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
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)
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
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
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
6
Q
type II diabetes incidence in obese
A
80%
10% in non-obese
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)
8
Q
NIDDM family history in non-obese/obese
A
yes/yes
9
Q
insulin secretion in response to glucose challenge in obese/non-obese
A
obese: low if corrected for obesity
non-obese: low
10
Q
severity of NIDDM in obese/non-obese
A
non-obese: usually mild; ketosis - resistant
obese: usually mild; ketosis-resistant
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
12
Q
causes of glucosuria (don’t overthink this)
A
due to high blood glucose
13
Q
causes for hyperlipidemia
A
increased fatty acid mobilization from fat cells
increased fatty acid oxidation - ketoacidosis
14
Q
role of glucagon
A
increased glucagon levels in the presence of increased blood glucose levels (????what????? - i don’t understand this)
15
Q
complications of diabetes
A
- cardiovascular - micro/macro angiopathies
- neuropathy - increased use of polyol pathway (aldose reductase), -> increased cytosolic water in neural cells
- nephropathy - renal vascular changes & changes in glomerular basement membrane
- ocular - cataracts, retinal microaneurysms, hemorrhage
- increased susceptibility to infections
16
Q
conventional therapy goals for diabetics
A
reduce acute symptoms -polyuria, dehydration, ketoacidosis
17
Q
intensive insulin therapy goals
A
keep blood glucose levels below 150 mg/dL
prevent/delay onset of complications
**increased risk of hypoglycemia
18
Q
ideal vs acceptable fasting glucose levels
A
70-90 vs 70-110
19
Q
ideal vs acceptable pre-meal glucose levels
A
70-105 vs 70-130
20
Q
ideal vs acceptable post-meal glucose levels
A
21
Q
ideal vs acceptable glycosylated hemoglobin (HbA1c)
A
6% vs
22
Q
what is HbA1c
A
covalent modification of protein by glucose
measurement of the Amadori product
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
24
Q
what is the polyol pathway?
A
polyol pathway
glucose -> aldose reductase -> sorbitol -> fructose
25
AGE pathway
Glyceraldehyde-3-P - > methylglyoxal -> AGE
26
complications related to the AGE pathway
AGE precursor methylglyoxal inhibits vasorelaxation
| stimulated by ACh/NO
27
structure of the insulin receptor
two alpha subunits (bind to ligand, represses beta subunits unless bound to insulin)
two beta subunits (transmembrane, contain tyrosine kinase catalytic domains)
28
downstream activation of the insulin R
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
29
insulin's effect on the liver
inhibits: glycogenolysis, ketogenesis, gluconeogenesis
stimulates: glycogen synthesis, triglycerid synthesis
30
insulin's effect on skeletal muscle
stimulates: glucose transport, amino acid transport
31
insulin's effect on adipose tissue
stimulates: triglyceride storage, glucose transport
32
glucose disposal in fasting states
75% is non-insulin-dependent: liver, GI, brain
25% is insulindependent in skeletal muscle
glucagon is secreted to prevent hypoglycemia
33
glucose disposal when fed
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
34
consequences of decreased serum FFA
enhances insulin action on skeletal muscle
| reduces hepatic glucose production
35
types of glucose transporters
```
Glut 1 (widely expressed)
Glut 2 (beta cells, liver)
Glut 3 (neurons)
Glut 4 (skeletal muscle, adipocytes)
```
36
Km of the different Glut Rs
Glut 1 Km = 1-2mM
Glut 2 Km = 15-20mM
Glut 3 Km
37
activity level of the glut Rs
Glut 1-3 are constitutive
| Glut 4 is insulin-induced
38
hormone producing cells in the islets of the pancreas
beta cells - insulin, amylin
alpha cells - glucagon
delta cells - somatostatin
39
function of the hormones produced by the islets of langerhans
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
40
what cleaves the C peptide in secretory granules?
