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Therapeutics 2 > Diabetes > Flashcards

Diabetes Flashcards

1
Q

What are the cardinal signs or “polys” for diabetes? (specifically, type I)

A
  • polydipsia (excessive thirst)
  • polyuria (excessive urination)
  • polyphagia (constant hunger/big appetite)
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2
Q

What are the diagnostic criteria for diabetes? A1C, FBG, OGTT, random plasma glucose

A

A1C >6.5
Fasting blood glucose > 126 mg/dL
2hr OGGT >200 mg/dL
random glucose >200 mg/L

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3
Q

What are characteristics of type I diabetes mellitus?

A
  • complete glucose intolerance
  • no functioning insulin-secreting pancreatic beta cells
  • dependent on exogenous insulin; tendency toward ketoacidosis
  • early age of onset (autoimmune)
  • family history often negative
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4
Q

What are common autoantibodies found in type I diabetics?

A

ICA- islet cell cytoplasmic autoantibodies
IAA- insulin autoantibodies

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5
Q

What does presence of c-peptide indicate in a diabetic?

A

Indicates that some beta cell mass is left; beta cells are still secreting insulin.

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6
Q

At what point does a type I diabetic begin to have abnormal FBG?

A

When >70% of beta cell mass is lost

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7
Q

What autoantigens are most associated with type I diabetes?

A

Islet antigen 2 (IA-2), phogrin (IA-2B), zinc transporter, glutamic acid decarboxylase, voltage gated Ca2+, vesicle-associated membrane protein2 (VAMP- 2)

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8
Q

What are characteristics of non-obese diabetes mellitus?

A
  • very small percent (10%)
  • onset around 25; maturity onset diabetes of the young
  • yes family history
  • low insulin secretion (insufficient for glycemic control)
  • includes mutations in specific proteins
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9
Q

What are characteristics of obese diabetes mellitus?

A
  • largest % of population (80%)
  • onset usually over 35yo
  • yes family history
  • insulin secretion low for body mass
  • insulin resistance in tissues + decreased BCM
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10
Q

What are consequences of lack of insulin?

A
  • hyperglycemia (decreased glucose uptake in cells, decreased glycogen synthesis, increased conversion of amino acids to glucose–ketoacidosis)
  • glucosuria (glucose in the urine)
  • hyperlipidemia (fatty acid mobilization from fat cells; ketoacidosis)
  • uninhibited glucagon (increased glucagon levels even with increased blood glucose levels)
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11
Q

What are complications of diabetes?

A
  • cardiovascular micro and macro angiopathies
  • Neuropathy
  • cataracts
  • nephropathy
  • susceptibility to infections
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12
Q

Goals of insulin therapy

A
  • reduce symptoms of diabetes
  • keep average blood glucose levels below 150mg/dL
  • prevent/delay onset of complications
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13
Q

What causes diabetic ketoacidosis?

A

uncontrolled oxidation of fatty acids (accumulation of ketone bodies) (byproduct organic acid)

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14
Q

What functional group in glucose makes it reactive?

A

aldehyde

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15
Q

What products can glucose be oxidized into?

A

reactive dicarbonyls
- glyoxal
- methylglyoxal

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16
Q

What is AGE/RAGE

A
  • AGE: advanced glycation end products
  • formed by oxidation products of glucose and proteins that bind irreversibly
  • results in loss of protein function
  • RAGE: receptor for advanced glycation end products
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17
Q

Where is RAGE located?

A
  • leukocytes and endothelial cells
  • cell surface proteins
  • peptides containing CML and CEL (lysine + glucose products) bind to RAGE and promote inflammation
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18
Q

What happens when rage is bound?

A

inflammation

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19
Q

What is aldose reductase pathway (polyol pathway)/ where is it located?

A
  • occurs in nerves; consumes large amounts of NADPH and causes oxidative damage of neurons
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20
Q

What pathway is aldose reductase in?

A

polyol pathway

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21
Q

What is a result of polyol pathway?

A

neuropathy

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22
Q

what/where is hexosamine pathway?

