Week 11 Diabetes Flashcards
b cells in the pancreas produce?
insulin
a cells in the pancreas produce?
glucagon
Type 1 diabetics require exogenous insulin to avoid severe hyperglycemia & the life-threatening catabolic state of _________.
ketoacidosis
6 indications for insulin therapy
- significant insulinopenia
- instability of glucose patterns (usually d/t significant insulinopenia)
- difficulty with hypoglycemia
- lifestyle needs
- achieving therapeutic goals
- weight loss
What is the most serious and common adverse reaction insulin injection?
hypoglycemia
Lispro, Aspart, Glulisine and Regular insulin are classified as?: Rapid/Short Acting Intermediate Acting Long Acting Mixed
Rapid/Short Acting
Glargine and Detemir are classified as?: Rapid/Short Acting Intermediate Acting Long Acting Mixed
Long acting
NPR (neutral protamine Hagedorn) insulin is classified as? Rapid/Short Acting Intermediate Acting Long Acting Mixed
Intermediate acting
How many minutes prior to a meal should regular insulin be administered?
30 minutes
clear insulin vs cloudy insulin?
clear = short or rapid-acting cloudy = long-acting
7 Symptoms of hypoglycaemia: neurogenic (autonomic)
trembling palpitations sweating anxiety hunger nausea tingling
8 symptoms of hypoglycaemia (neuroglycopenic)
difficulty concentrating confusion weakness drowsiness vision changes difficulty speaking headache dizziness
CI to insulin
hypersensitivity
hypoglycemia
precautions of insulin
- liver or kidney disease
- lactation (exogenous insulin is excreted into breastmilk)
In non-diabetic individual, 40-50% of insulin secreted by pancreas is extracted during its first passage through the liver. Consequently, the kidney plays a smaller role in disposing of insulin secreted in non-diabetic individual than in disposing of insulin injected into diabetic patients. Endogenously secreted insulin is degraded by liver, exogenous insulin is primarily eliminated by the kidney.
The kidneys play an important role in the clearance of insulin from the systemic circulation. Insulin has a molecular weight of 5734 and is therefore freely filtered at the glomerulus and then extensively reabsorbed by the proximal tubule. Of the total renal insulin clearance, approximately 60% occurs by glomerular filtration and 40% by extraction from peritubular vessels. Insulin in the tubular lumen enters the proximal tubular cell by carrier-mediated endocytosis and is then transported into lysosomes where it is metabolized into amino acids that are released into peritubular vessels by diffusion. In addition to luminal clearance via glomerulal filtration, the kidneys clear insulin from the post-glomerular peritubular circulation. These intrarenal pathways of insulin removal involve both receptor and non-receptor mediated uptake. The net effect is that less than 1% of filtered insulin appears in final urine.
Name 7 drugs that decrease hypoglycaemic effect of insulin
OC corticosteroids diltiazem diuretics estrogens niacin thyroid hormones
Name 7 drugs that increase hypoglycaemic effect of insulin
alcohol ACE inhibitors b blockers salicylates fluoroquinolones tetracycline sulfonamides
What percentage of diabetic population is type 2 DM?
90-95%
7 major diabetes complications
cerebrovascular disease retinopathy coronary heart disease nephropathy neuropathy PVD in lower limbs ulceration & amputation for diabetic foot
abnormalities of b-cell function in type 2 diabetes?
- disrupted pulsatile insulin response
- decreased first phase
- increased proinsulin/insulin ratio
- decreased b-cell responsiveness to glucose
- decreased insulin production
what is somatostatin
also known as growth hormone-inhibiting hormone (GHIH)
Somatostatin is secreted in several locations in the digestive system:
stomach
intestine
delta cells of the pancreas
Somatostatin: A hormone that is widely distributed throughout the body, especially in the hypothalamus and pancreas, that acts as an important regulator of endocrine and nervous system function by inhibiting the secretion of several other hormones such as growth hormone, insulin, and gastrin.
T2DM is marked by blunted _________ response and inadequate __________ suppression after meals.
insulin
glucagon
inherited influences on insulin resistance?
Largely unidentified!
- insulin receptor
- glucose transporter
- signaling proteins
these are rare mutations!!
acquired influences on insulin resistance?
overeating overweight inactivity aging medications illness hyperglycemia elevated FFAs in blood & tissues
what percentage of people with DM are estimated to be overweight or obese?
