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Endo/Eye/Derm - Women/Men > EXAM 4 Diabetes Dr. Roane > Flashcards

EXAM 4 Diabetes Dr. Roane Flashcards

1
Q

At what concentration of glucose do we find glucose in the urine?

A

200 mg/dl
-> saturation of glucose transporter, so it exceeds the maximum transporter (Tm) in the kidneys -> spills in the urine

-in Type 1 and 2:
causes:
Polyuria
Polydipsia (thirsty)
Polyphagia (hunger)

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2
Q

Characteristic Type 1 diabetes

A

Absence of Insulin
-IDDM (insulin-dependent DM)
-Juvenile onset
-T-cell mediated autoimmune contribution to etiology (may have a viral and genetic component)

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3
Q

Characteristic Type 1 diabetes

A

-NIDDM (non-insulin-dependent DM)
-adult onset
-obesity-related (55%)
-idiopathic
-significant but diffuse genetic component

-no insulin problem
insulin receptor insensitivity
treated with a variety of drugs + insulin

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4
Q

How do the pancreas and kidney react to high blood glucose?

A

Pancreas: ß-cells release insulin into the blood

Muscle cells and other cells: use glucose as energy source or convert it into glycogen (storage)

Kidney: converts glucose to glycogen, fats and proteins

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5
Q

How do the pancreas and the kidney react to low blood glucose?

A

Pancreas: alpha-cells release glucagon into the blood

Kidney: converts glycogen into glucose - GLYCOGENOLYSIS

also Gluconeogenesis: producing glucose form non-carbs

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6
Q

Which organs absorb glucose from the blood?

A

-Liver
-Muscle and Fat
-Brain
-RBC
-heart
-kidneys etc.

path: glucose gets from the stomach -> arteries -> liver

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7
Q

Which organs absorb glucose in response to insulin (insulin-sensitive)?

A

Muscle, fat
-Liver

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8
Q

Which organs are not insulin-sensitive in regards to glucose absorption?

A

-Brain
-RBC
-kidney
-heart
-> they always take up glucose

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9
Q

What is the main effect of insulin?

A

in general:
insulin binds to insulin receptor -> signal pathway
-> activation of GSV (glut4 storage vesicle containing glucose transporter)
-> Glucose uptake (glucose goes into the cells along the gradient)

different pathways in different tissues

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10
Q

What triggers glucose uptake in skeletal muscles?

A

-insulin
-exercise
-> muscle contraction triggering GSV production (glut4 transporter)

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11
Q

Overview drugs

A

-GLP-1: more insulin secretin
-DPP4i, Sulfonylureas, Glitinides: more insulin secretion
-SGLT2i: pee out glucose
TZDs: insulin receptor sensitizers
-metformin: probably involved in hepatic glucose output, also sensitizers
-alpha-glucosidase inhibitors: blocking the absorption of glucose

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12
Q

What is the function of the pancreas

A

-secretion of insulin and glucagon
-secretion of pancreatic enzymes and pancreatic juice into the intestine

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13
Q

Which cells within the pancreas secrete glucagon and insulin?

A

Islet cells
alpha cells: secrete glucagon
ß-cells: secrete insulin

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14
Q

How is the active form of insulin formed?

A

Preproinsulin -> Proinsulin -> Insulin

-one long chain: A and B chain connected by C-chain
-C-chain gets cleaved off -> A and B chain connected by a disulfide bridge

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15
Q

What are the drugs that stimulate insulin secretion?

A

-Sulfonylureas
-Meglitinides
-GLP-1 agonists
-DPP-4 inhibitors

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16
Q

Pathway of insulin release in ß-cells

A

Glucose uptake -> metabolized to G6P -> pyruvate
-> ATP in the Krebs cycle
-> ATP binds to K(+) channels and it closes (depolarization causing an action potential -> that opens voltage-gated Ca+ channels -> Ca+ binds to vesicles and causes the fusion with the membrane and insulin release

-also through GLP-1 (released from the intestine) binding to the GLP-1 receptor
-> activates cAMP -> PKA -> causes insulin release

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17
Q

What is the MOA of Sulfonylureas (SU’s)?