A

F6P accumulates; causes changes in protein function

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23
Q

What is rate-limiting step of glucose utilization?

A

fructose-6-phosphate –> G3P

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24
Q

What happens in the protein kinase C pathway?

A

Buildup of G3P activates protein kinase C inappropriately; protein modification

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25
Q

What is the AGE pathway?

A

buildup of G3P (due to oxidative stress), oxidized glucose (methylglyoxal) reacts with proteins to form AGE; causes loss in protein function and chronic inflammation

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26
Q

What is the effect of methylglyoxal on cardiovascular tone?

A
  • ACh and Nitric Oxide unable to relax smooth muscle
  • local control of cardiovascular tone lost
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27
Q

What kind of receptor is the insulin receptor?

A
  • receptor tyrosine kinase
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28
Q

What is the role of a-subunits in the insulin receptor?

A
  • represses the catalytic activity of the beta subunit
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29
Q

How does insulin binding activate the insulin receptor?

A
  • relieves the repression of beta subunit catalytic activity by binding
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30
Q

What is the role of beta subunits in the insulin receptor?

A
  • contain tyrosine kinase catalytic domains
  • autophosphorylate
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31
Q

Phosphorylation of what causes a rise in lipogenesis when insulin binds to the insulin receptor?

A

MAPK

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32
Q

What causes an increase in glycolysis when insulin binds to the insulin receptor?

A

PI3K

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33
Q

What is the effect of insulin binding ?

A
  • increased lipogenesis
  • increased glycolysis
  • increased glycogen synthesis
  • increased gluconeogenesis
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34
Q

What is the impact of insulin on the liver?

A
  • inhibits glycogenolysis
  • inhibits ketogenesis
  • inhibits gluconeogenesis
  • stimulates glycogen synthesis
  • stimulates triglyceride synthesis
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35
Q

What is the impact of insulin on the skeletal muscle?

A
  • stimulates glucose transport and amino acid transport
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36
Q

What is the impact of insulin on the adipose tissue?

A
  • stimulates triglyceride storage
  • stimulates glucose transport
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37
Q

Where does glucose get disposed/ used in the fasting state?

A
  • 75% non-insulin dependent: Liver, GI, Brain
  • 25% insulin dependent: skeletal muscle
  • glucagon is secreted
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38
Q

Where does glucose get disposed/used in the fed state?

A
  • 80-85% is insulin depended in skeletal muscle (glut-4 transporters)
  • 4-5% is insulin dependent in adipose tissue
  • glucagon secretion is inhibited
  • insulin inhibits release of FFA from adipose tissue
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39
Q

How do serum FFA levels impact insulin action/sensitivity?

A
  • decreased serum FFA enhances insulin action and reduces hepatic glucose production
  • increased FFA levels may decrease insulin sensitivity
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40
Q

Which glucose transporter stimulates secretion of insulin?

A

GLUT2 (located in beta cells; tells beta cells when to secrete insulin)
gets last dibs per km

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41
Q

What does glut3 do?

A
  • located in nervous system; transports glucose to neurons
  • gets first dibs per km
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42
Q

Which glucose transporter is insulin induced?

A

GLUT4!
located on skeletal muscle and adipocytes

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43
Q

What do pancreatic alpha cells produce?

A

glucagon

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44
Q

What do pancreatic beta cells produce?

A

insulin, amylin

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45
Q

what do pancreatic delta cells produce?

A

somatostatin

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46
Q

Effect of glucagon?

A

stimulates glycogen breakdown; increases blood glucose

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47
Q

Effect of somatostatin?

A

General inhibitor of insulin/glucagon secretion

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48
Q

Effect of insulin?

A

Stimulates uptake and utilization of glucose

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49
Q

effect of amylin?

A

co-secreted with insulin to slow gastric emptying, decrease food intake, and inhibit glucagon secretion; also reduced blood glucose

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50
Q

How is insulin processed?

A

Cleaved to A&B chains and c-peptide by proconvertases; causes oxidative stress if too much insulin is produced; b-cell death

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51
Q

What Regular human insulins are available?

