DM part 1

Question 1

Describe the pathology of DM type 1

Answer 1

1) Autoimmune destruction of pancreatic islet B cells
2) Of varying rate  fast in some and slow in others
3) Also, of varying severity
Incomplete islet destruction and avoidance of ketosis
Age-related loss of remaining beta cells leads to eventual insulin dependence
4) MC arises in children and young adults

Question 2

What are the genetic factors of T1DM pathology?

Answer 2

1) Linked to HLA haplotypes
2) Family members of probands are at increased lifetime risk
-For instance: a child with mother that has type 1 is at 3% lifetime risk
-A child with father that has type 1 has 6% lifetime risk
-Higher concordance between monozygotic twins

Question 3

What are the environmental factors of T1DM pathology?

Answer 3

1) Risk decreases as population under study moves toward the equator
-Higher in Scandinavian countries, less so in equatorial ones
-Risk does change when people emigrate
2) Breastfeeding in first 6 months appears to be protective
3) “Hygiene hypothesis” of public health
-Less infxn (especially parasitic) = increased autoimmune disease

Question 4

Describe the “odd duck” T1DM pathology

Answer 4

1) 5% of people with type I have no evidence of B cell autoimmunity = “idiopathic type 1”/ “type 1B”
2) Primarily occurs in East Asian and Sub-Saharan Africa

Question 5

Pt with T1DM:
1) Describe why polyuria/polydipsia occurs
2) Describe why weight loss occurs

Answer 5

1) Insulin failure > sustained hyperglycemia > osmotic diuresis > loss of glucose, free water, electrolytes in the urine
2) Diuresis > Lowered plasma volume
-Depletion of glycogen, triglycerides > amino acids are diverted to form glucose (and ketone bodies) > decreased muscle mass
-Fat is converted to energy > loss of subcutaneous fat

Question 6

Pt with T1DM:
1) Describe why dizziness occurs
2) Describe why weakness occurs

Answer 6

1) Lowered plasma volume > postural hypotension
2) Decrease in potassium + increased catabolism of muscle protein > generalized weakness

Question 7

Pt with T1DM:
1) Describe why blurred vision occurs
2) Describe why paresthesia occurs

Answer 7

1) Lenses are exposed to hyperosmolar fluids
2) Hyperglycemia > neurotoxicity > temporary dysfunction of peripheral sensory nerves

Question 8

Pt with T1DM: Describe why nausea/ vomiting occurs

Answer 8

1) Diuresis > dehydration
-Ketoacidosis exacerbates dehydration
2) N/V > abdominal pain
3) N/V complicates oral fluid replacement

Question 9

Pt with T1DM:
1) Describe why Kussmaul breathing (tachypnea) occurs
2) Describe why fruity breath occurs

Answer 9

1) As CO2 rises, the patient attempts to “breath it off” through increased respiration
2) Ketone bodies > exhaled acetone

Question 10

Pt with T1DM: Describe why decreased level of consciousness occurs

Answer 10

Increased ketone bodies > ketoacidosis > worsened dehydration > hyperosmolality > disrupted nerve function within the brain

Question 11

Describe acute onset T1DM

Answer 11

1) Acute onset = abrupt onset polyurea, thirst, blurred vision, weight loss, paresthesia and AMS
-Weight loss is also a feature of subacute onset, and is obviously more gradual in these cases

Question 12

Describe subacute onset of T1DM

Answer 12

1) Subacute onset = Loss of fat and muscle mass are features of subacute wt. loss
-Paresthesia is often a subacute finding as well, and, regardless of timing, will clear with the normalization of glycemic levels

Question 13

Describe the keys to Dx of T2DM

Answer 13

1) Obese, Polyuria and polydipsia, but probably no ketonuria
2) May be asymptomatic at first
3) Probably over 40 years old
4) Hypertension, dyslipidemia, atherosclerosis
5) Blood glucose of > 126 after an overnight fast on more than one occasion OR blood glucose > 200 two hours after 75g oral glucose OR A1C > 6.5%

Question 14

T2DM pathology:
1) What does Tissue insensitivity to insulin mean?
2) What makes it different from T1?

