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Learning Objectives Flashcards

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1
Q

Know the causes and recognize the manifestations of diabetes.

A

Polydipsia, polyuria, polyphagia
High blood glucose levels –> glucose in urine/excessive water loss –> dehydration and thirst
Inability to utilize glucose as fuel –> decresed body weight –> excessive hunger

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2
Q

Criteria for diagnosis of diabetes?

A

A1C >/= 6.5%
OR
fasting plasma glucose >/= 126 mg/dL
OR
2-h plasma glucose >/= 200 mg/dL
OR
random plasma glucose >/= 200 mg/dL with symptoms of diabetes

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3
Q

Know the types of diabetes and understand their differences.

A

Type 1 - Insulin-dependent DM: glucose intolerance; no functioning insulin-secreting pancreatic beta cells, autoimmune response that specifically targets pancreatic beta cells; early age onset; family history often negative
Type 2 - Non-insulin dependent DM: for the most part, they retain the ability to secrete insulin in response to glucose, but not enough to maintain healthy glucose levels; age of onset under 25 for non-obese and over 35 for obese; family history is positive; non-obese cause is mutations in specific proteins, obese cause is insulin resistance/decrease beta cell mass

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4
Q

Know the effects of insulin on the metabolic defects of diabetes.

A

Stimulates uptake and utilization of glucose

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5
Q

Know the effects of glucagon on the metabolic defects of diabetes.

A

Stimulates glycogen breakdown, increases blood glucose

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6
Q

Know the effects of somatostatin on the metabolic defects of diabetes.

A

General inhibitor of glucagon secretion

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7
Q

Explain the mechansim of insulin release by pancreatic beta cells.

A

Insulin synthesis in the beta cell
Synthesized as a single peptide (proinsulin) and deposited in secretory granules –> in the granules, it is cleaved into A and B chains and then C (connecting) peptide by proconvertases

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8
Q

Know the role of the alpha subunit of the insulin receptor.

A

The regulatory unit of the receptor
Represses the catalytic activity of the beta subunit
Repression is relieved by insuling binding

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9
Q

Know the role of the beta subunit of the insulin receptor.

A

Contain the tyrosine kinase catalytic domains
autophosphorylation

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10
Q

Know the effect of the tyrosine kinase activity of the insulin receptor.

A

Insulin activates the insulin receptor tyrosine kinase, which phosphorylates and recruits different substrate adaptors
Increase lipogenesis, increase glycolysis, increase glycogen synthesis, decrease gluconeogenesis, cell growth and proliferation with increased DNA and RNA synthesis

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11
Q

Given the name of an insulin preparation, know its rate of onset and duration of action and what modifications account for these properties.

A

Ultra rapid onset/very short action
Rapid onset/short action
Intermediate onset/action
Slow onset/long action

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12
Q

Ultra rapid onset/very short action

A

Lispro (humalog)
Aspart (novolog)
Glulisine (apidra)

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13
Q

Lispro (humalog)

A

Onset: 0.25 (5-15 min)
Duration: 6-8
Has reversed positions of P28 and K29 on insulin B chain, resulting in decreased self-association; changes position of proline and lysine prevent dimerization

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14
Q

Aspart (novolog)

A

Onset: 0.25 (5-15 min)
Duration: 3-5 (short)
Proline 28 in B chain is switched to Aspartate –> disrupts dimerization

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15
Q

Glulisine (apidra)

A

Onset: 0.25 (5-15 min)
Duration: 3-5 (short)
Asn 3 and Lys 29 in B chain are switched to Lys and Glu –> disrupts dimerization

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16
Q

Rapid onset/short action

A

Regular (R)

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17
Q

Regular (R)

A

Onset: 0.5-1
Duration: 8-12

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18
Q

Intermediate onset/action

A

NPH (N)

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19
Q

NPH (N)

A

Onset: 1-1.5
Duration: 24
Protamine bound with insulin –> tissue proteases break down protamine –> free insulin –> slow absorption, long duration of action
Has pronounced peak

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20
Q

Slow onset/long action

A

Glargine (lantus)
Detemir (levemir)
Degludec (tresiba)

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21
Q

Glargine (lantus)

A

Onset: 1-1.5
Duration: >24
Asn 21 of A-chain is changed to Gly + 2 Arg residues added to the end of the B-chain
Clear solution @ pH of 4; solubility of peptide changes at physiological pH –> not soluble and precipitates (i.e. post-injection)
No pronounced peak

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22
Q

Detemir (levemir)

A

Onset: 1-2
Duration: >24
Thr 30 of B-chain is deleted, and Lys 29 is myristylated –> binds serum albumin extensively, creates soluble sink of insulin for long release of insulin
FA side chain with amide bond linkage

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23
Q

Degludec (tresiba)

A

Onset: 1
Duration: >24
Thr 30 of B-chain is replaced by gamma-Glu/C16 fatty acid –> binds serum albumin extensively via dicarboxylic acid moiety, uses intermediate glutamate linker

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24
Q

Understand how insulins are utilized to effect tight gylcemic control.

