Diabetes mellitus Flashcards
What is diabetes? Generally speaking, how is it caused?
Chronic non-communicable disease characterised by hyperglycaemia
Caused by relative insulin deficiency or resistance or both
What is the main different between type 1 and type 2 diabetes?
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
What are the risk factors for type 2 diabetes?
- Overweight/obese
- Increasing age:
- mitochondrial dysfunction and inflammation - Family history/genes:
- GKRP
- PPARG - Ethnicity
What are the different causes of insulin resistance?
- Obesity
- Intrinsic:
- mitochondria dysfunction
- oxidative stress
- endoplasmic reticulum stress - Extrinsic:
- accumulation of lipids and their metabolites or increased concentrations of circulating free fatty acids
- chronic inflammation
- altered adipokine levels - Hyperinsulinaemia:
- increases lipid synthesis and exacerbates insulin resistance
What common alterations (in terms of receptors etc) can lead to insulin resistance?
- 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
What activates Serine/Threonine kinases and what effect does this have?
Activated by:
- pro-inflammatory cytokines
- saturated FFAs
- amino acids
Effect:
- phosphorylate IRS –> reduces its Tyr phosphorylation –> increasing its degradation –> Act activation –> Glut 4 translocation
How can insulin resistance associated with obesity or pregnancy be compensated for?
- 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
Give examples of obesity/insulin resistance genes?
- leptin
- leptin receptor
- PC1
- POMC
- MC4 receptor
- insulin receptor
- PPAR-gamma
Give examples of beta-cell dysfunction/growth genes.
- HNF1 alpha
- HNF4 alpha
- Kir6.2
- TCF7L2
- Mitochondrial
Is (plasma) glucagon excessive or deficient in diabetes (type 1+2)?
Excessive (hyperglucagonaemia)
- T1D: poorly controlled/untreated
- T2D: defect of insulin secretion, resistance of alpha cells to insulin and/or hyperglycaemia
Describe the other forms of diabetes (apart from Type 1 and 2).
- Maturity onset diabetes of the young:
- autosomal dominant
- pancreatic beta cell dysfunction - Gestational diabetes:
- increased complications in 2nd ½ of pregnancy
- increased risk of T2D after - Latent autoimmune diabetes of adults:
- 5-10% of phenotypic “T2DM”
- progression to insulin dependence is faster - Type 3c diabetes:
- diseases of the exocrine pancreas
How is diabetes diagnosed?
- One abnormal plasma glucose:
- random >/= 11.1 mol/L
- fasting >/= 7 mmol/L
- in the presence of symptoms: polyuria, polyphagia, polydipsia - Two fasting venous plasma glucose samples in the abnormal range (>/=7 mmol/L) in asymptomatic patients
- HbA1c: >/= 48 mmol/mol (6.5%) = cut-off point between normal and diabetes
Explain the classes and subtypes of anti-diabetic drugs.
- Insulin:
- rapid acting
- intermediate acting
- long acting - Sensitisers (increased sensitivity of cells to insulin):
- biguanides
- thiazolidinediones
- lyn kinase activators - Secretagogues (increase insulin release):
- sulfonylureas
- meglitinide (non-sulfonylurea) - Alpha-glucosidase inhibitors
- 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 - Glycosurics:
- SGLT-2 inhibitors
*also bile acid sequestrants (but not a class)
Give examples of biguanides.
Metformin
Phenoformin
Buformin
Explain the MOA of Metformin.
- inhibits complex I of the mitochondrial resp chain
- this increases AMPK activation
- AMPK activation improves insulin receptor function, improves glucose transport, and reduces fatty acid synthesis
- all of this improves insulin sensitivity
- reduces cAMP levels
- this reduced PKA activity
- this results in inhibition of glucoeneogenic pathways in hepatocytes
- also increases GLP-1
What is the MOA of sulfonylureas and meglitinides?
- sulfonylureas and meglitinides inhibit potassium-sensitive ATP channels
- this increases the induction of membrane depolarisation
- voltage-gated Ca2+ channels remains open
- continues influx of Ca2+ insulin granules to fuse with beta cell membrane
- insulin is released
What is the role of GLP-1?
- inhibit glucagon secretion and hepatic glucose production
- augments glucose-induced insulin secretion
- slows gastric emptying
- promotes satiety
Give examples of DPP-4 inhibitors.
- sitagliptin
- vildagliptin
- saxagliptin
Describe the MOA of DPP-4 inhibitors, using Sitagliptin as an example.
- sitagliptin competitively inhibits dipeptidyl peptidase 4
- this prevents the breakdown of LGP-1 and GIP
- inhibiting the breakdown of these peptides results in increased secretion of insulin and suppression of glucagon release
What is the MOA of thiazolidinediones?
- activate peroxisome proliferator-activated receptors (nuclear receptors)
- when activated the receptor binds to DNA in complex with retinoid X receptor
- increases and decreases transcription of specific genes
- mainly increases the amount of fatty acids in adipocytes, reducing fatty acids in circulation
- the effect of this is that cells are more dependent on oxidation of carbs (glucose) for energy
- reduces blood glucose levels
Give examples of SGLT-1 inhibitors.
- Dapagliflozin
- Canagliflozin
- Empagliflozin
What is the MOA of SGLT-2 inhibitors?
- block the reuptake of glucose in the renal tubules
- increases the amount of glucose lost in the urine
- mild weight loss, mild reduction of blood glucose and little risk of hypoglycaemia
Give examples of thiazolidinediones.
- Pioglitazone
- Rosiglitazone
Give examples of alpha-glucosidase inhibitors.
- Miglitol
- Acarbose
- Voglibose
