Part 18: Diabetes Flashcards
1
Q
the regulation of insulin and glucagon secretion is controlled by circulating blood ____ levels
A
glucose
2
Q
under normal conditions, there is a ____ (low/high) level of basal insulin release
A
low
3
Q
large secretions of insulin from the pancreas happens in response to ____
A
elevations in blood glucose, like after meals
4
Q
insulin secretion closely mirrors blood ___ spikes
A
glucose
5
Q
glucose from food sources is absorbed in the GI tract into the blood, then stimulating the ____ to release insulin
A
pancreas
6
Q
insulin is made by ___ cells in the pancreas
A
B
7
Q
____ and ____ nerve stimulation also promote insulin release
A
incretins & vagus
8
Q
insulin circulates in the blood and stimulates insulin receptors on tissues like the ____, ___ and _____ cells
A
liver, adipose, muscle
9
Q
what is the effect of activating insulin receptors in target tissue cells?
A
these cells with start taking up glucose
10
Q
what are the 2 possible fates of the glucose that is taken up by cells that were stimulated by insulin?
A
- used immediately in glycolysis for energy production
2. stored for later metabolic use
11
Q
insulin promotes the making and storage of ___, ___ and ____
A
glycogen, triglycerides, and protein
12
Q
what is the primary job of the pancreatic B cells?
A
insulin production and secretion
13
Q
glucose is able to enter beta cells via the ____ transporters on the surface of the cells
A
GLUT 2
14
Q
t/f glucose must be transported across cell membranes
A
t
15
Q
when glucose levels rise after a meal, the level of ___ also rises
A
ATP
16
Q
ATP made by B cells binds to ____ channels and causes them to ____ (open/close)
A
ATP-dependent K; close
17
Q
the closing of the ATP-dependent K channels results in membrane ____ which causes the _____ (opening/closing) of voltage gated Ca channels
A
depolarization; opening
18
Q
Ca influx into beta cells results in Ca-mediated exocytosis of _____ into the blood
A
insulin
19
Q
what are the steps of B cells making insulin?
A
- glucose comes in by GLUT-2
- glucose metabolized to make ATP, which activates ATP-dependent K channels and closes them, which depolarizes the membrane
- depolarization opens voltage-gated Ca channels
- Ca influx causes Ca-mediated exocytosis of insulin into the blood
20
Q
insulin receptors are ____ type receptors
A
tyrosine kinase
21
Q
insulin receptors have ___transmembrane portions and ligand binding causes ___ of the 2 subunits
A
2; dimerization
22
Q
when the insulin receptor dimerizes, the intracelllar portions come togther and the _____ domains phosphorylate each other, this is called ___
A
intrinsic kinase; autophosphorylation
23
Q
the key process involved in glucose homeostasis involves the activation of the ___ kinase, which causes an increase in the trafficking of _____ to the cell membrane
A
pi3; GLUT-4
24
Q
____ transporters are critical, as they are the primary way to get glucose into target cells
A
GLUT-4
25
MAP kinase pathways are also activated and promote ___ and ___
cellular growth and proliferation
26
what are the 5 main steps of the cellular mechanism of insulin?
1. insulin binds to insulin receptors of target tissue cells
2. the kinase domains of the receptor undergo autophoshporylation, starting intracellular signalling cascades
3. insulin response substrates (IRS) activate phosphatidylinositol-3kinase (PI3-K) and the mitogen-activated protein kinase (MAPK) signalling cascades
4. GLUT-4 glucose transporters are trafficked to the cell membrane, which allows glucose to enter the target tissue cells
5. MAPK pathways promote cellular growth and proliferation
27
glucagon is a counter hormone to ____
insulin
28
where is glucagon made?
pancreatic a cells
29
glucagon is secreted when blood glucose levels are _____(high/low)
low
30
glucagon stimulates the release of ____ from hepatocytes
glucose
31
glucagon binds to a ____ receptors
glucagon
32
what type of receptors are glucagon receptors?
gpcr
33
glucagon receptors are located on ____ cells
hepatocytes in the liver
34
glucagon receptors are ____ coupled
Gs
35
activated glucagon receptors activate adenyl cyclase and increase levels of ___ which activates ___, which mediates cellular processes aimed to increase blood glucose levels
cAMP; PKA
36
when glucagon receptors are activated, glycogen stores are broken down in a process called ____ and new glucose is made in cells from other biochem building blocks in a process called ____
glycogenolysis; gluconeogenesis
37
glucagon receptor activation causes a ____ 9decrease or increase) in glycolysis and glycogenesis
decrease
38
when is the typical onset of type 1 diabetes?
juvenile (early onset)
39
Type 1 diabetes is characterized by a destruction of _____ cells in the pancreas
beta cells
40
type 1 diabetes presents as a ____ disease early in life
autoimmune
41
in type 1 diabetic patients, do they have some ability to make insulin?
no, no ability to make insulin
42
what is the onset of type 2 diabetes?
late onset
43
type 2 diabetes is usually secondary to other health problems like ____
obesity
44
type 2 diabetes is usually a multi-factorial ____ disease
metabolic
45
what is the issue with the B cells in type 2 diabetes?
beta cells in the pancreas are less responsive to glucose and insulin secretion after a meal
46
there is often insulin ____ of target cells in type 2 diabetes
resistance
47
are there non-pharm treatments for type 1 diabetes?
no
48
what are the non-pharm treatments for type 2 diabetes?
diet, exercise, smoking cessation
49
what is the pharm treatment for type 1 diabetes?
