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FHB - Endocrine & Reproductive > Lecture 10 (77): Metabolic Homeostasis > Flashcards

Lecture 10 (77): Metabolic Homeostasis Flashcards

1
Q 
The following are conditions of\_\_\_\_\_\_\_ (prolonged fast state)
Starvation
Cancer
Burns
Trauma
Severe infection
Psychological 
Drug abuse

What 3 things occur?

A

WASTING

  1. Proinflammatory cytokines
  2. Activation of HPA axis
  3. Dysregulation of growth hormone and IGF-I
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2
Q

Brain needs constant supply of glucose – approx. _____ per day

What is the initial source of energy during starvation?

How much protein is broken down?

A
  1. 180g/day
  2. Initial source: 80% from fat stores,
    release of FFAs,
    breakdown of liver glycogen,

breakdown of proteins (about 300g/day).

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3
Q

Because there is about 300g/day of protein breakdown, what is activated? (hormone)

A

increased AA’s and liver glycogen depletion will activate GH

  • which will promote the repute of PROTEIN
    = METABOLIC SWITCH
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4
Q

What happens in a PROLONGED fasting state? (2-3 days)

What is used as an energy source for the brain?

What is reduced?

What continues, but SLOWS tremendously?

A
  1. METABOLIC SWITCH
    - ketone bodies used as energy source
    - protective mechanism induced by GH due to low blood glucose
  2. Reduced reliance on glucose as fuel source
  3. Protein breakdown (20g/day now, instead of 300)
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5
Q

Obese :

BMI greater than _____ (at least 20% of population)

Waist-Hip ratio greater than _____ (men) or ____ (women) indicates significant risk for cardiovascular disease and diabetes

A
  1. 30
  2. Men = 0.95
    Women = 0.85
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6
Q

What are the 4 criteria that classify something as METABOLIC syndrome?

A
  1. VISCERAL OBESITY:
    waist >40 in. men, 35 in. women
  2. INSULIN RESISTANCE:

**fasting glucose > 100 mg/dl

  1. DYSLIPIDEMIA:
    TGs > 150 mg/dl,
    HDL 135/80
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7
Q

What are the 4 criteria that classify something as METABOLIC syndrome?

A
  1. VISCERAL OBESITY:
    waist >40 in. men, 35 in. women
  2. INSULIN RESISTANCE:

**fasting glucose > 100 mg/dl

  1. DYSLIPIDEMIA:
    TGs > 150 mg/dl,
    HDL 135/80

* PRE-DIABETIC SYNDROME*

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8
Q

What is the primary hormone produced by WHITE ADIPOSE tissue?

What is the TG storage cell?

What are 2 important transcription factors?

A

Primary hormone produced = Leptin

Adipocyte – TG storage cell

Important Transcription Factors:

A)Sterol regulatory binding protein 1C (SREBP-1C)

B) PPARγ
Nuclear steroid hormone receptor (ligand = LIPIDS)
Regulates TG storage and adipocyte differentiation

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9
Q

What transcription factor does the following describe:

  1. transcription factor Promotes TG synthesis
  2. Activated by lipids and insulin
  3. Increases glucokinase “trapping” glucose inside cells.
A

SREB 1c

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10
Q

What is the function of PPARγ?

What time of receptor is it?

What does it regulate

What can it be used to treat? (name of drug?)

How does it work?Side effect?

A

Nuclear steroid hormone receptor (ligand = LIPIDS)

1) Regulates TG storage
2) adipocyte differentiation

Thiazolidinediones (TZD) – PPARγ agonists used to treat insulin resistance and Type 2 diabetes mellitus
“Rosiglitazone = Avandia”

PPARγ induces differentiation of adipocytes – makes more fat cells (more fat cells = less glucose in the blood since it is being taken up by GLUT4)

side effect: WEIGHT GAIN

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11
Q

What produces leptin?

What is it in direct relationship with?

A

Adipocytes

Direct relationship between plasma leptin and total fat

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12
Q

Which of the following stimulate appetite and which inhibit:

  1. AGRP
  2. aMSH
  3. CART
  4. Neuropeptide Y

How does Leptin effect them?

A

Stimulators of APPETITE

  1. Neuropeptide Y
  2. Agouti-Related Peptide (AGRP)

**Leptin inhibits these causing decreased food intake

Inhibitors

  1. αMSH – cleaved from POMC
  2. Cocaine-amphetamine regulated transcript (CART)

**Leptin stimulates these decreasing food intake

(LEPTIN: inhibits the stimulators, and stimulates the inhibitors of appetite)

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13
Q

Paradox: obese humans have high leptin levels. Why?