A

humulin
novolin

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52
Q

What are the ultra rapid-onset, very short acting insulins?

A
  • Lispro (Humalog)
  • Aspart (Novolog)
  • Glulisine (Apidra)
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53
Q

What are the rapid onset/ medium- to short acting insulins?

A

Regular (R) human insulin
- Humulin, Novolin

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54
Q

What are the intermediate acting insulins?

A

NPH (N)

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55
Q

What are the slow-onset, long acting insulins?

A
  • glargine (Lantus)
  • detemir (Levemir)
  • degludec (Tresiba)
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56
Q

How did the lente insulins work?

A

zinc/insulin precipitates; larger complex size of insulin and zinc = more prolonged absorption

57
Q

How does NPH insulin work?

A

Complex of protamine and insulin;
protamine binds insulin ionically; slow absorption, long duration of action.

58
Q

How does lispro (humalog) work?

A
  • reverse positions of amino acids on insulin B chain; prevents formation of dimer and hexamer.
  • monomeric insulin absorbed rapidly
  • onset in 5-15 minutes
59
Q

How does insulin aspart (novolog) work?

A
  • amino acids changed to prevent dimer
  • reverse positions of amino acids on insulin B chain; prevents formation of dimer and hexamer.
  • monomeric insulin absorbed rapidly
  • onset in 5-15 minutes
60
Q

How does glulisine (Apidra) work?

A
  • amino acids changed to prevent dimer
  • reverse positions of amino acids on insulin B chain; prevents formation of dimer and hexamer.
  • monomeric insulin absorbed rapidly
  • onset in 5-15 minutes
61
Q

How was insulin glargine (lantus) work?

A
  • solubility altered at physiologic pH
  • clear, buffered solution at pH = 4
  • precipitates when neutralized at pH = 7
  • once daily injection
62
Q

How does insulin detemir work? (levemir)

A
  • binds extensively to serum albumin; added fatty acid chain that binds
  • slowly released from albumin binding sites over time
  • once or twice daily injection
63
Q

How does insulin degludec work?

A
  • binds serum albumin; added fatty acid chain
  • same as levemir + intermediate glutamate linker
  • injected once daily
64
Q

What are common insulin pre-mixtures?

A
  • NPH + Regular (humulin 70/30)
  • NPL (neutral protamine Lispro + Lispro)
    Humalog 75/25 or Humalog 50/50
65
Q

What is Afrezza?

A

Regular human insulin in a dry powder

66
Q

What are the characteristics of Afrezza?

A

Rapid onset; short duration of action

67
Q

What are contraindications for Afrezza?

A

Asthma and COPD; may decrease FEV

68
Q

Which insulins are injected subQ?

A

All of them

69
Q

Which insulins can be used with an infusion pump?

A

Buffered Regular; Also fast acting: lispro, aspart, glulisine

70
Q

Which insulins can be used IV?

A

Regular only (for hyerglycemia or ketoacidosis or hyperkalemia)

71
Q

Mode of action for insulin?

A
  • decreased liver glucose output
  • increased fat storage
  • increased glucose uptake
72
Q

What is hypoglycemia?

A
  • blood glucose less than 60 mg/dL
  • too much insulin
73
Q

Signs of hypoglycemia?

A

tremors, weakness, fatigue, sweating, hunger, irritability, tachycardia, blurred vision, seizures, coma
- treat with glucose or glucagon

74
Q

side effects of insulin?

A

lipodystrophy- changes in subcutaneous fat at any overused injection site. can include lipohypertrophy or lipoatrophy

75
Q

What causes lipoatrophy?

A

antibodies against insulin

76
Q

Agents that increase blood glucose

A

catacholamines, thyroid hormone, isonazid, glucocorticoid, calcitonin, phenothiazines, oral contraceptives, somatropin, morphine

77
Q

agents that increase risk of hypoglycemia

A

ethanol, ACE inhibitors, fluoxetine, somatostatin, anabolic steroids, MAO inhibitors, B-blockers, vigorous exercise

78
Q

What is treatment for type I diabetes?

