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Met2 > Diabetes mellitus > Flashcards

Diabetes mellitus Flashcards

1
Q

What is diabetes? Generally speaking, how is it caused?

A

Chronic non-communicable disease characterised by hyperglycaemia
Caused by relative insulin deficiency or resistance or both

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2
Q

What is the main different between type 1 and type 2 diabetes?

A

Type 1:
- chronic autoimmune condition characterised by immune (T-cell) mediated disruption of the pancreatic beta cells within the islets of Langerhans = insulin deficiency

Type 2:
- chronic progressive disease characterised by abnormal insulin action and secretion

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3
Q

What are the risk factors for type 2 diabetes?

A
  1. Overweight/obese
  2. Increasing age:
    - mitochondrial dysfunction and inflammation
  3. Family history/genes:
    - GKRP
    - PPARG
  4. Ethnicity
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4
Q

What are the different causes of insulin resistance?

A
  1. Obesity
  2. Intrinsic:
    - mitochondria dysfunction
    - oxidative stress
    - endoplasmic reticulum stress
  3. Extrinsic:
    - accumulation of lipids and their metabolites or increased concentrations of circulating free fatty acids
    - chronic inflammation
    - altered adipokine levels
  4. Hyperinsulinaemia:
    - increases lipid synthesis and exacerbates insulin resistance
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5
Q

What common alterations (in terms of receptors etc) can lead to insulin resistance?

A
  • decrease in the number of insulin receptors
  • decrease in the catalytic activity of the receptor
  • increased activity of Tyr phosphatase
  • increased Ser/Thr phosphorylation of the receptor or of IRS
  • decreased PI3K/Akt activity
  • decreased levels and function of GLUT4
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6
Q

What activates Serine/Threonine kinases and what effect does this have?

A

Activated by:

  • pro-inflammatory cytokines
  • saturated FFAs
  • amino acids

Effect:
- phosphorylate IRS –> reduces its Tyr phosphorylation –> increasing its degradation –> Act activation –> Glut 4 translocation

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7
Q

How can insulin resistance associated with obesity or pregnancy be compensated for?

A
  • New beta cells can be generated (either replicated from mature beta cells or neogenesis from precursors)
  • As well as number, beta cell size increases
  • increased beta cell function
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8
Q

Give examples of obesity/insulin resistance genes?

A
  • leptin
  • leptin receptor
  • PC1
  • POMC
  • MC4 receptor
  • insulin receptor
  • PPAR-gamma
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9
Q

Give examples of beta-cell dysfunction/growth genes.

A
  • HNF1 alpha
  • HNF4 alpha
  • Kir6.2
  • TCF7L2
  • Mitochondrial
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10
Q

Is (plasma) glucagon excessive or deficient in diabetes (type 1+2)?

A

Excessive (hyperglucagonaemia)

  • T1D: poorly controlled/untreated
  • T2D: defect of insulin secretion, resistance of alpha cells to insulin and/or hyperglycaemia
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11
Q

Describe the other forms of diabetes (apart from Type 1 and 2).

A
  1. Maturity onset diabetes of the young:
    - autosomal dominant
    - pancreatic beta cell dysfunction
  2. Gestational diabetes:
    - increased complications in 2nd ½ of pregnancy
    - increased risk of T2D after
  3. Latent autoimmune diabetes of adults:
    - 5-10% of phenotypic “T2DM”
    - progression to insulin dependence is faster
  4. Type 3c diabetes:
    - diseases of the exocrine pancreas
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12
Q

How is diabetes diagnosed?

A
  1. One abnormal plasma glucose:
    - random >/= 11.1 mol/L
    - fasting >/= 7 mmol/L
    - in the presence of symptoms: polyuria, polyphagia, polydipsia
  2. Two fasting venous plasma glucose samples in the abnormal range (>/=7 mmol/L) in asymptomatic patients
  3. HbA1c: >/= 48 mmol/mol (6.5%) = cut-off point between normal and diabetes
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13
Q

Explain the classes and subtypes of anti-diabetic drugs.

A
  1. Insulin:
    - rapid acting
    - intermediate acting
    - long acting
  2. Sensitisers (increased sensitivity of cells to insulin):
    - biguanides
    - thiazolidinediones
    - lyn kinase activators
  3. Secretagogues (increase insulin release):
    - sulfonylureas
    - meglitinide (non-sulfonylurea)
  4. Alpha-glucosidase inhibitors
  5. Peptide analogs:
    - injectable incretin mimetics (GLP-1 and GIP)
    - Injectable glucagon-like peptide analogs and agonists
    - Gastric inhibitory peptide analogs
    - Dipeptidyl peptidase-4 inhibitors
    - Injectable amylin analogues
  6. Glycosurics:
    - SGLT-2 inhibitors

*also bile acid sequestrants (but not a class)

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14
Q

Give examples of biguanides.

A

Metformin
Phenoformin
Buformin

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15
Q

Explain the MOA of Metformin.