A
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25
Understand the clinical significance of HbA1c levels and how it may relate to other long-term complications of diabetes.
HbA1C is the total of the exposure of the erythrocytes to the glucose concentration within the bloodstream (amount of blood sugar, glucose, attached to hemoglobin) Want to keep average blood glucose levels below 150 mg/dL (HbA1C less than or equal to 6%) Ex. above 6% range, start to see an increase in retinopathy
26
Know the mechanism of action of thiazolidinediones.
Decrease insulin resistance or improve target cell response to insulin - activators of peroxisome proliferator-activated receptor gamma (PPARgamma), a transcription factor Main target - adipocytes Also - liver and skeletal muscle
27
Thiazolidinediones in adipocytes
Enhances adipocyte differentiation Enhances FFA uptake into Sub-Q fat Reduces serum FFA Shifts lipids into fat cells from non-fat cells
28
Thiazolidinediones in liver and skeletal muscle
Liver - enhances glucose uptake and reduces hepatic glucose production Skeletal Muscle - enhances glucose uptake
29
Know the adverse effects of thiazolidinediones.
Rosiglitazone Pioglitazone - restricted prescribing due to cardiovascular toxicities; associated with increased risk of bladder cancer; some hepatotoxicity Both - contraindicated in NYHA class III or IV heart failure; peripheral edema; increased fracture risk - TdZs decrease differentiation of mesenchymal stem cells in osteoblasts
30
Know the drug interactions of thiazolidinediones.
Resistin: mRNA levels decrease in repsonse to thiazoladinediones Adiponection: mRNA levels increase in response to thiazoladinediones TNFalpha: mRNA levels decrease in response to thiazoladinediones
31
Know the mechanism of action of sulfonylureas.
Agents that enhance insulin secretion Bind to sulfonylurea receptors on the K+ ATP channel --> inactivates K+ channel --> reduces efflux of K+ from cell and decreases polarization --> activates voltage sensitive Ca+ channels --> increase Ca+ and activity of microfilaments --> increased exocytosis of insulin containing granules, stimulating insulin secretion Must have functioning beta cells
32
Know the adverse effects of sulfonylureas.
Lasting and prolonged hypoglycemia (due to long half life) - misdiagnosed as stroke and has led to permanent neurological damage and death GI problems Risk of cardiovascular events Weight gain and increased number of secondary failures (persistent secretion of insulin puts ER stress on beta-cells, decreases ability to secrete insulin, have to go on insulin
33
Know the drug interactions of sulfonylureas.
These drugs enhance the action of sulfonylureas and increase the risk of hypoglycemia: salicylates, phenylbutazone, sulfonamides, clofibrate Cause the displacement of sulfonylureas from plasma protein binding --> increases the free concentration of sulfonylureas, stimulating more insulin secretion Last 3 may also decrease the metabolism of sulfonylureas by liver Drugs having their own hypoglycemic effects which may be additive to the sulfonylureas: alcohol associated with severe sulfonylurea hypoglycemic rxns and high dose saclicylates Drugs which cause hyperglycemia which in turn oppose the action of sulfonylureas and insulin therapy: oral contraceptives, epinephrine, thiazide diuretics, corticosteroids, thyroid
34
Know the mechanism of action of glinides.
Like sulfonylureas - bind to K+ ATP channel
35
Know the adverse effects of glinides.
CV events/mortality
36
Know the drug interactions of glinides.
37
Know the mechanism of action of metformin.
Reduces insulin resistance/lipotoxicity Antihyperglycemic agent Decreases blood glucose concentrations in NIDDM without the concentration falling below normal MOA - activator of AMP-activated kinase (AMPK) Increases the efficiency or sensitivity to insulin in liver, fat, and muscle cells; liver - decreased gluconeogenesis; muscle and fat cells - increased glycolysis, glucose uptake
38
Metformin action in liver
Indirectly affects AMPK Metformin (cation) transported into the cell --> binds to complex 1 of ETC --> inhibits complex 1, disrupts ETC --> phosphorylation of ADP to ATP --> elevated AMP levels --> AMPK, inhibits lipid and cholesterol synthesis; increase in AMP also inhibits fructose-1,6-bisphosphate --> short circuits gluconeogenesis pathway --> lowers blood glucose levels Lactate normallu converted to pyruvate and is excreted this way; this route is inhibited and you can't get rid of lactic acid
39
