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Block 10 Week 2 > Duan: Insulin & Oral Hypoglycemics > Flashcards

Duan: Insulin & Oral Hypoglycemics Flashcards

1
Q

Adjusting the amount of (blank) secreted from pancreatic (blank) cells is central in the glucose homeostasis process.

A

insulin; beta cells

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2
Q

Produce, store, and release (secrete) insulin into the blood at appropriate times in response to blood glucose levels (secretes when blood sugar is high)

A

beta cells

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3
Q

What happens to insulin in the post-absorptive period?

What happens to insulin after ingestion of a meal?

A

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)

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4
Q

These cells secrete glucagon when blood glucose is low; glucose is released from tissues back into the blood

A

alpha cells

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5
Q

Where is insulin synthesized? What is it synthesized from?

A

synthesized in the beta cells of the pancreatic islets of Langerhans; synthesized from proinsulin

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6
Q

Insulin is formed by proteolysis of proinsulin which yields (blank), (blank) and four basic amino acids

A

insulin; C-peptide

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7
Q

Describe the structure of insulin

A

insulin has two chains, A & B, joined by two disulfide bonds & one intrachain bond (A chain)

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8
Q

The biologically active form of insulin is the (blank)

A

monomer

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9
Q

What happens when blood glucose is low? What happens when blood glucose is high?

A

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

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10
Q

Describe how glucagon & insulin levels regulate each other

A

glucagon stimulates insulin release;

insulin inhibits the release of glucagon

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11
Q

These food stuffs stimulate insulin secretion

A

glucose (orally ingested glucose has a great capacity to stimulate insulin secretion)
amino acids
fatty acids & ketones

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12
Q

By what autonomic mechanisms is insulin release regulated?

A

ventrolateral (vagal) & ventromedial (sympathetic) hypothalamus

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13
Q

Sympathetic nerve stimulation (exercise, hypoxia, hypothermia, trauma or burns) inhibits insulin secretion through (blank) activation. But (blank) activation increases insulin secretion

A

alpha receptor; beta2

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14
Q

Parasympathetic (vagal) stimulation or cholinomimetic drugs activate (blank) receptors to increase insulin release.

A

M receptors

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15
Q

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.

A

GLUT 1; glucokinase;

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16
Q

So when glucose enters cells and becomes G6P, what downstream effect does this have?

A

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.

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17
Q

What other factors act in a synergistic fashion to stimulate insulin release?

A

neurotransmitters (ACh) & hormones (glucagon-like peptide 1) act together with glucose to enhance the secretion of insulin

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18
Q

How is insulin degradation initiated in most tissues?

A

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

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19
Q

What effects does insulin have on the liver?

A

decreased glucose production
increased uptake of glucose & glycolysis
increased TG synthesis
increased protein synthesis

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20
Q

What effects does insulin have on muscle?

A

decreased glucose production
increased uptake & glycolysis
increased glycogen deposition
increased protein synthesis

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21
Q

What effects does insulin have on adipose tissue?

A

decreased glucose production
increased uptake & glycolysis
decreased intracellular lipolysis
increased lipogenesis & LPL activity

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22
Q

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)

A

liver, muscle, fat;
glucose, aa, fatty acids;
glycogen, protein, fat

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23
Q

Glucose transportation: translocation of (blank) transporters to the cell membrane.

A

GLUT

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24
Q

Glucose metabolism: increasing (blank) activity, stimulating glycogen synthase and inhibiting glycogen phosphorylase.

A

glucokinase

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25
Q

Insulin regulates gene transcription of many proteins including crucial metabolic enzymes.
Promotes uptake of (blank) into cells.

A

K+

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26
Q

The insulin receptor is this kind of receptor

A

tyrosine kinase

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27
Q

Lack of functional β-cells prevents mitigation of elevated glucose levels and associated insulin responses. 5-10% of US cases (18/100,000)

A

Type 1 diabetes mellitus

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28
Q

What are the two types of Type 1 diabetes mellitus?

A

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)

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29
Q

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).

A

Type II diabetes mellitus

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30
Q

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?
A

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

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31
Q

Which type of diabetes has a stronger genetic association?