A

Possible obesity-induced leptin resistance

-Mouse – leptin deficient therefore appetite is uncontrolled = mouse gets very fat

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14
Q

What is insulin resistance?

What are plasma glucose levels?

Insulin levels? (receptors)

What happens to the pancreas over time?

A
  1. Insulin does not efficiently transport glucose into cells (MUSCLE & ADIPOSE CELLS with GLUT 4 - insulin dependent)
  2. Plasma glucose levels are high – saturating**
  3. Insulin levels are high – hyperinsulinemia downregulates insulin receptors

Gradual process – can take decades to develop into diabetes

4, Over time pancreas reduces insulin output leading to diabetes mellitus

  1. Beta cell depletion or “exhaustion” will cause conversion from Type 2 to Type 1 diabetes.
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15
Q

What causes the conversion from Type 2 to type 1 diabetes mellitus?

what causes diabetes insidipidus?

A

Beta cell destruction due to insulin resistance

Destruction of Posterior Pituitary (no ADH/Vasopressin)

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16
Q

What is the relationship of C peptide to insulin?

How is this in an obese patient?

A

As C peptide rises, as does insulin

OBESE PATIENT:
same spike in plasma glucose
EXHAGGERATED RESPONSE IN INSULIN  but not enough to deal with blood glucose levels
**OVERCOMPENSATION

17
Q

What are the 3 diagnostic tests for Type 2 Diabetes mellitus?

What are the pre-diabetic levels?

Diabetic?

WHICH IS THE BEST TEST?

A
  1. Diagnosis: Elevated HbA1C:
    ≥48mMol/l (6.5%) (ADA, 2010)

Measures average blood glucose concentrations over a longer period of time.

  1. Fasting blood glucose: pre: 100-125 mg/dl
    T2DM: 126+
  2. Oral Glucose tolerance test: 8 hour fast; glucose measured before and 2h post consumption of 75g glucose

pre: 140-199 mg/dL
T2DM: 200+

**ELEVATED HbA1c = BEST TEST - average over time (since patients might alter their habits if they know they have a doctor’s appointment coming up) **

18
Q

What can be measured to clinically test how well the pancreas is functioning?

What drugs increase insulin formation?

A
  1. C - peptide

2. Sulfonylureal Drugs

19
Q

What are the 3 symptoms of Type 2 DM?

What is it characterized by?

A
  1. Polyphagia – excessive hunger due to inability of cells to utilize glucose “cellular starvation”
  2. Polyuria – excess glucose in blood leads to increased plasma osmolarity, excessive water and sodium loss (Na - dragged with water)
  3. Polydipsia – excessive thirst due severe dehydration

Characterized by: impaired beta cell function and insulin resistance

20
Q

What are the following drugs used for? How?

  1. Sulfonylureas:
    “Glyburide”, “Glipizide”
  2. Biguanides :
    “Metformin”
  3. Alpha-glucosidase inhibitors “Precose” “Glyset”
A
  1. Sulfonylureas – “Glyburide”, “Glipizide”
    action:
    Close ATP-dependent K+ channels in beta cells - causing insulin release
    - cell can depolarize and release more insulin
  2. Biguanides – “Metformin” (MAIN TYPE OF TX)
    - Inhibits hepatic gluconeogenesis
    - Increases insulin receptor activity making cells more sensitive to insulin
    - increased glucose uptake
  3. Alpha-glucosidase inhibitors “Precose” “Glyset”
    - Delays intestinal absorption of carbohydrates

NEW DRUG:

FARSIGA  new drug  kidney does NOT take up glucose
side effect: yeast infection/bladder infection (food for bacteria)

21
Q

What are some proposed mechanisms of Beta Cell dysfunction?

A 
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
22
Q

What do incretins do?

A

INCRETIN = GLP 1

  • made in intestine in response to HIGH CARB LOAD
  • they will potentiate insulin release from pancreatic beta cell
  • overproduction of incretins will lead to dysregulation
23
Q

What is DMT1 characterizes by?

When is the onset?

What is destroyed?

Tx?

A
  1. KETOACIDOSIS in the absence of insulin therapy
  2. Juvenile onset – approx. 2-5% of diabetes cases
  3. Destruction of pancreatic beta cells – insulin dependent
  4. Treatment – insulin injections,
    close monitoring of blood glucose levels,
    diet
24
Q

Describe how T1 DM can lead to a COMA (4 steps)

A
  1. Decreased Insulin + Increased Counterregulatory Hormones
  2. FFA release – hepatic precursor for ketone acids
  3. Metabolism of ketone bodies for energy results in increased blood acidity (H+)
  4. Diabetic coma: severe dehydration and acidosis
25
Q

Why is T2DM considered starvation in the midst of plenty?

