Exam 2 - Diabetes Hockerman Flashcards
1
Q
3 P’s of diabetes
A
polydipsia -> inc in thirst
polyuria -> inc urination
polyphagia -> inc appetite
2
Q
criteria for the diagnosis of diabetes (4)
A
A1C greater than or equal to 6.5%
OR
fasting plasma glucose greater than or equal to 126
OR
2-h plasma glucose greater than or equal to 200 mg/dL during an OGTT
OR
a random plasma glucose greater than or equal to 200 mg/dL with symptoms
3
Q
99% of type 1 diabetics have antibodies against which antigen?
A
IA-2 (islet antigen 2)
4
Q
“non-obese” type 2 diabetes is due to ?
A
mutations in specific proteins
5
Q
“obese” type 2 diabetes is due to ?
A
insulin resistance/decreased BCM (beta cell mass)
6
Q
4 consequences of lack of insulin (slide 12)
A
-hyperglycemia
-glucosuria
-hyperlipidemia
-uninhibited glucagon
7
Q
increase fatty acid oxidation leads to _____
A
ketoacidosis
8
Q
current insulin therapy goals: keep average blood glucose levels below ___ mg/dL
A
150
9
Q
an A1C of greater than ___ leads to more risk of retinopathy
A
6
10
Q
oxidation products of glucose react irrev. with proteins to form ?
A
advanced glycation end-products
11
Q
what molecules are theorized to account for many long-term complications of diabetes?
A
advanced-glycation end-products
12
Q
glyoxal and methylglyoxal are advanced glycation end-products that turn into CML and CEL respectively, which bind to _____ and promote inflammation
A
RAGE (receptor for advanced glycation end-products)
13
Q
mechanism of cell damage initiated by hyperglycemia (4 pathways)
A
-polyol pathway
-hexosamine pathway
-protein kinase C pathway
-AGE pathway
14
Q
which pathway is the major cause of neuropathy for patients with hyperglycemia?
a. polyol pathway
b. hexosamine pathway
c. protein kinase C pathway
d. AGE pathway
A
a. polyol pathway
15
Q
insulin receptor role of alpha subunits
A
regulatory unit of the receptor
(represses the catalytic activity of beta subunit; repression is relieved by insulin binding)
16
Q
insulin receptor role of beta subunits
A
contains the tyr kinase catalytic domain (autophosphorylation)
17
Q
insulin effects on liver: what processes does it inhibit? (3 things)
A
glycogenolysis
ketogenesis
gluconeogenesis
18
Q
insulin effects on liver: what does it stimulate? (2 things)
A
glycogen synthesis
triglyceride synthesis
19
Q
insulin effects on skeletal muscle: what does it stimulate? (2 things)
A
glucose transport
amino acid transport
20
Q
insulin effect on adipose tissue: what does it stimulate? (2 things)
A
triglyceride storage
glucose transport
21
Q
fasting state:
___% is non-insulin dependent: liver, GI, brain
___% insulin dependent in skeletal muscle
A
75%; 25%
22
Q
fed state:
80-85% is insulin-dependent in _____ _____
4-5% is insulin-dependent in _____ _____
A
skeletal muscle; adipose tissue
23
Q
insulin inhibits release of ___ ___ ___ from adipose tissue
A
free fatty acids
24
Q
decreased serum free fatty acids effects (slide 25):
enhances insulin action on _____ _____
reduces _____ glucose production
A
skeletal muscle; hepatic
25
what is the Km of glut 2?
