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Pharmacology Exam 1 > Insulin & Diabetes > Flashcards

Insulin & Diabetes Flashcards

1
Q

definition of Type 1 Diabetes

A

Insulin-Dependent Diabetes Mellitus (IDDM)

glucose intolerance characterized by no functioning insulin-secreting pancreatic beta cells, dependency on exogenous insulin and a tendency towards ketoacidosis

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2
Q

incidence and onset of type 1 diabetes

A

incidence = 10% of diabetic population

early age of onset (mean =12) but may see in adults (e.g. age 35)

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3
Q

causes for Type 1 DM?

A

thought to be caused by antibodies that destroy pancreatic beta cells
antibodies may be triggered by viruses, chemicals, etc. in genetically predisposed individuals

famiy hx often negative

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4
Q

what are some autoantigens associated with type 1 diabetes

A 
insulin
islet antigen 2 (IA-2)
phogrin (IA-2beta)
zinc transporter (ZnT-8)
glutamic acid ecarboxylase (GAD65)
voltage-gated Ca2+ (Ca 1.3)
vesicle-associated membrane protein-2 (VAMP-2)

IA-2: 57% sensitivity, 99% selectivity in Type 1 diabetes

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5
Q

what would increase risk for developing Type 1 Diabetes

A

antibodies against one or more beta-cell proteins -> increased risk for Type 1 Diabetes

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6
Q

type II diabetes incidence in obese

A

80%

10% in non-obese

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7
Q

age of onset of type 2 diabetes in non-obese/obese

A

non-obese: often under age 25, Maturity Onset Diabetes of the Young (MODY)

obese: usually over 35 (AODM)

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8
Q

NIDDM family history in non-obese/obese

A

yes/yes

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9
Q

insulin secretion in response to glucose challenge in obese/non-obese

A

obese: low if corrected for obesity

non-obese: low

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10
Q

severity of NIDDM in obese/non-obese

A

non-obese: usually mild; ketosis - resistant

obese: usually mild; ketosis-resistant

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11
Q

causes for hyperglycemia

A

decreased glucose uptake in cells where glucose uptake is insulin-dependent

decreased glycogen synthesis

increased conversion of amino acids to glucose

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12
Q

causes of glucosuria (don’t overthink this)

A

due to high blood glucose

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13
Q

causes for hyperlipidemia

A

increased fatty acid mobilization from fat cells

increased fatty acid oxidation - ketoacidosis

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14
Q

role of glucagon

A

increased glucagon levels in the presence of increased blood glucose levels (????what????? - i don’t understand this)

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15
Q

complications of diabetes

A
  1. cardiovascular - micro/macro angiopathies
  2. neuropathy - increased use of polyol pathway (aldose reductase), -> increased cytosolic water in neural cells
  3. nephropathy - renal vascular changes & changes in glomerular basement membrane
  4. ocular - cataracts, retinal microaneurysms, hemorrhage
  5. increased susceptibility to infections
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16
Q

conventional therapy goals for diabetics

A

reduce acute symptoms -polyuria, dehydration, ketoacidosis

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17
Q

intensive insulin therapy goals

A

keep blood glucose levels below 150 mg/dL
prevent/delay onset of complications
**increased risk of hypoglycemia

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18
Q

ideal vs acceptable fasting glucose levels

A

70-90 vs 70-110

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19
Q

ideal vs acceptable pre-meal glucose levels

A

70-105 vs 70-130

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20
Q

ideal vs acceptable post-meal glucose levels

A
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21
Q

ideal vs acceptable glycosylated hemoglobin (HbA1c)

A

6% vs

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22
Q

what is HbA1c

A

covalent modification of protein by glucose

measurement of the Amadori product

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23
Q

why is the measurement of HbA1c significant

A

oxidation products of glucose react irreversibly with proteins to form Advanced Glycation End-products

loss of normal protein function
acceleration of aging process

theorized to account for long-term complications of diabetes

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24
Q

what is the polyol pathway?