A

INCREASED GLUCONEOGENESIS (and patients are still eating)  HYPERGLYCEMIA

  • BUT INSULIN RESISTANT!
  • however, no ketogenesis

Main point: depends whether insulin is present or not

26
Q

Mental acuity is a function of _____

A

OSMOLALITY

-MENTAL FUNCTION  depends on hydration status
go from alert state to stuperous
lead to COMA  direct result from DEHYDRATION

27
Q

What is released in a PROTEIN ONLY meal?

When insulin is present:
AA from protein stimulate ____ which stimulates_____(liver).

This then stimulates glucose uptake in muscle, proliferation of visceral organ tissues; inhibits proteolysis.

____ opposes insulin lipogenesis***

A

GLUCAGON

  1. GH
  2. IGF-I
  3. GH
28
Q

What inhibits insulin induced lipogenesis?

A

GH!!!

ratio of insulin & GH determine whether lipids are made

29
Q

How is the following different in STARVATION:

  1. insulin
  2. glucose
  3. _____ stimulate glucagon, anything inhibit?
  4. GH?
  5. IGF1?
  6. Cortisol?
A
  1. No insulin
  2. Low glucose
  3. Catecholamines stimulate glucagon – nothing inhibits
  4. GH increases due to increased AA (proteolysis)

No IGF-I – no neg. feedback on GH* (lipolysis)

Cortisol – stress
Permissive effects on lipolysis, glycogenolysis

30
Q

What are the following in Type 1 DM:

  1. insulin
  2. glucose
  3. _____ stimulate glucagon, anything inhibit?
  4. GH?
  5. IGF1?
  6. Cortisol?

How is starvation and T1DM different?

A

No insulin

HIGH 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

TYPE1 = GLUCOSE IS HIGH!

31
Q

What are the following for Type 2 DM:

  1. insulin
  2. glucose
  3. _____ stimulate glucagon, anything inhibit?
  4. CORTISOL?

WHAT is the distinguishing factor between type 1 and type 2

A
  1. RELATIVE insulin deficiency - some insulin, maybe not effective
  2. HIGH glucose
  3. Catecholamines stimulate glucagon, insulin inhibits
  4. Cortisol – stress
    Permissive effects on lipolysis, glycogenolysis

*** Insulin inhibits ketogenesis

32
Q

What genes are associated with a predisposition for Type 2 DM?

A

Most genes identified affect beta cells (development, proliferation, survival, function).

**Most highly associated genetic polymorphism is in transcription factor 7-like 2 (TCF72)

Wnt signaling pathway; coactivator of beta-catenin
**

33
Q

Islet neogenesis occurs during _____.

Beta cell replication continues during childhood/adolescence but is stable _____

_____ important for both islet neogenesis and beta cell proliferation

______ downstream targets regulate beta cell proliferation

A

embryonic development

in adults

  1. PDX-1!!!
  2. TCF72!!!
34
Q

Which is responsible for the following:

  1. downstream targets regulate beta cell proliferation
  2. important for both islet neogenesis and beta cell proliferation
  3. Endocrine cell development
A
  1. TCF72
  2. PDX - 1
  3. Neurogenin 3 = key for endocrine cell development
    (beta, alpha etc..)
35
Q

What are 2 environmental factors that serve as risk factors for T2DM? (for each)

  1. Impaired beta cell proliferation during childhood
  2. Increased propensity for insulin resistance
A

1.

a) Malnutrition
b) Maternal factors during pregnancy

a) High caloric diet (obesity)
b) Lack of physical activity

36
Q

Acquired organ dysfunction for glucose homeostasis
is REVERSIBLE true or false?

What is usually impaired 1st or 2nd phase of insulin secretion?

A

TRUE

  • First phase insulin secretion impaired – key early characteristic of disease (eventually 2nd phase is also impaired)
  • Hyperglycemic conditions result in organ dysfunction (liver, adipose, pancreas)
37
Q

What drug can be used to alleviate First Phase Insulin release Impairment?

What type of drug is this?

What is a side effect?

A

EXENATIDE

  • GLP-1 agonist (incretin mimetics)

** Pancreatic Toxicity**

38
Q

What initially happens to the B cell mass in Early stages of type 2 DM?

Insulin secretion?

What about mid and late stages?

A

INCREASE proliferation of Beta cells in response to insulin resistance
- also increase insulin secretion

Mid/late = both decrease

  • beta cells eventually die

FHB - Endocrine & Reproductive (17 decks)

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