A

insulin + diet + exercise

79
Q

What is treatment for type II diabetes?

A

tiered:
I) diet and exercise
II) diet and exercise and antidiabetic drugs
III) diet and exercise and antidiabetic drugs and insulin

80
Q

What are 2 components of pathophysiology of type II diabetes?

A

insulin resistance in target tissues; reduced insulin secretion

81
Q

Which drugs increase insulin secretion?

A
  • sulfonylureas
  • meglitinides
  • incretins
82
Q

Which drugs limit hepatic glucose output?

A
  • metformin
  • thiazolidinediones
83
Q

Which drugs inhibit glucagon secretion?

A
  • incretins
    -amylin
84
Q

Which drugs limit glucose reabsorption?

A
  • SGLT-2 Inhibitors
85
Q

Which drugs increase glucose uptake and utilization?

A
  • thiazolidinediones
  • metformin
86
Q

What are the sulfonylureas?

A

tolbutamide, tolazamide, chlorpropamide, glyburide, glipizide, glimepiride

87
Q

What are the meglitinides?

A

nateglinide, repaglinide

88
Q

How do sulfonylureas work?

A
  • increased release of insulin
  • increased beta cell sensitivity to glucose and increase glucose-stimulated insulin release
89
Q

are sulfonylureas glucose dependent?

A

no

90
Q

What molecule do sulfonylureas act as in the pancreatic beta cell?

A

ATP

91
Q

What are the 1st gen sulfonylureas?

A

tolbutamide, tolazamide, Chlorpropamide

92
Q

What are the 2nd gen sulfonylureas?

A

glipizide, glyburide, glimepiride

93
Q

Meglitinide MOA?

A
  • acts like sulfonylurea BUT short duration of action and quick onset; taken preprandially
  • non-sulfonylurea hypoglycemic agent
94
Q

Meglitinide MOA?

A

Katp Channel blocker

95
Q

Sulfonylurea MOA?

A

Katp Channel blocker

96
Q

What are adverse effects of sulfonylureas?

A
  • prolonged hypoglycemia due to long half life
  • risk of cardiovascular events/ mortality
  • GI problems
  • Weight gain
  • may lead to decrease in BCM
97
Q

What are drugs that interact with sulfonylureas?

A
  • salicylates
  • phenylbutazone
  • sulfonamides
    reduce metabolism/displace from plasma proteins = increase in free concentration
  • alcohol
98
Q

What drugs cause hyperglycemia/oppose the action of insulin and sulfonylureas?

A
  • oral contraceptives
  • corticosteroids
  • epinephrine
  • thyroid hormone
  • thiazide diuretics
99
Q

What are the GLP-1R agonists?

A

Exenatide, Liraglutide, Lixenatide, Dulaglutide, Semaglutide

100
Q

What is the GLP-1 and GIP dual agonist?

A

Tirzepatide (mounjaro)

101
Q

What are the DPP-IV inhibitors?

A

Saxagliptan, sitagliptan, linagliptan, alogliptan

102
Q

What is an amylin analogue?

A

pramlintide

103
Q

What does GLP-1 stand for?

A

glucagon-like peptide 1

104
Q

What does DPP-IV do?

A

It is a protease that degrades GIP and GLP-1

105
Q

What are incretins?

A

hormones released by the small intestine

106
Q

What does GLP-1 do?

A

GLP-1 is secreted from cells in the intestine; stimulates insulin secretion through cAMP pathway, suppresses glucagon secretion, slows gastric emptying, reduces food intake, increases b-cell mass and maintains b-cell function, improves insulin sensitivity.

107
Q

is GLP-1 glucose dependent?

A

Yes! Insulin secretion by stimulation by GLP-1 is glucose dependent

108
Q

What does the GLP-1 receptor do?

A

Signals to increase cAMP and Ca2+ (amplified insulin secretion)

109
Q

What is liraglutide (victoza)?

A

GLP-1 analogue; can be co-administered with metformin and TzDs
injected daily; is a small peptide

110
Q

What is dulaglutide? (trulicity)

A

GLP-1 agonist;
injected weekly; binds to antibody with disulfide bond

111
Q

When are GLP-1s contraindicated?