A

polyol pathway

glucose -> aldose reductase -> sorbitol -> fructose

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25
Q

AGE pathway

A

Glyceraldehyde-3-P - > methylglyoxal -> AGE

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26
Q

complications related to the AGE pathway

A

AGE precursor methylglyoxal inhibits vasorelaxation

stimulated by ACh/NO

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27
Q

structure of the insulin receptor

A

two alpha subunits (bind to ligand, represses beta subunits unless bound to insulin)
two beta subunits (transmembrane, contain tyrosine kinase catalytic domains)

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28
Q

downstream activation of the insulin R

A

binds to insulin -> autophosphorylation of beta subunits ->

route a) Shc phosphorylation -> MAPK -> lipogenesis & cell growth/prolif/up DNA/RNA synth

route b) phosphorylation of P13K (lipogenesis) -> PKB, PDK1 -> both up glycolysis

PKB also recycles Glut4 R to cell membrane
PDK1 activates aPKC which also ups Glut4 R expressoin

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29
Q

insulin’s effect on the liver

A

inhibits: glycogenolysis, ketogenesis, gluconeogenesis
stimulates: glycogen synthesis, triglycerid synthesis

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30
Q

insulin’s effect on skeletal muscle

A

stimulates: glucose transport, amino acid transport

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31
Q

insulin’s effect on adipose tissue

A

stimulates: triglyceride storage, glucose transport

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32
Q

glucose disposal in fasting states

A

75% is non-insulin-dependent: liver, GI, brain
25% is insulindependent in skeletal muscle
glucagon is secreted to prevent hypoglycemia

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33
Q

glucose disposal when fed

A

80-85% is insulin-dependent in skeletal muscle
4-5% is insulin-dependent in adipose tissue
glucagon secretion is inhibited
insulin inhibits release of FFA from adipose tissue

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34
Q

consequences of decreased serum FFA

A

enhances insulin action on skeletal muscle

reduces hepatic glucose production

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35
Q

types of glucose transporters

A 
Glut 1 (widely expressed)
Glut 2 (beta cells, liver)
Glut 3 (neurons)
Glut 4 (skeletal muscle, adipocytes)
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36
Q

Km of the different Glut Rs

A

Glut 1 Km = 1-2mM
Glut 2 Km = 15-20mM
Glut 3 Km

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37
Q

activity level of the glut Rs

A

Glut 1-3 are constitutive

Glut 4 is insulin-induced

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38
Q

hormone producing cells in the islets of the pancreas

A

beta cells - insulin, amylin
alpha cells - glucagon
delta cells - somatostatin

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39
Q

function of the hormones produced by the islets of langerhans

A

glucagon - stimulates glycogen breakdown, increases blood glucose

somatostatin - general inhibitor of secretion

insulin - stimulates uptake & utilization of glucose

amylin - co-secreted with insulin, slows gastric emptying, decreases food intake, inhibits glucagon secretion

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40
Q

what cleaves the C peptide in secretory granules?

A

proconvertases

leaves A and B chains intact

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41
Q

ultra rapid onset/very short action recombinant insulins

A

lispro
aspart
glulisine

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42
Q

rapid onset/short action insulin

A

regular

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43
Q

intermediate onset/action

A

NPH

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44
Q

slow onset/long action

A

glargine
detemir
degludec

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45
Q

what is the purpose of mimicking natural insulin secretion patterns

A

to provide flexibility/convenience in dosing

basal levels vs preprandial dose

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46
Q

what is NPH insulin

A

Neutral Protamine Hagemdorn; or isophane
injected subQ

basically insulin bound to protamine, which is released upon encountering tissue proteases
slow absorption, long duration of action

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47
Q

lispro insulin characteristics

A
  1. reversal of P28 and K29 on insulin B chain-> decreased self association
  2. dissociates insulin dimer & hexamer formation seen in regular insulin
  3. onset is 5-15 minutes compared to regular (30-60)
  4. injected immediately before meals
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48
Q

aspart insulin characteristics

A

human, except P28 switched to Aspartate
onset 5-15 minutes, short duration
injected before meals

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49
Q

glulisine insulin characteristics

A

human, except Asn3 and Lys29 swapped to Lys & Glu
rapid onset: 5-15 min, short duration
injected immediately before meals

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50
Q

glargine characteristics

A

Asn 21 of alpha chain is changed to Glycine, 2 Arg added to beta chain
clear solution @pH 4.0, precipitates when neutralized (post-injection)

once daily injection, slow & steady release over 24 hrs, no peak

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51
Q

detemir characteristics

A

Thr30 on beta chain is deleted, Lys29 is myristylated (FA)
Binds serum albumin extensively
clear solution, injected twice daily