Answer 14

1) “Insulin resistance” with non-immune loss of pancreatic B cells
2) Because B cell function is impaired not entirely lost, there is sufficient insulin production to prevent ketoacidosis, but they cannot prevent sustained hyperglycemia

Question 15

T2DM pathology:
1) Is there a genetic component?
2) If not, why? If so, describe

Answer 15

1) Strong genetic component: Concordance in monozygotic twins within one year of diagnosis!
2) 143 loci have been discovered that are risk variants for type II DM
Beta cell development
Fat mass and obesity risk

Question 16

Pathophys:
Though a ubiquitous feature of the disease, the prevalence of obesity among pts with T2DM (type two diabetes) varies between racial groups; describe this difference

Answer 16

30% Chinese and Japanese
60-70% among north Americans

Question 17

Pathophys:
Visceral obesity is correlative with insulin resistance; explain what this means

Answer 17

1) Fat in the omental and mesenteric regions is more associated than subcutaneous abdominal fat
2) Called “metabolic obesity” refers to those without overt obesity, but high amounts of visceral fat
3) Exercise may be protective against accumulation of visceral fat, even if sub q fat is present (think sumo wrestlers)

Question 18

Patient: Describe skin manifestations of T2DM

Answer 18

1) Elevated glucose > poor wound healing > chronic skin infections
-Generalized pruritis and sometimes frequent genital infection
a) Chronic candidal vulvovaginitis is common
b) Less common is balanoposthitis
2) High insulin levels > stimulation of fibroblasts and keratinocytes > hyperpigmented and hyperkeratotic skin > “acanthosis nigricans”
-This manifestation is very closely correlated with high levels of insulin resistance!
-Common at nape of neck and axilla and groin

Question 19

Patients with T2DM: Describe the body habitus

Answer 19

Obesity:
1) Central obesity; even if not significantly obese, fat deposits upper body (abdomen, chest, neck, face)
2) Waist > 40 inches in men and > 35 inches in women

Question 20

Patients with T2DM: What are the general DM Sx

Answer 20

Polyuria/polydipsia
Fatigue

Question 21

1) Describe urine glucose and DM
2) What are the exceptions (in the form of nondiabetic glycosuria)?

Answer 21

1) High concentrations of glucose in the blood = high levels in the urine
2) Genetic mutations, kidney disease, pregnancy

Question 22

Describe blood ketones and urine

Answer 22

1) Breakdown of triglycerides for energy in the absence of available glucose to the cell > ketone bodies
2) Labs are looking for beta hydroxybutyrate and aceto-acetate

Question 23

Describe serum glucose and DM

Answer 23

1) Plasma glucose of 126 mg/dL or higher on more than one occasion after at least 8 hours of fasting is diagnostic of diabetes
2) Plasma glucose 100-125 mg/dL associated with impaired glucose tolerance > “prediabetes”

Question 24

What must occur for the oral glucose tolerance test to be accurate?

Answer 24

1) The test must be performed in the morning because of diurnal variation in glucose tolerance
2) The patient must consume at least 150-200 g of carbohydrate daily for three days prior
3) False positives occur in malnourished, bedridden or severe infection
4) Pts should not smoke or exercise prior to the test

Question 25

Oral glucose tolerance test: 1) When is it done? 2) What is the pt given? 3) When do you Dx?

Answer 25

1) If initial fasting glucose is < 126, but diabetes is suspected then this test can be done 2) Morning of, pt is given 75g of glucose in 300mL of water 3) Blood glucose is obtained at 0 and 120 minutes after ingestion a) A fasting > 126 or 2 hour > 200, the diagnosis is made b) A 2-hour value of 140-199 denotes impaired glucose tolerance

Question 26

Describe Hemoglobin A1c diagnostics

Answer 26

1) HbA1c circulates with RBCs whose life span lasts up to 120 days, it reflects the state of glycemia over the preceding 8-12 weeks -However, the level is weighted more heavily toward recent glucose levels (over the previous month) 2) Therefore, significant changes in HbA1c can be noted with short-term (one month) changes in average plasma glucose levels 3) For initial diagnosis, HbA1c >6.5% is diagnostic for DM HbA1c 5.7%-6.4% is prediabetic 4) And they don’t need to fast!