15-20 mM
26
which glut is insulin-induced?
a. glut 1
b. glut 2
c. glut 3
d. glut 4
d. glut 4
27
which glut is expressed in neurons?
a. glut 1
b. glut 2
c. glut 3
d. glut 4
c. glut 3
28
where is glut 4 expressed? (2 places)
skeletal muscle
adipocytes
29
4 pancreatic polypeptide hormones to know
-glucagon
-somatostatin
-insulin
-amylin
30
glucagon function (2; slide 28)
-stimulates glycogen breakdown
-increases blood glucose
31
which polypeptide hormone stimulates glycogen breakdown and increases BG?
a. glucagon
b. somatostatin
c. insulin
d. amylin
a. glucagon
32
which polypeptide hormone is a general inhibitor of secretion?
a. glucagon
b. somatostatin
c. insulin
d. amylin
b. somatostatin
33
which polypeptide hormone stimulates uptake and utilization of glucose?
a. glucagon
b. somatostatin
c. insulin
d. amylin
c. insulin
34
which polypeptide hormone is co-secreted with insulin, slows gastric emptying, decreases food intake, and inhbits glucagon secretion?
a. glucagon
b. somatostatin
c. insulin
d. amylin
d. amylin
35
in secretory granules, proinsulin is cleaved to A and B chains, and C (connecting) peptide by __________
proconvertases
36
human insulin cDNA in plasma expressed in E. Coli
a. Humulin
b. Novolin
c. Glargine
d. Degludec
a. Humulin
(recombinant)
37
human insulin cDNA in plasmid expressed in transformed yeast
a. Humulin
b. Novolin
c. Glargine
d. Degludec
b. Novolin
(recombinant)
38
ultra rapid onset/very short action insulin (3 of them)
lispro (Humalog)
aspart (Novolog)
glulisine (Apidra)
39
rapid onset/short action insulin (1)
regular (R)
40
intermediate onset/action insulin (1)
NPH (N)
41
slow onset/long action insulin (3 of them)
glargine (Lantus)
detemir (Levemir)
degludec (Tresiba)
42
the "lente" insulins include which element?
zinc
43
why does NPH insulin have a slow absorption and long duration of action?
it is bound to protamine and needs to be broken down by tissue proteases to yield free insulin, which is then released into the bloodstream
44
which insulin is made by reversing positions of P28 and K29 on insulin B chain?
Lispro insulin (Humalog)
45
when are Humalog, Novolog, and Apidra injected, before or after meals?
immediately before meals
46
what modification is made to the beta chain for insulin aspart (Novolog)?
proline 28 switched to aspartate
47
what modification is made to the beta chain for insulin glulisine (Apidra)?
asparagine 3 (Asn 3) and Lys 29 are switched to Lys and Glu
48
what modifications are made to insulin to make insulin glargine (Lantus)? (2 of them)
-Asn 21 of a-chain is changed to Gly
-2 Arg residues added to end of b-chain (30 & 31)
49
insulin glargine is a clear solution at what pH?
pH 4 (precipitates when neutralized; post injection)
50
what modifications are made to the b-chain for insulin detemir (Levemir)? (2 of them)
Thr 30 is deleted
Lys 29 is myristylated (fatty acid modification)
51
what modifications are made to the b-chain in insulin degludec (Tresiba)?
Thr 30 is replaced by gamma-Glu/C16 fatty acid
52
which 3 insulins are extensively bound to serum albumin?
-insulin detemir (Levemir)
-insulin degludec (Tresiba)
-semaglutide (Ozempic)
53
for multi-dose insulin regimens, when are fast onset, short acting insulins taken?
before meals
54
for multi-dose insulin regimens, when are long, or intermediate acting insulins taken? (2 options)
at bedtime
OR
at bedtime and after breakfast
55
what are the 2 components of a Humulin mixture?
NPH (neutral protamine hagedorn) + regular
(Humulin 70/30 or 50/50)
56
what are the 2 components of a Humalog mixture?
NPL (neutral protamine lispro) + Lispro
(Humalog 75/25 or 50/50)
57
what are the 2 components of Ryzodeg?
70% degludec + 30% aspart
58
inhaled insulin example
Afrezza
59
Afrezza has _____ onset, _____ duration of action than subQ injection
a. rapid; longer
b rapid; shorter
c. slow; longer
d. slow; shorter
b. rapid; shorter
60
Afrezza contraindications
pts with asthma and COPD (may reduce lung function; decreased FEV)
61
what kind of particle does Afrezza use?
technosphere particle (FDKP + polysorbate 80)
62
3 modes of action of insulin in diabetics
1. dec liver glucose output
2. inc fat storage
3. inc glucose uptake
63
hypoglycemia is BG < ?