52
Q

degludec characteristics

A

similar to detemir
Thr30 of b-chain is replaced by gamma-Glu/C16 FA
binds serum albumin extensively
clear solution, injected twice daily

53
Q

common multi-dose insulin regimens

A

fast onset, short acting taken before meals

long, or intermediate acting taken at bedtime or at bed time and after breakfast

54
Q

routes of administration for insulin

A

subcutaneous - all preparation
insulin infusion pump - buffered regular (also rapidly acting - Lyspro, Aspart, Glulisine)
IV - Regular
inhalation - Afrezza

55
Q

characteristics of afrezza

A

inhaled insulin
regular human insulin in dry powder
rapid onset, shorter duration of action than subQ
used as pre-prandial

56
Q

when is afrezza contraindicated

A

contraindicated in patients with asthma and COPD

may reduce lung function (drops FEV)

57
Q

adverse reactions to insulin (aside from the general systemic manifestations)

A

hypoglycemia - blood glucose

58
Q

how are the adverse reactions of insulin treated

A

treated with glucose or glucagon

59
Q

agents which increase blood glucose

A

catecholamines, glucocorticoids, oral contraceptives,
thyroid hormone, calcitonin, somatropin,
isoniazid, phenothiazines, morphine

60
Q

agents which may increase the risk of insulin hypoglycemia

A

ethanol, ACE inhibitors, somatostatin
fluoxetine, anabolic steroids, MAO inhibitors
beta adrenergic blockers (mask manifestations of hypoglycemia)

61
Q

treatments for type 1 DM

A

insulin+diet+exercise

62
Q

treatments for type 2 DM

A

diet + exercise
diet+exercise+oral antidiabetic drugs +/- GLP-1 analogs (SQ)
diet+exerise+insulin

63
Q

requirement for sulfonylurea

A

must have functioning beta cells

64
Q

effects of sulfonylureas on beta cell insulin release

A

1) binds to sulfonylurea Rs
2) inactivates K+ channels
3) decreased cell polarization
4) activates voltage sensitive Ca2+ channels
5) increases Cai++ and activity of microfilaments
6) increased exocytosis of insulin containing granules

65
Q

in high glucose states, what is the condition of K+ channel and Ca2+ channel?

A

K+ channel is closed and bound to ATP

Ca2+ channel is open -> myosin filaments release insulin granules

66
Q

in low glucose states, what is the condition of K+ channel and Ca2+ channel?

A

ADP binds to sulfonylurea R and opens K+ channel

Ca2+ channel is closed

67
Q

examples of sulfonylurea

A

1st gen: tolbutamide, tolazamide, chlorpropamide

2nd gen: glyburide, glipizide, glimepiride

68
Q

function of sulfonylureas

A

bind to and close K+ channel

69
Q

which generation of sulfonylureas have higher potency

A

2nd generation of sulfonylureas have higher potency

70
Q

duration of 1st gen sulfonylureas

A

tolbutamide - 6-12 hours
tolazamide 12-14 hours
chlorpropamide 24-72 hours

71
Q

duration of 2nd gen sulfonylureas

A

glipizide 12-24 hrs
glyburide 24 hrs
glimepiride 24 hrs

72
Q

characteristic of repaglinide (prandin)

A 
mechanism of action similar to sulfonylureas 
quick onset, short duration (t1/2 1 hr)
preprandial tablet (0.5-4mg)
73
Q

characteristics of nateglinide (starlix)

A 
in pancreas vs CV tissue
shorter t1/2 than prandin
60-120mg preprandial
synergistic with metformin
also glufast not yet approved by FDA)
74
Q

adverse effects of sulfonylureas

A

lasting and prolonged hypoglycemia (due to long half life)

has been misdiagnosed as stroke in elderly -> permanent neurological damage + death

GI problems

weight gain & increased #s of 2ndary failures

75
Q

what is an adverse effect of enhancing the action of sulfonylureas

A

increase the risk of hypoglycemia

76
Q

drugs that displace sulfonylureas from protein binding sites

A

salicylates
phenylbutazone*
sulfonamides*
clofibrate*

*may also decrease the metabolism of sulfonylureas by liver

77
Q

additive drugs to sulfonylureas

A

alcohol (excessive acute intake)

high dose salicylates

78
Q

drugs that oppose sulfonylurea action

A 
oral contraceptives
corticosteroids
epinephrine
thryoid
thiazide diuretics
79
Q

why does oral glucose stimulate larger insulin response than IV glucose

A

because there is an incretin effect

80
Q

function of GLP-1

A 
stimulates insulin secretion
suppresses glucagon secretion
slows gastric emptying
reduce food intake
increases beta cell mass & maintains its function
improves insulin sensitivity
enhances glucose disposal
81
Q