Question 27

HbA1c: 1) How often do you check it? 2) What can it help you eval? Give an example

Answer 27

1) Typically checked at 3–4-month intervals 2) The blood sugar of patients of both types of DM, even if they are monitoring blood at home -Ex: HbA1c values between 6.9%-7.1% range from 125-205 mg/dL glucose

Question 28

Give 3 examples of when HbA1c can be falsely low

Answer 28

1) Test can be confounded by hemoglobin variant traits = falsely low -Pts with high levels of Hb F 2) Test can be confounded by conditions that shorten erythrocyte survival or decreases mean erythrocyte age = falsely low -Hemolytic anemia -Recovery from acute blood loss 3) Also confounded by certain treatments = falsely low -Fe therapy -EPO therapy for chronic CKD

Question 29

1) Give an example of when HbA1c can be falsely high 2) What does alternate testing include?

Answer 29

1) Conditions that increase erythrocyte survival = falsely raise HbA1c -Splenectomy, hereditary spherocytosis, iron deficiency anemia 2) Fructosamine

Question 30

Fructosamine: 1) What is it? 2) What does it reflect? 3) When would it be falsely low?

Answer 30

1) Glycosylation of serum albumin 2) Reflects the state of glycemic control over the last 1-2 weeks 3) Falsely low in protein losing enteropathy, hepatic disease, and nephrotic syndrome

Question 31

Fructosamine: Give 2 examples of when this test is helpful

Answer 31

1) In setting of abnormal hemoglobin or hemolytic states 2) If assessment of glycemia must be done over a short timeframe

Question 32

Lipids in DM: 1) What affects lipids? What can lead to an increase? 2) How does this relate to T1DM?

Answer 32

1) Lipids are affected by insulin. Deficient control of hyperglycemia leads to increase in lipid 2) In T1DM, this elevation is slight, and returns to normal with proper management

Question 33

Describe lipids in T2DM

Answer 33

1) Patients develop “diabetic dyslipidemia” -High triglycerides (300-400) -Low HDL (less than 30) 2) A change in LDL particles, smaller and less dense -This allows them to carry higher amounts of free cholesterol -And they are also more atherosclerotic 3) Patients who do not normalize with effect treatment of their DM, of course, need work up for primary dyslipidemia

Question 34

Sulfonylureas: 1) What is the MOA? 2) What happens to sulfonylureas?

Answer 34

1) Binds to sulfonylurea receptor on beta cells inside the pancreas, which, of course, stimulates insulin release 2) They get metabolized by the liver and then excreted through the kidneys and a little bit in the bile

Question 35

Sulfonylureas: 1) What should you watch out for? 2) What is another adverse rxn? 3) What do <0.1% of pts get?

Answer 35

1) Hypoglycemia 2) Include wt gain (especially in the first year) 3) Hematologic toxicity (leukopenia, thrombocytopenia)

Question 36

Sulfonylureas: Which 1st gen has a short duration of action (6-10 hrs), and is therefore safe to use in renal disease because its metabolism is not linked to kidney function?

Answer 36

Tolbutamide

Question 37

Sulfonylureas: What is a rare effect of tolbutamide?

Answer 37

1) Rarely, pts get prolonged hypoglycemia with this one – usually due to med reaction: 2) Antibacterial sulfonamides (sulfisoxazole) or the azole antifungals

Question 38

Sulfonylureas: Which 1st gen can cause prolonged hypoglycemia, esp in older adults with decreased renal clearance, and flushing?

