Diabetes Diagnosis and Management 1 and 2 Flashcards
What is the criteria for diagnosing diabetes mellitus in nonpregnant adults?
Patient has one of the following:
A1C > 6.5%
Fasting plasma glucose >126 mg/dL (fasting = no caloric intake for at least 8hr)
2hr plasma glucose >200mg/dL during properly performed 75g oral glucose tolerance test (OGTT)
in a patient with classic symptoms of hyperglycemica or hyperglycemic criss, a random plasma glucose >200mg/dL
What are normal ooral glucose tolerance test (OGTT) results?
75g glucose orally at time 0
30 min < 200 mg/dL
60min < 200 mg/dL
90min < 200 mg/dL
120min < 240 mg/dL
What is normal plasma fasting glucose?
< 100 mg/dL
What are the categories for increased risk for diabetes (prediabetes)?
Impaired fasting glucose (IFG): fasting plasma glucose 100 mg/dL to 125 mg/dL
Impaired glucose tolerance (IGT): 2hr plasma glucose in the 75g OGTT 140 mg/dL t 199 mg/dL
HbA1c 5.7-6.4%
How do you screen for diabetes or prediabetes in asymptomatic adults?
test all at age 45; if normal, retest every 3yrs
prediabetes = test anually
women with hx of gestational diabetes should be tested every 3yrs
testing should be considered in adults who are obese or overweight and who have one or more additional risk factors:
- first degree relative with diabetes
- physical inactivity
- high-risk race/ethnicity
- hypertension
- low HDL
- acanthosis nigricans
- women with polycystic ovarian syndrome
What are the classifications of diabetes mellitus?
Type 1 diabetes mellitus = insulin dependent/juvenile diabetes
Type 2 diabetes mellitus = non-insulin dependent diabetes mellitus
gestational diabetes
monogenic formes of diabetes - genetic defects in beta cell function (MODY or neonatal diabetes syndromes)
diseases of the pancreas - pancreatitis, cystic fibrosis, hemochromatosis
excess hormones that antagonize insulin - growth hormone, cortisol, glucagon, epinephrine
latent autoimmune diabetes of adults
What is gestational diabetes mellitus?
some hormonal events of pregnancy may unmask a genetic susceptibility to type 2 diabetes
similar to type 2 DM (assoc with insulin resistance)
What is latent autoimmune diabetes of adults?
autoimmune form of diabetes (onset later than type 1 DM)
autoimmune destruction of beta cells progresses more gradually than in type 1 DM, so patients with LADA don’t usually require insulin treatment at the onset of diabetes
LADA patients usually are not obese, not insulin resistant, and have no family history of diabetes
markers of immune destruction of beta cells (antibodies to islet cells) can be demonstrated in LADA patients as well as in patients with type 1 DM
- eventually most beta cells are destroyed and patients will require insulin treatment
what are the glycemic recommendations for many nonpregnant adults with diabetes?
Preprandial glucose = 80-130 goal (non diabetic = 70-99)
Peak postprandial glucose = <180 (nondiabetic = < 140)
Hemoglobin A1c = < 7 (nondiabetic = 4.5-5.6)
what do you consider when choosing an appropriate A1c goal for patients with diabetes?
<7 for many nonpregnant patients with diabetes
may not be appropriate for older patients with multiple coexisting chronic illnesses, hypoglycemia vulnerability, long duration of diabetes, existing complications of diabetes, cognitive impairment, etc
risks of intensive treatment may outweigh the potential benefits in patients
what is the firstline treatment for type 2 diabetes?
Metformin
Metformin decreases hepatic glucose output by inhibiting gluconeogenesis
excessive hepatic glucose production increases hyperglycemica and hepatic glucose output is the major contributor to hyperglycemia in the fasting condition
also stimulates AMP-activated protein kinase - plays an important role in a variety of metabolic processes
What are the advantages of metformin?
Extensive experience
promotes modest weight loss or weight neutral
no hypoglycemia
low cost
may decrease CVD events
what are the disadvantages of metformin?
GI side effects (diarrhea, cramping)
avoid in patients with chronic kidney disease and eGFR < 30ml/min
- kidneys are the main route of elimination
if patients with eGFR < 60mL/min are scheduled for radiologic studies with iodinated contrast material, metformin should be stopped prior to the study and eGFR should be rechecked
metformin treatment increases risk of vitamin B12 deficiency
lacic acidosis
What pharmacologic agents have a high glucose-lowering effect?