60 mg/dL
64
_____ is the preferred fuel for the nervous system
glucose
65
4 adverse reactions to insulin (slide 55)
-lipodystrophy
-lipoatrophy
-lipohypertrophy
-antibodies against insulin
66
which insulin preparation is not genetically modified?
a. lispro
b. glulisine
c. NPH
d. aspart
c. NPH
67
which insulin preparation has the longest duration of action?
a. lispro
b. aspart
c. glulisine
d. glargine
d. glargine
68
what is lipodystrophy?
a. loss of fat in subq tissue
b. accumulation of fat in subq tissue
c. changes in fat at over used injection site
c. changes in fat at over used injection site
69
what is lipoatrophy?
a. loss of fat in subq tissue
b. accumulation of fat in subq tissue
c. changes in fat at over used injection site
a. loss of fat in subq tissue
70
what is lipohypertrophy?
a. loss of fat in subq tissue
b. accumulation of fat in subq tissue
c. changes in fat at over used injection site
b. accumulation of fat in subq tissue
71
ethanol inhibits gluconeogenesis, and may __________ the risk of insulin hypoglycemia
a. increase
b. decrease
a. increase
72
two classes of drugs that enhance insulin secretion
sulfonylureas, meglitinides
73
for sulfonylureas, the pt must have functioning _____ cells
beta
74
effects of sulfonylureas on beta cell insulin release (6 steps; slide 62)
1. binds to sulfonylurea receptors
2. inactivates K+ channel
3. decreased cell polarization
4. activates voltage sensitive Ca+ channels
5. inc Cai2+ and activity of microfilaments
6. inc exocytosis of insulin containing granules
75
nateglinide and repaglinide are part of what drug class?
meglitinides
76
1st gen sulfonylureas (3 of them)
-tolbutamide
-tolazamide
-chlorpropamide
77
2nd gen sulfonylureas (3 of them)
-glipizide
-glyburide
-glimepiride
78
which are more potent?
a. 1st gen sulfonylureas
b. 2nd gen sulfonylureas
b. 2nd gen sulfonylureas
79
which is false about Repaglinide (Prandin)?
a. it is a non-sulfonylurea hypoglycemic agent
b. its MOA is same as sulfonylureas
c. it has a slow onset and long duration of action
d. taken before each meal
c. it has a slow onset and long duration of action
(quick onset, short duration of action t1/2 ~ 1 hour)
80
which sulfonylurea has the lowest potency?
a. tolazamide
b. chlorpropamide
c. glyburide
d. glimepiride
e. tolbutamide
f. glipizide
e. tolbutamide
81
which drugs are non-sulfonylurea Katp channel blockers?
meglitinides
82
nateglinide is very specific for Katp channels in _____ vs _____ tissue
pancreas; CV
83
nateglinide has a shorter half-life than prandin i.e. less risk of __________
hypoglycemia
84
of these 3, which has the longest half life, and thus the highest risk of prolonged hypoglycemia?
a. glipizide
b. glimepiride
c. glyburide
c. glyburide
85
one adverse effect of sulfonylureas includes weight gain and increased number of _____ _____
secondary failures
86
2 drugs that have their own hypoglycemic effects which may be additive to the sulfonylureas (bolded on slide 73)
-alcohol
-high dose salicylates
87
what is the incretin effect?
oral glucose stimulates a larger insulin response than IV glucose in humans
88
GLP-1: stimulated insulin secretion is
a. glucose-independent
b. glucose-dependent
b. glucose-dependent
89
GLP-1 is secreted from which cells in the intestine?
