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2016 Endocrine > Test 2 Diabetes Pathophysiology part 2 > Flashcards

Test 2 Diabetes Pathophysiology part 2 Flashcards

1
Q

Q: which is NOT released by the beta-cells of the pancreas?

a. C-peptide
b. Insulin
c. Glucagon
d. Amylin

A

c. Glucagon

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2
Q

Q: Someone who has good blood glucose control over years is less likely to develop:

a. Retinopathy
b. Peripheral vascular disease
c. Cerebrovascular disease

A

a. Retinopathy-microvascular (has to do with control of glucose)

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3
Q

Q: What hormone is responsible for increasing blood glucose through promotion of glycogenolysis and gluconeogenesis

a. Insulin
b. GLP-1
c. Amylin
d. Glucagon

A

d. Glucagon

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4
Q

Non-Pharmacologic Diabetes Treatments

A
  • Non-pharmacological treatments (always recommend)
    • Diet—Decrease glucose/insulin spikes
      • Well balanced – keep glucose from spiking too much
      • Not a lot of processed simple sugars
    • Physical activity—Increase glucose utilization and uptake by GLUT4
      • Profound effect – significantly increases the level of GLUT4 that is available on cells(transporters that help pull glucose in from circulation)
    • Weight Loss – may help to control Type 2 DM
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5
Q

Pharmacological Diabetes Treatment

A
  • Insulin
  • Sulfonylureas
  • Meglitinides
  • Biguanides
  • Thiazolidinediones
  • a-Glucosidase inhibitors
  • Incretin mimetics
  • Amylin analog
  • SGLT2 inhibitor
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6
Q

Normal vs Diabetic Patients

A
  • Normal:
  • You eat food, gut absorption of carbohydrates causes postprandial hyperglycemia.
    • Gut releases GLP1 and GIP to pancreas (incretin effect)
      • helps increase insulin and decreases glucagon
      • causes hepatic cells decrease glucose production
      • peripheral muscle increases glucose uptake
      • adipose tissue increase fat production
  • Diabetes:
  • You eat food, gut absorption of carbohydrates causes postprandial hyperglycemia.
    • Gut releases about 50% less GLP1 and GIP to pancreas which decreases the incretin effect
      • less the help to pancreas to release insulin impairing insulin release
      • since insulin release is impaired the glucagon is not as strongly inhibited
      • hepatic cells don’t as strongly decrease glucose production
      • peripheral muscle have less glucose uptake
      • adipose tissue lipolyse fat increasing glucose
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7
Q

Insulin Mechanism

A
  • Insulin
    • Required for Type 1 DM
    • Also can be given for Type 2 DM (especially later after they’ve had DM for a while)
  • Goal of therapy
    • Mimic normal insulin secretion
      • Basal (mimics the low pulses→supresses gluconeogenesis)
        • Give long-acting to mimic basal
      • Prandial/Bolus (mimics insulin after meals-acute response)
        • Give short acting to mimic bolus
  • Source—recombinant DNA
    • human insulin→low allergenicity
    • not proinsulin like natural so does NOT increase C-peptide
  • Strength—usually 100 units/ml (U-100)
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8
Q

Insulin Preparations differ on:

A
  • Onset (how quickly will insulin peak and drop glucose)
  • Duration of action (how long will it be active?)
  • Absorption (different absorption rates from injection site vary their onset and DOA)
  • Route (SC, IV, intranasal)
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9
Q

Insulin by duration/onset

A
  • Rapid acting (short onset, short duration)
    • Glulisine
    • Lispro
    • Aspart
  • Short acting (a bit longer onset and duration)
    • Regular
  • Intermediate acting (a bit more time til onset, intermediate duration)
    • NPH
  • Long/Ultra-long acting:
    • Detemir
    • Glargine
    • Degludec
      • Ryzodeg (70% degludec + 30% aspart)
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10
Q

Inhaled insulin

A
  • Afrezza—rapid acting insulin (bolus), inhalation use
    • Cough, dry mouth, hypoglycemia possible
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11
Q

“Artificial pancreas”