A

-they bind to SU receptors (subunit of ATP-sensitive K(+) channels (K+ channels are also found in multiple organs like the brain, heart, etc - negative effects)

they are closing ATP-sensitivte K(+) channels
-> K+ stays inside -> depolarization -> action potential occurs and activates voltage-gated Ca+ channels -> insulin release

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18
Q

Examples of Sulfonylureas

A

1st gen (not often used anymore)
-Tolbutamide
-Tolazamide

2nd gen
-Glyburide (Diabeta)
-Glipizide (Glucotrol)
-Glimeparide (Amaryl)

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19
Q

How are 2nd generation Sulfonylureas different from 1st gens?

A

2nd gens are:
-more potent
-more lipophilic
->better in achieving therapeutic levels
->BUT more likely to cause hypoglycemia

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20
Q

When do Meglitinides most likely work?

A

at high glucose levels -> closing ATP-sensitive K+ channels
-> therefore less likely to cause hypoglycemia
-> but not often used

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21
Q

Examples of Meglitinides

A

-Repaglinide (Prandin)
-Nateglinide (Starlix)

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22
Q

MOA of GLP-1 agonists

A

binds to GLP-1 receptors on ß-cells
-activates signaling pathway: cAMP -> PKA -> stimulates insulin release

-inhibits glucagon release

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23
Q

GLP-1 and GIPs are considered what type of molecules?

A

Incretins
-> hormones that are released after a meal to stimulate insulin release

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24
Q

What are other helpful effects of GLP-1

A

-may increase ß-cell mass (pancreas makes more ß-cells, tropic effect)

-Decreases gastric acid secretion and delays
gastric emptying

-decreases appetite (may cause nausea)
-probably decreases
glucose absorption Ra (rate of appearance) and HGO (hepatic glucose output)

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25
Q

Meaning of glucose Ra

A

glucose rate of appearance - tells how fast glucose enters the bloodstream (from food or the body’s glucose production)

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26
Q

Where is GLP-1 released physiologically?

A

intestinal L-cells
-> stimulated by carbohydrates, fats, and amino acids in the intestine

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27
Q

What is the half-life of GLP-1 and what causes its degradation?

A

t1/2 = 2 minutes
-> degraded by the enzyme dipeptidyl peptidase-4 DPP-4

28
Q

Examples of GLP-1 agonists

A

-tide –> meas peptide (must be injected)

1st: Exenatide (Byetta) -> synthetic version of exendin-4 (ioslated from glia monsters)

-liraglutide (Victoza)
-albiglutide (Tanzeum)
-dulaglutide (Trulicity)
-semaglutide (Ozempic)

29
Q

Which of the GLP-a agonists are resistant to DPP-4?

A

-albiglutide (Tanzeum)
-dulaglutide (Trulicity)

-semaglutide (Ozempic, Wegovy) - injected 1x week
->Rybelsus (oral)

they cause significant weight-loss

30
Q

Which of the GLP-agonists doesnt need to be injected?

A

semaglutide
oral form: Rybelsus

due to the technology SNAC which protects it from digestion and he’s with absorption through the gastric mucosa!!!

-the bioavailability = <1%
-long half-life: 150h

31
Q

What is the MOA of Tirzepatide (Mounjaro)?

A

-agonist of GLP-1 and GIP

-GIP (another incretin-like molecule released from pancreatic intestine cells -> in response to meal):

2 molecules?
glucose-dependent insulinotropic peptide OR
gastric inhibitory peptide (inhibits gastric secretion and gastric emptying)

-> stimulates insulin release

32
Q

What are the risks/ADE of GLP-1 and GIP agonists?

A

-N&V
-gastroparesis (slow or no movement of the food from the stomach to the small intestine)

-extreme, rapid weight-loss

-may increase infection risk (GLP-receptors on macrophages -> lowers readiness of response of macrophages)

-may increase thyroid cancer

33
Q

What is the MOA of Dipeptidyl peptidase-4 inhibitors?

A

-gliptin
Sitagliptin
saxagliptin
linagliptin
alogliptin

blocking the DPP-4 enzyme
-> enhances the natural action of GLP-1

34
Q

What is the function of insulin receptors in general?

