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
