Duan: Insulin & Oral Hypoglycemics Flashcards
Adjusting the amount of (blank) secreted from pancreatic (blank) cells is central in the glucose homeostasis process.
insulin; beta cells
Produce, store, and release (secrete) insulin into the blood at appropriate times in response to blood glucose levels (secretes when blood sugar is high)
beta cells
What happens to insulin in the post-absorptive period?
What happens to insulin after ingestion of a meal?
basal levels of circulating insulin are maintained through constant beta-cell secretion; after a meal, a burst of insulin is secreted in response to elevated glucose & amino acids levels (when glucose levels return to the basal level, insulin secretion returns to basal level, too)
These cells secrete glucagon when blood glucose is low; glucose is released from tissues back into the blood
alpha cells
Where is insulin synthesized? What is it synthesized from?
synthesized in the beta cells of the pancreatic islets of Langerhans; synthesized from proinsulin
Insulin is formed by proteolysis of proinsulin which yields (blank), (blank) and four basic amino acids
insulin; C-peptide
Describe the structure of insulin
insulin has two chains, A & B, joined by two disulfide bonds & one intrachain bond (A chain)
The biologically active form of insulin is the (blank)
monomer
What happens when blood glucose is low? What happens when blood glucose is high?
low blood glucose –> glucagon released from alpha cells of pancreas –> liver releases glucose into blood
high blood glucose –> insulin released by beta cells of the pancreas –> fat cells take in glucose from blood
Describe how glucagon & insulin levels regulate each other
glucagon stimulates insulin release;
insulin inhibits the release of glucagon
These food stuffs stimulate insulin secretion
glucose (orally ingested glucose has a great capacity to stimulate insulin secretion)
amino acids
fatty acids & ketones
By what autonomic mechanisms is insulin release regulated?
ventrolateral (vagal) & ventromedial (sympathetic) hypothalamus
Sympathetic nerve stimulation (exercise, hypoxia, hypothermia, trauma or burns) inhibits insulin secretion through (blank) activation. But (blank) activation increases insulin secretion
alpha receptor; beta2
Parasympathetic (vagal) stimulation or cholinomimetic drugs activate (blank) receptors to increase insulin release.
M receptors
Glucose is the stimulate or insulin release from beta cells. Glucose is transferred into beta cells via (blank). Then, glucose is quickly phosphorylated by (blank), which is the rate limiting step in glucose metabolism in the beta cell. The product glucose-6-phosphate enters the glycolytic pathway, producing ATP and causing changes in NADPH and the ratio of ATP/ADP.
GLUT 1; glucokinase;
So when glucose enters cells and becomes G6P, what downstream effect does this have?
G6P enters the glycolytic pathway & produces ATP. Increased ATP inhibits the ATP-sensitive K+ channel, which depolarizes the cell membrane & opens Ca++ channels. Increased intracellular Ca++ causing insulin containing granules to fuse with the plasma membrane & release insulin & C-peptide into the circulation.
What other factors act in a synergistic fashion to stimulate insulin release?
neurotransmitters (ACh) & hormones (glucagon-like peptide 1) act together with glucose to enhance the secretion of insulin
How is insulin degradation initiated in most tissues?
insulin binds to its receptor –> the insulin-receptor complex is internalized –> proteolytic degradation of insulin via hydrolysis of the disulfide link between the A & B chains –> the receptor returns to the cell surface
What effects does insulin have on the liver?
decreased glucose production
increased uptake of glucose & glycolysis
increased TG synthesis
increased protein synthesis
What effects does insulin have on muscle?
decreased glucose production
increased uptake & glycolysis
increased glycogen deposition
increased protein synthesis
What effects does insulin have on adipose tissue?
decreased glucose production
increased uptake & glycolysis
decreased intracellular lipolysis
increased lipogenesis & LPL activity
The principle targeting tissues for insulin regulation of glucose are (blank x3).