SC insulin
50
what is the pharm treatment for type 2 diabetes?
antihyperglycemic agents, insulin (late in disease), control systemic complications
51
what is the primary common feature between type 1 and type 2 diabetes?
hyperglycemia
52
elevated blood glucose levels can have what clinical presentation?
fatigue, increased thirst (polydipsia), frequent urination (polyuria), exercise intolerance and dyspnea
53
why does diabetes make people tired?
glucose cant enter cells to be used as energy
54
what can happen in extreme and prolonged cases of diabetes due to glucose getting trapped in the blood?
ketoacidosis, cognitic impairments, visual impairment, renal dysfunction, CVD, circulatory problems
55
what is the 1st line treatment for type 2 diabetes?
lifestyle: reducing weight, increasing exercise, reducing sugar intake
56
what are 2nd line & adjunct pharm treatments for type 2 diabetes?
metformin, insulin secretagogues, incretin agents or gliflozins (all anti-hyperglycemics)
57
as type 2 diabetes progresses, insulin-producing ability of the pancreas often ____ (increases or decreases)
decreases
58
what are the 3 main goals of insulin replacement therapy?
1. closely mimic physiologic secretion of insulin
2. regulate blood glucose levels, prevent hyperglycemia
3. minimize risks of hypoglycemia
59
t/f insulin therapy mimics the physiologic release of insulin to prevent hypoglycemia between meals
t
60
why does insulin need to be given SC and cant be given PO?
it is a peptide hormone that is too big and would be broken down in the stomach
61
t/f IV insulin can be given in hospital
t
62
t/f protein/peptide therapeutics must be carefully stored to prevent degradation
t
63
what is the MOA of insulin replacement therapy?
insulin gets absorbed into the systemic circulation and activates insulin receptors on target cells, which increases the presence of GLUT-4 transporters, allowing glucose uptake into these cells for metabolism (just like how endogenous insulin would work)
64
there are many different types of insulin and their key differences are related to ______ variations between formulas
PK
65
what is the effect of the PK variations between formulas of insulin?
affects the rate of absorption at the site of administration
66
when is rapid acting insulin given?
just before a meal
67
what is the onset of action of rapid onset insulin?
5-15 min
68
what is the duration of action of rapid acting insulin?
3-4 hrs
69
when does regular insulin need to be given ?
30 min before a meal
70
what is the onset of action for regular insulin?
30-60 minutes
71
what s the duration of action for regular insulin?
6-8 hours
72
intermediate and long acting insulin provide ____ insulin levels between meals and between bolus insulin doses
low, basal
73
what is the onset time for intermediate insulin?
2-4 hours
74
what is the duration of action for the intermediate insulin>
10-20 HRS
75
what is the onset time of long acting insulin?
~1 hour, but there is no peak
76
what is the duration of action of long acting insulin?
~17-24 hours
77
what can happen if insulin administration and glucose intake are mismatched?
hyper or hypo glycemia
78
what experimental treatments for type 1 diabetes are being trialed?
beta cell transplats, stem cell and gene therapy
79
what is A1C?
a parameter that can be measured in routine blood tests which provides a more longitudinal picture of how well a patient's blood glucose is controlled
80
A1C is the abbreviated term used to describe ____
the glycosylated form of hemoglobin
81
when glucose levels are elevated for a long time, proteins in the blood, such as hemoglobin in RBCs can become ______
glycosylated
82
the % of RBC that have been glycosylated is indicated by the %____
A1C
83
the %A1C is used to indicate the extent and duration of ____ in patients
blood glucose elevations
84
an RBC typically circulates in the blood for about 3 months, so the % A1C value can be seen as ____
a 3 month running avg of blood glucose control
85
in most cases, the desirable % A1C is below ___ %
7
86
what is typically the first pharm choice for type 2 diabetes>
metformin
87
why is metformin the 1st pharm choice for type 2 diabetes?
acts by several mechanisms to reduce blood glucose levels and improve glucose utilazation by cells
88
the most significant pharm effect of metformin involves the stimulation of ____ pathways in the liver to reduce de novo synthesis of ___
AMP kinase; glucose
89
by metformin blocking AMP kinase pathways to make new glucose, what does it force the body to do?
use stored glucose (such as fat)
90
metformin improves ____ of target cells so that glucose can be taken up and metaboliszed more effectively
insulin sensitivity
91
metformin reduces the absorption of ____ from dietary sources in the GI tract, forcing the body to use up its stores
glucose
92
t/f patients typically experience weight loss when starting metformin
t
93
what happens if metformin alone is not enough to llower A1C to the target range?