Metformin
Sulfonylureas
TZDs
GLP-1 agonists
Insulins
What pharmacologic agents have a low glucose-lowering effectiveness?
Meglitinides
DPP-4 inhibitors
SGLT2 inhibitors
alpha-glucosidase inhibitors (AGIs)
Amylin mimetics (pramlintide)
What pharmacologic agents make a patient gain weight?
Increase appetite: insulin, sulfonylureas, meglitinides
affect adipose tissue metabolism: thiazolidinediones
What pharmacologic agents make a patient lose weight?
metformin
GLP-1 receptor agonists
SGLT-2 inhibitors
What pharmacologic agents are weight neutral?
DPP-4 inhibitors
What drugs are associated with reduced cardiovascular risk?
SGLT2 inhibitor empagliflozin
GLP-1 receptor agonist liraglutide
What is the mechanism of action for sulfonylureas?
insulin secretagogue that closes beta cell K+-ATP channels causing insulin release (independent of prevailing glucose)
*functional beta-cells necessary*
sulfonylureas close K+-ATP channel -> depolarization -> calcium influx -> release of insulin storage granules -> insulin release
What are the advantages of sulfonylureas?
low cost
effective if sufficient beta cell function remains
What are the disadvantages of sulfonylureas?
hypoglycemia
efficacy wanes over time
What is the mechanism of action of meglitinides?
not sulfonylureas, but they also interact with K-ATP channels stimulating insulin release
What are the advantages of meglitinides?
shorter half-life than sulfonylureas so less likely to cause hypoglycemia
what are the disadvantages of meglitinides?
frequent administration (with meals) because of short half-life
lower efficacy than sulfonylureas (A1c lowering of 0.5-1%)
What is the mechanism of action for thiazolidinediones (TZDs)
improves insulin sensitivity
transcription factor - ligand for nuclear peroxisome proliferator-activated receptor gamma
effects in adipose tissue: decreases production of inflammatory mediators, increases production of adiponectin (adiponectin enhances insulin sensitivity), and decreases lipolysis and FFA release
What are the advantages of pioglitazone?
improves insulin sensitivity and glucose uptake in muscle and adipose tissue
decreases hepatic glucose output (improved liver insulin sensitivity)
does NOT increase insulin secretion, so it does NOT cause hypoglycemia
more ‘durable’ effect than sulfonylureas or metformin - may improve beta cell heath
What are the disadvantages of pioglitazone?
weight gain
fluid retention (increased risk of edema and/or heart failure)
anemia
increased risk of bone fractures
increased risk of bladder cancer
What is the mechanism of action of GLP-1 receptor agonists [incretin mimetics]?
exenatide, liraglutide
bind to GLP-1 receptors
augment glucose-stimulated insulin secretion (GSIS)
slows gastric emptying, which enhances satiety/promotes weight loss
what are the advantages of GLP-1 receptor agonists?
augment glucose-stimulated insulin secretion (GSIS), so no hypoglycemia
weight loss
efficacy high (HbA1c decrease approx 1-1.5%)
more durable effect than sulfonylureas - may improve beta cell health
liraglutide decreases cardiovascular risks
what are the disadvantages of GLP-1 receptor agonists?
injectable, but fixed dose (once or twice daily or once weekly)
GI side effects (nausea/vomiting)
high cost
may increase risk of pancreatitis
may increase risk of thyroid C cell tumors/medullary thyroid carcinoma
What is the mechanism of action of dipeptidyl peptidase-4 inhibitors (DPP-4)?
sitagliptin, saxagliptin, linagliptin, alogliptin
block action of DPP-4 enzymes to prolong activity of endogenous GLP-1 and GIP (incretins enhance glucose-stimulated insulin secretion)
inhibits the inhibition on GLP-1 and GIP
What are the advantages of DPP-4 inhibitors?
no hypoglycemia (unless used with drugs that cause hypoglycemia)
well-tolerated
oral
weight neutral
What are the disadvantages of DPP-4 inhibitors?
efficacy is intermediate (decrease HbA1c approx 0.5-1%)
high cost
What is the mechanism of action of sodium-glucose cotransportor 2 (SGLT2) inhibitors?
empagliflozin
inhibit kidney reabsorption of filtered glucose so more glucose is excreted in the urine
What are the advantages of SGLT2 inhibitors?
no hypoglycemia (unless used with drugs that cause hypoglycemia)
oral administration
glucose (energy) loss in urine promotes weight loss
empagliflozin improves cardiovascular risks
empagliflozin slows progression of diabetic nephropathy
What are the disadvantages of SGLT2 inhibitors?
increased urinary tract and genital infections
osmotic diuresis, dehydration
may increase fracture risk
risk of lower limb amputation with canagliflozin
rare cases of ketoacidosis
not effective if eGFR < 45ml/min
What is the sodium-glucose cotransporter (SGLT2)?