A

-activation of signal pathway -> transportation of Glut4 to the membrane
-lipid synthesis
-protein synthesis
-glycogen synthesis
-inhibition of gluconeogenesis

35
Q

What is the function of insulin receptors in adipose tissue?

A

-Promote uptake and storage of fats in various forms
-Promote glucose uptake
Glucose → glycerol-3-phosphate → TG (by adding FFA)

36
Q

What is the function of insulin receptors in muscle cells?

A

promote glucose uptake
-working muscle takes up glucose independent of insulin, but it is also facilitated by insulin

37
Q

What is the function of insulin receptors in the liver?

A
  • promote glucose uptake and conversion to
    FFA, and glycogen synthesis

-also inhibits gluconeogenesis

38
Q

Which drugs are considered insulin sensitizers?

A

-Thiazolidindiones (TZD’s): pioglitazone
-Biguanides: metformin

39
Q

What is the MOA for metformin?

A

it has multiple (pleiotropic), not fully understood
the main MOA:
-inhibits hepatic glucose output (-> considered antihyperglycemic rather than hypoglycemic)

-may have insulin-sensitizing effect - activating
AMPKinase
-> reduces microvascular events (MI, stroke) according to the UKPDS study

40
Q

What is a common side effect of Metformin, and what is a serious but rare one?

A

common: diarrhea

rare: lactic acidosis (serious)

41
Q

Which transporter enables metformin to get into the liver to perform its MOA?

!!!

A

OLC-1
organic cationic transporter 1
genetic variation may lead to an altered response

42
Q

How does metformin work in the liver?

A

-reduces effects of glucagon (would stimulate glyconeogenesis) by inhibiting the second messenger system (cAMP)

Explained:
-weakly inhibits electron transport in the mitochondria-> reduces ATP levels which would be required for the adenylate cyclase to make cAMP
-> since cAMP goes down we end up with more AMP

-> AMP inhibits adenylate cyclase (-> leads to even less cAMP) and also activates the enzyme AMPK (may inhibit tumor growth)

->since cAMP goes down there is less activity of gluconeogenesis

43
Q

Which part of the Mitochondrial electron transport is inhibited by metformin?

!!!

A

Complex I

44
Q

What is the effect of increasing the enzyme AMP kinase in the mitochondria?

A

-inhibits tumor growth
-Insulin receptor sensitivity
-Glucose uptake
-Mitochondrial biogenesis
-Fatty acid oxidation

45
Q

ADE of Metformin

A

-lactic acidosis (rare), dangerous
-may cause nausea and loss of appetite
-can inhibit B12 and folate absorption

-not metabolized
t1/2 plasma: 6.5h, blood: 17h (longer probably bc bound to RBC)

46
Q

Thiazolidinediones (TZSs) are agonists of which receptors?

A

PPAR-gamma receptors

-Troglitazone (w/drawn due to hepatic toxicity)
-Rosiglitazone (Avandia - withdrawn)
-Pioglitazone (Actos)

47
Q

How do PPAR-gamma receptors work physiologically?

A

At the adipose tissue

fatty-acid bind to PPAR-alpha
prostaglandin, leukotrienes bind to PPAR-gamma

-> activate transcription of factors that promote insulin receptor activity
-> uptake of glucose and lipids
-> secretion of adiponectin (antidiabetic) from fat tissue

48
Q

Rosiglitazone MOA

A

-Insulin sensitizer
-makes insulin work better via action on adipocytes -> also better glucose uptake
-may decrease hepatic glucose output

49
Q

What to be cautious about when using Rosiglitazone?

A

liver damage

50
Q

MOA of alpha-glucosidase inhibitors

A

-inhibits the absorption of glucose from the small
intestine

-blocks the enzymes that breakdown long chains of glucose units (such as in starch: rice, potatoes, bread) -> Lowers post-prandial blood glucose;
good for pts. with unusually high blood glucose
following meals

51
Q

Examples of alpha-glucosidase inhibitors

A

-Acarbose (Precose)
derived from a Bacterial oligosaccharide
Inhibits sucrase, glucoamylase and pancreatic amylase

-Miglitol (Glyset): synthetic nitrogen-sugar

-> they are taken prior to food

52
Q

What causes the side effects of alpha-glucosidase inhibitors?