GLP-1 R signaling

A

associated with Gs, Gq, and G(beta)(gamma)

Gs-> AC -> cAMP -> Glucose stimulated insulin secretion
Gq->PLC-> Ca2+-> GSIS
Gby-> PI3K-> glucose-stimulated ERK1/2 phosphorylation (GSEP) -> gene transcription & beta cell prolif

82
Q

incretin response in type 2 diabetics is

A

incretin response is decreased

83
Q

strategies for GLP-1 in Type 2 Diabetics

A

provide a long-lasting GLP-1 analog

prevent degradation of endogenous GLP-1

84
Q

benefits of GLP-1

A

reduces hyperglycemia with low risk hypoglycemia
weight loss
increase beta cell mass?

85
Q

GLP-1 analogs

A

exenatide
liraglutide
albiglutide
dulaglutide

86
Q

characteristics of exenatide

A

activates GLP-1 R, from Gila monster saliva
enhances 1st phase secretion
longer t1/2 than GLP-1

87
Q

risks of using exenatide

A

nausea & vomiting, risk of pancreatitis

88
Q

exenatide is coadministered with

A

metformin, TzDs, or sulfonylureas

twice daily injections or once/week

89
Q

characteristics of liraglutide

A

t1/2 of 13 hours, injected once daily

90
Q

liraglutide is co-administered iwth

A

metformin, TzDs, and sulfonlyureas

91
Q

risks associated with liraglutide

A

nausea, vomiting, pancreatitis

risk of thyroid tumors - monitor

92
Q

characteristics of albiglutide

A

DDP-IV resistant, GLP-1 dimer
fused to serum albumin
very long half life
injected subQ once a week

93
Q

side effects of albiglutide

A

nausea, vomiting ,pancreatitis

94
Q

characteristics of dulaglutide

A

injected subQ once/week

slows release of GLP-1 agonist peptides from IgG Fc by reducing # of disulfide bonds in linker region

95
Q

risks of dulaglutide

A

thyroid C-cell tumors

contraindicated in patients with a family history of medullary thyroid cancer

96
Q

function of DPP-4 (dipeptidyl peptidase 4)

A

degrades GLP-1

97
Q

examples of DPP-4 inhibitors

A

sitagliptin
saxagliptin
linagliptin
alogliptin

98
Q

purpose of DPP-4 inhibitors

A

enhance actions of endogenous GLP-1

99
Q

characteristics of DPP-4 inhibitors

A 
administered orally, once daily
reduce hyperglycemia & HbA1c
lower risk of hypoglycemia
may facilitate weight loss
may be co-administered with metformin, TzDs
100
Q

metaboliism and excretion of DPP-4 inhibitors

A

sitagliptin & alogliptin - not extensively metabolized, excxreted in urine
linagliptin - not extensively metabolized, excreted in feces
saxagliptin - CYP3A4/5 substrate, major metabolite is active -> excreted in urine

101
Q

side effects of DPP 4 inhibitors

A 
nausea
vomiting
constipation
headache
severe skin rxns

also reduced WBC, ups infections
potential increased risk of cancers

102
Q

where are DPP-4 also present

A

on immune cells

103
Q

example and characteristics of amylin analog

A

pramlintide (symlin)

co-secreted with insulin, subQ
slows gastric emptying, decreases food intake, inhibits glucagon secretion
blunts postprandial rise in blood glucose
useful in Type I & 2 DM