ileal L cells
90
2 potential outcomes of GLP-1 receptor signaling (slide 78)
-glucose-stimulated insulin secretion (GSIS)
-gene transcription and beta-cell proliferation
91
the incretin effect is diminished in which diabetics?
type 2
92
insulin is _____ and causes weight _____
a. anabolic; loss
b. anabolic; gain
c. catabolic; loss
d. catabolic; gain
b. anabolic; gain
93
GLP-1R agonists (5 drugs)
-exenatide (Exendin 4; Byetta)
-lixisenatide (Adlyxin)
-liraglutide (Victoza)
-dulaglutide (Trulicity)
-semaglutide (Ozempic; Rybelsus)
94
which GLP-1R agonist is derived from Gila Monster saliva?
exenatide
95
basal insulin is _____-acting
a. fast
b. slow
b. slow
(it is taken between meals and before bedtime to control blood sugar outside of eating)
96
exenatide activates _____ receptor and enhances _____ phase secretion
GLP-1; 1st
97
contraindication for exenatide, liraglutide, dulaglutide, lixisenatide, semaglutide (Ozempic)
family history of medullary thyroid cancer
(risk of thyroid C-cell tumors)
98
GLP-1 analogs common side effects (2 of them)
-N/V
-pancreatitis
99
true or false: exenatide is only available as a once weekly injection
false
(twice daily or once weekly injections)
100
we should monitor _____ levels when taking liraglutide (Victoza)
calcitonin
101
what modifications are made to create liraglutide? (2 of them)
-glu and arg added
-fatty acid added to glu linker
102
what amino acid is inserted to make dulaglutide?
valine
(increases susceptibility to proteolysis)
103
GLP-1 agonist peptides are _____ released from IgG Fc domain by reduction of _____ bonds in linker region
slowly; disulfide
104
how often is dulaglutide (Trulicity) injected?
once weekly
105
when is lixisenatide (Adlyxin) injected?
once daily, before breakfast
106
difference between structure of lixisenatide and exenatide
lixisenatide is exenatide with a polylysine tail
107
soliqua is a combo of what two insulins?
glargine and lixisenatide
108
which insulin has these modifications?
2-aminoisobutyrate inserted
Hydrophilic spacer and fatty acid added to lysine
a. exenatide
b. dulaglutide
c. liraglutide
d. semaglutide
e. lixisenatide
d. semaglutide
(Ozempic)
109
half life for semaglutide (Ozempic)
1 week
(it is extensively bound to serum albumin)
110
only orally available GLP-1R agonist
semaglutide oral (Rybelsus)
111
3 important structural things to know about Rybelsus
-dimethylalanine added
-hydrophilic spacer and C-18 fatty acid added to lysine
-salcaprozate is in complex (makes molecule more absorbable in GI tract)
112
Rybelsus is absorbed from what organ?
stomach
113
Rybelsus has a low oral bioavailability, so the strength of medication is _____ than injections
higher
114
basal insulin/GLP-1R agonist combination drugs (2 of them)
-Soliqua -> glargine + lixisenatide
-Xultophy -> degludec + liraglutide
115
which drug is a GLP-1 & GIP dual agonist?
tirzepatide (Mounjaro)
116
Mounjaro:
full _____ receptor agonist
biased _____ receptor -> preferential coupling to cAMP over _____
-GIP
-GLP-1
-beta-arrestin
117
how does Mounjaro maintain GLP-1 effect?
reduces internalization (desensitization) of GLP-1 receptor to maintain GLP-1 effect
118
how often is Mounjaro injected?
once weekly
119
what enzyme degrades GLP-1?
dipeptidyl peptidase 4 (DPP-4)
120
4 drugs that are DPP-4 inhibitors (GLP-1 modulators)
-sitagliptin (Januvia)
-linagliptin (Tradjenta)
-saxagliptin (Onglyza)
-alogliptin (Nesina)
121
how often are Januvia, Onglyza, Tradjenta, and Nesina taken?
a. once weekly
b. once daily
c. twice daily
d. every other day
b. once daily
(these are all oral drugs)
122
which drug is extensively metabolized?
a. Januvia
b. Nesina
c. Tradjenta
d. Onglyza
d. Onglyza
(the other 3 are not)
123
which is not excreted in urine (kidney)?
a. Januvia
b. Onglyza
c. Tradjenta
d. Nesina
c. Tradjenta
(excreted in feces (liver))
124
Onglyza is a substrate of which cyp?
