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ENDO > 185-187 Diabetes > Flashcards

185-187 Diabetes Flashcards

1
Q

What are the normal criteria for fasting glucose and 2 hr glucose?

A

fasting: < 100 mg/dl

2 hr glucose: < 140 mg/dl

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2
Q

What is the criteria for impaired glucose tolerance?

A

2 hr glucose > 140 and < 200 mg/dl

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3
Q

What is the criteria for impaired fasting glucose?

A

fasting glucose 100-125 mg/dl

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4
Q

What is the diagnostic criteria for diabetes?

A

fasting glucose > 126 mg/dl, 2 hr glucose > 200 mg/dl

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5
Q

What is HbA1c? What is it used for?

A

glycosylated hemoglobin where the extent of glycosylation is proportional to the ambient glucose concentration

it provides a measure of glucose control over ~120 day period

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6
Q

What is the mechanism of type 1 diabetes?

A

autoimmune disease with destruction of pancreatic beta-cells and absolute deficiency of insulin

Cytotoxic T-cells are activated after presentation of beta-cell specific antigens

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7
Q

What are the symptoms of type I diabetes?

A

polyuria, weight loss, fatigue

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8
Q

What genes are associated with type I diabetes production?

A

HLA D3 or D4 alleles

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9
Q

What islet cell antibodies may be present in type I diabetics?

A

islet cell autoantibodies, glutamic acid decarboxylase autoantibodies, insulinoma associated 2 autoantibodies, insulin autoantibodies, ZnT8 autoantibodies

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10
Q

What are the acute effects of insulin deficiency on each of the following:

1) triglycerides
2) hepatic glucose
3) free faty acids
4) blood glucose levels
5) urine glucose levels

A

1) in absence of insulin –> proteolysis and breakdown of triglycerides
2) hepatic glucose output increases secondary to glycogenolysis and gluconeogenesis
3) free fatty acids metabolized (produces ketoacids and decreases pH)
4) hyperglycemia (secondary to increased hepatic glucose output and decreased peripheral uptake)
5) hyperglycemia leads to glycosuria (causing dehydration and electrolyte loss)

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11
Q

What is diabetic ketoacidosis?

A

hyperglycemia + secondary decrease in plasma pH due to increased production of ketoacids

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12
Q

What is the treatment for diabetic ketoacidosis?

A

1) insulin therapy (IV infusion)
2) fluids to correct dehydration
3) electrolyte depletion (specifically potassium)

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13
Q

Which type of diabetes is more prone to ketoacidosis?

A

type I diabetes (due to absolute depletion of insulin)

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14
Q

What genes are associated with type II diabetes?

A

many genetic loci, most associated with beta cell function (but some associated with insulin resistance)

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15
Q

What is the pathogenesis of insulin resistnace in type II diabetes?

A

complex metabolic disorder with genetic components

leads to inflammation and ectopic accumulation of lipid metabolites

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16
Q

What is the mechanism of hyperglycemia in type II diabetes?

A

hyperglycemia is secondary to the interaction between insulin resistance (decreased peripheral utilization of glucose and increased hepatic glucose output) and inadquate beta-cell compensation for insulin resistance

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17
Q

What is the goal of therapy for type II diabetes?

A

reduce peripheral insulin resistance, decrease hepatic glucose output, and increase insulin levels/secretion

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18
Q

What is the mechanism of sulfonylureas?

A

bind to sulfonylurea receptor on beta-cells, leading to increased insulin secretion

efficacy dependent on functional beta-cells

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19
Q

What is the mechanism of meglitinides?

A

increase insulin secretion via binding to a site on the sulfonylurea receptor (different than the site that sulfonylureas bind to)

onset quicker than sulfonylureas

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20
Q

What is the action of GLP-1 analogues/inhibitors of GLP-1 degradation?

A

1) stimulates glucose-dependent insulin secretion
2) stimulates beta cell proliferation
3) prevents beta cell apoptosis
4) inhibits gastric motility

also inhibits appetitte, leading to weight loss

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21
Q

What is the effect of DPP-IV inhibitors?

A

a drug for type II diabetes with an oral preparation that is effective in lowering blood glucose but is not associated with weight loss

inhibits the degradation of GLP-1

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22
Q

What is the effect of metformin?

A

decreases hepatic glucose output

also leads to an increase in basal and postprandial blood lactate (and thus increased risk of lactic acidosis)

often used as first line therapy

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23
Q

What is the effect of thiazolidinediones?

A

it enhances insulin sensitivity in the fat and muscle by activating nuclear receptor peroxisome proliferatior activated receptor gamma (PPAR-gamma)

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24
Q

What is the mechanism of alpha-glucosidase inhibitors?

A

competitive inhibitor of brush border alpha-glucosidase, reducing post-prandial glucose absorption

only slightly decreases A1c

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25
Q

What is the effect of amylin analogues?