104
Q

examples and characteristics of alpha-glucosidase inhibitors

A

Acarbose & Miglitol

MoA: decrease absorption of carbohydrate from intestine via blocking alpha glucosidases on brush border (sucrase, maltase, glucoamylase)

acarbose minimaly absorbed, miglitol completely absorbed

105
Q

adverse effects of alpha-glucosidase inhibitors

A

diarrhea, nausea, flatulence

acarbose: liver damage possible at doses > 100 mg tid

106
Q

purpose of inhibiting sodium glucose transporter 2

A

decrease threshold for glucose excretion in urine

reduce blood glucose levels

107
Q

examples of SGLT2 inhibitors

A 
natural product: phlorzin
others: end in gliflozin 
ipragliflozin
dapagliflozin
canagliflozin
empagliflozin
tofogliflozin
luseogliflozin
108
Q

shared characteristics between SGLT2 inhibitors

A

orally active
indicated for Type 2 DM as adjunct to diet&exercise
decreases A1c
weight loss

109
Q

shared risks between SGLT2 inhibitors

A

increased risk of genital/UTI infections
increased urine flow/volume depletion
increased risk of hypoglycemia with SU and insulin
contraindicated in patients with renal impairment

110
Q

unique risk for dapagliflozin

A

do not use in patients with bladder cancer

111
Q

causes of insulin resistance

A

polymorphisms in insulin signaling pathway proteins (rare)
obesity - especially accumulation of fat in the abdominal cavity
inactivity

112
Q

effect of insulin resistance on skeletal muscle, adipose tissue, and liver

A

skeletal muscle - impaired glucose uptake

adipose tissue - impaired glucose uptake, impaired inhibition of lipolysis, mobilization of FAs to other tissues

live - impaired inhibition of glucose output (via gluconeogenesis or glycogenolysis)

113
Q

obesity-induced insulin resistance - role of FA

A

FFA levels are increased in obese people
acutely raising FFA levels causes insulin resistance
acute lowering of plasma FFA levels reduces chronic insulin resistance

predominant effect is on insulin-stimulated glucose transport

114
Q

molecular level polymorphisms related to insulin resistance

A

insulin receptor polymorphism - Ser instead of Tyr phosphorylated -> inhibits signaling

promoted by FA uptake, lipid by-products, inflammatory mediators

115
Q

how does obesity induced inflammation lead to insulin resistance

A

resident macrophages normally release IL-10 which increases insulin sensitivity in the lean state

in obese states, plaques lead to MCP-1 secretion, macrophages infiltrate and release TNFalpha, IL-6, and MCP-1 decreasing adiponectin and increasing insulin resistance

116
Q

metformin characteristis

A

activator of AMP-activated kinase (AMPK)
increases efficiency/sensitivity to insulin in liver, fat, and muscle cells
a. drops liver gluconeogenesis
b. ups glycolysis & glucose uptake in fat/m. cells

117
Q

advantages of metformin over sulonylureas

A

rarely causes weight gain

rarely causes hypoglycemia

118
Q

contraindications for metformin

A

contraindicated in disorders that increase the tendency toward lactic acidosis

decreases vitamin B-12 absorption

119
Q

common side effects of metformin

A

nausea, vomiting, diarrhea

120
Q

function of thiazolidinediones

A

activators of peroxisome proliferator-activated receptor gamma (PPAR-gamma)

target mainly adipocytes -. enhances differentiation, FFA uptake, reduces serum FFA, shifts lipids from non-fat cells into fat cells

121
Q

otehr targets of TzDs

A

liver -enhances glucose uptke, reduces hepatic glucose prodution
sk. muscle - enhances glucose uptake

122
Q

examples of TzDs

A

rosiglitazone

pioglitazone

123
Q

restrictions of TzDs

A

restricted due to cardiovascular toxicities, NO for CHF
pioglitazone can also increase risk of bladder cancer
some hepatotoxicity

124
Q

factors regulated by PPARgamma

A 
resistin (elevated in NIDDM)
adiponectin (down in NIDDM)
TNFalpha (up in NIDDM)
Leptin (up in obesity/NIDDM)
angiotensinogen (up in obesity)
plasminogen activator inhibitor 1 (up in obesity)
125
Q

TzDs’ effects on PPARgamma regulated factors

A

resistin - mRNA leels drop in response to TzDs
adiponectin-mRNA levels up in response
TNFalpha - mRNA levels drop
leptin - missing leptin or the leptin R -> obese/diabetic

126
Q

key parameters that metformin and TzDs affect

A

metformin reduces HbA1c 1.0-1.25

TzDs reduce FFAs moderately and stimulate adiponectin significantly. also reduces peripheral edema moderately.

TzDs decrease differentiation of mesenchymal stem cells into osteoblasts

Pharmacology Exam 1 (7 decks)

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