Metformin action in skeletal muscle
Major site of rapid increase in GLUT4 activity AMP accumulates during exercise while ATP is used up --> activate AMPK which phophorylates TBC1D1/4 which promotes GTPase activity of Rab --> helps Rab hydrolyze GTP --> Rab dissociates from GLUT4, allowing translocation to the membrane and increasing glucose uptake in skeletal muscle
40
Know the advantage of metformin over sulfonylureas.
Rarely causes hypoglycemia Rarely causes weight gain
41
Know the contraindications of metformin.
Contraindicated in those disorders which increase the tendency toward lactic acidosis Decreased vit. B-12 absorption Effects on blood lipid profile - decreased serum triglycerides, decreased serum LDL, reduces risk of adverse cardiovascular events
42
Understand the role of adipokines in the development of type 2 diabetes.
Resistin: elevated in type 2 diabetes Adiponectin: decreased in type 2 diabetes TNFalpha: increased in type 2 diabetes
43
Know the physiological and molecular basis for GLP-1 analong and amylin therapy in the treatment of diabetes.
GLP-1 levels may be decreased in type 2 diabetes - want to provide a long-lasting GLP-1 analog and prevent degradation of endogenous GLP-1 GLP-1 potentiates excitation-secretion and excitation-transcription coupling in the beta-cell, stimulated by uptake of glucose from lumen into bloodstream cAMP pathway: increase insulin secretion ERK1/2 pathway: increase in beta-cell proliferation and protection from apoptosis Amylin: co-secreted with insulin, slows gastric emptying and decreases food intake, inhibits glucagon secretion, blunts postprandial rise in blood glucose Increase incretin effect - oral glucose elicits higher insulin secretory responses than does IV glucose; by stimulating insulin secretion in a glucose-dependent manner, they ensure that postprandial glucose levels do not increase excessively
44
Glucagon-like peptide 1 analogs
Exenatide, liraglutide, dulaglutide, lixisenatide, semaglutide
45
Exenatide (Exedin 4, Byetta)
39 a.a. peptide from gila monster saliva Activates GLP-1 receptor, enhances 1st phase secretion of insulin in response to glucose Fairly stable in-vivo because it is not a great substrate for DPP-IV --> resistance to degradation Contraindicated in pts with family history of medullary thyroid cancer, risk of thyroid C-cell tumors SEs: nausea, vomiting, pancreatitis
46
Liraglutide (Victoza)
hGLP-1 aa7-37 FA enhances duration of action by binding to serum albumin SEs: nausea, vomiting, pancreatitis, risk of thyroid tumors - monitor calcitonin levels
47
Dulaglutide (Trulicity)
GLP-1 agonist peptides slowly released from IgG Fc domain by reduction of disulfide bonds in linker region Contraindicated in pts with family history of medullary thyroid cancer, risk of thyroid C-cell tumors SEs: nausea, vomiting, pancreatitis
48
Lixisenatide (Adlyxin)
Derivative of exenatide (exenatide with polylysine tail) 44 a.a. peptide GLP-1 receptor agonist Contraindicated in pts with family history of medullary thyroid cancer, risk of thyroid C-cell tumors SEs: nausea, vomiting, pancreatitis
49
Semaglutide (Ozempic)
31 a.a. peptide GLP-1 receptor agonist 2-aminoisobutyrate reduces susceptibility to cleavage Extensively bound to serum albumin - t1/2 ~ 1 week Contraindicated in pts with family history of medullary thyroid cancer, risk of thyroid C-cell tumors SEs: nausea, vomiting, pancreatitis
50
Semaglutide oral (Rybelsus)
Dimethylalanine decreases its susceptibility to protealysis Hydrophilic spacer and C-18 FA Salcaprozate makes it more absorbable from GI tract Poor bioavailability
51
Basal insulin/GLP-1 receptor agonist combos
Soliqua Xultophy
52
Tirzepatide (Mounjaro)
Dual agonist, can activate both receptors Full GIP receptor agonist, biased GLP-1 receptor - preferential coupling to cAMP over beta-arrestin (activates pathway you want) Reduces internalization (desensitization) of GLP-1 receptor to maintain GLP-1 effects Reduces A1C and body weight more effectively than GLP-1 receptor agonists
53
Glucagon-like peptide 1 modulators
These are inhibitors of DPP-IV (enzyme that degrades GLP-1) Sitagliptin (januvia), saxagliptin (onglyza), linagliptin (tradjenta), alogliptin (nesina) These enhance actions of GLP-1 Reduce hyperglycemia and HgbA1c, lower risk of hypoglycemia, considered weight neutral SEs: nausea, vomiting, constipation, headache, severe skin reactions, pancreatitis, joint pain, HF DPP-IV also present on immune cells - reduced WBC counts, infections, potential increased risk of cancers
