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MBBS II ERS > L42 -Insulin and anti-diabetic agents > Flashcards

L42 -Insulin and anti-diabetic agents Flashcards

1
Q

List some complications of hyperglycemia and hypoglycemia?

A

Hyper = nephropathy, neuropathy, retinopathy, stroke, gangrene, heart attack

Hypo = fatigue, nausea, dizziness, coma, confusion

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2
Q

Define the spectrum of type I DM?

A
  • Type 1 IDDM
  • Type 1.5 latent autoimmune diabetes of adulthood (LADA)
  • Type 1B – idiopathic diabetes
  • Maturity onset diabetes of young: single gene mutation (MODY)
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3
Q

Briefly define the cause of IDDM and NIDDM?

A

IDDM = Autoimmune disease that causes pancreatic islet cell destruction = lack of insulin production

NIDDM = combined defect of insulin secretion and insulin resistance

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4
Q

Treatment strageties for Type 1, 2 DM and GDM?

A

Type 1 = Diet, exercise, Insulin-dependent

Type 2 = Diet, exercise, Anti-diabetic drug, Insulin (1/3)

GDM = Diet, Insulin, Anti-diabetic drugs

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5
Q

Which insulin precursors are used to evaluate insulin function?

A

Preproinsulin = signal sequence + C peptide = determine ability to secrete insulin

Proinsulin and C peptide = determine dynamic range of B cell function

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6
Q

Describe the 24-h physiological insulin secretion trend?

A

almost identical to 24-hour glucose profile

|&raquo_space; admin of exogenous insulin should mimic the pattern of endogenous insulin secretion

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7
Q

Compare basal and bolus insulin admin.?

A

1) Basal insulin: Mimics normal pancreatic basal insulin secretion
- Long lasting
- Smooth, peakless to avoid hypoglycaemia

2) Bolus insulin: Give before meals
- Short duration
- Avoid
hypoglycaemia

Both predictable and reproducible

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8
Q

List 4 principal types of insulin prearation based on acting time?

A

– Short acting : Regular human insulin (Humulin®, Novolin®)

– Rapid onset and ultrashort-acting: Insulin Lispro and Insulin Aspart

– Intermediate acting: protamine (NPH) and lente

– Long acting : Insulin Glargine, Insulin Detemir

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9
Q

Explain how regular human insulin/ Humulin®/ Novolin® extends it’s onset and duration of action?

A

1) self-aggregate in antiparallel fashion to form active dimers
2) stabilize around Zn2+ = inactive hexamers = cannot bind to insulin

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10
Q

Indications for regular human insulin injection? Define the onset and acting time?

A

Short onset: 30min, peak 1-2h

Short acting: 5-8h

Bolus injection for diabetic ketoacidosis, Changing insulin requirements (e.g. infection, post-op)

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11
Q

Give 4 limitations of regular human insulin?

A
  • Inconvenient admin. before meal
  • Risk of hypoglycaemia if delayed meal
  • Mismatch with postprandial hyperglycaemia peak
  • Late postprandial hypoglycaemia
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12
Q

Describe the structure of insulin Lispro?

A

Anti-aggregation: Reverse the 2 amino acids (Proline 28, Lysine 29) at C-terminal of B-chhain

> > prevents hexameric formation

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13
Q

Define the onset and acting time of Insulin Lispro. Give one advantage?

A
  • Rapid onset = 10-15 min (taken just before meal)
  • Ultrashort acting = 2-4h
  • Peak effect 30-60 min

Mimics endogenous insulin secretion = improves postprandial glucose control without risk of hypoglycemia between meals

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14
Q

Describe the structure of Insulin Aspart?

A

Substitute the B-chain proline 28 with aspartic acid

|&raquo_space; rapidly breaks into biologically active monomer after subcutaneous injectio

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15
Q

Define the onset and acting time of Insulin Aspart?

A

 Rapid onset (10-20 min)

 Ultrashort acting: 2-4 hours

 Peak effect: 1 hour

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16
Q

Name 2 intermediate acting insulin.