Answer 38

Chlorpropamide

Question 39

Sulfonylureas: Describe Glyburide (2nd gen)

Answer 39

1) Also metabolized in liver, but unlike 1st generation sulfonylureas, its metabolites are still active and have hypoglycemic activity 2) This hypoglycemia is especially potent in elderly patients with reduced kidney function

Question 40

Sulfonylureas: Describe glipizide (2nd gen)

Answer 40

1) Gets metabolized in the liver, with about 10% is excreted unchanged in the urine Should not be used in patients with liver failure 2) Preferable to glyburide in older patients and those with kidney disease 3) Better if taken with food, just before a meal, to avoid hypoglycemia

Question 41

List and describe 2 other groups of meds that act on beta cells

Answer 41

1) Meglitinide analogs -Repaglinide is similar to glyburide -Acts up on sulfonylurea receptor, closing ATP sensitive K channel -Also causes wt gain and hypoglycemia 2) D-phenylalanine derivative -Nateglinide also acts upon the ATP-sensitive K channel -Same side effects as above

Question 42

Biguanides (metformin): 1) What is the MOA? 2) Describe dosing

Answer 42

1) MOA: reduces hepatic gluconeogenesis 2) Max dose is 2500 mg daily: almost never used b/c 2000 appears to have maximal benefit Titrate to this dose slowly! GI upset: diarrhea, N/V, abdominal discomfort, anorexia Use lower doses in pts with GFR between 30-45 and in pts at high risk for AKI Stop if Cr above 1.7 or GFR < 30

Question 43

Biguanides: 1) What is the benefit? 2) What is a vitamin related risk?

Answer 43

1) “Euglycemic” or “antihyperglycemic” Rather than hypoglycemic medicine In other words, hypoglycemia is not a risk 2) Effects calcium-dependent absorption of Vit B12 Periodic screens make sense after years of use Consider Ca repletion

Question 44

What is a rare risk of biguanides?

Answer 44

dermatologic or hematologic toxicity

Question 45

Lactic acidosis has been reported what what? Describe

Answer 45

Biguanides: -More common with phenformin (another drug in this class that no one uses) -Persons that develop this usually have risk factors that should have contraindicated its use -Kidney, liver, cardiorespiratory insufficiency, alcoholism

Question 46

Describe biguanides and AKI

Answer 46

-AKI in pts that receive contrast dye while taking medication -Usually, it will be held on scheduled studies involving dye

Question 47

Glitazones (Thiazolidinediones): 1) MOA? 2) Explain

Answer 47

1) Sensitize peripheral tissues to insulin 2) Bind to peroxisome proliferator activated receptor gamma (PPAR-gamma) Effect gene expression

Question 48

Glitazones (Thiazolidinediones): What do they do? How can you use these?

Answer 48

1) Lower A1c by 1-2 % 2) Can be used solo, or with metformin or sulfonylureas, or insulin -When combined with insulin, they decrease the required dosage

Question 49

Glitazones (Thiazolidinediones): 1) Benefits? 2) What are some side effects?

Answer 49

1) Do not cause hypoglycemia Some small studies show that they can improve fatty liver disease 2) Rosiglitazone associated with increased LDL (along with HDL) Pioglitazone lowered triglycerides and increased HDL, with no consistent change in LDL Wt. gain, especially if combined with sulfonylurea or insulin Some is fluid, some is fat mass

Question 50

Glitazones (Thiazolidinediones): What are the safety concerns?

Answer 50

1) Edema in 3-4% of pts receiving monotherapy and 10-15% also receiving insulin > may result in heart failure 2) Contraindicated in patients with DM and NY heart association class III and IV HF 3) Associated with macular edema > rare side effect that resolved with cessation

Question 51

Glitazones (Thiazolidinediones): Which caused fatal liver failure and isn’t around anymore? Explain

Answer 51

Troglitazone (The remaining have not been shown to cause liver failure FDA still recommends against using in liver patients or pts with ALT 2.5 x normal; prescreen liver panel before starting)

Question 52

Glitazones: 1) Describe the fracture risk 2) Is there a risk of anemia? 3) What are there conflicting studies on?

Answer 52

1) In women Between 1 and 2 per 100 pt years Some evidence suggesting higher risk in post menopausal women 2) 4% of patients and may be dilutional effect 3) Pioglitazone and bladder cancer

Question 53

GLP-1 receptor agonists: 1) Which is more effective, glucose PO or IV? 2) What do incretins do? When? 3) GLP-1 has many beneficial effects, including what?

