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233 2nd midterm > Type 2 Diabetes Part 1 > Flashcards

Type 2 Diabetes Part 1 Flashcards

1
Q

Pathology of Obesity-Related T2D

name 5 locations that are related to obesity progression and the effects

A
  1. Skeletal Muscle Insulin Resistance
  2. Pancreas: Hyperinsulinemia, Hyperglucagonemia
  3. Liver: Increased Hepatic Glucose Production & Triacylglycerol Secretion
  4. Brain: Increased appetite
  5. Adipocytes: Increased Adiposity & Inflammation

Control blood sugar levels < 7%, macrovascular is not controlled well

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2
Q

Pathology of Obesity-Related T2D

describe Skeletal Muscle Insulin Resistance

A
  • First develop skeletal muscle insulin resistance
  • Skeletal muscles take up a lot of glucose by action of insulin, but it is not taking in glucose
  • islet beta cells work harder to secrete more insulin so it can get in
    • Beta cell dysfunction first or skeletal muscle first?
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3
Q

Pathology of Obesity-Related T2D

describe Hyperinsulinemia, Hyperglucagonemia

A
  • beta cells work harder to secrete more insulin
  • alpha cells also secrete more glucagon to increase glucose in blood
  • leads to alpha and beta cell dysfunction
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4
Q

Pathology of Obesity-Related T2D

describe Increased Hepatic Glucose Production & Triacylglycerol Secretion

A
  • glucagon acts on liver to make glucose through gluconeogenesis
  • elevated production contributing to high blood sugar levels
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5
Q

Pathology of Obesity-Related T2D

describe Increased appetite

A
  • Insulin is satiety factor - tells hypothalamus you are full
  • Impaired satiety
  • increase appetite contributing to obesity
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6
Q

Pathology of Obesity-Related T2D

describe Increased Adiposity & Inflammation

A
  • adipose builds
  • chronic low grade info that leads to release of cytokines that can cause insulin resistance
  • Lipid starts to build up, circulating lipids increased,
  • excess storage of fat that leads negative effect on insulin signaling and sensitivity
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7
Q

what is T2D initially characterized by?

what may happen as the disease progresses?

A

– Initially characterized by insulin resistance, hyperinsulinemia and hyperglycemia
➢Hyperglycemia also due to excessive hepatic glucose
production (hyperglucagonemia)
– As disease progresses, beta-cell dysfunction and/or
destruction may take place (due to stress)
➢Insulin therapy is beneficial at this stage
➢Insulin secretagogues may no longer be as effective

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8
Q

what are the targets for glucose-lowering in T2D? (2 general)

A
  • overcome insulin resistance

- insulin independent methods of glucose-lowering

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9
Q

what 2 ways can be used to overcome insulin resistance?

A

– Increase insulin secretion
➢Insulin secretatagogues*
➢Incretin-based therapies

– Increase insulin sensitivity
➢Thiazolidinediones*
➢Metformin?*

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10
Q

what 3 ways can be used to as insulin-independent methods of glucose-lowering?

A

– Decrease hepatic glucose production
➢Metformin*

– Increase glucose excretion
➢Sodium-glucose cotransporter-2 inhibitors

– Prevent dietary glucose absorption
➢α-glucosidase inhibitors*

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11
Q

Secretagogues - sulfonylureas

Types of sulfonylureas? what is their difference

A

1st Generation Sulfonylureas
– Tolbutamide, Chlorpropamide, Acetohexamide

  • 2nd Generation Sulfonylureas
  • Glyburide [or glibenclamide] (Diabeta®, generics)
  • Glipizide (Glucotrol®)
  • Glimepiride (Amaryl®) [some references suggest this is a 3rd gen]

– 2nd gen More potent, have a shorter half-life, fewer side effects
- needs less strength to exert the same effect

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12
Q

Secretagogues - sulfonylureas

MOA?
what is the normal pathway?
what about sulfonylureas?
receptors?

A
  • Agents bind to and inhibit KATP channels
  • May also reduce hepatic clearance of insulin

• GLUT 2 is the transporter for glucose in beta cell
(not insulin sensitive, always present)
• Metabolized leading to formation of ATP which closes KATP channels which prevents K+ efflux and induces depolarization
• K+ stays in the cell, Ca2+ flows in to induce response to tell insulin granules to release insulin

Sulfonylureases bypass the process:
• Sulfonylureas bind the sulfonylurea receptor/subunit of the KATP channel
• Inhibition of KATP channels prevents K+ efflux and induces depolarization
• Activates Ca2+ channels and subsequent Ca2+ influx, leading to exocytosis of insulin from insulin granules

Chronic use - beta cell dysfunction as there is only so much insulin

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13
Q

Secretagogues - sulfonylureas

AE? (4)

A

• Lower risk of drug-drug interactions with 2nd generation agents (more selective

  1. Can cause hypoglycemia
    – Glyburide, chlorpropamide, and glipizide are most
    likely for prolonged risk
    - Chlorpropamide: most, long duration of action and half life, it should be avoided in seniors
  2. Hyponatremia (chlorpropamide): secondary action on vasopressin
  3. Weight gain: insulin is anabolic hormone
  4. Cardiovascular complications?
    – Interference with ischemic preconditioning (Activation of KATP channels in the heart induces preconditioning)
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14
Q

Secretagogues - Non-sulfonylurea (meglitinide
analogues)

Name 2
what are they derived from?

A

– Derivatives of benzoic acid or
phenylalanine
• Repaglinide (GlucoNorm®)
• Nateglinide (Starlix®)

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15
Q

Secretagogues - Non-sulfonylurea (meglitinide
analogues)

MOA?