80-90%
why should healthy bodyweight be encouraged in DM patients who are overweight or obese?
A modest weight loss of 5 to 10% of initial body weight can substantially improve insulin sensitivity and glycemic, blood pressure and lipid control.
9 ss and sxs of diabetes
unusual thirst freq. urination weight change (loss or gain) extreme fatigue or lack of energy blurred vision frequent or recurring infections (vaginitis/pruritis) cuts & bruises that are slow to heal tingling/numbness in hands or feet trouble getting/maintaining erection
**type 2 can be asymptomatic!
lab findings on urinalysis?
looking for ketones in the urine.
Ketones are a metabolic product produced when fat is metabolized. Ketones increase when there is insufficient insulin to use glucose for energy.
Urine tests are also done to look for the presence of protein in the urine, which is a sign of kidney damage.
Urine glucose measurements are less reliable than blood glucose measurements and are not used to diagnose diabetes or evaluate treatment for diabetes. They may be used for screening purposes.
fasting blood glucose findings in diabetes?
A blood sample will be taken after an overnight fast. A fasting blood sugar level less than 100 mg/dL (5.6 mmol/L) is normal. A fasting blood sugar level from 100 to 125 mg/dL (5.6 to 6.9 mmol/L) is considered prediabetes. If it’s 126 mg/dL (7 mmol/L) or higher on two separate tests, you have diabetes.
oral glucose tolerance test in diabetes?
For this test, you fast overnight, and the fasting blood sugar level is measured. Then you drink a sugary liquid, and blood sugar levels are tested periodically for the next two hours. A blood sugar level less than 140 mg/dL (7.8 mmol/L) is normal. A reading of more than 200 mg/dL (11.1 mmol/L) after two hours indicates diabetes. A reading between 140 and 199 mg/dL (7.8 mmol/L and 11.0 mmol/L) indicates prediabetes.
Hg A1c (glycated hemoglobin) test in diabetes?
This blood test indicates your average blood sugar level for the past two to three months. It measures the percentage of blood sugar attached to hemoglobin, the oxygen-carrying protein in red blood cells. The higher your blood sugar levels, the more hemoglobin you’ll have with sugar attached. An A1C level of 6.5 percent or higher on two separate tests indicates that you have diabetes. An A1C between 5.7 and 6.4 percent indicates prediabetes. Below 5.7 is considered normal.
what are the goal blood glucose levels for fasting?
4-7 mmol/L
what are the goal blood glucose levels 1-2 hours post meals?
5-11 mmol/L
what is the goal HbA1C?
<7%
What did the 2008 ACCORD study find in regards to intensive DM treatment and mortality?
higher risk for mortality with intensive DM treatment
What is the brand name of the only biguanide?
metformin
true or false?
metformin promotes insulin secretion
false
(sulfonylureas do, though!)
therefore hyperinsulinemia is not a problem & risk of hypoglycaemia is far less than with sulfonylureas
what is the mechanism of action of metformin?
- reduction of hepatic gluconeogenesis
- slows intestinal absorption of sugars (no effect on pancreatic cells)
- improves peripheral glucose uptake & utilization (peripheral receptor sites)
PK of metformin?
absorption, distribution, metabolism, excretion
- absorption: oral
- not bound to serum proteins
- not metabolized
- excretion via urine
what is the only oral hypoglycaemic agent proven to decrease CV mortality?
biguanide
metformin
2 adverse effects of metformin?
- lactic acidosis (CI in renal dysfunction!)
- GI discomfort in up to 50% pts! (diarrhea, nausea, anorexia, metallic taste)
7 CIs to metformin?
HF (can cause acute renal failure) >80 yo renal disease (risk of lactic acidosis) metabolic acidosis lactation iodinated contrast materials caution in surgery
3 drug interactions w/metformin?
- alcohol - may increase risk lactic acidosis
- cimetidine, furosemide, nifedipine - can increase metformin levels by ~60%
- may interfere with absorption of B12
how many times per day must a patient take metformin?
2-3 x/day with meals
what happens if a patient doesn’t respond to metformin after 4 weeks of max dose treatment?
sulfonylurea may be added
mechanism of action of thiazolidinediones?
- lower insulin resistance
- agonists for PPARy (peroxisome proliferator-activated receptor-y); activation of this receptor regulates transcription of several insulin-responsive genes => increased insulin sensitivity in adipose tissue, liver & skeletal muscle
- does not increase insulin secretion from b cells of pancreas
PK of thiazolidinediones
pioglitazone (Actos), rosiglitazone (Avandia)
- well absorbed after oral administration
- extensively bound to serum albumin
- both undergo extensive metabolism by CYP
what is the thiazolidinedione connection to CHF?