A

type II

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32
Q

Which type of diabetes has a linkage to MHC class II HLA genes?

A

type I

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33
Q

How does the pathogenesis of type I differ from type II DM?

A

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

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34
Q

How do the islet cells differ in type I vs type II DM?

A

type 1: insulitis, marked atrophy & fibrosis of beta cells, beta cell depletion

type 2: no insulitis, mild beta cell depletion, focal atrophy & amyloid deposition

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35
Q

In diabetic patients, (blank) pose a risk of hypoglycemia due to their inhibition of catecholamines’ gluconeogenesis and glycogenolysis effects.

A

beta-blockers

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36
Q

What are the symptoms of diabetes?

A 
Polyuria (urinating frequently)
Polydipsia (very thirsty)
Continuous hunger
Weight loss
Other symptoms
Fatigue
Dry skin
Frequent infections
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37
Q

What are the complications of diabetes?

A 
Retinopathy
Feet ulceration
Nephropathy
Cardiomyopathy
Neuropathy
Loss of sensibility in inferior extremities (legs)
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38
Q

Treatment & control of diabetes?

A

lifestyle changes –> increase physical activity, diet high in fruits in veggies, optimize body weight
medications –> insulin, hypoglycemics, oral agents

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39
Q

There are six classes of oral hypoglycemics that can be used to treat diabetes. What are they?

A 
insulin secretagogues
insulin sensitizers
alpha-glycosidase inhibitors
dipeptidyl-peptidase-4 inhibitors
glucagon like peptide analogue
sodium glucose cotransporter 2 inhibitors
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40
Q

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?

A 
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
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41
Q

What are the different forms of insulin analogues?

A

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

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42
Q

Rapid acting insulin analogs

Also classified as ultrashort acting forms due to more rapid onset & shorter duration of action

A 
Insulin Aspart (NovoRapid)
Insulin Glulisine (Apidra)
Insulin Lispro (Humalog)
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43
Q

(blank) insulin is given 15 minutes prior to a meal and has its peak effect 30-90 minutes after injection

**rapid-acting insulin analogue

A

Lispro

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44
Q

(blank) can be given anywhere from 15 minutes prior to 20 minutes after beginning a meal.

**rapid-acting insulin analogue

A

Glulisine

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45
Q

Short acting insulins

A 
Insulin Regular (Humulin-R)
Insulin Regular (Novolin Toronto)
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46
Q

Intermediate acting insulins

A 
Insulin NPH (Humulin-N)
Insulin NPH (Novolin NPH)
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47
Q

Long acting basal insulin analgogues

A 
Insulin glargine (Lantus)
Insulin detemir (Levemir)
48
Q

The most common and serious adverse effects of insulin is (blank) due to an inappropriately large dose of insulin or insufficient caloric intake

A

hypoglycemia

49
Q

(blank) consumption promotes hypoglycemic response.

A

ethanol

50
Q

Short term symptoms of hypoglycemia?

Long term symptoms?

A

sweating, hunger, palpitations, tremor & anxiety, MS changes

long effects: neuroglycopenic symptoms - difficulty concentrating, weakness, drowsiness, unconsciousness

51
Q

Other side effects of insulin

A

hypokalemia (insulin moves K+ IN cells)
weight gain
injection problems

52
Q

Usually short acting forms of insulin are combined with (blank) to achieve blood glucose control

A

longer acting preparations

53
Q

The initial calculation of the basal/background and bolus doses of insulin requires estimating total daily insulin (TDI) dose. How do you do this?

A

TDI requirement = body weight (in lbs) / 4 = body weight (kg) * 0.55

ex: weight 160 lbs
160/4 = 40 units of insulin

54
Q

What is the basal/background insulin dose?

A

40-50% of total daily insulin dose

ex: TDI was 40 units, so 40 * 50% = 20 units of insulin

55
Q

What is the carbohydrate coverage ratio?

A

CHO coverage ratio = 500 / TDI dose

ex: TDI was 40 units, so 500/40 = 12
1 unit of insulin for every 12gCHO

56
Q

What is the high blood sugar correction factor?

A

1800 / TDI

Ex: TDI was 40 units, so 1800 / 40 = 45
1 unit of insulin drops blood sugar by 45mg/dl

57
Q

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.