A

Risk or family history of thyroid cancer; monitor calcitonin

112
Q

What is semaglutide? (ozempic/wegovy)

A

GLP-1 agonist with long fatty acid tail; binds to serum albumin; injected once weekly.

113
Q

What is Rybelsus?

A

Oral semaglutide; GLP-1 agonist; dosed daily due to poor absorption

114
Q

What are Soliqua/Xulotophy?

A

basal insulin/GLP-1 receptor agonist combos

115
Q

What is mounjaro?

A

Both a full GIP receptor agonist & GLP-1 receptor agonist; preferential binding to cAMP; reduces internalization of GLP-1 receptor to prevent desensitization.
Weekly subQ injection

116
Q

What do DPP-4 inhibitors do?

A

Inhibit incretin (GLP-1) proteolysis; enhance actions of endogenous GLP-1; competitive inhibitor for proteolysis; technically positive allosteric modulators of GLP-1

117
Q

What are the DPP-4 inhibitors?

A

Sitagliptan (januvia), Linagliptan (Trajenta)

118
Q

DPP-4 inhibitor administration?

A

Oral; once daily; low risk for hypoglycemia; weight neutral
- can be co-administered with metformin and TzDs

119
Q

Where is januvia excreted?

A

Kidney

120
Q

Where is Tradjenta excreted?

A

Liver

121
Q

Where is onglyza metabolized/excreted?

A

Kidney; active major metabolite

122
Q

DPP-IV inhibitor side effects

A

Nausea, vomiting, constipation, HA, Skin rxn, pancreatitis, joint pain, HF exacerbation; risk for increased infections and cancer???

123
Q

What is pramlinitide? (symlin)

A

Amylin analogue; slows gastric emptying, decreases food intake, inhibits glucagon secretion; used in conjunction with insulin; blunts postprandial rise in BG

124
Q

What are the a-glucosidase inhibitors?

A

acarbose, miglitol– look like sugars

125
Q

What are the SGLT-2 ingibitors?

A

Canagliflozin, empagliflozin, dapagliflozin, ertugliflozin

126
Q

MOA for a-glucosidase inhibitors?

A

decrease absorption of carbohydrate from the intestine: inhibits sucrase, maltase, gluocoamylase = less glucose in blood stream after meal

127
Q

Adverse effects of a-glucosidase inhibitors?

A

diarrhea, nausea, flatulence; risk of liver damage from acarbose

128
Q

SGLT-2 inhibitor MOA/Strategy

A

Reduce blood glucose levels by preventing reabsorption of glucose (and sodium) into blood through the SGLT-2 transporter

129
Q

SGLT-2 inhibitor in therapy

A

indicated TIDM with diet and exercise; can be used with metformin and sulfonylureas

130
Q

SGLT-2 side effects and risks

A
  • genital/UTI infections risk
  • hypotension
  • increased risk of DKA
  • contraindicated in patients with renal impairment
  • lower limb amputation with invokana
131
Q

What are the drug classes that reduce insulin resistance?

A
  • biguanides (metformin)
  • Thiazolidinediones (pioglitazone)
132
Q

What causes insulin resistance?

A

obesity and inactivity

133
Q

How does increasing free fatty acids impact insulin?

A

causes insulin resistance in the cells and tissues

134
Q

activation of what by excess fatty acids causes insulin resistance?

A

MTOR

135
Q

What is the MOA for Metformin? (a biguanide)

A

activator of AMP-activated kinase (AMPK) helps with cell signaling and insulin sensitivity; skeletal muscle in liver

136
Q

What is the MOA for thiazolidinediones?

A

Works primarily in adipocytes; enhance FFA uptake; reduces serum FFA

137
Q

THIAZOLIDINEDIONES contraindications

A

bad liver function (may cause hepatotoxicity); Heart failure;
DO NOT USE IN GESTATIONAL DIABETES

138
Q
A

Therapeutics 2 (9 decks)

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