Endocrinology 11 Flashcards
Explain changes in metabolism as a result of starvation.
What other conditions will resemble this state?
Proinflammatory cytokines
Activation of HPA axis
Dysregulation of growth hormone and IGF-I
these are stressors to body which cause activation of HPA axis that will stay chronically elevated. activation of pro-inflamm. cytokines… and dysregulation of GH and IGF-1 need insulin present
Starvation Cancer Burns Trauma Severe infection Psychological Drug abuse
starvation causes dominant catabolic state… WASTING.
How is starvation similar to what occurs w exercise?
Initial source: 80% from fat stores, release of FFAs, breakdown of liver glycogen, breakdown of proteins (about 300g/day).
metabolic state of starvation (similar to what induce w exercise) initially break down glycogen in liver and lots of fat stores (this is where initial fuel source will come from for glucose to get to brain)
use up all liver glycogen stores in about 2.5 days
if fast continues no longer have glycogen stores to draw upon
initial days of fast- break down proteins v quickly
break down about 300g per day. by breaking all down you supply necessary substrates for gluoconeogenesis
after deplete glycogen stores, and start breaking down lots of fat, you want to preserve protein breakdown so you get a shift…metabolic switch
Describe the prolonged fast- metabolic switch.
Metabolic switch – ketone bodies used as energy source for brain
Reduced reliance on glucose as fuel source
Protein breakdown continues (approx. 20g/day)
Describe the four factors of Metabolic syndrome.
presence of
Visceral obesity - waist great than 40 in in men, 35 in. women
Insulin resistance - fasting glucose greater than 100mg/dl
Dyslipidemia - TGs greater than 150mg/dl, HDL less than 40mg/dl
Hypertension -BP is greater than 135/80
all 4 of these things classify diagnosis of metabolic syndrome. doesn’t mean T2DM. put puts you at risk to develop T2DM
WHITE ADIPOSE TISSUE
Describe adipocyte.
Primary hormone produced?
Important TF?
Adipocyte – TG storage cell
Primary hormone produced = Leptin
main hormone is leptin (prod. by adipocytes TG storage cell)
What are 1C (SREBP-1C) and PPARgamma?
Describe function.
Imp. TF:
Sterol regulatory binding protein 1C (SREBP-1C)
Promotes TG synthesis
Activated by lipids and insulin
Increases glucokinase “trapping” glucose inside cells.
PPARgamma
Nuclear steroid hormone receptor-its ligand is fat or lipids
Regulates TG storage and adipocyte differentiation
How could PPARgamma be targeted to treat insulin resistance and T2DM?
Thiazolidinediones (TZD)
“Rosiglitazone = Avandia”
nuclear steroid hormone receptor, promotes TG synthesis and adipocyte differentiation
makes more fat cells
-get more adipocytes being made, more cells to store TG and promote TG synthesis
and have more insulin receptors bc have more fat cells
so will increase peripheral sensitivity to insulin actions
Increased fat storage
Side effect of TZDs is weight gain
but gain weight bc making more fat cells. But majority of pt w T2DM also have problems w obesity
Describe the relationship between Leptin and total fat.
Produced by adipocytes
Direct relationship between plasma leptin and total fat
Describe the hypothalamic regulators of appetite.
What are the stimulators? The inhibitors?
Stimulators (neurons in the hypothalamus-Arcuate nucleus)
- Neuropeptide Y
- Agouti-Related Peptide (AGRP)
- *Leptin inhibits these causing decreased food intake
Inhibitors
alphaMSH – cleaved from POMC (binds MC4R melanocortin receptors)
Cocaine-amphetamine regulated transcript (CART)
**Leptin stimulates these decreasing food intake
overall net function is to decrease food intake
What happens to a leptin deficient mouse?
LEPTIN DEFICIENT MICE ARE MORBIDLY OBESE
Mouse – leptin deficient therefore appetite is uncontrolled = mouse gets very fat
Describe the leptin activity and presence in an obese human.
Obese humans have high leptin levels due to high fat. But, increased leptin does not inhibit appetite
Possible obesity-induced leptin resistance
-dysregulation of hypothalamic neurons and they are resistant to effects of leptin
What is insulin resistance?
Describe insulin's activity? Plasma glucose levels? Insulin levels? Implications? Pancreas activity? Beta cells?
Insulin does not efficiently transport glucose into cells (GLUT4 transporters not trafficked to membrane. not enough glucose from blood into cells, so plasma glucose levels are v high and they saturate all those insulin independent transporters (LOTS going into liver and pancreas in those low affinity transporters…) but glucose levels high in blood so it will saturate those)
Plasma glucose levels are high - saturating
Insulin levels are high – hyperinsulinemia downregulates insulin receptors
Gradual process – can take decades to develop into diabetes
Over time pancreas reduces insulin output leading to diabetes mellitus
Beta cell depletion or “exhaustion” will cause conversion from Type 2 to Type 1 diabetes.