A

5 units

58
Q

Oral hypoglycemics are orally effective and useful primarily in the treatment of (blank)

A

type 2 DM when these pts fail to respond to non-medical interventions

59
Q

What are the first generation sulfonylureas (insulin secretagogues)? Second generation?

A

tolbutamide, chlorpropamide

glyburide, glipizide, glimepiride

60
Q

What is the mechanism of action of the sulfonylureas (insulin secretagogues)?

A

block ATP-sensitive K+ channels, resulting in depolarization –> opening of Ca++ channels –> Ca++ influx promotes insulin secretion

61
Q

Short acting sulfonylureas

vs

Intermediate acting sulfonylureas

vs

Long acting sulfonylureas

A

short acting: tolbutamide (6-12hrs)

intermediate acting: glipizide & glyburide

long acting: chloropropamide, glimepiride (~24hrs)

62
Q

When should sulfonylureas be used clinically?

A

type 2 DM ONLY!

best with patients who are 40+yo & pts with type 2 DM

63
Q

Second generation sulfonylureas reduce A1C values by (blank)%

A

1-2

64
Q

Adverse effects of sulfonylureas?

A

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

65
Q

What are the two non-sulfonylureas that are insulin secretagogues?

A

Rapaglinide

Nateglinide

66
Q

How do the non-sulfonylureas work? MOA?

A

block the same K-ATP channels as sulfonylureas and cause secretion of insulin

67
Q

Non-sulfonylureas typically lower the A1C value by (blank)%

A

0.5-1.0%

68
Q

What is the biguanide (insulin sensitizer) we should know? It is the principal biguanide used in clinics

A

Metformin

69
Q

How does metformin work? What does it require to be present in order to be effective?

A

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

70
Q

The only oral hypoglycemic agent shown to reduce cardiovascular mortality

A

metformin

71
Q

What effect does metformin have on lipids?

A

decreases hyperlipidemia (decreased LDL, VLDL, and increased HDL)

72
Q

When is metformin used clinically?

A

first line medication for treatment of type 2 DM

73
Q

What are the two forms of release of metformin?

A

immediate release

or

extended-release formulation if a patient is experiencing GI effects

74
Q

Adverse effects of metformin?

A 
not associated with hypoglycemia (unless combined with other agents)
lactic acidosis (serious esp with phenformin & buformin)
drug interactions
75
Q

Metformin is contraindicated in these patients…

A

renal insufficiency
hepatic insufficiency
CHF & conditions with hypoxemia, dehydration, or sepsis
metabolic acidosis

76
Q

What are the two thiazolidinediones (insulin sensitizers)?

A

Pioglitazone

Rosigglitazone

77
Q

What is the mechanism of action of the thiazolidinediones?

A

Active nuclear peroxisome proliferator-activated receptor gamma (PPARgamma)
increase insulin sensitivity in adipocytes, hepatocytes, & skeletal muscle
increase insulin-dependent glucose disposal
decrease insulin resistance

78
Q

When are thiazolidinediones used clinically? Which one can be used in combo with insulin?

A

used for type 2 DM;

pioglitazone can be used in combo with insulin, while rosiglitazone should not be

79
Q

Thiazolidinediones undergo extensive (blank) metabolism

A

P450

80
Q

Adverse effects of thiazolidinediones?

A 
fatal hepatotoxicity (must monitor hepatic function)
decrease/interact with oral contraceptives
possible link with bladder cancer (pioglitazone)
81
Q

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

A

Pioglitazone

82
Q

What is the alpha-glucosidase inhibitor we should know?

A

Acarbose

83
Q

What is the mechanism of action of acarbose (alpha-glucosidase inhibitor)?

A

inhibits the intestinal alpha-glucosidases (hydrolyze carbohydrates to their components)
also blocks pancreatic alpha-amylase (hydrolyzes complex starches to oligosaccharides in the small intestine)

84
Q

Acarbose decreases A1C levels by (blank)%

A

0.5-1.0%

85
Q

When are alpha-glucosidase inhibitors used clinically? When are they taken?

