Diabetes Diagnosis and Management 1 and 2

Question 1

What is the criteria for diagnosing diabetes mellitus in nonpregnant adults?

Answer 1

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

Question 2

What are normal ooral glucose tolerance test (OGTT) results?

Answer 2

75g glucose orally at time 0

30 min < 200 mg/dL

60min < 200 mg/dL

90min < 200 mg/dL

120min < 240 mg/dL

Question 3

What is normal plasma fasting glucose?

Answer 3

< 100 mg/dL

Question 4

What are the categories for increased risk for diabetes (prediabetes)?

Answer 4

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%

Question 5

How do you screen for diabetes or prediabetes in asymptomatic adults?

Answer 5

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

Question 6

What are the classifications of diabetes mellitus?

Answer 6

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

Question 7

What is gestational diabetes mellitus?

Answer 7

some hormonal events of pregnancy may unmask a genetic susceptibility to type 2 diabetes

similar to type 2 DM (assoc with insulin resistance)

Question 8

What is latent autoimmune diabetes of adults?

Answer 8

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

Question 9

what are the glycemic recommendations for many nonpregnant adults with diabetes?

Answer 9

Preprandial glucose = 80-130 goal (non diabetic = 70-99)

Peak postprandial glucose = <180 (nondiabetic = < 140)

Hemoglobin A1c = < 7 (nondiabetic = 4.5-5.6)

Question 10

what do you consider when choosing an appropriate A1c goal for patients with diabetes?

Answer 10

<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

Question 11

what is the firstline treatment for type 2 diabetes?

Answer 11

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

Question 12

What are the advantages of metformin?

Answer 12

Extensive experience

promotes modest weight loss or weight neutral

no hypoglycemia

low cost

may decrease CVD events

Question 13

what are the disadvantages of metformin?

Answer 13

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

Question 14

What pharmacologic agents have a high glucose-lowering effect?

Answer 14

Metformin

Sulfonylureas

TZDs

GLP-1 agonists

Insulins

Question 15

What pharmacologic agents have a low glucose-lowering effectiveness?

Answer 15

Meglitinides

DPP-4 inhibitors

SGLT2 inhibitors

alpha-glucosidase inhibitors (AGIs)

Amylin mimetics (pramlintide)

Question 16

What pharmacologic agents make a patient gain weight?

Answer 16

Increase appetite: insulin, sulfonylureas, meglitinides

affect adipose tissue metabolism: thiazolidinediones

Question 17

What pharmacologic agents make a patient lose weight?

Answer 17

metformin

GLP-1 receptor agonists

SGLT-2 inhibitors

Question 18

What pharmacologic agents are weight neutral?

Answer 18

DPP-4 inhibitors

Question 19

What drugs are associated with reduced cardiovascular risk?

Answer 19

SGLT2 inhibitor empagliflozin

GLP-1 receptor agonist liraglutide

Question 20

What is the mechanism of action for sulfonylureas?

Answer 20

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

Question 21

What are the advantages of sulfonylureas?

Answer 21

low cost

effective if sufficient beta cell function remains

Question 22

What are the disadvantages of sulfonylureas?

Answer 22

hypoglycemia

efficacy wanes over time

Question 23

What is the mechanism of action of meglitinides?

Answer 23

not sulfonylureas, but they also interact with K-ATP channels stimulating insulin release

Question 24

What are the advantages of meglitinides?

Answer 24

shorter half-life than sulfonylureas so less likely to cause hypoglycemia

Question 25

what are the disadvantages of meglitinides?

Answer 25

frequent administration (with meals) because of short half-life

lower efficacy than sulfonylureas (A1c lowering of 0.5-1%)

Question 26

What is the mechanism of action for thiazolidinediones (TZDs)

Answer 26

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

Question 27

What are the advantages of pioglitazone?

Answer 27

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

Question 28

What are the disadvantages of pioglitazone?

