Term
|
Definition
• Small endogenous protein synthesized in
the pancreas
• secretion
- Low basal rates continuously released
- Boluses released in response to stimuli • Glucose • Incretins • Vagal nerve stimulation |
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Term
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Definition
Here, we have a pancreatic beta cell. And as you can see on the surface, we have glucose transporters, potassium channels, as well as calcium channels. All of these work together to ultimately result in insulin secretion, which you see in the center of the cell there. In a resting beta cell, you'll notice that there is ATP present. However, it's in low levels. ATP will work on the potassium channel, and you'll ultimately see potassium exiting that beta cell resulting in blockade of that calcium channel.
In the secreting beta cell state, we have the glucose transporter. Glucose enters the cell. It's then metabolized into ATP. So we have very high levels of ATP that results in blockade of that potassium channel. This ultimately results in depolarization. And that calcium channel that was blocked with the low ATP levels opens up. We have calcium entering the cell. We have higher levels of calcium, which then triggers release of insulin into circulation. |
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Term
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Definition
• Cleared via liver and renal pathways
- Endogenous insulin = 60% hepatic clearance
- Exogenous insulin = 60% renal clearance
• Half-life circulating insulin = 3–5 minutes |
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Term
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Definition
• Promotes storage of fat and glucose
• Influences cell growth
• Promotes tissue metabolic functions |
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Term
|
Definition
Anti-catabolic effects
• Inhibits glycogenolysis
• Fatty acid and amino
acid inhibition to
keto acids
• Inhibits amino acid
conversion to glucose
Anabolic effects
• Increased glucose
storage as glycogen
• Increased triglyceride
synthesis
• Increased VLDL
synthesis |
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Term
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Definition
• Increased protein
synthesis
• Increased glycogen
synthesis |
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Term
| Insulin Effects: Adipose Tissue |
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Definition
• Increased triglyceride
storage
• Triglyceride hydrolysis
from lipoproteins
• Intracellular lipase
inhibition
• Fatty acid esterification |
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Term
|
Definition
- Human insulin:
• Regular (R)
• Neutral protamine hagedorn (NPH)
- Human insulin analogs:
• Insulin lispro
• Insulin aspart
• Insulin glulisine
• Insulin glargine
• Insulin detemir
• Insulin degludec |
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Term
|
Definition
Lispro
Aspart
Glulisine
Rapid, onset: 5–15min peak: 1–1.5hr duration: 3–4hr
Regular
Short, onset 30–60min, peak 2 hr. duration: 6–8 hr |
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Term
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Definition
Insulin Type Onset (hr) Peak (hr) Duration (hr)
NPH Intermediate 2–4 6–7 10–20
Levemir Long 0.5–1 - 17
Glargine Long 0.5–1 - ~24
Degludec Long 0.5–1.5 - >42 |
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Term
|
Definition
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Term
|
Definition
• Dry powder formulation
of regular insulin
• After inhalation:
- Peak level: 12–15
minutes
- Maximum effect: 1 hour
- Duration of action: 3
hours |
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Term
has Adverse Effects:
- Cardiovascular
• Peripheral edema
- Dermatologic
• Erythema at injection site
• Injection site pruritis
- Endocrine/Metabolic
• Hypoglycemia
• Hypokalemia
• Weight gain
- Local
• Hypertrophy at injection site
• Lipoatrophy at injection site
- Hypersensitivity
• Anaphylaxis
• Hypersensitivity reaction |
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Definition
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Term
| Which insulin below is appropriate to use as a basal insulin? |
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Definition
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Term
| Pathophysiology: Type II Diabetes |
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Definition
[image]
In the management of type 2 diabetes, there's been a tremendous growth in non-insulin regimens. Classically, with the pathophysiology of type 2 diabetes, we focus on a triumvirate-- first, impairment of insulin secretion because our beta cells are tired. They're not secreting enough insulin. Next, there's decreased glucose uptake, known as insulin resistance. Lastly, there's increased glucose production from the liver. All this culminates into hyperglycemia. |
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Term
| The Ominous Octet Transition |
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Definition
[image]
Research has shown that type 2 diabetes is much more complicated, and it's transitioned to this ominous octet. So we see decreased insulin secretion resulting in hyperglycemia; decreased effects of incretin hormones; increased lipolysis; increased glucose re-absorption-- so we're holding onto more glucose from the kidneys; decreased glucose uptake from the muscle-- so we still have that underlying insulin resistance; neurotransmitter changes; increased hepatic glucose production; and lastly, increased glucagon secretion from the islet of alpha cells in the liver.