Insulin stimulates utilization and storage of (blank x3) while inhibits breakdown of (blank x3)
liver, muscle, fat;
glucose, aa, fatty acids;
glycogen, protein, fat
Glucose transportation: translocation of (blank) transporters to the cell membrane.
GLUT
Glucose metabolism: increasing (blank) activity, stimulating glycogen synthase and inhibiting glycogen phosphorylase.
glucokinase
Insulin regulates gene transcription of many proteins including crucial metabolic enzymes.
Promotes uptake of (blank) into cells.
K+
The insulin receptor is this kind of receptor
tyrosine kinase
Lack of functional β-cells prevents mitigation of elevated glucose levels and associated insulin responses. 5-10% of US cases (18/100,000)
Type 1 diabetes mellitus
What are the two types of Type 1 diabetes mellitus?
Autoimmune type I diabetes mellitus (type IA): Antibodies against pancreatic b-cells and to glutamic acid decarboxylase
Non autoimmune or idiopathic type I diabetes mellitus (type 1B)
The pancreas retains some β-cell function but effective insulin response is inadequate for the glucose level. Actual insulin levels may be normal or supra-normal but it is ineffective (insulin resistance).
Type II diabetes mellitus
How do type 1 and type 2 diabetes differ in the following ways:
onset? weight? blood insulin level? presence of antibodies against islet cells? ketoacidosis common or rare?
type 1: onset before 20yo, normal weight, markedly decreased blood insulin, anti-islet cell antibodies present, ketoacidosis common
type 2: onset after 30yo, obese, increased blood insulin early on & moderately decreased later, no antibodies, ketoacidosis is rare
Which type of diabetes has a stronger genetic association?
type II
Which type of diabetes has a linkage to MHC class II HLA genes?
type I
How does the pathogenesis of type I differ from type II DM?
type 1: autoimmune destruction of beta cells mediated by immune cells
type 2: insulin resistance in skeletal muscle, adipose tissue, & liver due to beta cell dysfunction & relative insulin deficiency
How do the islet cells differ in type I vs type II DM?
type 1: insulitis, marked atrophy & fibrosis of beta cells, beta cell depletion
type 2: no insulitis, mild beta cell depletion, focal atrophy & amyloid deposition
In diabetic patients, (blank) pose a risk of hypoglycemia due to their inhibition of catecholamines’ gluconeogenesis and glycogenolysis effects.
beta-blockers
What are the symptoms of diabetes?
Polyuria (urinating frequently) Polydipsia (very thirsty) Continuous hunger Weight loss Other symptoms Fatigue Dry skin Frequent infections
What are the complications of diabetes?
Retinopathy Feet ulceration Nephropathy Cardiomyopathy Neuropathy Loss of sensibility in inferior extremities (legs)
Treatment & control of diabetes?
lifestyle changes –> increase physical activity, diet high in fruits in veggies, optimize body weight
medications –> insulin, hypoglycemics, oral agents
There are six classes of oral hypoglycemics that can be used to treat diabetes. What are they?
insulin secretagogues insulin sensitizers alpha-glycosidase inhibitors dipeptidyl-peptidase-4 inhibitors glucagon like peptide analogue sodium glucose cotransporter 2 inhibitors
What should you HbA1C be according to the American Diabetes Association?
What should your fasting glucose levels be like?
Postprandial glucose levels?
Blood pressure?
LDL?
HDL?
TGs?
less than 7.0% 70-130 fasting less than 180 post-prandial bp less than 130/80 LDL less than 100 or less than 70 with CVD HDL greater than 40 or 50 TG less than 150
What are the different forms of insulin analogues?
rapid-acting - onset in 10-15 minutes, last ~4hrs
short-acting - onset in 20 minutes, last ~6.5hrs
intermediate-acting - onset in 1-3hrs, last up to 18hrs
long-acting - onset in 90 mins, last up to 24hrs
Rapid acting insulin analogs
Also classified as ultrashort acting forms due to more rapid onset & shorter duration of action
Insulin Aspart (NovoRapid) Insulin Glulisine (Apidra) Insulin Lispro (Humalog)
(blank) insulin is given 15 minutes prior to a meal and has its peak effect 30-90 minutes after injection
**rapid-acting insulin analogue
Lispro
(blank) can be given anywhere from 15 minutes prior to 20 minutes after beginning a meal.
