce this. You can also have incretins that may be fucked up when constantly stimulated by high fat and high carb diet, not to mention inflammatory responses adding to the problem and inflaming islets.

Question 30

T1DM - how is it characterized, when does it appear, what does it mean if you have this?

Answer 30

Characterized by ketoacidosis in absence of insulin therapy. Happens in juvenile onset and is about 2-5% of diabetes cases. You get destruction of pancreatic beta cells (autoimmune) -- insulin dependent.

Question 31

Treatment for T1DM

Answer 31

Insulin injections, close monitoring of glucose levels, diet

Question 32

Cause of diabetic coma

Answer 32

dehydration which occurs after increase in blood acidity

Question 33

Flow of diabetic ketoacidosis

Answer 33

usually occurs in T1DM Decreased insulin and increased counterregulatory hormones --> FFA release (hepatic precursor for ketone acids) --> metabolism of ketone bodies for energies makes blood acidic --> diabetic coma, due to acidosis and dehydration (primary reason)

Question 34

When would you typically see ketoacidosis in a T2DM patient

Answer 34

if they are becoming T1 or if they are obese

Question 35

In what kind of diabetes do you get hyperosmotic, hyperglycemic state?

Answer 35

both

Question 36

does insulin resistance exist in T1DM?

Answer 36

no - they're actually so sensitive to insulin they could be overwhelmed by it easily

Question 37

Risk factors for T2DM

Answer 37

Genetic predisposition (most genes impact beta cells, but some are linnked to insulin signaling, glucose transport, or obesity) - most associated is for Wnt signaling pathway in growth and development of beta cells Environment (impaired beta cell profliferation during child hood due to malnutrition or maternal factors in pregnancy); insulin resistance propensity increased due to diet or lack of exercise; acquired organ dysfunction for glucose homeostasis)

Question 38

Neurogenin 3

Answer 38

key for endocrine cell development

Question 39

Early pancreatic progenitor genes

Answer 39

PDX1 and NXX6.1