A
  • Medtronic MiniMed670G
    • approved September 28, 2016!!! Available in Spring 2017
  • Closed loop pump system
    • sensors and pumps working together
    • has sensors that checks blood glucose every 5 min and adjusts insulin delivery.
    • It delivers insulin when needed→high glucose and doesn’t if not no need→low glucose
  • Delivers basal insulin only, user must program bolus (prandial) doses based on the carb intake of meal
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12
Q

Insulin Adverse Effects

A
  • Insulin Adverse Effects
    • Hypoglycemia
      • confusion, may lose their balance and fall – common in elderly
      • due too taking too much insulin or not eating when expected
      • Action is independent of glucose in the blood
    • Weight gain
      • insulin promotes lipogenesis (fat production) and pulls excess blood glucose into the cells→stored as glycogen and fatty acids)
    • Insulin allergy (much less common now-animal is no longer used)
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13
Q

Sulfonylureas MOA

A
  • Sulfonylureas
    • MOA—increase insulin release from beta-cells in pancreas by closing KATP channels through the sulfonylurea receptor; insulin secretagogues
      • Sulfonylureas block ATP-dependent K+ channel →results in insulin release
      • Also decreases serum glucagon (an indirect effect mediated via insulin – do not directly affect alpha-cells)
  • Insulin secretion is independent of glucose
    • will cause insulin secretion regardless of glucose levels
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14
Q

Sulfonylureas Adverse Effects

A
  • Insulin secretion is independent of glucose
    • Risk of hypoglycemia—action is independent of glucose levels
      • Similar effect to insulin injections
  • Weight gain
    • 1-3 kg (2 – 7 lb – affects the patient’s ability to monitor and regulate their blood sugar)
  • CV mortality increase? (glyburide especially, not very common in others)
    • Sulfonylurea receptor present in some amount in cardiac myocytes and vascular smooth muscle – blocking activity at theses sites increases the patient’s risk of CV mortality
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15
Q

Sulfonylurea classes

A
  • First generation—Less potent, more SE – NOT RESPONSIBLE FOR THESE
    • Tolbutamide
    • Chlorpropamide
    • Tolazamide
  • Second generation—safer and more commonly used today
    • Glyburide
      • Most problematic 2nd gen
      • Non-hypoglycemic metabolites
        • though some metabolites have a mild hypoglycemic effect (although low potency)
      • Flushing possible with alcohol use
    • Glipizide – has a slightly shorter half-life
    • Glimepiride
  • Glipizide and glimepiride have less complications than glyburide
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16
Q

Non-Sulfonylureas MOA

A
  • Repaglinide
  • Nateglinide
    • (aka: Meglitinides or Glinides)
      • Block ATP-sensitive potassium channels in beta cells to increase insulin release
      • Also insulin secretagogues, although slightly different binding site from sulfonylureas (share 2 of 3 binding sites with sulfonylureas)
17
Q

Repaglinide

A
  • Repaglinide (non-sulfonylurea)
    • Hypoglycemia possible
      • if meal smaller than expected or if insufficient carbs
      • MOA is independent of blood glucose levels
    • Weight gain – insulin secretagogues
    • Glucuronidation required for metabolism
      • Glucuronidation inhibitors will increase half-life significantly (gemfibrozil).
        • Decrease repaglinide dose.
18
Q

Nateglinide

A
  • Nateglinide (non-sulfonylurea)
    • D-Phenylalanine derivative
    • Risk of hypoglycemia and weight gain
19
Q

Q: Would combining a meglitinide with a sulfonylurea improve therapy?

A

No.

Work on 2 out 3 of the same binding sites – work essentially through the same mechanism

20
Q

Biguanide MOA

A
  • Metformin
    • Only available Biguanide in the US – Phenformin has been discontinued in the US
  • MOA—not fully understood
    • Seems to increase insulin sensitivity (hepatic & muscle)
    • Increased sensitivity involves activation of AMP kinase (AMPK – part of 2nd messenger system) - SENSITIZER
    • Decreases hepatic glucose formation (especially gluconeogenesis in the liver; also glycogenolysis)
    • Stimulation of uptake of glucose and glycolysis in muscle (including increase GLUT4) – “exercise pill”
  • Mechanism is not dependent on functioning beta-cells – sensitizing insulin-resistant patient to the effects of insulin
  • Not 1st line in Type 1 DM
21
Q