A

 Protamine (NPH) insulin

 Lente insulin

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17
Q

Describe the structure of Protamine (NPH) insulin and Lente insulin

A

Neutral protamine Hagedorn (NPH) insulin = mixture of insulin + protamine

Lente insulin = mixture of 30% semilente + 70% ultralente insulin (very insoluble, delayed onset and prolonged duration of action)

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18
Q

Define the onset and acting time of NPH insulin?

A

Insulin bound to protamine slowly dissolves

Intermediate onset: peak 4-10h
Intermediate acting: 10-18h

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19
Q

Define the onset and acting time of Lente insulin?

A

Zinc-bound insulin slowly dissolves:

Intermediate onset: peak 4-10h
Intermediate acting: 10-18h

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20
Q

Name 2 long-acting insulin?

A

Insulin Glargine (Lantus)

Detemir Insulin (Levemir)

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21
Q

Describe the structure and MoA of Insulin Glargine?

A
  1. Attach 2 arginines to the B chain c-terminal
  2. Substitute asparagine with glycine at A21 (A chain)

Isoelectric point shifted to pH 7.0 (close to body pH)

> > precipitates in the subcutaneous milieu&raquo_space; stabilizes insulin hexamers
slow, consistent absorption into systemic circulation

22
Q

Describe the structure and MoA of Detemir Insulin?

A
  1. Add myristic acid (FA) to lysine at position B29
  2. Omit threonine in position B30

fatty acid causes it to bind to albumin
» slow release, extended circulating life

23
Q

Define the acting time of Insulin Glargine and Detemir insulin?

A

Insulin Glargine = Ultra-long-acting (maximum activity maintained for >=24 hours)

Detemir insulin = Long acting, 23 hours

24
Q

List some complications of insulin therapy?

A
  1. Hypoglycemia: confusion, weakness, coma…
  2. Insulin allergy, immune resistance
  3. Lipodystrophy at injection sites (use multi-site injection)
  4. Abuse: Development of type 2 diabetes + lifetime dependency
25
Q

List 2 classes and examples of insulin secretogogues?

A

Sulfonylureas:

  • 1st gen = chlorpropamide, tolbutamide
  • 2nd gen***** = glipizide, glimepiride, glibenclamide

Non-sulfonylureas:
- meglitinide analogs: repaglinide, nateglinide

26
Q

MoA of sulfonylureas?

A

1) Bind extracellularly to a high-affinity receptor
2) close the associated inward rectifier ATP-sensitive K+ channel in pancreatic β-cell
3) membrane depolarization&raquo_space; opens voltage-gated Ca2+ channel
4) Ca2+ entry&raquo_space; exocytosis of insulin secretion

27
Q

Indication and resistance of Sulfonylureas?

A
  • Type 2 patients with residual β-cell function
  • adjunctive to nutritional, exercise therapy

Primary failure = 1/4 fail to respond
Secondary failure = lose response over time

28
Q

Define the acting time and ADR of Sulfonylurea?

A

Long duration of action (12-48 hours)

  • Weight gain: increase appetite, decrease glucose excretion
  • Hypoglycaemia
  • GI disturbances, Rashes
  • Cross placenta and deplete fetal insulin
29
Q

MoA and indication of Non-sulfonylureas/ Meglitinide analogs?

A

At functioning pancreatic β cells:
- Bind to a distinct site on sulfonylurea receptor of ATP-sensitive K+ channels» very rapid, transient insulin secretion

  • Control post-prandial glucose
30
Q

Indication and onset and acting time of Meglitinide analogs?

A

controlling postprandial glucose

 Rapid onset
 Short duration of actions (~2 hours)

31
Q

ADR of Meglitinide analogs?

A

 Hypoglycemia (incidence much lower than sulfonylureas)

 Weight gain

32
Q

Name one class of Incretin mimetics and give 2 examples

A

Glucagonlike peptide (GLP) analogues/agonist:

exenatide (GLP-1 agonsit), liraglutide (GLP-1 analog)

33
Q

MoA of Incretin mimetics?

A

Analogues of endogenous incretins: GI hormones secreted after food ingestion:

Include glucagon-like peptide-1 (GLP-1), gastric inhibitory peptide (GIP)

> > stimulate glucose-dependent insulin secretion from B-cell
+
glucagon release from alpha cell

34
Q

Describe the endogenous degradation of Incretins?