54
Metabolism + excretion of GLP-1 modulators
Januvia + nesina: not extensively metabolized, excreted in urine Tradjenta: not extensively metabolized, excreted in feces Onglyza: CYP3A4/5 substrate, major metabolite it active, excreted in urine
55
Amylin Analog
Pramlintide (symlin) Co-secreted with insulin Slows gastric emptying (decrease peak glucose conc.), decreases food intake (decrease blood glucose levels), inhibits glucagon secretion Blunts postprandial rise in blood glucose Used in both type 1 and type 2 diabetes
56
alpha-glucosidase inhibitors
Acarbose (precose), Miglitol (glyset) MOA: decrease the absorption of carbohydrate from the intestine via inhibition of gut alpha-glucosidases - sucrase, maltase, glucoamylase SEs: GI - diarrhea, nausea, flatulence Acarbose: risk of liver damage at doses > 100 mg tid
57
SGLT2 inhibitors
Canagliflozin, empagliflozin, dapagliflozin, ertugliflozin Decrease the threshold for glucose excretion in urine; reduce blood glucose levels SEs: genital/UT infections, increased urine flow/volume depletion/hypotension, increased risk of diabetic ketoacidosis Contraindicated in pts with renal impairment (increased risk of lower limb amputation)
58
Insulin resistance
Decreased responsiveness to insulin Causes: polymorphisms in insulin signaling pathway proteins, obesity, inactivity
59
Given a structure of an anti-diabetic drug, know its mechanism of action.
60
Know what drugs can effect blood glucose levels, particularly in diabetics.
Agents that increase blood glucose levels include: catecholamines, glucocorticoids, oral contraceptives, thyroid hormone, calcitonin, somatropin, isoniazid, phenothiazines, morphine Agents that increase the risk of insulin hypoglycemia: ethanol, ACE inhibitors, fluoxetine, somatostatin, anabolic steroids, MAO inhibitors, beta adrenergic blockers, vigorous unaccustomed exercise
61
Ethanol inhibits
gluconeogenesis
62
Beta adrenergic blockers
Ephinephrine stimulates the release of glucose, beta blockers block this Can also mask some of the symptoms of hypoglycemia
63
Explain mechanisms of insulin resistance in obesity.
Decreased responsiveness to insulin Obesity is one cause, especially accumulation of fat in the abdominal cavity Free fatty acid levels are increased in obese people, acutely raising FFA levels causes insulin resistance; acute lowering of plasma FFA levels reduses chronic insulin resistance Predominant effect is on insulin-stimulated glucose transport Obese state: hypertrophied adipocytes - monocyte gets into infiltrated macrophage --> increase in circulating TNFalpha, IL-6, and MCP-1 --> decreases adiponectin --> adipocytes hypertrophy
64
Explain mechanisms of insulin resistance in pregnancy.
Maternal insulin resistance due to: inability of target tissues to respond to insulin; insulin doesn't cross placenta, but glucose does; factors secreted by placenta into maternal circulation Placental hormones suspected in gestational insulin resistance: CRH-cortisol: increase as pregnancy progresses, glucocorticoids oppose insulin action; progesterone: increases as pregnancy progresses; placental GH: released during last half of gestation, may contribute to insulin resistance; placental lactogens: increases as pregnancy progresses, contributes to insulin resistance
65
Gestational diabetes
Normal changes in insulin sensitivity and metabolism Early pregnancy: increased insulin response due to growth of placenta, increase maternal fat storage Late pregnancy: reduced insulin sensitivity due to growth of fetus Normally compensated by increased insulin secretion Gestational diabetes: hyperglycemia during pregnancy in otherwise non-diabetic women; appears around week 24 in the rapid growth stage of gestation after fetus has formed; fetus has access to excessive glucose, it produces high levels of insulin and stores the excess glucose as fat
66
Fetal programming
increased risk of developing type 2 diabetes: mother 30-50%, child increased risk
67
Hormones that increase beta-cell mass during pregnancy
Prolactin: increases as pregnancy progresses, stimulates beta-cell proliferation; mutations in the PRL receptor are associated with GDM Placental lactogen activates PRL and GH receptors
68
Treatment of gestational diabetes
Diet: eat small meals, complex carbs, avoid sugary foods Insulin: gold standard, doesn't cross placenta Glyburide: may harm fetus Metformin: crosses placenta, but doesn't harm fetus Thiazoladinediones: not used

Diabetes (6 decks)

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