Biguanide Side Effects

A
  • Metformin
    • Hypoglycemia is uncommon
      • “Euglycemic” agent – sensitizes the patient to insulin action, but does not cause hypoglycemia on its own
    • Seriously impaired kidney function can lead to accumulation of metformin – issues regarding lactic acid
  • Metformin Adverse Effects
    • GI (upset, diarrhea, anorexia) – especially when starting treatment
      • Lessen with time and if taken with food
    • No weight
      • No significant increase or loss in body weight is seen with use
22
Q

Thiazolidinediones MOA

A
  • Pioglitazone
  • Rosiglitazone
  • (aka: TZDs, Glitazones)
    • MOA—Agonists at PPAR-y (peroxisome proliferator activator receptor-y) – may also have activity at PPAR-a
      • Nuclear receptor (regulate gene transcription – increases and decreases)
      • PPAR-y receptors mostly found in adipose (fat) cells, but also in muscle cells
      • Increase differentiation of adipocytes (stem cells → adipocytes – increases fat cell production)
      • Encourages redistribution of fat from central (visceral) to peripheral (mostly done subcutaneous) – not adding visceral fat to diabetic patient
        • The more fat cells we have taking glucose out of circulation, the better off the patient will be
      • Increases secretion of adiponectin (don’t need to know)
  • Require insulin be present to work (they increase insulin mediated glucose uptake)
    • give the body more cells to take more glucose out of circulation
    • Can be your own or injected.
  • Raise HDL levels a bit, and conflicting effects on LDL and TG
    • PPAR-a non-specific effects
  • Full activity could take 1-3 months to be seen
    • influencing differentiation of cells - may take a while to see effects but may see weight gain before then.
23
Q

Thiazolidinediones Adverse Events

A
  • Pioglitazone
  • Rosiglitazone
    • Full activity could take 1-3 months to be seen – influencing differentiation of cells - may take a while to see effects but may see weight gain before then.
  • Weight gain (peripheral & subcutaneous, not visceral) – not increasing fat around the organs
  • Cardiovascular concerns
    • May cause or exacerbate CHF (plasma volume expansion), MI, stroke
    • Both have a black box regarding CHF
  • Increased bone fractures and decreased hematocrit
    • promoting differentiation of stem cells into fat cells (may have been bone cells or blood cells)
    • Shunting from osteogenesis and red blood cell production to adipocyte differentiation
24
Q

a-Glucosidase Inhibitors MOA

A
  • Acarbose
  • Miglitol
    • MOA—Inhibition of a-glucosidase (breaks complex carbs to simple carbs) in intestines
      • Delay digestion and absorption of starches and disaccharides because they can’t get absorbed as complex carbs
      • Result: carbohydrates that are not absorbed, but pass through GI
25
Q

a-Glucosidase adverse effects

A
  • Acarbose
  • Miglitol
  • No weight gain
  • No effect on plasma lipids
  • No hypoglycemia – may occur if combined with insulin/insulin secretagogue
    • Digestional (due to fermentation)—Flatulence, diarrhea, abdominal pain, bloating
      • May be severe enough to inhibit use
26
Q

Incretin Facilitators MOA

A
  • Incretin Facilitators – increase insulin secretion
    • GLP1 Receptor Agonists (injectables)
      • Giving a supra-physiological dose (well above what the body would have had – have more potent effect than DDP-4 inhibitor)
    • DPP-4 Inhibitors – degrades GLP1→ increases overall incretin effect (oral)
      • Stop degradation of Incretins→ stop degradation of what body has already made
      • Much more subtle effect than GLP1 agonist
27
Q