CYP3A4/5
(major metabolite is active)
125
side effects of DPP-4 inhibitors (3 of them; highlighted in red on slide 96)
-pancreatitis
-joint pain
-heart failure
126
DPP-4 is present on immune cells, which can lead to _____ WBC counts, which leads to increased _____ and potential increased risk of cancers
reduced; infections
127
which drug is an amylin analog?
pramlintide (Symlin)
128
which drug blunts postprandial rise in blood glucose, and is used in conjunction with insulin?
pramlintide (Symlin)
129
pramlintide (Symlin) is useful for which patients?
a. type 1 diabetes
b. type 2 diabetes
c. both
c. both
130
tolbutamide MOA
a. activation of Katp channels
b. prolonged block of Katp channels
c. activation of GLP-1 receptors
d. short duration block of Katp channels
b. prolonged block of Katp channels
131
the acute increase in insulin secretion observed with GLP-1 is
a. result of direct and persistent activation of the Katp channel
b. result of activation of the ERK1/2 pathway
c. glucose independent
d. glucose dependent
d. glucose dependent
132
two alpha-glucosidase inhibitors drugs to know
Acarbose (Precose)
Miglitol (Glyset)
133
alpha-glucosidase inhibitors MOA
dec absorption of carbohydrate from the intestine via inhibition of gut alpha glucosidases
134
3 gut alpha glucosidases to know
sucrase, maltase, glucoamylase
135
alpha-glucosidase inhibitors are taken _____ meals
a. with
b. without
a. with
136
which is completely absorbed?
a. Acarbose
b. Miglitol
b. Miglitol
(Acarbose is only minimally absorbed)
137
adverse effect of Acarbose and Miglitol
GI- diarrhea, nausea, flatulence
138
Acarbose has risk of _____ damage at doses > 100 mg tid
liver
139
SGLT2 inhibitors MOA
they inhibit SGLT2 in the PCT, to prevent reabsorption of glucose (in kidney) and facilitate its excretion in urine
140
SGLT2 inhibitors are derived from what natural product? What functional group of this molecule is responsible for why it doesn't last very long?
phlorizin; ether group
141
SGLT2 inhibitors drugs to know (5 of them)
-empagliflozin (Jardiance)
-canagliflozin (Invokana)
-dapagliflozin (Farxiga)
-ertugliflozin (Steglatro)
-bexagliflozin (Benzavvy)
142
SGLT2 inhibitors cause an increase in what 3 things?
-inc risk of genital/UT infections
-inc urine flow/volume depletion/hypotension
-inc risk of DKA
143
SGLT2 inhibitors contraindications
pts with renal impairment
144
SGLT2 inhibitors have an increased risk of ____ ____ ____
lower limb amputation
145
what class of drug is metformin in?
biguanides
146
most common cause of insulin resistance
obesity
(especially accum of fat in the abdominal cavity)
147
raising _____ levels causes insulin resistance
FFA
148
2 drugs that are thiazoladinediones
-pioglitazone (Actos)
-rosiglitazone (Avandia)
149
Insulin resistance can be due to polymorphisms in insulin receptor. What modification did we talk about in class?
ser (instead of tyr) phosphorylation of insulin receptor and insulin receptor substrate proteins
(inhibits signaling; promoted by FA uptake, lipid by-products, inflammatory mediators)
150
metformin is classified as an __________ agent
antihyperglycemic
151
metformin has a lower risk for _____ _____ than the older biguanides
lactic acidosis
152
metformin MOA
activator of AMP-activated kinase (AMPK)
(inc efficiency or sensitivity to insulin in liver, fat, and muscle cells)
153
what is metformin's effect in the liver?
dec gluconeogenesis
154
what is metformin's effect in muscle and fat cells?
inc glycolysis, glucose uptake
155
metformin action in skeletal muscle (3 steps)
-AMP accumulates during exercise and activates AMPK
-AMPK phosphorylates TBC1D1/4 which promotes GTPase activity of Rab
-Rab dissociates from GLUT4 allowing translocation
156
metformin decreases which vitamin's absorption?
