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MCM test 3 > 12- Diabetes Case Study > Flashcards

12- Diabetes Case Study Flashcards

1
Q

Type II diabetes is multifactoral and encompasses many genes. What do those genes do?

A 
B cell formation
B cell function insulin secretion 
Regulate fasting glucose levels
BMI regulation
Adipocyte differentiation
insulin pathway regulation

Many different polymorphisms inheritted collectively

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2
Q

What kinds of pancreas glands are present?

What do they do?

A

Exocrine- duct, secrete enzymes that digest food

Endocrine- secretes hormones. Glucagon and insulin
— islets of langerhans: regulate hormone secretion

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3
Q

Transcription factors related to glucagon and insulin

A

Foxo1- Bind to IRE (insulin response element), regulate downstream of insulin signaling.
– ex. negatively regulate adipogenesis. When stimulated by insulin, Foxo1 is excluded from the nucleus and unable to prevent transcription of PPAR y

Pdx1- glucose dependent insulin production
– insulin promoter, critical for pancreatic development

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4
Q

Insulin biosynthesis pathway

A
  1. pre proinsulin, cleaved amino terminal
  2. proinsulin, cleavage of internal 31 aa residue = C peptide, A chain, B chain (B and A connected by disulfide bond)
    - – C peptide is marker of insulin.
  3. All three pieces are secreted together.
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5
Q

Secretion of insulin pathway

What are the phases?

A

Glucose enters through GLUT2 > Glycolysis > Increase in ATP : ADP > Closes K+ channel > depolarization opens up Ca2+ channels > Ca rushes in moves vesicles to surface > Rlease insulin

1st phase- 10-15 min after meal, stored insulin secreted
2nd phase- genes turned on, 2-3 hours.

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6
Q

What is the key regulator of insulin secretion?

What is the level glucose plasma needs to go above to stimulate insulin synthesis?

A

Glucose, >3.9mmol/L

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7
Q

What comprises the insulin receptors?

A

two alpha (extra membrane) and two beta (trans/intra)

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8
Q

Where do you find GLUT2? GLUT4

A

GLUT2- liver, pancreas

GLUT4- skeletal muscle and adipose (insulin dependent)
– Insulin releases GLUT4 from stored vesicles.

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9
Q

Glucagon stimulates gycogenolysis and gluconeogenesis where?

A

liver and renal medulla

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10
Q

Where does glycolysis happen in the body when insulin is produced?

A

Liver, via PFK II enzyme.

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11
Q

What happens in the glucagon world?

A

gluconeogenesis, glycogenolysis, ketogenesis ( for brain

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12
Q

What happens to glycolysis in diabetes?

A

Reduced phosphorylation in liver (glucokinase is insulin dependant)
Glucagon modifies enzymes
Reduced activity of PFK I and PFK II
Reduced rate of glycolysis

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13
Q

What happens to gluconeogenesis in people with diabetes?

A

Increased rate due to:
Increased availability of substrates
Increased activity and concentration of enzymes

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14
Q

What happens to glycogenesis and glycogenolysis in people with diabetes?

A

Glycogenesis- Inhibited due to reduced activity of glycogen synthase

Glycogenolysis- stimulated due to increased activity of phosphorylase

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15
Q

Sorbitol pathway

How is it related to diabetic cataracts?

A

Increase in glucose > Aldose Reductase > sorbitol

Sorbitol increases cell osmolality, generates reactive oxygen species, leads to other types of cell dysfunction

Diabetic cataracts is the result of osmolysis by sorbitol accumulation.

2nd option leads to neuropathy, nephropathy, retinopathy, vascular complications

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16
Q

Two ways to get diabetic cataracts

A
  1. low lens glutathione

2. aldose reductase induced osmatic stress

17
Q

What happens to lipid metabolism in diabetics?

A

Lipid mobilization for energy. Trying to make glucose even though hyperglycemic.

Liver takes up free FA= fatty liver

Broken down to Acetyl CoA to TCA (also ketone bodies)

Ketosis- in liver

18
Q

What are the 3 ketone bodies?

A

acetone, acetoacetate, B-hydroxybutyrate

19
Q

Hypokalemia

A

body K is low, false hyperkalemia because nonfunctioning Sodium Potassium ATPase pump.

20
Q

C peptide test

What is c peptide?

What do the c peptide levels tell you?

What is used to mark it?