A

delays gastric emptying and inhibits post-prandial glucagon secretion

leads to decline in A1c and weight loss

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26
Q

What are SGLT2 inhibitors? What do they do?

A

part of a family of glucose transporters that are expressed in the proximal renal tubule

they shift the glucose threshold for excretion to the left such that glucosuria occurs at physiologic glucose levels

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27
Q

What are the clinical effects of SGLT2 inhibitors?

A

decreases fasting glucose (without hypoglycemia), A1c

weight loss

increases urine volume and hematocrit, decreases blood pressure

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28
Q

What are the adverse effects of SGLT2 inhibitors?

A

increase in incidence of lower genitourinary infections, no increase in upper UTIs, possible association with bladder or breast cancer

29
Q

What are the major microvascular complications of diabetes?

A

retinopathy, nephropathy, neuropathy

30
Q

What is the mechanism of complications in diabetes associated with the polyol pathway?

A

increase flux of glucose and other sugars through the polyol pathway –> consumes NADPH –> not enough NADPH to regenerate reduced glutathione (induces oxidative stress)

31
Q

What is the mechanism of complications in diabetes associated with advanced glycation endproducts?

A

intracellular glucose increases formation of advanced glycation end products, which alters proteins/ECM components and forms ROS

32
Q

What is the mechanism of complications in diabetes associated with protein kinase C?

A

increased activation of protein kinase C that has downstream effects leading to endothelial complications

33
Q

What is the unifying hypothesis for diabetic complications?

A

high flucose flux results in increased ROS formation by the mitochondria –> ROS results in DNA damage with activation of PARPs –> activation of PARPs inactivates GAPDH –> inhibited GAPDH increases delivery of glycolytic intermediates to the mitochondria (which further increases ROS production)

34
Q

What are the major macrovascular complications?

A

ischemic heart disease (leading cause of death)

35
Q

What were the major results of the look AHEAD trial?

A

looked at intesnive lifestyle intervention in obese and overweight diabetic patients

1) intervention group achieved weight loss and reduced weight circumference
2) higher remission in intervention group
3) CV risk factors improved in intervention group
4) intervention had no effect on CV outcomes

36
Q

Describe the features that T1 and T2 diabetes have in common and how they differ in their underlying pathogenesis?

A

common features: hyperglycemia, altered protein/fat metabolism, micro- and macrovascular complications, underlying genetic susceptibility

T1DM: autoimmune disease with absolute insulin deficiency, susceptible to ketoacidosis

T2DM: underlying insulin resistance and insufficient beta cell compensation, relative insulin deficiency (no dependence)

37
Q

Describe the general goals and approaches of insulin therapy, including how different types of insulin can be used to recapitulate best as possible normal physiology.

A

goal = get as close to normal physiology as possible (and maintain as close to normal glucose levels without hypoglycemia)

use a combination of short and long acting insulins (long to provide a “background” insulin level and short acting for each meal)

38
Q

Why does an absolute deficiency of insulin result in development of diabetic ketoacidosis?

A

no insulin leads to increased hepatic glucose output (due to glycogenolysis and gluconeogensis) + decreased glucose transport into skeletal muscle and adipose tissue = hyperglycemia

in absence of insulin, breakdown of triglycerides occurs in adipose tissue –> FFAs are released in metabolized into ketoacids

39
Q

How does the therapeutic strategy used for the treatment of type 2 diabetes relate to the underlying pathophysiology of the disease?

A

insulin resistance + insufficient beta cell compensation –> increased hepatic gluconeogensis

therapeutic strategy: address the underlying abnormalities (insulin resistance, relative insulin deficiency, increased hepatic gluconeogenesis)

40
Q

What is the mechanism of insulin action?

A

binds insulin receptors (tyrosine kinase) –> dimerize and autophosphorylate –> activates PI3K (activates glycogen synthase and translocates glucose to plasma membrane) and through Ras (promotes cell growth and differentiation)

41
Q

What is the duration of action of lispro insulin?

A

peaks 30-90 mins, duration of 3-4 hours

slower peak and longer duration than regular insulin

42
Q

What are short-acting insulin drugs?

A

regular insulin, aspart insulin, lispro insulin, glulisine insulin

43
Q

What are long-acting insulin drugs?

A

NPH insulin, glargine insulin, detemir insulin

44
Q

What are the adverse effects of insulin treatment?

A

hypoglycemia (leading to seizures, coma, or death)

45
Q

What is the treatment of hypoglycemia?

A

glucose (orally or IV)

if glucose unavailable, glucagon can be given

can also use diazoxide

46
Q

What receptors do sulfonyluras bind to?

A

ATP-sensitive K channels on beta cells, leading to calcium influx and insulin secretion

47
Q

What are the names of currently used sulfonylureas?