Answer 53

1) PO 2) Activate insulin release i3n response to oral glucose 3) Low post-prandial hyperglycemia Delay of gastric emptying

Question 54

GLP-1 receptor agonists: 1) What does GIP do? 2) What are the benefits of GLP-1 receptor agonists?

Answer 54

1) Also aids in insulin production 2) All those of GLP-1 -Plus, their insulin stimulatory effect is modest compared to sulfonylureas, so less hypoglycemia -Decreased appetite

Question 55

GLP-1 receptor agonists: Describe Exenatide (Bydureon)

Answer 55

Injection via fixed dose pens BID Long-acting form: weekly Lowers A1c by an additional 0.4-0.6% when added to metformin or sulfonylurea, over 30 wks Pts also had 3–6-pound wt. loss Not recommended if GFR < 30

Question 56

GLP-1 receptor agonists: Describe Liraglutide (Victoza, Saxenda)

Answer 56

1) Studied in multiple trials from about 6mo to a year 2) Lowered A1c on average 0.6% when combined with metformin, sulfonylurea, or thiazolidinedione 3) Ave. wt. loss 1-6 lbs. 4) Repeat study in pts with DM and CVD showed that it lowered death from cardiovascular causes; average wt. loss about 5 lbs.; lowered BP and had fewer episodes of hypoglycemia

Question 57

GLP-1 receptor agonists: Describe Dulaglutide (Trulicity)

Answer 57

1) Weekly sub q dose 2) Lowers A1c by 0.7-1.6% 3) Wt. loss 2-7 lbs.

Question 58

GLP-1 receptor agonists: Describe Lixisenatide (Adlyxin)

Answer 58

-Synthetic analog of exendin -Once daily shot before breakfast -A1c Lowered 0.4-0.6% -Wt. loss 2-6 lbs.

Question 59

GLP-1 receptor agonists: Describe Semaglutide (Ozempic)

Answer 59

-GLP-1 synthetic -Weekly shot -Lowers A1c by 1.5-1.8 -This one has a pill for, too (Rybelsus)

Question 60

GLP-1 receptor agonists: 1) How much do these meds lower the A1c on average? 2) How much weight does the patient lose?

Answer 60

1) 1% ish 2) 5ish lbs

Question 61

GLP-1 receptor agonists: Describe the prevalence of 3 side effects

Answer 61

1) Nausea!: 11-40% 2) Vomiting!: 4-13% 3) Diarrhea!: 9-17% (a lot of times due to starting on high dose)

Question 62

GLP-1 receptor agonists: What are the health risks?

Answer 62

1) Increased risk of pancreatitis -Was severe (hemorrhagic or necrotizing) in 6 cases -Two people died -Around 1 pt per 1000 patient years

Question 63

Dual GIP/GLP-1 receptor agonist: Give an example and describe it

Answer 63

Tierzepatide (Mounjaro) Analog of GIP hormone Prolonged action with once weekly dosing

Question 64

Dual GIP/GLP-1 receptor agonist: Describe this

Answer 64

A1c reduction between 1.9 and 2.6% Wt. loss between 12.4 and 25.8 lbs. Benefits: improved lipid profile, lowered BP, reduced fatty liver Side effect profile comparable to other GLP-1s (N/V/D) Slightly higher rate of pancreatitis 0.23 pts per 100 years of exposure

Question 65

DDP-4 inhibitors: What is the MOA?

Answer 65

MOA: stops the breakdown of GLP-1 and GIP

Question 66

DDP-4 inhibitors: List and describe 3 of these drugs

Answer 66

1) Sitagliptin (Januvia) A1c drops by 0.5% Cut the dose in ½ if Cr clearance less than 30 2) Alogliptin (Nesina) A1c drops by about 0.5% Drop the dose by ½ if Cr clearance 30-60 Drop it by ½ again if Cr clearance < 30 3) Linagliptin (Tradjenta) A1c drops by about 0.5% Excreted through the bile primarily No dose adjustment in renal disease

Question 67

DDP-4 inhibitors: What are the side effects?