proconvertases
| leaves A and B chains intact
41
ultra rapid onset/very short action recombinant insulins
lispro
aspart
glulisine
42
rapid onset/short action insulin
regular
43
intermediate onset/action
NPH
44
slow onset/long action
glargine
detemir
degludec
45
what is the purpose of mimicking natural insulin secretion patterns
to provide flexibility/convenience in dosing
| basal levels vs preprandial dose
46
what is NPH insulin
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
47
lispro insulin characteristics
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
48
aspart insulin characteristics
human, except P28 switched to Aspartate
onset 5-15 minutes, short duration
injected before meals
49
glulisine insulin characteristics
human, except Asn3 and Lys29 swapped to Lys & Glu
rapid onset: 5-15 min, short duration
injected immediately before meals
50
glargine characteristics
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
51
detemir characteristics
Thr30 on beta chain is deleted, Lys29 is myristylated (FA)
Binds serum albumin extensively
clear solution, injected twice daily
52
degludec characteristics
similar to detemir
Thr30 of b-chain is replaced by gamma-Glu/C16 FA
binds serum albumin extensively
clear solution, injected twice daily
53
common multi-dose insulin regimens
fast onset, short acting taken before meals
long, or intermediate acting taken at bedtime or at bed time and after breakfast
54
routes of administration for insulin
subcutaneous - all preparation
insulin infusion pump - buffered regular (also rapidly acting - Lyspro, Aspart, Glulisine)
IV - Regular
inhalation - Afrezza
55
characteristics of afrezza
inhaled insulin
regular human insulin in dry powder
rapid onset, shorter duration of action than subQ
used as pre-prandial
56
when is afrezza contraindicated
contraindicated in patients with asthma and COPD
| may reduce lung function (drops FEV)
57
adverse reactions to insulin (aside from the general systemic manifestations)
hypoglycemia - blood glucose
58
how are the adverse reactions of insulin treated
treated with glucose or glucagon
59
agents which increase blood glucose
catecholamines, glucocorticoids, oral contraceptives,
thyroid hormone, calcitonin, somatropin,
isoniazid, phenothiazines, morphine
60
agents which may increase the risk of insulin hypoglycemia
ethanol, ACE inhibitors, somatostatin
fluoxetine, anabolic steroids, MAO inhibitors
beta adrenergic blockers (mask manifestations of hypoglycemia)
61
treatments for type 1 DM
insulin+diet+exercise
62
treatments for type 2 DM
diet + exercise
diet+exercise+oral antidiabetic drugs +/- GLP-1 analogs (SQ)
diet+exerise+insulin
63
requirement for sulfonylurea
must have functioning beta cells
64
effects of sulfonylureas on beta cell insulin release
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
in high glucose states, what is the condition of K+ channel and Ca2+ channel?
K+ channel is closed and bound to ATP
| Ca2+ channel is open -> myosin filaments release insulin granules
66
in low glucose states, what is the condition of K+ channel and Ca2+ channel?
ADP binds to sulfonylurea R and opens K+ channel
| Ca2+ channel is closed
67
examples of sulfonylurea
1st gen: tolbutamide, tolazamide, chlorpropamide
| 2nd gen: glyburide, glipizide, glimepiride
68
function of sulfonylureas
bind to and close K+ channel
69
which generation of sulfonylureas have higher potency
2nd generation of sulfonylureas have higher potency
70
duration of 1st gen sulfonylureas
tolbutamide - 6-12 hours
tolazamide 12-14 hours
chlorpropamide 24-72 hours
71
duration of 2nd gen sulfonylureas
glipizide 12-24 hrs
glyburide 24 hrs
glimepiride 24 hrs
72
characteristic of repaglinide (prandin)
```
mechanism of action similar to sulfonylureas
quick onset, short duration (t1/2 1 hr)
preprandial tablet (0.5-4mg)
```
73
characteristics of nateglinide (starlix)
```
in pancreas vs CV tissue
shorter t1/2 than prandin
60-120mg preprandial
synergistic with metformin
also glufast not yet approved by FDA)
```
74
adverse effects of sulfonylureas
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
what is an adverse effect of enhancing the action of sulfonylureas
increase the risk of hypoglycemia
76
drugs that displace sulfonylureas from protein binding sites
salicylates
phenylbutazone*
sulfonamides*
clofibrate*
*may also decrease the metabolism of sulfonylureas by liver
77
additive drugs to sulfonylureas
alcohol (excessive acute intake)
| high dose salicylates
78
drugs that oppose sulfonylurea action
```
oral contraceptives
corticosteroids
epinephrine
thryoid
thiazide diuretics
```
79
why does oral glucose stimulate larger insulin response than IV glucose
because there is an incretin effect
80
function of GLP-1
```
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
GLP-1 R signaling
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
incretin response in type 2 diabetics is
incretin response is decreased
83
strategies for GLP-1 in Type 2 Diabetics
provide a long-lasting GLP-1 analog
| prevent degradation of endogenous GLP-1
84
benefits of GLP-1
reduces hyperglycemia with low risk hypoglycemia
weight loss
increase beta cell mass?