A

rapidly degraded by dipeptidyl peptidase-4 (DPP-4)

35
Q

Describe the structure of incretin mimetics to resist DDP-4 degradation?

A

Exenatides = only 53% homology with GLP = decrease degradation by DPP-4

Liraglutide = fatty acid chain added, complex binds to albumin = decrease degradation by DPP-4

36
Q

Indication of incretin mimetics? ADR?

A

Exenatide = Type 2 DM, decrease appetite and gastic emptying, WEIGHT LOSS*****

Liraglutide = WEIGHT LOSS*****

ADR: GI disturbances, Dizziness, Headache

37
Q

Name 2 DDP-4 inhibitor and MoA?

A

Dipeptidyl peptidase-4 (DPP-4) inhibitors / incretin enhancers

Sitagliptin, vidagliptin

inhibit DPP-4-mediated degradation of active GLP-1&raquo_space; increase insulin secretion

38
Q

Indication and ADR of DDP-4 Inhibitor?

A

monotherapy / combination therapy for long term glucose control

ADR: URTI, Sore throat, Diarrhea

39
Q

Name 2 insulin sensitizers?

A

Biguanides (metformin)

Thiazolidinediones: rosiglitazone , pioglitazone

40
Q

MoA of Metformin?

A

1) Activating AMP-activated protein kinase (AMPK) in liver:
a) ↓ gluconeogenic genes (PEPCK, G6Pc) to decrease glucose production
b) ↓ fatty acid synthesis, ↑ fatty acid oxidation

2) Modulates gut microbiota

41
Q

Indication of Metformin? C/O?

A
  • Obese with insulin resistance
  • Lower CVD complications
  • Decrease DM-related cancers

C/O:
- Renal, hepatic diseases, Alcoholism, Severe Infection

42
Q

ADR of Metformin?

A

GI disturbances

metformin- associated lactic acidosis (MALA)

Long-term use = vitamin B12 deficiency

43
Q

MoA of Thiazolidinediones (rosiglitazone,pioglitazone) ?

A

insulin-sensitizing drugs:

bind to peroxisome proliferator-activated receptor γ (PPARγ, nuclear hormone receptor) in adipose tissue (fat), muscle, liver

1) decrease insulin resistance
2) anti-inflammatory effects
3) Improve lipid profiles

44
Q

Indication, risks and ADR of Thiozolidinediones?

A

prevention of type 2 diabetes

Risks:

  • Rosiglitazone > heart attack
  • Bladder cancer (Pioglitazone)

ADR:
weight gain, fluid retention

45
Q

Name 2α-Glucosidase inhibitors ?

A

Acarbose

Miglito

46
Q

MoA of α-Glucosidase inhibitors ?

A

Competitive inhibitor of α-glucosidase

> > block postprandial digestion, absorption of starch, disaccharides from small intestine

> > inhibits glucose absorption

47
Q

Indication of α-Glucosidase inhibitors ?

A

Combo therapy to control glucose

Weak anti-diabetic effect, no hypoglycaemia
No effect on body weight

48
Q

ADR of α-Glucosidase inhibitors ?

A

Not absorbed into the bloodstream

Local GI ADR:
 Flatulence
 Diarrhoea
 Abdominal pain/cramp

49
Q

Name 2 Sodium glucose transporter protein-2 (SGLT2)

inhibitors?

A

Dapagliflozin

Canagliflozin

50
Q

MoA of SGLT-2 inhibitors?

A

Act on kidney (proximal tubule):

Decrease active glucose reabsorption

> > increase urinary
glucose excretion

51
Q

Indication of SGLT-2 inhibitors? ADR?

A

Decrease CVD mortality and morbidity

Control Type 2 DM

 Genital infection  Polysuria

52
Q

Which anti-diabetic drug can cause MALA? Explain the mechanism.

A

Metformin: Metformin-asso.-lactic-acidosis: rare, fatal

Inhibition of Pyruvate dehydrogenase, mitochondria transport of reducing agents
» Enhance anaerobic metabolism&raquo_space; turn pyruvate into lactate

MBBS II ERS (37 decks)

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