A
  1. inhibits complex I of the mitochondrial resp chain
  2. this increases AMPK activation
  3. AMPK activation improves insulin receptor function, improves glucose transport, and reduces fatty acid synthesis
  4. all of this improves insulin sensitivity
  5. reduces cAMP levels
  6. this reduced PKA activity
  7. this results in inhibition of glucoeneogenic pathways in hepatocytes
  8. also increases GLP-1
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16
Q

What is the MOA of sulfonylureas and meglitinides?

A
  1. sulfonylureas and meglitinides inhibit potassium-sensitive ATP channels
  2. this increases the induction of membrane depolarisation
  3. voltage-gated Ca2+ channels remains open
  4. continues influx of Ca2+ insulin granules to fuse with beta cell membrane
  5. insulin is released
17
Q

What is the role of GLP-1?

A
  • inhibit glucagon secretion and hepatic glucose production
  • augments glucose-induced insulin secretion
  • slows gastric emptying
  • promotes satiety
18
Q

Give examples of DPP-4 inhibitors.

A
  • sitagliptin
  • vildagliptin
  • saxagliptin
19
Q

Describe the MOA of DPP-4 inhibitors, using Sitagliptin as an example.

A
  1. sitagliptin competitively inhibits dipeptidyl peptidase 4
  2. this prevents the breakdown of LGP-1 and GIP
  3. inhibiting the breakdown of these peptides results in increased secretion of insulin and suppression of glucagon release
20
Q

What is the MOA of thiazolidinediones?

A
  1. activate peroxisome proliferator-activated receptors (nuclear receptors)
  2. when activated the receptor binds to DNA in complex with retinoid X receptor
  3. increases and decreases transcription of specific genes
  4. mainly increases the amount of fatty acids in adipocytes, reducing fatty acids in circulation
  5. the effect of this is that cells are more dependent on oxidation of carbs (glucose) for energy
  6. reduces blood glucose levels
21
Q

Give examples of SGLT-1 inhibitors.

A
  • Dapagliflozin
  • Canagliflozin
  • Empagliflozin
22
Q

What is the MOA of SGLT-2 inhibitors?

A
  1. block the reuptake of glucose in the renal tubules
  2. increases the amount of glucose lost in the urine
  • mild weight loss, mild reduction of blood glucose and little risk of hypoglycaemia
23
Q

Give examples of thiazolidinediones.

A
  • Pioglitazone

- Rosiglitazone

24
Q

Give examples of alpha-glucosidase inhibitors.

A
  • Miglitol
  • Acarbose
  • Voglibose
25
Q

What is the OA of alpha-glucosidase inhibitors?

A
  1. slow the digestion of carbohydrates int he small intestine
  2. glucose enters the bloodstream more slowly
26
Q

What are the acute complications of DM?

A
  1. Ketoacidosis:
    - continual use of fatty acids for energy leads to production of ketone bodies
    - blood and urine acid levels rise, dehydration, coma, death
    - potentially life-threatening
  2. Hypoglycaemia:
    - can be due to high insulin doses/ taking insulin before a meal/skipping meals
    - diabetic coma
27
Q

What are the chronic complications of DM?

A 
1. Hyperglcyaemia:
Macrovascular effects:
- atherosclerosis --> cardiovascular events 
Microvascular effects:
- nephropathy
- neuropathy
- retinopathy
- amputation
  1. Dyslipidaemia:
    - ectopic fat deposition (skeletal muscle + liver)
    - exacerbation of insulin resistance
    - microvascular complications
28
Q

What are the different types of retinopathy causes by DM?

A
  1. Proliferative:
    - fragile new blood vessels form (grow on vitreous chamber)
    - new vessels can bleed
    - reduced vision –> separation in areas of retina
  2. Non-proliferative:
    - dilation of retinal veins and micro aneurysms
    - internal haemorrhaging and oedema
    - oedema in centra retina = main cause of vision loss
29
Q

What is the result of hyper activation of Protein Kinase C (PKC) on blood vessels (as a result of increased blood glucose)?

A
  • increased permeability
  • increased occlusion
  • increased ROS levels
  • increased inflammation
  • mitochondrial dysfunction
30
Q

What is the result of hyper activation of Advance Glycation End-product (AGE) pathway (as a result of increased blood glucose)?

A
  • increased macrovascular complications: compromised nutrient and O2 supply to heart, brain, extremities = stroke, MI, CHF, amputation etc.
  • enhanced LDL uptake into atherosclerotic plaques
  • glycation of apolipoprotein
  • glycation of LDLR + LDL –> impaired cholesterol clearance
  • LDL-induced pro-inflammatory cytokine formation
31
Q

What are the characteristics of diabetic nephropathy?

A
  • proteinuria
  • glomerular hypertrophy
  • decreased GFR
  • renal fibrosis
32
Q

What are the different types of neuropathy associated with DM?

A
  1. Peripheral: pain/loss of feeling in hands, arms, feet and legs
  2. Autonomic: changes in digestions, bowel and bladder control, erectile dysfunction etc
  3. Proximal: pain in thighs + hips, weakness in legs
  4. Focal: affect any nerve in the body - causes pain or weakness

Met2 (26 decks)

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