85
GLP-1 analogs
exenatide
liraglutide
albiglutide
dulaglutide
86
characteristics of exenatide
activates GLP-1 R, from Gila monster saliva
enhances 1st phase secretion
longer t1/2 than GLP-1
87
risks of using exenatide
nausea & vomiting, risk of pancreatitis
88
exenatide is coadministered with
metformin, TzDs, or sulfonylureas
| twice daily injections or once/week
89
characteristics of liraglutide
t1/2 of 13 hours, injected once daily
90
liraglutide is co-administered iwth
metformin, TzDs, and sulfonlyureas
91
risks associated with liraglutide
nausea, vomiting, pancreatitis
| risk of thyroid tumors - monitor
92
characteristics of albiglutide
DDP-IV resistant, GLP-1 dimer
fused to serum albumin
very long half life
injected subQ once a week
93
side effects of albiglutide
nausea, vomiting ,pancreatitis
94
characteristics of dulaglutide
injected subQ once/week
| slows release of GLP-1 agonist peptides from IgG Fc by reducing # of disulfide bonds in linker region
95
risks of dulaglutide
thyroid C-cell tumors
| contraindicated in patients with a family history of medullary thyroid cancer
96
function of DPP-4 (dipeptidyl peptidase 4)
degrades GLP-1
97
examples of DPP-4 inhibitors
sitagliptin
saxagliptin
linagliptin
alogliptin
98
purpose of DPP-4 inhibitors
enhance actions of endogenous GLP-1
99
characteristics of DPP-4 inhibitors
```
administered orally, once daily
reduce hyperglycemia & HbA1c
lower risk of hypoglycemia
may facilitate weight loss
may be co-administered with metformin, TzDs
```
100
metaboliism and excretion of DPP-4 inhibitors
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
side effects of DPP 4 inhibitors
```
nausea
vomiting
constipation
headache
severe skin rxns
```
also reduced WBC, ups infections
potential increased risk of cancers
102
where are DPP-4 also present
on immune cells
103
example and characteristics of amylin analog
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
examples and characteristics of alpha-glucosidase inhibitors
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
adverse effects of alpha-glucosidase inhibitors
diarrhea, nausea, flatulence
acarbose: liver damage possible at doses > 100 mg tid
106
purpose of inhibiting sodium glucose transporter 2
decrease threshold for glucose excretion in urine
| reduce blood glucose levels
107
examples of SGLT2 inhibitors
```
natural product: phlorzin
others: end in gliflozin
ipragliflozin
dapagliflozin
canagliflozin
empagliflozin
tofogliflozin
luseogliflozin
```
108
shared characteristics between SGLT2 inhibitors
orally active
indicated for Type 2 DM as adjunct to diet&exercise
decreases A1c
weight loss
109
shared risks between SGLT2 inhibitors
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
unique risk for dapagliflozin
do not use in patients with bladder cancer
111
causes of insulin resistance
polymorphisms in insulin signaling pathway proteins (rare)
obesity - especially accumulation of fat in the abdominal cavity
inactivity
112
effect of insulin resistance on skeletal muscle, adipose tissue, and liver
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
obesity-induced insulin resistance - role of FA
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
molecular level polymorphisms related to insulin resistance
insulin receptor polymorphism - Ser instead of Tyr phosphorylated -> inhibits signaling
promoted by FA uptake, lipid by-products, inflammatory mediators
115
how does obesity induced inflammation lead to insulin resistance
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
metformin characteristis
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
advantages of metformin over sulonylureas
rarely causes weight gain
| rarely causes hypoglycemia
118
contraindications for metformin
contraindicated in disorders that increase the tendency toward lactic acidosis
decreases vitamin B-12 absorption
119
common side effects of metformin
nausea, vomiting, diarrhea
120
function of thiazolidinediones
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
otehr targets of TzDs
liver -enhances glucose uptke, reduces hepatic glucose prodution
sk. muscle - enhances glucose uptake
122
examples of TzDs
rosiglitazone
| pioglitazone
123
restrictions of TzDs
restricted due to cardiovascular toxicities, NO for CHF
pioglitazone can also increase risk of bladder cancer
some hepatotoxicity
124
factors regulated by PPARgamma
```
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
TzDs' effects on PPARgamma regulated factors
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
key parameters that metformin and TzDs affect
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