SGLT2 in early proximal tubule (90% of glucose reabsorption)
in healthy people, renal glucose reabsorption is so efficient that no glucose is ‘spilled’ in the urine, and maximum kidney capacity for glucose reabsorption has not been reached
What happens when SGLT2 is saturated?
When blood glucose is high, the filtered load of glucose is so high that most of the glucose carrier proteins become saturated and glucose reabsorption reaches a constant maximal rate called the tubular transport maximum (Tm). Additional glucose cannot be reabsorbed, so it is “spilled” into the urine. Glucosuria causes an osmotic diuresis (high urine volume), which explains the symptoms of polyuria and nocturia in patients with poorly controlled diabetes.
What is tubuloglomerular feedback?
kidney anatomy facilitates communication between specialized cells lining kidney tubules (macula densa cells of the distal tubule) and the cells that regulate blood flow through the glomerular capillaries
macula densa cells can adjust glomerular hydrostatic pressure by signaling dilation or constriction of the afferent arteriole and efferent arteriole
what does increased pressure in glomerular capillaries do and how is this associated to diabetes?
can cause hyperfiltration (increase GFR), which occurs in the early stages of diabetes
what mechanism can increase pressure within glomerular capillaries?
via tubuloglomerular feedback
in pt with hyperglycemia, the increased reabsorption of glucose and sodium within the proxyimal tubule (via SGLT) changes the composition of fluid within the distal tubule
less sodium reaches the distal tubule, so distal tubule sodium concentration appears abnormally low -> increase in hydrostatic pressure
What happens with sustained increases in pressure within the glomerular capillaries?
sustained increases in pressure within glomerular capillaries contribute to kidney damage in patients with diabetes - diabetic nephropathy
What does empagliflozin do in terms of kidney disease?
SGLT2 inhibitor
decreases the development of kidney disease in patients with type 2 diabetes
kidney protective effects of empagliflozin may be related to restoration of normal kidney tubuloglomerular feedback
by eliminating the excess reabsorption of glucose and sodium within the proximal tubule, more sodium chloride flows past the macula densa, which leads to constriction of the afferent arteriole
what other drugs are used to reduce intraglomerular pressure?
angiotensin converting enzyme (ACE) inhibitors, such as ramipril
angiotensin receptor blockers (ARBs), such as losartan
these drugs oppose the constricting effects of angiotensin II ont he efferent arteriorle
dilation of the efferent arteriole reduces glomerular hydrostatic pressure, which protects the delicate glomerular cells that filter plasma
ACE inhibitors and ARBs can delay the onset and/or progression of diabetic nephropathy in patients with diabetes
What are the insulin treatments?
insulin is injected subcutaneously
healthy person secretes equivalent of 40 units/day
basal insulins (long-acting insulin analogs)
- glargine
- detemir
- degludec
bolus insulins (rapid-acting insulin analogs) - closely mimic the shape of endogenous insulin peaks following meals
- lispro
- aspart
- glulisine
short-acting insulin
- regular crystalline zinc insulin
intermediate-acting insulin
- NPH isophane
how does regular insulin compare to rapid-acting insulin analogs?
because the onset of action of regular insulin is approx 30mins, patients using regular insulin need to inject it aprpoximately 30mins prior to a meal
regular insulin has a duration of action up to 5-7hrs, so it is necessary for pt to ingest snacks between measl to prevent hypoglycemia
rapid-acting insulin analogs can be injected immediately before a meal and their shorter duration of action is much less likely to cause hypoglycemia prior to the next meal
What is basal insulin?
endogenous insluin does not drop to zero during fasting
basal insulins (glargine, detemir) have a slow onset of action and long duration (nearly peakless)
usually injected once a day to provide a small constant amount of insulin that mimics the baseline of endogenous insulin
what is a basal-bolus insulin regimen?