A

same as sulf

– Bind to a different site of the KATP channel
– More selective for the beta cell KATP channel than the cardiac KATP channel
– Rapid onset and short duration of action due to more
rapidly dissociating from the receptor (although still
have risk of hypoglycemia, severity and frequency of
hypoglycemia is lower)

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16
Q

α-Glucosidase Inhibitors

name 3
how potent compared to other diabetic drugs?
what are they?

A

– Acarbose
– Miglitol
– Voglibose

  • Least potent of diabetic drugs
  • Substrates for alpha-1,4- glucosidase which are enzymes that break down sugars into glucose (disaccharides)
17
Q

α-Glucosidase Inhibitors

MOA?

A

– Competitive inhibitor of intestinal αglucosidase, an enzyme responsible for breakdown of disaccharides (e.g. sucrose, maltose)
– Delays and decreases absorption of monosaccharides
– Reduces postprandial glucose rise

Extra:

  • Amylase breaks straches into maltose
  • enterocytes have microvilli where the a-glucosidase is present and hydrolyzes saccharide bond, release glucose into absorption
  • Acarbose nitrogen protects from hydrolyzing the bond, competitive inhibitor, delay abs of carbs into blood stream
18
Q

α-Glucosidase Inhibitors

AE?
when to take it?
what to do with hypoglycemic episode?

A

– Take with meal (first bite of food)
– Does not cause hypoglycemia (Not related to insulin)
– Significant GI complications (flatulence, carbs not digested so bacteria does it)
– Hypoglycemic episodes require glucose

Cannot use table sugar if hypoglycemic person on a-glucosidase inhibitors MUST take free glucose

19
Q

Thiazolidinediones

Name 3
what are they?

A

Rosiglitazone (Avandia®), Pioglitazone (Actos®) & Troglitazone (Rezulin®) (original)

Agonists of peroxisome-proliferator-activated receptor
gamma (PPARγ, nuclear receptor highly expressed in
adipose tissue)

insulin sensitizers

20
Q

Thiazolidinediones

MOA
how long does it take?

increase insulin sensitivity

A

– Agonists of PPARγ
– Promote uptake & storage of fatty acids into adipose
tissue (prevents excess fat from being stored in other
organs)
– Improves muscle insulin sensitivity
– Takes 6-12 weeks to reach full effect

  • Increases differentiation of maturation of adipocytes which will store more fat and away from other organs
  • Excess fat in muscle and liver causing hepatic and insulin resistance
    • putting fat where it should be
  • Takes 2-3 months to work
  • Lipid is used as fuel source for energy
  • Type 2 diab - Elevated lipid is always delivered to muscle, has more fat stored in organ
  • Lower circulating lipid levels, decreased delivery to muscle, when it use the excess fat stored, it dissipates over time and doesn’t get replenished
  • Insulin sensitivity is restored and can cause glucose to enter muscle, decrease gluconeogenesis
21
Q

Thiazolidinediones

AE (3)

A

– Fluid retention (can aggravate pre-existing heart failure)
– Cardiovascular (… and now cancer) complications limiting use of rosiglitazone and pioglitazone
- rosi disproved for cardio
– Weight gain - fat into adipocytes

CV death is number 1 death cause for T2D ppl, so drugs must undergo CV outcome studies

22
Q

Metformin (Glucophage®, Generics)

drug class?
what line of therapy?

A
  • Drug Class: biguanides

* First line therapy for type 2 diabetes

23
Q

Metformin (Glucophage®, Generics)

MOA?

A

– Exact mechanism remains unknown
– Most common beliefs…
• MOA related to adenosine 5’monophosphateactivated protein kinase (AMPK), a major cellular regulator of energy metabolism
• Inhibits glucagon signaling in the liver
• *Decreases glucose production in the liver (hepatic
gluconeogenesis) - MOST LIKELY
• Promotes glucose uptake by skeletal muscle?

24
Q

Metformin (Glucophage®, Generics)

describe pathway of AMPK

A

AMPK inhibits acetyl CoA carboxylase (ACC) to reduce hepatic lipid content

  • AMPK inhibits ACC
  • ACC synthesizes malonyl CoA which inhibits fat oxidation
  • Low ACC - increases fat oxidation in liver, lowers hepatic lipid accumulation
  • inhibit glucagon signaling prevents activating hepatic gluconeogenesis
  • Decreased hepatic glucose production and subsequent blood glucose levels
25
Q

Metformin (Glucophage®, Generics)

AE?

A

– Does not cause hypoglycemia, insulin sparing
– Weight neutral or no weight gain
- Weight loss GDF 15 increase secretion (grwoth diff factor)
– GI symptoms most common side effect
– *Lactic acidosis? (more for phenformin), build up of lactate due to it being renal excreted so ppl with renal failure should not use it
– Vitamin B12 absorption??? (take calcium supplements)

26
Q

what drugs bind and inhibit KATP channels?

A

Insulin secretagogues

sulfonylureas
and meglitinide analogues

27
Q

what drugs prevent breakdown of disaccharides to

monosaccharides (e.g. glucose)

A

α-glucosidase inhibitors prevent postprandial

rises in blood glucose levels

28
Q

what drugs are PPARy agonists?

A

Thiazolidinediones
increase fat storage in adipose tissue and reduce fat
storage in muscle and liver, thereby improving
insulin sensitivity

29
Q

what drugs reduce hepatic glucose production

A

Metformin is the first-line therapy for type 2

diabetes

233 2nd midterm (13 decks)

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