additional antihyperglycemic agents ae considerd based on patient factprs
94
t/f some anti-hyperglycemics also have CV benefits, so if a patient has CV concerns on top of diabetes, these are typically chosen
t
95
____ and ____ (anti-hyperglycemics) have been shown to have clinical benefit in patients with type 2 diabetes
empagliflozin and liraglutide
96
the gliflozin drug class is relatively new, with the fist agent approved in Canada in the year ____
2014
97
what is teh MOA of the gliflozin class such as empagliflozin?
inhibit the SGLUT2 glucose transporter in the kidney, which reduces the reabsorption of glucose from the urine, lowering blood glucose
98
normally, ____% of glucose is reabsorbed at the proximal convoluted tuble
98
99
gliflozins target SGLT2 trnasporters in which part of the renal system?
the proximal convoluted tubule
100
why does empagliflozin help with CVD?
reduces BP by getting rid of more solute (glucose) through urination
101
t/f bc empagliflozin causes more glucose excretion in the urine, it also causes more water excretion, lowering BP
t
102
t/f the BP lowering effect of empagliflozin can be bad for normotensive patients
t
103
why can empagliflozin lead to more UTIs?
more glucose in the urine allows bacteria to multiply rapidly in the bladder
104
liraglutide is a ____ receptor agonist
GLP-1
105
liraglutide belongs to which class of drugs?
incretin agents (class of antihyperglycemic)
106
what is the MOA of incretins like liraglutide?
naturally secreted in the GI tract when food is consumed, bind to GLP-1 on B cells and increase insulin secretion and when on GLP-1 on A cells, signals that glucose is on the wasy , so there is no need to secrete glucogon or make new glucose
107
do incretins like liraglutide increase or decrease gluconeogenesis?
decrease
108
GLP-1 activation enhances the closing of K channels and opening of Ca channels through a ____mediated pathway
cAMP
109
the GLP-1 receptor is a ___ coupled G protein receptor
Gs
110
activation of the GLP-1 receptor causes an increase in ___, which activates ___, which phosphorylates _____ in the cell, allowing more ____entry, which enhances the release of ___
cAMP, PKA, ion channels, Ca, insulin
111
normally, GLP-1 is broken down quickly ny an enzyme called ____
DPP4
112
the half life of endogenous GLP-1 is only ____, so the boose in insulin secretion is only trnasient
a few min
113
can the GLP-1 pathway cause insulin secretion on its own?
no, glucose needs to be present to initiate the closing of the K channels and cause depolarization
114
why is using liraglutide on GLP-1R more efficient that the endogenous hormone?
it has a much longer half-life
115
what is the MOA of DPP4 inhibitors like sitagliptin?
prolong the presence of endogenous GLP-1, causeing more insulin release
116
t/f sitagliptan has good oral F and T1/2 that only needs to be dose once daily
t
117
what is the oral f of sitagliptan?
85%
118
what is the t1/2 of sitagliptan?
12 hours
119
how is liraglutide administered?
Sc injection
120
t/f sitagliptide relies on the body's production of GLP-1 in the GI tract
t
121
does sitagliptaide have any addded benefit for CVD?
no
122
what is a down fall of the gliflozins and liraglutide?
very $$$
123
t/f older agents like glyburide are less $$
t
124
glyburide belongs to what class of AHGs?
insulin secretagogues
125
what is the MOA of insulin secretagogues like glyburide?
bind to receptors on the beta cells and stimulate them to release insulin from the pancreas
126
secretagogues are only effective if ____ and ____
the pacreas is able to make insulin and the process is independennt of glucose
127
glyburide blocks ____
ATP K channels
128
when glyburide binds to the K channels, this results in beta cells becoming ____
depolarized
129
the depolarization of b cells caused by glyburide causes an influx of ___ ions and a release of ___
Ca; insulin
130
how can glyburide cause insulin release independent of glucose?
removes the need for ATP to open the K channels, which would have needed the breakdown of glucose
131
what is a clinical downfall of glyburide?
can cause high levels of circulating insulin without the influx of glucose from a meal can cause hypogylcemia
132
what are the presenting symptoms of hypoglycemia?
sudden onset of hunger, weakness, increased HR, which can result in dizziness, falls
133
reversal of hypoglycemia can be achieved by administering __
glucose
134
what is the ideal formulatiion to give glucose to a patient who is hypoglycemic?
something that dissolves readily or fruit juice bc they can be quickly absorbed by the GI tract
135
prolonged periods of hypoglycemia can result in ___
ketoacidosis
136
why can prolonged periods of hypoglycemia result in ketoacidosis?
cells begin to breakdown ketones for energy
137
can ketoacidosis be life-threatening>
yes
138
which AHG agents are notorious for causing hypoglycemia?
secretagogues
139
diabetic ___ can lead to vision loss
retinopathy
140
diabetic renal dysfuction can become so severe that pts require ___
dialysis
141
t/f diabetic pts are at higher risk for CVD and MI
t
142
t/f there is an increased risk of infection in diabetes
t
143
why is peridontal disease higher in diabetic patients
dry mouth (?)
144
t/f diabetic pts can experience peripheral neurpathies
t