A

glipizide, glyburide, glimepiride

48
Q

What are the adverse effects and durg interactions of sulfonylureas?

A

adverse effects: hypoglycemia, weight gain, GI side effects, cholestatic jaundice, agranulocytosis, aplastic and hemolytic anemia, interactions with alcohol metabolism

drug interactions: sulfonamides, salicylates, clofibrate)

49
Q

What are the adverse effects and drug interactions of meglitinides?

A

hypoglycemia

potentiates repaglinide (competes for plasma protein binding)

50
Q

What are the names of GLP-1 mimetics/agonists?

A

exenatide, liraglutide, semaglutide

51
Q

What is the mechanism of GLP-1 mimetics?

A

acts through GPCR to activate the cAMP/PKA pathway and PKC/PI3K –> enhances insulin biosynthesis and secretion

52
Q

What are the adverse effects and drug interactions of GLP-1 agonists?

A

diarrhea, nausea, vomiting, hemorrhagic pancreatitis, contraindicated in renal failure

interacts with antibiotics and oral contraceptives

53
Q

What is an example of a DPP-4 inhibitor?

A

sitagliptin

54
Q

What receptor does metformin act on?

A

AMP kinase - decreases hepatic glucose production

55
Q

What are the adverse effects and drug interactions for metformin?

A

GI toxicity, nausea, cramps, diarrhea, decreased B12 absorption, lactic acidosis

interacts with cimetidine, furosemide, and nifedipine

56
Q

What is the mechanism of thiazolidinediones?

A

increase sensitivity to insulin via the PPAR-gamma, leading to increased glucose uptake and utilization in skeletal muscle, increased glucose uptake and decreased FA production in adipose tissue

57
Q

What are the side effects and drug interactions of thiazolidinediones?

A

weight gain, edema, CHF risk, bone fractures

interacts with rifampin (CYPs)

58
Q

What is the mechanism of alpha-glycosidase inhibitors?

A

interferes with the hydrolysis of dietary disaccharides and complex carbohydrates –> delays glucose absorption

59
Q

What are the side effects and drug interactions of acarbose?

A

abdominal pain, flatulence

reduced absorption of some drugs (like digoxin)

60
Q

What is the mechanism of amylin analogs?

A

mimics the function of insulin and binds amylin receptors in the hindbrain

slows gastric emptying, decreases post prandial glucose concentrations

61
Q

What is the mechanism of bile acid binding resins?

A

unknown

62
Q

What is the mechanism of bromocryptine?

A

increases dopaminergic activity in the hypothalamus

leads to decreased postprandial glucose without increased insulin

63
Q

What is the general treatment sequence of type 2 diabetes?

A

metformin –> add SGLT-2 inhibitor –> add GLP-1 agonist –> add DPP-4 inhibitor –> add insulin (can consider adding insulin earlier)

64
Q

Insulin acts through:

a) GPCRs
b) tyrosine kinase associated membrane receptors
c) closing membrane potassium channels
d) increasing calcium release
e) steroid-like mechanism with receptors acting as heterodimers

A

b) tyrosine kinase associated membrane receptors

65
Q

Glargine insulin:

a) is rapid acting because it promotes receptor dimerization
b) is rapid acting because it is rapidly absorbed from injection sites
c) is rapidly acting because it is a better substrate for proteases
d) is long acting because it contains the basic protein protamine
e) is long acting because it forms microprecipitates in subcutaneous tissue

A

e) is long acting because it forms microprecipitates in subcutaneous tissue

66
Q

A class of oral hypoglycemic agents that act by promoting transcription of insulin-sensitive genes in muscle and adipose tissue are the:

a) biguanides (e.g. metformin)
b) sulfonylureas (e.g. glyburide)
c) meglitinides (e.g. rapaglnide)
d) thiazolidinediones (e.g. pioglitazone)
e) alpha-glycosidase inhibitors (e.g. acarbose)

A

d) thiazolidinediones (e.g. pioglitazone)

67
Q

A class of drugs used to treat type 2 diabetes whose primary mechanism is to decrease glucose production are:

a) biguanides (metformin)
b) sulfonylureas (glyburide)
c) dipeptidyl peptidase-4 inhibitors (sitagliptin)
d) alpha glucosidase inhibitors (acarbose)
e) thiazolidinediones (pioglitazone)

A

a) biguanides (metformin)

68
Q

Which of the following is true?

a) exenatide opens K channels in beta cells
b) metformin decreases hepatic glucose production by inhibiting AMP kinase
c) canaglifrozin inhibits renal potassium/glucos transporters
d) use of pioglitazone should be avoided in patients with heart failure or acute liver disease

A

d) use of pioglitazone should be avoided in patients with heart failure or acute liver disease

ENDO (19 decks)

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