A

type 2 DM;

taken with first bite of meal

86
Q

Acarbose is poorly absorbed here but exerts its effects here

A

intestinal lumen

87
Q

Adverse effects of alpha-glucosidase inhibitors (Acarbose)?

A

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

88
Q

When are alpha-glucosidase inhibitors contraindicated?

A

IBS, intestinal disorders, increased gas formation in the intestine, diabetic ketoacidosis or cirrhosis

89
Q

Naturally occurring hormones that the gut releases throughout the day; the level of active incretins increases significantly when food is ingested.

A

Incretins

90
Q

Two major incretins that facilitate the response of the pancreas & liver to glucose fluctuations through their actions of beta and alpha cells

A

GIP - glucose-dependent insulinotropic peptide

glucagon-like peptide 1 (GLP-1)

91
Q

What happens to the effect of incretins in type 2 diabetes?

A

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

92
Q

DPP-4 inhibitor (incretin-based therapy)

A

Sitagliptin (Januvia)

93
Q

What is the mechanism of action of the DPP-4 inhibitors?

A

reduce blood glucose levels by inhibiting DPP-4 & increasing levels of GIP & GLP-1

94
Q

When are the DPP-4 inhibitors (Sitagliptin) used clinically?

A

type 2 DM alone or in combo with metformin or a thiazolidinedione

**fewer side effects, but lower efficacy

95
Q

Important adverse effects of DPP-4 inhibitors, like Sitagliptin?

A

Heart failure (saxagliptin)
pacreatitis
renal failure & hypersensitivity reactions
rare nausea & common cold-like symptoms
no significant hypoglycemia when used alone

96
Q

What is the glucagon-like peptide analogue we should know?

A

Exenatide

97
Q

What is the mechanism of action of the glucogon-like peptide analogues?

A

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

98
Q

When is the GLP-1 analogue exenatide used clinically?

A

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

99
Q

Main adverse effects of GLP-1 analogues like exenatide?

A

GI disorders - acid/sour stomach, belching, diarrhea, indigestion

100
Q

What is the sodium glucose cotransporter 2 inhibitor that we should know?

A

Jardiance (empagliflozin)

101
Q

How do sodium glucose cotransporter (SGLT) 2 inhibitors work?

A

block reabsorption of glucose by the kidneys, increasing glucose excretion in urine & lowering blood sugar in patients with diabetes

102
Q

Jardiance (SGLT2 inhibitor) is contraindicated in these patients…

A

patients with kidney problems

103
Q

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?

A

within 3-6 months

104
Q

If your initial A1C is less than 8.5%, what should you do?

A

start metformin

or

reassess in 2-3 months then decide on starting metformin

105
Q

If your initial A1C is greater than 8.5%, what should you do?

A

start metformin

&

consider combo therapy to reduce A1C by more than 1.5

106
Q

What should you do if your patient already has symptoms from hyperglycemia & metabolic compensation?

A

start insulin +/- metformin

107
Q

These diabetic therapies can cause hypoglycemia…

A

insulin
insulin secretagogues
sulfonylureas

108
Q

These diabetic therapies cause the most weight gain

A

insulin

TZD

109
Q

These diabetic therapies have the greatest effects on lowering A1C

A

insuln

GLP-1 receptor agonists

110
Q

This diabetic therapy is safe regardless of the GFR

A

repaglinide

111
Q

Again, what should be done for patients if glycemic targets are not achieved with lifestyle management within 2-3 months?

A

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

112
Q

(blank) should be the initial drug used for overweight patients

A

metformin

113
Q

If glycemic targets are not met within 3-6 months, what should be done?

A

add other classes of antihyperglycemic agents to metformin regimen

114
Q

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

A

long acting analogues

115
Q

When bolus insulin is added to antihyperglycemic agents, (blank) may be used instead of regular insulin to reduce the risk of hypoglycemia

A

rapid-acting analogues

116
Q

A useful measure of glucose control over the prior 3-6 months, hyperglycemic episodes result in the nonspecific glycosylation of various proteins.

A

HA1C

117
Q

What is the trade off between standard & intensive treatment of diabetes?

A

intensive treatment leads to more frequent hypoglycemic events, but a substantial decrease in incidence of long-term complications like retinopathy & nephropathy

Block 10 Week 2 (8 decks)

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