highly effective in glycemic control, but the use of prandial insulins (rapid-acting) requires that prandial insulin dose be matched to carbohydrate content of meals, which requires more frequent glucose self-monitoring
for pt reluctant to take multiple daily insulin injections, basal insulin can be combined with non-insulin agents that enhance prandial (meal time) insulin secretion (DPP-4 inhibitors, meglitinides, or GLP-1 reveptor agonists such as exenatide)
insulin can also be admin using a pump (subcut needle attached via catheter to a pump and insulin chamber), which can provide a basal insulin infusion rate plus the capacity to admin a bolus with meals or snacks
Describe continuous subcutaneous insulin infusion (CSII) therapy.
dose calculators for bolus (mealtime) insulin admin and ability to program multiple basal rates during any 24hr period
candidates for insulin pump therapy:
- pt w/ type 1 diabetes who have not achieved A1c goal using ‘basal-bolus’ multiple daily inj of insulin if they are willing to use a pump w/ appropriate training
- pt w/ type 2 diabetes who have inadequate glycemic control despite lifestyle mods, oral agents, intensive insulin therapy, and other injectable diabetes medications
What is continous glucose monitoring (CGM)?
tech available for continuous monitoring of subcut glucose concentrations, which can be helpful in pt w/ frequent episodes of hypoglycemia (assoc w/ exercise, hypoglycemia unawareness)
CGM + pump -> alarm sistum that suspends insulin admin once glucose below threshold value
Describe hypoglycemia.
in healthy persons, blood glucose rarely drops below 70 mg/dL because this is usually the threshold for activation of counter-regulatory hormone systems & symptoms do not develop until glucose drops below 60 mg/dL
even before glucose drops below 70, a person w/ diabetes treated with insulin or insulin secretagogues may develop symptoms of hypoglycemia if blood glucose drops at a rapid rate due to increased insulin
What are the signs and symptoms of hypoglycemia?
tremor, palpitations, and tachycardia are caused by the adrenomedullary response to hypoglycemia
in patients treated with beta-adrenergic antagonists, these symptoms can be blunted
patients taking beta-adrenergic antagonists may find it more difficult to perceive that they are developing hypoglycemia
What is the treatment of hypoglycemia?
for patients with diabetes, blood glucose ‘alert value’ is <70
- should consist of ingestion of glucose or carb-containing foods (15g of carbs)
fat may delay gastric emptying and prolong the time required for glucose absorption
if severe and cannot swallow, injection of glucagon
what is the recommended action for hypoglycemia at the alert value of <70 mg/dL?
treat with rapidly absorbed carbohydrate
adjust dose of glucose lowering agents
what is the recommended action of clinically significant hypoglycemia < 54 mg/dL?
serious risk of falls, motor vehicle accidents, or other injury
urgent treatment recommended
what is the recommended action of severe hypoglycemia?
hypoglycemia that causes severe cognitive impairment
external assistance required for recovery
What is hypoglycemia unawareness?
frequent episodes of hypoglycemia can dampen usual counter-regulatory adrenomedullary epinephrine response during a subsequent hypoglycemic episode = hypoglycemic-associated autonomic failure (HAAF)
other parts of ANS may function normally in pt with HAAF fewer catecholamine-mediated symptoms (palpitations, tremor), these patients may not recognize hypoglycemia - may need to rely on others to help them recognize symptoms assoc with neuroglycopenia (confusion, loss of concentration)
What is exercise-induced hypoglycemia in patients treated with insulin?
in absence of exercise, glucose uptake in muscle depends primarily on insulin (in muscle, insulin causes transloc of intracellular GLUT4 glucose transporters to the plasma membrane, which permits an increase in muscle glucose uptake)
when a healthy person exercises, insulin secretion is suppressed
during exercise, the decreased insulin to glucagon ratio allows the liver to increase glucose production (through glycogenolysis and gluconeogenesis) and export glucose into the bloodstream
increased hepatic glucose output can provide sufficient circulating glucose for exercising muscle
muscle increases translocation of intracellular GLUT4 to the plasma membrane even without insulin, which allows muscle cells to bypass insulin and independently increase glucose uptake
What happens if a patient with diabetes takes insulin prior to exercise?
once exogenous insulin has been administered, the insulin to glucagon ratio will remain high, preventing gluconeogenesis and glycogenolysis
muscle will take up additional glucose during exercise -> plasma glucose decrease because the liver is not able to export sufficient glucose to maintain a normal blood glucose concentration
exercise-induced hypoglycemia can be avoided if patient consumes additional carbs and may be necessary before, during, and after exercise
the risk of hypoglycemica persists even after exercise is finished, because muscle will continue to take up glucose in order to replenish muscle glycogen stores