Thiazolidinediones cause or exacerbate CHF; observe pts closely after tx initiation or dose incr. for s/sx incl. excessive, rapid wt gain, dyspnea, and/or edema; manage CHF based on current care standards if s/sx develop and consider D/C or dose reduction; contraindicated in pts w/ NYHA Class III-IV CHF and not recommended in pts w/ symptomatic CHF
what is Amanda (rosiglitazone) connection to myocardial ischemia?
available data inconclusive on myocardial ischemia risk w/ rosiglitazone; meta-analysis of 42 studies (primarily placebo-controlled) showed incr. risk of myocardial ischemic events incl. angina and MI; other studies have not confirmed or excluded risk
Why is Avandia not included in Canadian, American and European guidelines?
Linked to 43% higher risk of heart attack (NEJM, 2007)
‘Disagreement’ as to its role in liver failure
“the FDA is in possession of clear unequivocal evidence that Avandia causes a wide variety of toxicities”
Although Avandia & Actos work to reduce insulin resistance, increased risk of heart attack and heart/liver failure have resulted in removal of Avandia from European, US, and Canadian DM guidelines
do you take thiazolidinedione with or without food?
- take with or without food
- once dose is taken, meal should not be delayed
what are the 2 classes of drugs that affect insulin secretion?
(insulin secretagogues)
sulfonylureas
meglitinide analogs
promote insulin release from b cells of pancreas
MOA of sulfonylureas?
- stimulation of insulin release from b cells of pancreas
- block ATP-sensitive K+ channels => depolarization, Ca++ influx, insulin exocytosis
- may reduce hepatic glucose production & increase peripheral insulin sensitivity
- reduces serum glucagon
- increases binding of insulin to target tissues & receptors
how much more potent are 2nd and 3rd generation sulfonylureas than 1st gen?
100x !
3 CIs for sulfonylureas?
- liver/kidney insufficiency
- obesity
- concurrent alcohol use
4 adverse effects of sulfonylureas?
hypoglycemia
CoQ10
weight gain
disulfiram reaction
2 drug interactions with sulfonylureas that increase hypoglycemic effect?
salicylates
sulfonamides
4 drug interactions with sulfonylureas that decrease hypoglycemic effect?
corticosteroids
thyroid agents
estrogens, OC
b-blockers/CCB/thiazide diuretics
MOA of meglitinides
repaglinide & nateglinide
- stimulate insulin secretion from pancreas
- efficacy: decreases HgA1C by 0.6-1%
PK of meglitinides
fast onset
short half life
LV metabolism by P450 3A4 (therefore watch for inhibitors/inducers of P450)
adverse reactions of meglitinides?
URTI
back pain
hypoglycemia
nateglinide - flu sxs
repaglinide - arthralgia
drug interactions for meglitinides?
NSAIDs!
CYP substrates
Inducers: carbamazepine (can decrease hypoglycemic effect)
Inhibitors: ketoconazole/miconazole ; erythromycin/clarithromycin
a-glucosidase inhibitor MOA
Located in the intestinal brush border, a-glucosidase enzymes break down carbohydrates into glucose for absorption.
a-glucosidase inhibitors reversibly inhibit a-glucosidase enzymes. When taken at the start of a meal, they delay the digestion of carbs = lower postprandial glucose levels.
Why do a-glucosidase inhibitors not cause hypoglycaemia?
they do not stimulate insulin release or increase insulin sensitivity
when must a-glucosidase inhibitors be taken?
must be taken with first bite of meal
why do we start a-glucosidase inhibitors at low dose once daily and gradually increase?
to minimize GI effects
flatulence (77%) b/c inhibits ability to breakdown CHO
diarrhea (33%)
abdominal cramps
increase of LV enzymes (rare)
what is amylin?
- hormone that is consecrated with insulin from b cells following food intake
- delays gastric emptying, decreases postprandial glucagon secretion, improves satiety
- pramlintide is a synthetic amylin analog
how is pramlintide (amylin analog) administered?
subcutaneously immediately prior to major meal
how is pramlintide (amylin analog) dosing affect by nausea?
dose can be increased once patient has not experienced nausea for 3 days