Answer 28

weight gain

fluid retention (increased risk of edema and/or heart failure)

anemia

increased risk of bone fractures

increased risk of bladder cancer

Question 29

What is the mechanism of action of GLP-1 receptor agonists [incretin mimetics]?

Answer 29

exenatide, liraglutide

bind to GLP-1 receptors

augment glucose-stimulated insulin secretion (GSIS)

slows gastric emptying, which enhances satiety/promotes weight loss

Question 30

what are the advantages of GLP-1 receptor agonists?

Answer 30

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

Question 31

what are the disadvantages of GLP-1 receptor agonists?

Answer 31

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

Question 32

What is the mechanism of action of dipeptidyl peptidase-4 inhibitors (DPP-4)?

Answer 32

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

Question 33

What are the advantages of DPP-4 inhibitors?

Answer 33

no hypoglycemia (unless used with drugs that cause hypoglycemia)

well-tolerated

oral

weight neutral

Question 34

What are the disadvantages of DPP-4 inhibitors?

Answer 34

efficacy is intermediate (decrease HbA1c approx 0.5-1%)

high cost

Question 35

What is the mechanism of action of sodium-glucose cotransportor 2 (SGLT2) inhibitors?

Answer 35

empagliflozin

inhibit kidney reabsorption of filtered glucose so more glucose is excreted in the urine

Question 36

What are the advantages of SGLT2 inhibitors?

Answer 36

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

Question 37

What are the disadvantages of SGLT2 inhibitors?

Answer 37

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

Question 38

What is the sodium-glucose cotransporter (SGLT2)?

Answer 38

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

Question 39

What happens when SGLT2 is saturated?

Answer 39

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.

Question 40

What is tubuloglomerular feedback?

Answer 40

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

Question 41

what does increased pressure in glomerular capillaries do and how is this associated to diabetes?

Answer 41

can cause hyperfiltration (increase GFR), which occurs in the early stages of diabetes

Question 42

what mechanism can increase pressure within glomerular capillaries?

Answer 42

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

Question 43

What happens with sustained increases in pressure within the glomerular capillaries?

Answer 43

sustained increases in pressure within glomerular capillaries contribute to kidney damage in patients with diabetes - diabetic nephropathy

Question 44

What does empagliflozin do in terms of kidney disease?

Answer 44

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

Question 45

what other drugs are used to reduce intraglomerular pressure?

Answer 45

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

Question 46

What are the insulin treatments?

Answer 46

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

Question 47

how does regular insulin compare to rapid-acting insulin analogs?

Answer 47

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

Question 48

What is basal insulin?

Answer 48

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

Question 49

what is a basal-bolus insulin regimen?

Answer 49

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

Question 50

Describe continuous subcutaneous insulin infusion (CSII) therapy.

Answer 50

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

Question 51

What is continous glucose monitoring (CGM)?

Answer 51

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

Question 52

Describe hypoglycemia.

Answer 52

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

Question 53

What are the signs and symptoms of hypoglycemia?

Answer 53

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

Question 54

What is the treatment of hypoglycemia?

Answer 54

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

Question 55

what is the recommended action for hypoglycemia at the alert value of <70 mg/dL?

Answer 55

treat with rapidly absorbed carbohydrate

adjust dose of glucose lowering agents

Question 56

what is the recommended action of clinically significant hypoglycemia < 54 mg/dL?

Answer 56

serious risk of falls, motor vehicle accidents, or other injury

urgent treatment recommended

Question 57

what is the recommended action of severe hypoglycemia?

Answer 57

hypoglycemia that causes severe cognitive impairment

external assistance required for recovery

Question 58

What is hypoglycemia unawareness?

Answer 58

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)

Question 59

What is exercise-induced hypoglycemia in patients treated with insulin?

Answer 59

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

Question 60

What happens if a patient with diabetes takes insulin prior to exercise?

Answer 60

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