A

C-peptide is produced in b cells of pancreas when proinsulin splits apart

C peptide levels give you an idea of how much insulin is being produced

ELISA (Enzyme-Linked Immunosorbent Assay)

    • creates color precipitate
    • rabbit antibody binds antigen, secondary antibody binds rabbit antibody. Metabolism causes light to be seen.
21
Q

Hemoglobin A1c

A

Tells you the amount of blood glucose
– (N terminal glycated B-hemoglobin) reaction between hemoglobin and glucose

irreversible non-enzymatic reaction (rate dependent on blood glucose concentration)

Lasts the lifetime of erythrocyte and can tell you levels for the last 2 to 4 weeks

22
Q

Advanced glycosylated end products (AGEs)

A

Mallard reaction( non enzyme) - glucose and amino acid

Irreversible - higher concentration lead to downstream tissue accumulations: collagen cross linking, microvascular complications.

23
Q

What do the receptors for AGEs induce?

A

RAGEs induce ECM production, inflammatory molecules, ROS.
Also decrease in NO.

Mainly on immune, neurons, endothelial, vascular and smooth muscle cells.

24
Q

Insulin binds to RTK pathway in skeletal muscle and adipose cells. What are the downstream affects?

A

Insulin binds Receptor Tyrosine Kinase > phosphorylates targets > downstream:

Glycogen synthesis (Akt, Gsk3)
Lipogenesis (Atp citrate lyase, Acly): citrate to aceCoA
Protein synthesis: mTOR (PI3K like kinase
Cell survival: Bad, MapK

25
Q

What stimulates Foxo1 transcription factor?

What does it bind to?

What processes does it inhibit? What does it activate?

A

Phosphorylated by Akt.

Binds to IREs (insulin response elements), decrease gluconeogenesis and glycogenolysis

Activates PPARy, adipogenesis

26
Q

What induces GLUT4 exocytosis?

What kind of coat is on GLUT4 endocytosis?

A

Insulin via the Akt/PI3K pathway, SNAREs

Clathrin

27
Q

Endothelial cell dysfunction pathway

A

Hyperglycemia > decrease eNOS > decrease NO > Increase ox stress > Increase inflamm mediators

Also ischemia leads to less white blood cells to fight infection

28
Q

Why are foot ulcers slow to heal in diabetics?

A

Lack of oxygen, nutrients due to ischemia.

29
Q
  1. Perforating collagenosis
  2. Granuloma
  3. Necrobiotic
A
  1. Collagen bundles end up invading epidermis.
  2. mass of granulation tissue, lymphocyte infiltration
  3. areas of necrosis with collagenolysis
30
Q

Kidney problems in diabetics, what is diabetic renal gloverulosclerosis

A

Basement membrane thickening and scaring to glomerular blood vessels.

Affected by AGEs

31
Q

What problems does fructose cause on diabetics?

A

ATP > AMP > Adenosine > IMP > Inosine > Uric acid

Gout!

Fruit juice, wine… high fructose

32
Q

What causes peripheral neuropathy?

And what symptoms?

A

Impaired circulation (ischemia) > impairment of axon/glia relationship (demyelination) > axonal injury (Wallerian degeneration)

Longest axons first- stocking and gloves defect in strength and sensation

motor deficit- muscle atrophy (loss of trophic effect), Neurotransmitter lost from damaged axon or schwann cells. Sensory deficit (tingling or pain)

33
Q

Wallerian degeneration

Chromatolysis

A

Wallerian: PNS regeneration resulting from damaged axons. Delayed in diabetics. Schwann cells guide new connection to be made (delayed)

Chromatolysis: Dissolution of Nissl bodies,

34
Q

Diabetic retinopathy

What are cotton wool spots?

A

micro aneurisms, veins dilated and tortorous. Arteries white and non-perfused, eventually absent of endo cells. loss of perisites, apoptosis of capillary epithelial cells.

cotton wool spots: failure of vascular resulting in ischemia

35
Q

Two stages of diabetic retinopathy

A
  1. preproliferative: increased size and # of intraretinal hemorrhages. most vision loss from macular edema
  2. Proliferative: Formation of new vessels
    - - can protrude to viterous, hemorrhage and cloud vission.
    - - detach retina
    - - can also cause secondary form of blindness, grow into other parts of the eye.
36
Q

What factors should we remember with angiogenesis in eye?

A

VEGF (VEGF R1 and R2)

PGEF- (pigment epithelial growth factor)

37
Q

Hyperglycemia inhibits G6PD resulting in low NADPH levels.

What happens next?

A

NADPH is an antioxidant to ONOO, so it will go up.

decreased NADPH, GSH and incerase ONOO will cause cell damage and lead to vasoconstriction

Back up will cause increase in F6P pathway (purine syn) and increase DAG pathway leading to microvascular plugging.

Resulting macular edema.

38
Q

Pathway of how hyperglycemia affects neuronal dysfunction

A

Hyperglycemia > ROS/RNS > PARP path > Gene expression > Neuronal dysfunction

MCM test 3 (12 decks)

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