**rapid-acting insulin analogue
Glulisine
Short acting insulins
Insulin Regular (Humulin-R) Insulin Regular (Novolin Toronto)
Intermediate acting insulins
Insulin NPH (Humulin-N) Insulin NPH (Novolin NPH)
Long acting basal insulin analgogues
Insulin glargine (Lantus) Insulin detemir (Levemir)
The most common and serious adverse effects of insulin is (blank) due to an inappropriately large dose of insulin or insufficient caloric intake
hypoglycemia
(blank) consumption promotes hypoglycemic response.
ethanol
Short term symptoms of hypoglycemia?
Long term symptoms?
sweating, hunger, palpitations, tremor & anxiety, MS changes
long effects: neuroglycopenic symptoms - difficulty concentrating, weakness, drowsiness, unconsciousness
Other side effects of insulin
hypokalemia (insulin moves K+ IN cells)
weight gain
injection problems
Usually short acting forms of insulin are combined with (blank) to achieve blood glucose control
longer acting preparations
The initial calculation of the basal/background and bolus doses of insulin requires estimating total daily insulin (TDI) dose. How do you do this?
TDI requirement = body weight (in lbs) / 4 = body weight (kg) * 0.55
ex: weight 160 lbs
160/4 = 40 units of insulin
What is the basal/background insulin dose?
40-50% of total daily insulin dose
ex: TDI was 40 units, so 40 * 50% = 20 units of insulin
What is the carbohydrate coverage ratio?
CHO coverage ratio = 500 / TDI dose
ex: TDI was 40 units, so 500/40 = 12
1 unit of insulin for every 12gCHO
What is the high blood sugar correction factor?
1800 / TDI
Ex: TDI was 40 units, so 1800 / 40 = 45
1 unit of insulin drops blood sugar by 45mg/dl
So, if S.D. is going to eat 60g of CHO for lunch. She needs to calculate that for every 12g of CHO, she will need 1 unit of insulin. So for lunch, she needs (blank) units of insulin.
5 units
Oral hypoglycemics are orally effective and useful primarily in the treatment of (blank)
type 2 DM when these pts fail to respond to non-medical interventions
What are the first generation sulfonylureas (insulin secretagogues)? Second generation?
tolbutamide, chlorpropamide
glyburide, glipizide, glimepiride
What is the mechanism of action of the sulfonylureas (insulin secretagogues)?
block ATP-sensitive K+ channels, resulting in depolarization –> opening of Ca++ channels –> Ca++ influx promotes insulin secretion
Short acting sulfonylureas
vs
Intermediate acting sulfonylureas
vs
Long acting sulfonylureas
short acting: tolbutamide (6-12hrs)
intermediate acting: glipizide & glyburide
long acting: chloropropamide, glimepiride (~24hrs)
When should sulfonylureas be used clinically?
type 2 DM ONLY!
best with patients who are 40+yo & pts with type 2 DM
Second generation sulfonylureas reduce A1C values by (blank)%
1-2
Adverse effects of sulfonylureas?
weight gain
hyperinsulinemia
hypoglycemia (esp with hepatic or renal insufficiency)
drug-drug interactions
**tolbutamide is associated with 2.5x risk of cardiovascular mortality due to arrhythmias & sudden death
What are the two non-sulfonylureas that are insulin secretagogues?