A

since the breakdown is blocked -> large carbohydrates enter the large intestine -> and interact with bacteria

-diarrhea
-flatulence
-bloating

53
Q

Where in the kidney is SGLT2 located?

A

proximal convoluted tube
-> SGLT2 is a co-transporter that takes up Na+ and glucose into the tubular cells -> GLUT2 takes glucose into the bloodstream

SGLT2 at the S1 segment of the proximal tube = 90%

SGLT1 at the S2/S3 segment of the proximal tube = 10%

54
Q

How do SGLT2 inhibitors affect Tmax (transporter)

A

lowers the maximum occupied glucose transporters
-> less glucose is reabsorbed into the bloodstream
-> so the Tmax will be reached faster and excretion into the urine will start earlier

55
Q

Examples of SGLT2 inhibitors

A

-Canagliflozin (Invokana)
-Dapagliflozin (farxiga)
-empagliflozin (Jardiance)

-empagliflozin/linagliptin (Glyxambi)
-empagliflozin/metformin (Synjardy)
-dapagliflozin/metformin (Xigduo XR)

-> Patients excrete 300kcal/day depending on glucose levels
-> common ADE: UTI

56
Q

Which drugs block SGLT1 and SGLT2 transporters?

A

Sotagliflozin (Inpefa)
-improves outcomes in heart failure - may be due to preventing Na+ reabsorption

57
Q

Stages of diabetes

A

HbA1c level:

Normal: <5.7

Prediabetic: 5.7 - 6.5

Diabetic: >6.5

58
Q

What is 1 unit of insulin?

A

-amountt required to lower blood glucose by 2.5 mmol/L in a fasted rabbit

-1U is the activity contained in 0.0347 mg of the
international standard of zinc insulin crystals

59
Q

How are the different types of Insulin categorized?

A

difference in :
-DNA recombinant techniques
-amino acid sequence
-concentration
-solubility
-time of onset
-duration of action

60
Q

How are insulin preparations different in their content?

A

-rapid-acting: clear solution at neutral pH, small amount of zinc to improve stability and shelf-life

-intermediate-acting (NPH): turbid suspensions at neutral pH with protamine in phosphate buffer

-long-acting (glargine, detemir): clear and soluble

61
Q

What is Glucose clamping?

A

used in studies to see how strong an insulin is

the rate of infusion of glucose needed to keep constant glucose levels (since insulin tries to push glucose back down you have to continuously give a certain amount of glucose to keep it stable)

-the higher the rate of glucose you have to give to keep it stable, the stronger the effect of that insulin is

62
Q

What is the best approach to mimic physiologic insulin release in response to glucose?

A

continuous glucose monitoring and an insulin pump that releases insulin that matches the amount of insulin needed

-releases basal (background) basal insulin to maintain metabolic homeostasis (stable blood glucose levels)
+
-short-acting insulting to match glucose peaks after a meal

63
Q

Which amino acids of the long chain cause changes in the duration of action?

A

B28 - Proline
B29 - Lysine

-Insulin lispro (Humalog): reversal of aa at position B28 and B29

-Insulin Aspart (Novolog): Aspartic acid replaces proline at B28

Insulin Glulisine (Apidra): Glutamic acid replaces lysine at B29

64
Q

How is intermediate-acting stabilized and the duration of action prolonged?

A

NPH Insulin
-Neutral Protamie Hagedorn
Neutral pH
Protamine is a stabilizing protein -> complexed with Zinc for better stabilization of insulin

-Isophane: all protamines and insulin are in a complex -> turbid suspension

-Lente Insulin (Humulin L): Insulin complexed with Zinc -> slowed absorption into the blood
-Ultralente: a mixture of crystallized lente and amorphous (non-particular) forms

65
Q

Slow-acting insulin - Glargine

A

Insulin Glargine (Lantus)

modification on the A chain
Glysin at A21
2x Arginine at C-terminus

-soluble in acid (under the skin), precipitates in neutral pH
->provides a stable baseline insulin action without peaks (predictable effects)

66
Q

Slow-acting insulin - detemir (Levemir)

A

-Threonine omitted from position B30
-14 carbon fatty acid added at B29

Endo/Eye/Derm - Women/Men (30 decks)

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