Luckily, this gives us more potential targets in the management of type 2 diabetes. And of course, the classic one is targeting that decreased insulin secretion. |
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Term
| Increase Endogenous Insulin Secretion Drugs |
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Definition
- Sulfonylureas
• Second Generation • Glyburide • Glipizide • Glimepiride
- Meglitinide analogs • Repaglinide
- D-phenylalanine derivatives • Nateglinide |
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Term
|
Definition
| Let's go back to that pancreatic beta cell. You'll see the glucose transporter, potassium channel, as well as the calcium channel. We'll have the sulfonylureas, repaglinide, and nateglinide come in, and it'll block that potassium channel. This will result in depolarization of that cell, resulting in an influx of calcium, raising intracellular calcium levels, which in turn results in insulin excretion out of that pancreatic beta cell. |
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Term
has Adverse Effects:
• Hypoglycemia
• Flushing with
alcohol ingestion |
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Definition
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Term
has Adverse effects:
• Hypoglycemia |
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Definition
Glipizide, Glimepiride (sulfonylurea)
• Repaglinide
• Nateglinide
(Meglitinide and DPD) |
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Term
Renally eliminated active
metabolites |
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Definition
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Term
• Shortest half-life
• Food delays absorption
• Contraindicated in significant
hepatic impairment |
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Definition
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Term
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Definition
| Glimepiride (sulfonylurea) |
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Term
• Fast onset of action
• Skip meal -> skip dose
• Hepatic metabolism |
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Definition
• Repaglinide
• Nateglinide |
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Term
| Metformin: Mechanism of Action |
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Definition
Activates AMP-activated protein kinase
(AMPK)-
-skeletal muscle effects:
• Decreased gluconeogenesis
• Decreased glycogenolysis
• Decreased fatty acid oxidation
-adipose tissue effects:
• Increased glucose uptake in
visceral fat
• Decreased lipogenesis
• Increased fatty acid oxidation
• Modulation adipokine secretion |
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Term
has Adverse Effects:
-Gastrointestinal: • Nausea, vomiting, diarrhea
-Endocrine: • Vitamin B12 deficiency
-Lactic Acidosis: • Rare • Associated with renal failure • Adjust dose in declining renal function • Check renal function annually |
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Definition
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Term
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Definition
Activate peroxisome proliferator-activated
receptor gamma
-Hepatic effects:
• Decreased gluconeogenesis
• Increased fatty acid oxidation
• Decreased lipid accumulation
-skeletal muscle effects:
• Increased glucose uptake
• Decreased lipid accumulation
-adipose tissue effects:
• Increased fatty acid uptake
• Increased lipogenesis
• Increased glucose uptake |
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Term
Has Adverse Effects:
• Fluid retention
• Contraindication:
NYHA class III and IV
HF
• Macular edema
• Decreased bone
mineral density
• Atypical fractures
• Weight gain |
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Definition
| Pioglitazone, Rosiglitazone (Thiazolidinediones) |
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Term
• Lowers triglycerides
• Increases HDL |
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Definition
| Pioglitazone (Thiazolidinediones) |
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Term
• Increases all lipid
values except
triglycerides
• Cardiac controversy |
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Definition
| Rosiglitazone (Thiazolidinediones) |
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Term
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Definition
• Gut hormones released in response to
oral glucose
• Principal hormones:
- GLP-1
- Glucose-dependent insulinotropic peptide
(GIP) |
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Term
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Definition
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Term
GLP-1 Hormone
• Rapidly degraded by: |
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Definition
• Dipeptidyl peptidase 4 (DPP-4)
• Endopeptidase 24.11
• Kidney
• Half-life: 1.5–5 minutes |
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Term
|
Definition
Exenatide
Liraglutide
Albiglutide
Dulaglutide |
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Term
Has Adverse Effects:
• Pancreatitis
• Nausea, vomiting, diarrhea
• Renal impairment and acute kidney injury
- Exenatide
• Thyroidal C-cell tumors
- Avoid in persons with history of
medullary thyroid cancer or multiple
endocrine neoplasia syndrome type 2 |
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Definition
Exenatide
Liraglutide
Albiglutide
Dulaglutide
(GLP-1 Receptor Agonists) |
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Term
has Adverse Effects:
• Nasopharyngitis, upper respiratory
infection
• Headaches
• Pancreatitis
- Sitagliptin, linagliptin
• Severe allergic reaction
• Hypoglycemia with insulin secretagogues
or insulin
• Increased risk of heart failure
- Saxagliptin |
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Definition
Sitagliptin
Saxagliptin
Linagliptin
Alogliptin
(DPP-4 Inhibitors) |
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Term
|
Definition
Now, the one area we haven't covered here is the increased glucose re-absorption. This is mainly controlled by the sodium-glucose co-transporter 2. Here, we'll have glucose entering the nephron. SGLT2 will reabsorb that glucose-- about 90% re-absorption. The rest is absorbed later on in the distal tubule. Ultimately, what this means is that there is no glucose in the urine.