Rapaglinide
Nateglinide
How do the non-sulfonylureas work? MOA?
block the same K-ATP channels as sulfonylureas and cause secretion of insulin
Non-sulfonylureas typically lower the A1C value by (blank)%
0.5-1.0%
What is the biguanide (insulin sensitizer) we should know? It is the principal biguanide used in clinics
Metformin
How does metformin work? What does it require to be present in order to be effective?
reduces plasma glucose levels by decreasing glucose production by the liver (blocks hepatic gluconeogenesis)
slows the intestinal absorption of sugars
increases peripheral glucose uptake
increases insulin sensitivity
**requires insulin to be effective, but does not promote insulin secretion
The only oral hypoglycemic agent shown to reduce cardiovascular mortality
metformin
What effect does metformin have on lipids?
decreases hyperlipidemia (decreased LDL, VLDL, and increased HDL)
When is metformin used clinically?
first line medication for treatment of type 2 DM
What are the two forms of release of metformin?
immediate release
or
extended-release formulation if a patient is experiencing GI effects
Adverse effects of metformin?
not associated with hypoglycemia (unless combined with other agents) lactic acidosis (serious esp with phenformin & buformin) drug interactions
Metformin is contraindicated in these patients…
renal insufficiency
hepatic insufficiency
CHF & conditions with hypoxemia, dehydration, or sepsis
metabolic acidosis
What are the two thiazolidinediones (insulin sensitizers)?
Pioglitazone
Rosigglitazone
What is the mechanism of action of the thiazolidinediones?
Active nuclear peroxisome proliferator-activated receptor gamma (PPARgamma)
increase insulin sensitivity in adipocytes, hepatocytes, & skeletal muscle
increase insulin-dependent glucose disposal
decrease insulin resistance
When are thiazolidinediones used clinically? Which one can be used in combo with insulin?
used for type 2 DM;
pioglitazone can be used in combo with insulin, while rosiglitazone should not be
Thiazolidinediones undergo extensive (blank) metabolism
P450
Adverse effects of thiazolidinediones?
fatal hepatotoxicity (must monitor hepatic function) decrease/interact with oral contraceptives possible link with bladder cancer (pioglitazone)
May cause or exacerbate congestive heart failure. After initiation and dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). Initiation of these drugs in patients with established NYHA Class III or IV heart failure is contraindicated
Pioglitazone
What is the alpha-glucosidase inhibitor we should know?
Acarbose
What is the mechanism of action of acarbose (alpha-glucosidase inhibitor)?
inhibits the intestinal alpha-glucosidases (hydrolyze carbohydrates to their components)
also blocks pancreatic alpha-amylase (hydrolyzes complex starches to oligosaccharides in the small intestine)
Acarbose decreases A1C levels by (blank)%
0.5-1.0%
When are alpha-glucosidase inhibitors used clinically? When are they taken?
type 2 DM;
taken with first bite of meal
Acarbose is poorly absorbed here but exerts its effects here
intestinal lumen
Adverse effects of alpha-glucosidase inhibitors (Acarbose)?
GI - flatulence, diarrhea, cramping - start with a low dose, don’t use in diabetics with intestinal pathology
hypoglycemia - can only be corrected with monosaccharide glucose tablets or gel
hepatitis - check liver enzymes before & during use
decreases metformin bioavailability when used in conjunction
When are alpha-glucosidase inhibitors contraindicated?
IBS, intestinal disorders, increased gas formation in the intestine, diabetic ketoacidosis or cirrhosis
Naturally occurring hormones that the gut releases throughout the day; the level of active incretins increases significantly when food is ingested.
Incretins
Two major incretins that facilitate the response of the pancreas & liver to glucose fluctuations through their actions of beta and alpha cells
GIP - glucose-dependent insulinotropic peptide
glucagon-like peptide 1 (GLP-1)
What happens to the effect of incretins in type 2 diabetes?
incretin effect is diminished - release of GLP-1 is defective & GLP-1 levels are increased
the insulinotropic response to GIP is diminished, but not absent
DPP-4 inhibitor (incretin-based therapy)
Sitagliptin (Januvia)
What is the mechanism of action of the DPP-4 inhibitors?
reduce blood glucose levels by inhibiting DPP-4 & increasing levels of GIP & GLP-1
When are the DPP-4 inhibitors (Sitagliptin) used clinically?
type 2 DM alone or in combo with metformin or a thiazolidinedione
**fewer side effects, but lower efficacy
Important adverse effects of DPP-4 inhibitors, like Sitagliptin?