GLP-1 receptor agonists

A
  • GLP-1 receptor agonists:
    • Exenatide
    • Liraglutide
    • Albiglutide
    • Dulaglutide
    • Lixisenatide
  • MOA:
    • GLP-1 receptor activation increases cAMP levels, increasing insulin synthesis and release in a glucose-dependent manner
    • Agonists at GLP-1 receptor—increase insulin synthesis and release in a glucose-dependent manner
      • Glucose is low → less of an effect at causing hypoglycemia
    • Increase cAMP, increase insulin synthesis and release (that is mostly dependent on increased glucose levels)
    • Also slows gastric empty rate & decrease feeding (by increasing satiety – eat less and feel full)
28
Q

GLP-1 Receptor Agonist Side Effects:

A
  • Exenatide
  • Liraglutide
  • Albiglutide
  • Dulaglutide
  • Lixisenatide
    • Nausea & vomiting—dose dependent (due primarily to satiety)
      • Really more of “fullness”
      • Eat slowly and don’t overeat – until they know how their body will respond to the medication
    • Weight loss
      • Caused by less eating, not increased metabolic rate (same fullness w/o same calories)
    • Pancreatitis risk may be increased
      • can inflame pancreas (not fully understood) – alert MD of abdominal pain

Not much hypoglycemia risk

29
Q

DPP-4 inhibitors MOA

A
  • Alogliptin
  • Sitagliptin
  • Saxagliptin
  • Linagliptin
    • MOA:
      • Block degradation of GLP-1 and GIP by dipeptidyl peptidase 4 (DPP-4), thus increasing levels of GLP-1 and GIP
        • In pancreatic b-cells, GLP-1 receptor activation increases insulin synthesis and release in a glucose-dependent manner
    • Given orally
      • May or may not see weight loss (much less common)
30
Q

DPP-4 Inhibitors Side Effects

A
  • Alogliptin
  • Sitagliptin
  • Saxagliptin
  • Linagliptin
    • May or may not see weight loss (much less common)
    • No satiety or gastric emptying effects (much more subtle effect)
    • Only physiological levels of GLP-1 are reached
    • May cause increased risk of pancreatitis
31
Q

Amylin Analogs

A
  • Pramlintide
    • Injectable (s.c.)
    • Not good at decreasing glucose levels-not drug expected in production
  • Amylin is made by b-cells in pancreas
    • Slows gastric emptying
    • Decreases appetite (not enough to cause significant weight loss)
    • Decreases glucagon release
32
Q

Amylin Analog Side Effects

A
  • Pramlintide
    • Weight loss – due to increased satiety and slowed gastric emptying (not as much as w/ GLP1 agonist)
    • Nausea, vomiting may occur – eat slowly and don’t overeat
33
Q

Sodium-glucose cotransporter 2 (SGLT2) inhibitor MOA

A
  • Canagliflozin
  • Dapagliflozin
  • Empaglifozin
  • MOA: Inhibition of sodium-glucose cotransporter 2 in proximal renal tubule
    • Bottom line: Less glucose reabsorption from urine (which means more glucose in urine) – calories are also gone
    • Insulin independent mechanism
    • Indicated for T2DM ONLY (may be useful in T1DM however watch for ketoacidosis )
34
Q

Sodium-glucose cotransporter 2 (SGLT2) inhibitor side effects

A
  • Canagliflozin
  • Dapagliflozin
  • Empaglifozin
    • Low to no risk of hypoglycemia – taking excess glucose that is filtered and letting the body get rid of it
    • Some weight loss may be experienced
    • Glucose in urine = greater risk of infections
      • Urinary tract infections in men and women
      • Yeast infections in women
    • Rare risk Euglycemic ketoacidosis
      • MOA is not fully understood
      • seen in T1DM who should not be taking it
      • T2DM seen with infection or some other predisposing factors
      • Less glucose→Less insulin→ less inhibition of gluconeogenesis →more gluconeogenesis → more ketone bodies→less inhibition of glucagon →ketoacidosis with no C-peptide.
        • Treatment: Not affecting blood glucose (don’t rehydrate, give insulin to stop ketone production)
        • Very rare, but if they get an infection, they should monitor ketone bodies in their urine
35
Q

Q: Which is NOT an insulin secretagogue? Select all

Sulfonylurea

A-glucosidase inhibitor

GLP-1 receptor agonist

Biguanides

A

A-glucosidase inhibitor

and

Biguanides

2016 Endocrine (19 decks)

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