Answer 67

Nasopharyngitis or URI Hypersensitivity rxn have been reported: Angio edema, anaphylaxis, Stevens-Johnson Undetermined frequency of pancreatitis Liver failure in alogliptin, but undetermined whether Nesina caused it Stop the med if there is liver failure

Question 68

SGLT-2 inhibitors (flozin drugs): 1) MOA? 2) Benefits? 3) Side effects?

Answer 68

1) pee out glucose 2) some have shown benefit in cardiovascular disease 3) efficacy reduced in CKD They can increase creatinine and decrease eGFR, esp if kidney impairment already exists Not recommended in pts with eGFR < 45 They all increase LDL

Question 69

SGLT-2 inhibitors: Health risks?

Answer 69

Health risks: increased incidence of genital mycotic infxn and UTI affecting 8-9% of pts Reported cases of pyelonephritis and septicemia Glycosuria can cause intravascular volume contraction and hypotension One study with canagliflozin showed increased risk of amputations; studies have not been repeated Canagliflozin causes decrease in bone mineral density of lumbar spine and hip Cases of DKA have been reported

Question 70

Human insulin comes in two types; what are they?

Answer 70

1) Regular insulin (R) 2) NPH insulin (N), which stands for Neutral Protamine Hagedorn insulin

Question 71

There are six analogs of human insulin; describe these

Answer 71

1) Three rapid acting: insulin, lispro, insulin aspart, insulin glulisine 2) Three long acting: insulin glargine, insulin detemir, insulin degludec

Question 72

All the insulins in the US are in a concentration of what?

Answer 72

100U/mL (U100); dispensed in 10-mL vials or 0.3 mL cartridges or prefilled disposable pins

Question 73

1) What 2 insulins are designed for sub q administration? 2) What can be given IV?

Answer 73

1) Raid acting insulin analogs and long-acting insulins 2) Regular insulin and insulin aspart

Question 74

Regular insulin (R): 1) When does it start working? 2) Peak action? 3) Duration?

Answer 74

1) Effect appears within 30 minutes after sub q injection 2) Peak action is 1-2 hours 3) Duration 6-8 hours

Question 75

Insulin Analogs: 1) Give 3 examples 2) When is onset? 3) When is peak potency? 4) What is duration?

Answer 75

1) Insulin lispro (Humalog); Insulin aspart (Novolog); Insulin glulisine (Apidra) 2) Onset happens in 5-15 minutes 3) All these reach peak potency in one hour 4) Duration 3-4 hours

Question 76

Immediate acting insulin; NPH: 1) Onset? 2) Peak? 3) Duration?

Answer 76

1) Onset of action is 2-4 hours Peak action is 6-7 hours Duration 10-20 hours

Question 77

Give the onset, duration, and peak for 3 types of long-acting insulin

Answer 77

1) Insulin glargine (Lantus) -Onset 30 min – 1 hour -Peak is flat -Duration about 24 hours 2) Insulin detemir (Levemir) -Onset 30 min – 1 hour -Peak is flat -Duration 17 hours 3) Insulin degludec (Tresiba) -Onset 30 min – 1 hour -Peak is flat -Duration more than 42 hours

Question 78

What is the most common complication of insulin?

Answer 78

Hypoglycemia

Question 79

Describe the 2 types of Sx of hypoglycemia (a complication of insulin)

Answer 79

1) Stimulation of autonomic nervous system a) Sympathetic: tachycardia, palpitations, sweating, tremulousness b) Parasympathetic: nausea, hunger 2) Insufficient glucose for normal CNS function -Irritability, confusion, blurred vision, tiredness, headache, difficulty speaking  Decreased LOC, seizure, coma

Question 80

Hypoglycemia: Below _____ is concerning for most providers; these effects become severe in the ______s

Answer 80

70; 50s

Question 81

Insulin complications: Describe Hypoglycemic unawareness

Answer 81

1) With repeated episodes of hypoglycemia, the body adapts 2) In these cases, autonomic symptoms don’t occur until the BG levels are much lower, and the first symptoms are those related to neuroglycopenia 3) This can be corrected with higher glucose levels, maintained over several weeks

Question 82

Insulin complications: What should you know abt beta blockers?

Answer 82

Be aware that beta blockers blunt the appearance of the autonomic symptoms of hypoglycemia