Heart failure (saxagliptin)
pacreatitis
renal failure & hypersensitivity reactions
rare nausea & common cold-like symptoms
no significant hypoglycemia when used alone
What is the glucagon-like peptide analogue we should know?
Exenatide
What is the mechanism of action of the glucogon-like peptide analogues?
augment the pancreas’ response to eating meals –> results in higher, more appropriate amounts of insulin that help lower the rise in blood sugar from eating. Once blood sugar levels decrease to normal values, the pancreas’ response to produce insulin is reduced
also suppresses pancreatic release of glucagon in response to eating, which helps stop the liver from overproducing sugar when it is unneeded
slows down gastric emptying –> decreases the rate at which meal-derived glucose appears in the bloodstream
When is the GLP-1 analogue exenatide used clinically?
As an adjunctive therapy, approved by the FDA as a substitute for mealtime insulin;
exenatide is indicated to improve glycemic control in patients with type 2 DM who are taking metformin, a sulfonylurea, thiazolidinediones, or a combination of metformin and sulfonylurea or thiazolidinediones, but who have not been able to achieve adequate control of blood glucose
Main adverse effects of GLP-1 analogues like exenatide?
GI disorders - acid/sour stomach, belching, diarrhea, indigestion
What is the sodium glucose cotransporter 2 inhibitor that we should know?
Jardiance (empagliflozin)
How do sodium glucose cotransporter (SGLT) 2 inhibitors work?
block reabsorption of glucose by the kidneys, increasing glucose excretion in urine & lowering blood sugar in patients with diabetes
Jardiance (SGLT2 inhibitor) is contraindicated in these patients…
patients with kidney problems
When treating diabetes, what is the time frame you are looking at? About how many months after diagnosis, should you be within your target A1C range?
within 3-6 months
If your initial A1C is less than 8.5%, what should you do?
start metformin
or
reassess in 2-3 months then decide on starting metformin
If your initial A1C is greater than 8.5%, what should you do?
start metformin
&
consider combo therapy to reduce A1C by more than 1.5
What should you do if your patient already has symptoms from hyperglycemia & metabolic compensation?
start insulin +/- metformin
These diabetic therapies can cause hypoglycemia…
insulin
insulin secretagogues
sulfonylureas
These diabetic therapies cause the most weight gain
insulin
TZD
These diabetic therapies have the greatest effects on lowering A1C
insuln
GLP-1 receptor agonists
This diabetic therapy is safe regardless of the GFR
repaglinide
Again, what should be done for patients if glycemic targets are not achieved with lifestyle management within 2-3 months?
metformin at time of diagnosis + lifestyle management
If A1C is greater than 8.5%, give antihyperglycemic agent + lifestyle management + consider combination therapy
If symptomatic hyperglycemia & metabolic decompensation, give initial med regimen containing insulin
(blank) should be the initial drug used for overweight patients
metformin
If glycemic targets are not met within 3-6 months, what should be done?
add other classes of antihyperglycemic agents to metformin regimen
When basal insulin is added to antihyperglycemic agents, (blank) may be used instead of intermediate-acting NPH to reduce the risk of nocturnal and symptomatic hypoglycemia
long acting analogues
When bolus insulin is added to antihyperglycemic agents, (blank) may be used instead of regular insulin to reduce the risk of hypoglycemia
rapid-acting analogues
A useful measure of glucose control over the prior 3-6 months, hyperglycemic episodes result in the nonspecific glycosylation of various proteins.
HA1C
What is the trade off between standard & intensive treatment of diabetes?
intensive treatment leads to more frequent hypoglycemic events, but a substantial decrease in incidence of long-term complications like retinopathy & nephropathy