In our type 2 diabetic patient, we might want to get rid of some of that glucose in the urine. So this is where SGLT2 inhibitors play a role. They block SGLT2, which causes the majority of glucose re-absorption, resulting in glycosuria. So patients are dumping glucose into their urine, thus lowering their plasma glucose levels. |
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Term
Has Adverse Effects:
• Increased genital infections
and UTIs
• Hypotension
• Diabetic ketoacidosis
- Type I DM |
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Definition
| Canagliflozin, Dapagliflozin, Empagliflozin (SGLT2 Inhibitors) |
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Term
has Adverse Effects:
• Increase in LDL
• Increased fracture
risk
• Decreased BMD
• Increased risk of leg
and foot
amputations |
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Definition
| Canagliflozin (SGLT2 Inhibitor) |
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Term
Contraindicated with
eGFR <45 mL/min |
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Definition
| Canagliflozin (SGLT2 Inhibitor) |
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Term
Has Adverse Effect:
• Increased breast
and bladder cancer
risk |
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Definition
| Dapagliflozin (SGLT2 Inhibitor) |
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Term
eGFR <60 mL/min
not recommended |
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Definition
| Dapagliflozin (SGLT2 Inhibitor) |
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Term
Has Adverse Effect:
• Increase in LDL |
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Definition
| Empagliflozin (SGLT2 Inhibitor) |
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Term
• Contraindicated with
eGFR <45 mL/min
• EMPA-REG study |
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Definition
| Empagliflozin (SGLT2 Inhibitor) |
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Term
| Type II DM Treatment Algorithm |
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Definition
Weight Loss + Exercise + Metformin ->
Metformin + Another Agent ->
Metformin + Two Other Agents ->
Metformin + More Complex Insulin Regimen +/- Non-Insulin Agent |
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Term
| Type II DM Treatment Considerations |
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Definition
• Agent efficacy
• Hypoglycemic risk
• Effect on weight
• Adverse effects
• Cost |
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Term
• Mr. G is a 58-year-old male
• PMH: Type II DM and HTN
• Trialed three months of metformin + nonpharmacologic
therapy
• Slight HbA1c lowering
-• Patient concerns:
• Weight gain
• Hypoglycemia |
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Definition
• Possible options:
• GLP-1 agonists
• DPP-4 inhibitor
• SGLT-2 inhibitor |
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Term
• Mrs. S is a 68-year-old female
• PMH: Type II DM, HTN, asthma
• Trialed on metformin for six months + nonpharmacologic
therapy
• HbA1c = 9%
• Patient concerns:
• Cost
• Injections |
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Definition
• Possible options:
• Sulfonylurea |
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Term
|
Definition
• Peptide synthesized in alpha cells of
pancreatic islets of Langerhans
• Metabolic effects:
- Glycogen catabolism
- Increases gluconeogenesis and ketogenesis |
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Term
| Glucagon: Mechanism of Action |
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Definition
Glucagon released from pancreatic
alpha cells ->
Binds to hepatic Gs protein-coupled
receptors ->
Glycogen catabolism via cAMP
increase ->
Increased blood glucose |
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Term
Has Adverse Effects:
-Cardiac
• Potent cardiac inotropic and chronotropic
effects • Via cAMP upregulation pathway
• Clinical implication: • Similar effects to beta-agonist |
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Definition
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Term
|
Definition
• Severe hypoglycemia
- Emergency treatment in patients unable to
take oral or intravenous glucose
• Endocrine diagnosis
- Classic research test to assess beta-cell
secretory reserve
• Beta-blocker overdose
- Increase cAMP production in heart with no
functional beta-receptors
• Bowel radiology
- Relaxes bowel aiding x-ray visualization |
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Term
| Which medication below is an appropriate treatment for hypoglycemia? |
|
Definition
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