B12
157
metformin effects on blood lipid profile: decreases serum _____ and _____
triglycerides; LDL
(reduces risk of adverse CV events)
158
what transcription factor do thiazolidinediones activate?
PPAR gamma (peroxisome proliferator-activated receptor gamma)
159
main target of thiazolidinediones
a. liver
b. skeletal muscle
c. adipocytes
c. adipocytes
160
why do thiazolidinediones have restricted prescribing?
due to CV toxicities
(CI in NYHA class III or IV heart failure)
161
true or false: thiazolidinediones can cause hypoglycemia
false
162
which is decreased in type 2 diabetics?
a. resistin
b. adiponectin
c. TNF alpha
b. adiponectin
163
which factor, when injected into mice, stimulates glucose export by the liver & insulin resistance?
a. resistin
b. TNF alpha
b. adiponectin
a. resistin
164
which factor reduces blood glucose and insulin resistance in diabetic mice?
a. TNF alpha
b. adiponectin
c. resistin
b. adiponectin
165
which factor stimulates lipolysis in white adipose tissue, & insulin resistance in skeletal muscle?
a. adiponectin
b. resistin
c. TNF alpha
c. TNF alpha
166
3 factors regulated by activation of PPAR gamma
resistin, adiponectin, TNF alpha
167
__________ decrease differentiation of mesenchymal stem cells into osteoblasts
thiazolidinediones (TdZ's)
168
Why is there an increased insulin response in early pregnancy? (2 of them; slide 124)
growth of placenta, increase maternal fat storage
169
During late pregnancy, why is there reduced insulin sensitivity?
growth of fetus
170
gestational diabetes definition
hyperglycemia during pregnancy in non-diabetic women
171
how is gestational diabetes diagnosed?
24-28 week OGTT
172
when does gestational diabetes usually appear?
around week 24 of gestation, in the rapid growth stage of gestation, after fetus has formed
173
how does gestational diabetes affect the growth of the fetus?
can lead to macrosomia ("Fat Baby"), because fetus has access to excessive glucose, it produces high levels of insulin and stores excess glucose as fat
174
true or false: insulin crosses the placenta, but glucose does not
false
(insulin does not cross placenta, glucose does)
175
which hormone is one of the main contributors to insulin resistance?
a. CRH- cortisol
b. placental GH (GH-V)
c. progesterone
d. placental lactogens (PL)
d. placental lactogens (PL)
176
which does not increase as pregnancy progresses like the others?
a. CRH- cortisol
b. progesterone
c. placental GH (GH-V)
d. placental lactogens (PL)
c. placental GH (GH-V)
(this is only released during last half of gestation, the others all increase as pregnancy progresses)
177
glucocorticoids _____ insulin action
oppose
178
how does prolactin inc beta-cell mass during pregnancy?
stimulates beta cell proliferation
179
mutations in which receptor are associated with gestational diabetes?
PRL (prolactin) receptor
180
placental lactogen activates PRL with _____ affinity and GH receptors with _____ affinity
high; low
181
gold standard drug for gestational diabetes
insulin (does not cross placenta)
182
glyburide vs metformin for gestational diabetes
glyburide works but may harm fetus (crosses placenta), while metformin crosses placenta but doesn't harm fetus
183
true or false: thiazoladinediones are not used for gestational diabetes
true
184
GIP (gastric inhibitory peptide) is secreted by which cells in the intestine?
duodenal K cells
