Diabetes Flashcards
(138 cards)
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)
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
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
4
Q
What are common autoantibodies found in type I diabetics?
A
ICA- islet cell cytoplasmic autoantibodies
IAA- insulin autoantibodies
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.
6
Q
At what point does a type I diabetic begin to have abnormal FBG?
A
When >70% of beta cell mass is lost
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)
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
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
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)
11
Q
What are complications of diabetes?
A
- cardiovascular micro and macro angiopathies
- Neuropathy
- cataracts
- nephropathy
- susceptibility to infections
12
Q
Goals of insulin therapy
A
- reduce symptoms of diabetes
- keep average blood glucose levels below 150mg/dL
- prevent/delay onset of complications
13
Q
What causes diabetic ketoacidosis?
A
uncontrolled oxidation of fatty acids (accumulation of ketone bodies) (byproduct organic acid)
14
Q
What functional group in glucose makes it reactive?
A
aldehyde
15
Q
What products can glucose be oxidized into?
A
reactive dicarbonyls
- glyoxal
- methylglyoxal
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
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
18
Q
What happens when rage is bound?
A
inflammation
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
20
Q
What pathway is aldose reductase in?
A
polyol pathway
21
Q
What is a result of polyol pathway?
A
neuropathy
22
Q
what/where is hexosamine pathway?
A
F6P accumulates; causes changes in protein function
23
Q
What is rate-limiting step of glucose utilization?
A
fructose-6-phosphate –> G3P
24
Q
What happens in the protein kinase C pathway?
A
Buildup of G3P activates protein kinase C inappropriately; protein modification
25
What is the AGE pathway?
buildup of G3P (due to oxidative stress), oxidized glucose (methylglyoxal) reacts with proteins to form AGE; causes loss in protein function and chronic inflammation
26
What is the effect of methylglyoxal on cardiovascular tone?
- ACh and Nitric Oxide unable to relax smooth muscle
- local control of cardiovascular tone lost
27
What kind of receptor is the insulin receptor?
- receptor tyrosine kinase
28
What is the role of a-subunits in the insulin receptor?
- represses the catalytic activity of the beta subunit
29
How does insulin binding activate the insulin receptor?
- relieves the repression of beta subunit catalytic activity by binding
30
What is the role of beta subunits in the insulin receptor?
- contain tyrosine kinase catalytic domains
- autophosphorylate
31
Phosphorylation of what causes a rise in lipogenesis when insulin binds to the insulin receptor?
MAPK
32
What causes an increase in glycolysis when insulin binds to the insulin receptor?
PI3K
33
What is the effect of insulin binding ?
- increased lipogenesis
- increased glycolysis
- increased glycogen synthesis
- increased gluconeogenesis
34
What is the impact of insulin on the liver?
- inhibits glycogenolysis
- inhibits ketogenesis
- inhibits gluconeogenesis
- stimulates glycogen synthesis
- stimulates triglyceride synthesis
35
What is the impact of insulin on the skeletal muscle?
- stimulates glucose transport and amino acid transport
36
What is the impact of insulin on the adipose tissue?
- stimulates triglyceride storage
- stimulates glucose transport
37
Where does glucose get disposed/ used in the fasting state?
- 75% non-insulin dependent: Liver, GI, Brain
- 25% insulin dependent: skeletal muscle
- glucagon is secreted
38
Where does glucose get disposed/used in the fed state?
- 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
39
How do serum FFA levels impact insulin action/sensitivity?
- decreased serum FFA enhances insulin action and reduces hepatic glucose production
- increased FFA levels may decrease insulin sensitivity
40
Which glucose transporter stimulates secretion of insulin?
GLUT2 (located in beta cells; tells beta cells when to secrete insulin)
gets last dibs per km
41
What does glut3 do?
- located in nervous system; transports glucose to neurons
- gets first dibs per km
42
Which glucose transporter is insulin induced?
GLUT4!
located on skeletal muscle and adipocytes
43
What do pancreatic alpha cells produce?
glucagon
44
What do pancreatic beta cells produce?
insulin, amylin
45
what do pancreatic delta cells produce?
somatostatin
46
Effect of glucagon?
stimulates glycogen breakdown; increases blood glucose
47
Effect of somatostatin?
General inhibitor of insulin/glucagon secretion
48
Effect of insulin?
Stimulates uptake and utilization of glucose
49
effect of amylin?
co-secreted with insulin to slow gastric emptying, decrease food intake, and inhibit glucagon secretion; also reduced blood glucose
50
How is insulin processed?
Cleaved to A&B chains and c-peptide by proconvertases; causes oxidative stress if too much insulin is produced; b-cell death
51
What Regular human insulins are available?
humulin
novolin
52
What are the ultra rapid-onset, very short acting insulins?