Why is obesity the highest risk factor for developing T2DM?
dont know why obesity causes pancreas to put out more insulin in response to exact same amount of blood glucose but that happens. thats why obesity is highest risk factor for developing type 2 diabetes.
Slide 20, (for same glucose in blood, obese person has higher plasma C peptide and plasma insulin)
How is T2DM diagnosed?
Diagnosis: Elevated HbA1C: greater or equal to 48mMol/l (6.5%)
Measures average blood glucose concentrations over a longer period of time.
Avg. red blood cell life span = 120 days. Glucose increases the number of glycosylated RBCs.
Fasting blood glucose: 100-125 mg/dl (pre-diabetes), 126+ T2DM
Define the characteristics of T2DM.
What are the symptoms?
What is the treatment goal?
*Characterized by impaired beta cell function and insulin resistance
Polyphagia – excessive hunger due to inability of cells to utilize glucose “cellular starvation”
Polyuria – excess glucose in blood leads to increased plasma osmolarity, excessive water and sodium loss
Polydipsia – excessive thirst due severe dehydration
Treatment goal = tight glycemic control
How can the following be used to treat T2DM?
- Sulfonylureas
- Biguanides – “Metformin”
- Alpha-glucosidase inhibitors “Precose” “Glyset”
Sulfonylureas – “Glyburide”, “Glipizide”
Close ATP-dependent K+ channels in beta cells causing insulin release
Biguanides – “Metformin”
Inhibits hepatic gluconeogenesis
Increases insulin receptor activity making cells more sensitive to insulin, increased glucose uptake
Alpha-glucosidase inhibitors “Precose” “Glyset”
Delays intestinal absorption of carbohydrates- these alpha slow things down to allow for beta cells to catch up
Describe:
PROPOSED MECHANISMS OF BETA CELL DYSFUNCTION
Islet amyloid buildup Endoplasmic reticulum stress Lipotoxicity Oxidative stress Glucose toxicity Beta cell differentiation – reduced expression of key beta cell genes Incretin hormone dysregulation Islet inflammation
How can T1DM be distinguished from T2?
How is it characterized?
What causes it?
Treatment?
Characterized by development of ketoacidosis in the absence of insulin therapy
Juvenile onset – approx. 2-5% of diabetes cases
Destruction of pancreatic beta cells – insulin dependent
Treatment – insulin injections, close monitoring of blood glucose levels, diet
get ketoacidosis bc no insulin… insulin REQ to take
autoimmune destruction of pancreatic beta -hard to tell when destruction begins but beta cell mass reaches threshold when get enough destroyed can’t make enough insulin and then don’t make any
in these individuals its like state of starvation (is in dominant catabolic state as if starving even though blood glucose levels are really high and they’re eating a lot - typically appetite is high
Explain the process and consequences of diabetic metabolism (low insulin, high glucose, excess glucagon) leading to diabetic ketoacidosis.
DIABETIC KETOACIDOSIS
Acute pathological condition – usually occurs in T1 DM diabetics
Decreased Insulin + Increased Counterregulatory Hormones
FFA release – hepatic precursor for ketone acids
Metabolism of ketone bodies for energy results in increased blood acidity (H+)
Diabetic coma: severe dehydration and acidosis
coma that occurs after mostly due to dehyrdation.
high blood glucose- causes all fluid in cells to come out of cells, into blood- shrinkage of neurons, coma. (coma is due to severe dehyhration. also have acidosis in blood
Describe some similarities/differences in T1 and T2DM.
in type 2 have RELATIVE insulin def. usually some insulin being made so you do not get ketogenesis in type 2.
-FFA go to liver and get some keotacidosis but anything that is left over, get more TG and this causes hyperlipidemia in Type1….
T1DM have hyperlipidemia even tho v thin
both cases, increased counter-reg hormones.
still get decreased protein syn. and increased proteolysis so increased aa
How does altered mental function result in T1DM?
MENTAL ACUITY IS A FUNCTION OF OSMOLALITY
mean plasma osmolality…as goes up, so does altered mental status…
Describe the normal fed state mixed meal:
Carbs
Fat
Protein
Protein only
Mixed meal:
Carbs – insulin
Fat – insulin
Protein – glucagon, insulin (some)
Protein meal:
Glucagon only, low insulin
Describe the presence of aa when insulin is present.
Describe actions of GH
When insulin is present:
AA from protein stimulate GH which stimulates IGF-I (liver).
IGF-I stimulates glucose uptake in muscle, proliferation of visceral organ tissues; inhibits proteolysis.
GH opposes insulin lipogenesis.
Describe the hormone regulation in starvation.
No (undetectable) insulin
Low glucose
Catecholamines stimulate glucagon – nothing inhibits
GH increases due to increased AA (proteolysis)
No IGF-I – no neg. feedback on GH
Cortisol – stress
Permissive effects on lipolysis, glycogenolysis
(this is exactly same in T1DM except HIGH glusose)