- Lispro (Humalog)
- Aspart (Novolog)
- Glulisine (Apidra)
53
What are the rapid onset/ medium- to short acting insulins?
Regular (R) human insulin
- Humulin, Novolin
54
What are the intermediate acting insulins?
NPH (N)
55
What are the slow-onset, long acting insulins?
- glargine (Lantus)
- detemir (Levemir)
- degludec (Tresiba)
56
How did the lente insulins work?
zinc/insulin precipitates; larger complex size of insulin and zinc = more prolonged absorption
57
How does NPH insulin work?
Complex of protamine and insulin;
protamine binds insulin ionically; slow absorption, long duration of action.
58
How does lispro (humalog) work?
- 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
How does insulin aspart (novolog) work?
- 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
How does glulisine (Apidra) work?
- 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
How was insulin glargine (lantus) work?
- solubility altered at physiologic pH
- clear, buffered solution at pH = 4
- precipitates when neutralized at pH = 7
- once daily injection
62
How does insulin detemir work? (levemir)
- 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
How does insulin degludec work?
- binds serum albumin; added fatty acid chain
- same as levemir + intermediate glutamate linker
- injected once daily
64
What are common insulin pre-mixtures?
- NPH + Regular (humulin 70/30)
- NPL (neutral protamine Lispro + Lispro)
Humalog 75/25 or Humalog 50/50
65
What is Afrezza?
Regular human insulin in a dry powder
66
What are the characteristics of Afrezza?
Rapid onset; short duration of action
67
What are contraindications for Afrezza?
Asthma and COPD; may decrease FEV
68
Which insulins are injected subQ?
All of them
69
Which insulins can be used with an infusion pump?
Buffered Regular; Also fast acting: lispro, aspart, glulisine
70
Which insulins can be used IV?
Regular only (for hyerglycemia or ketoacidosis or hyperkalemia)
71
Mode of action for insulin?
- decreased liver glucose output
- increased fat storage
- increased glucose uptake
72
What is hypoglycemia?
- blood glucose less than 60 mg/dL
- too much insulin
73
Signs of hypoglycemia?
tremors, weakness, fatigue, sweating, hunger, irritability, tachycardia, blurred vision, seizures, coma
- treat with glucose or glucagon
74
side effects of insulin?
lipodystrophy- changes in subcutaneous fat at any overused injection site. can include lipohypertrophy or lipoatrophy
75
What causes lipoatrophy?
antibodies against insulin
76
Agents that increase blood glucose
catacholamines, thyroid hormone, isonazid, glucocorticoid, calcitonin, phenothiazines, oral contraceptives, somatropin, morphine
77
agents that increase risk of hypoglycemia
ethanol, ACE inhibitors, fluoxetine, somatostatin, anabolic steroids, MAO inhibitors, B-blockers, vigorous exercise
78
What is treatment for type I diabetes?
insulin + diet + exercise
79
What is treatment for type II diabetes?
tiered:
I) diet and exercise
II) diet and exercise and antidiabetic drugs
III) diet and exercise and antidiabetic drugs and insulin
80
What are 2 components of pathophysiology of type II diabetes?
insulin resistance in target tissues; reduced insulin secretion
81
Which drugs increase insulin secretion?
- sulfonylureas
- meglitinides
- incretins
82
Which drugs limit hepatic glucose output?
- metformin
- thiazolidinediones
83
Which drugs inhibit glucagon secretion?
- incretins
-amylin
84
Which drugs limit glucose reabsorption?
- SGLT-2 Inhibitors
85
Which drugs increase glucose uptake and utilization?
- thiazolidinediones
- metformin
86
What are the sulfonylureas?
tolbutamide, tolazamide, chlorpropamide, glyburide, glipizide, glimepiride
87
What are the meglitinides?
nateglinide, repaglinide
88
How do sulfonylureas work?
- increased release of insulin
- increased beta cell sensitivity to glucose and increase glucose-stimulated insulin release
89
are sulfonylureas glucose dependent?
no
90
What molecule do sulfonylureas act as in the pancreatic beta cell?
ATP
91
What are the 1st gen sulfonylureas?
tolbutamide, tolazamide, Chlorpropamide
92
What are the 2nd gen sulfonylureas?
glipizide, glyburide, glimepiride
93
Meglitinide MOA?
- acts like sulfonylurea BUT short duration of action and quick onset; taken preprandially
- non-sulfonylurea hypoglycemic agent
94
Meglitinide MOA?
Katp Channel blocker
95
Sulfonylurea MOA?
Katp Channel blocker
96
What are adverse effects of sulfonylureas?
- prolonged hypoglycemia due to long half life
- risk of cardiovascular events/ mortality
- GI problems
- Weight gain
- may lead to decrease in BCM
97
What are drugs that interact with sulfonylureas?
- salicylates
- phenylbutazone
- sulfonamides
**reduce metabolism/displace from plasma proteins** = increase in free concentration
- alcohol
98
What drugs cause hyperglycemia/oppose the action of insulin and sulfonylureas?
- oral contraceptives
- corticosteroids
- epinephrine
- thyroid hormone
- thiazide diuretics
99
What are the GLP-1R agonists?
Exenatide, Liraglutide, Lixenatide, Dulaglutide, Semaglutide
100
What is the GLP-1 and GIP dual agonist?
Tirzepatide (mounjaro)
101
What are the DPP-IV inhibitors?
Saxagliptan, sitagliptan, linagliptan, alogliptan
102
What is an amylin analogue?
pramlintide
103
What does GLP-1 stand for?
glucagon-like peptide 1
104
What does DPP-IV do?
It is a protease that degrades GIP and GLP-1
105
What are incretins?
hormones released by the small intestine
106
What does GLP-1 do?
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
is GLP-1 glucose dependent?
Yes! Insulin secretion by stimulation by GLP-1 is glucose dependent
108
What does the GLP-1 receptor do?
Signals to increase cAMP and Ca2+ (amplified insulin secretion)
109
What is liraglutide (victoza)?
GLP-1 analogue; can be co-administered with metformin and TzDs
injected daily; is a small peptide
110
What is dulaglutide? (trulicity)
GLP-1 agonist;
injected weekly; binds to antibody with disulfide bond
111
When are GLP-1s contraindicated?
Risk or family history of thyroid cancer; monitor calcitonin
112
What is semaglutide? (ozempic/wegovy)
GLP-1 agonist with long fatty acid tail; binds to serum albumin; injected once weekly.
113
What is Rybelsus?
Oral semaglutide; GLP-1 agonist; dosed daily due to poor absorption
114
What are Soliqua/Xulotophy?
basal insulin/GLP-1 receptor agonist combos
115
What is mounjaro?
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
What do DPP-4 inhibitors do?
Inhibit incretin (GLP-1) proteolysis; enhance actions of endogenous GLP-1; competitive inhibitor for proteolysis; technically positive allosteric modulators of GLP-1
117
What are the DPP-4 inhibitors?
Sitagliptan (januvia), Linagliptan (Trajenta)
118
DPP-4 inhibitor administration?
Oral; once daily; low risk for hypoglycemia; weight neutral
- can be co-administered with metformin and TzDs
119
Where is januvia excreted?
Kidney
120
Where is Tradjenta excreted?
Liver
121
Where is onglyza metabolized/excreted?
Kidney; active major metabolite
122
DPP-IV inhibitor side effects
Nausea, vomiting, constipation, HA, Skin rxn, pancreatitis, joint pain, HF exacerbation; risk for increased infections and cancer???
123
What is pramlinitide? (symlin)
Amylin analogue; slows gastric emptying, decreases food intake, inhibits glucagon secretion; used in conjunction with insulin; blunts postprandial rise in BG
124
What are the a-glucosidase inhibitors?
acarbose, miglitol-- look like sugars
125
What are the SGLT-2 ingibitors?
Canagliflozin, empagliflozin, dapagliflozin, ertugliflozin
126
MOA for a-glucosidase inhibitors?
decrease absorption of carbohydrate from the intestine: inhibits sucrase, maltase, gluocoamylase = less glucose in blood stream after meal
127
Adverse effects of a-glucosidase inhibitors?
diarrhea, nausea, flatulence; risk of liver damage from acarbose
128
SGLT-2 inhibitor MOA/Strategy
Reduce blood glucose levels by preventing reabsorption of glucose (and sodium) into blood through the SGLT-2 transporter
129
SGLT-2 inhibitor in therapy
indicated TIDM with diet and exercise; can be used with metformin and sulfonylureas
130
SGLT-2 side effects and risks
- genital/UTI infections risk
- hypotension
- increased risk of DKA
- contraindicated in patients with renal impairment
- lower limb amputation with invokana
131
What are the drug classes that reduce insulin resistance?
- biguanides (metformin)
- Thiazolidinediones (pioglitazone)
132
What causes insulin resistance?
obesity and inactivity
133
How does increasing free fatty acids impact insulin?
causes insulin resistance in the cells and tissues
134
activation of what by excess fatty acids causes insulin resistance?
MTOR
135
What is the MOA for Metformin? (a biguanide)
activator of AMP-activated kinase (AMPK) helps with cell signaling and insulin sensitivity; skeletal muscle in liver
136
What is the MOA for thiazolidinediones?
Works primarily in adipocytes; enhance FFA uptake; reduces serum FFA
137
THIAZOLIDINEDIONES contraindications
bad liver function (may cause hepatotoxicity); Heart failure;
DO NOT USE IN GESTATIONAL DIABETES
138
