-Glucagon is released from a cells and upper GI if blood glucose is low
-Stimulates glycogen breakdown and gluconeogenesis in the liver
-Insulin released from B cells if blood glucose is high
-Stimulates the liver, adipose and muscle to take up glucose
-The liver is central to controlling glucose levels
-Diabetes occurs when regulation of blood glucose is disrupted.
-Due to disruption of an individuals ability to handle glucose
-Might not yet appear to have diabetes but may have hyperinsulinemia due to lower insulin sensitivity
-Full diabetes progresses when beta-cell failure surpasses a critical threshold usually~90%
Insulin as a last resort
Routine use subcutaneously
Emergency use IV
-Formulations can differ in duration (rapid-acting to long-acting peakless forms)
-Altering amino acids in the insulin structure can usefully alter insulin kinetics, modified insulins are labelled ‘designer’
-prevent dimer formation allowing more active monomers to be bioavailable and used rapidly.
-decreased solubility at neutral pH, which forms aggregates that slowly dissolve.
Long acting + Short-acting for before meals
Flexible requires more understanding of your blood glucose levels and how meals and activities affect them.
Sulphonylureas (TOLBUTAMIDE, ETC)
Thiazolidinediones (Glitazones) (PIOGLITAZONE)
Alpha-Glucosidase inhibitor (ACARBOSE)
Incretin mimetics (EXENATIDE, ETC)
DPP-4 Inhibitors-gliptins (SITAGLIPTIN, ETC)
Act on mitochondria to change ratio of AMP:ATP
Increased AMP activates protein kinase which;
-inhibits glucagon signalling + gluconeogenic path
-inhibits FA synthesis (AMPK)
Takes time to work as uses regulatory gene networks
Interferes with beta cell ion channels to potentiate insulin secretion
Well tolerated but can lead to weight gain
-Block ATP-sensitive K+ channels in membrane
-Causes B cell to depolarise and leads to insulin secretion
-Only work if B cells of the pancreas are functional.
Lead to less weight gain.
-Increased insulin sensitivity and lowers blood glucose in T2D
-Normal effects of insulin increase
-Can cause weight gain and fluid retention
Another example is ROSIGLITAZONE
Used as an additive to metformin and sulphonylureas.
-Delays carbohydrate absorption in the small intestine reducing the postprandial spike in glucose.
Causes a more even intake of glucose.
Side effects of flatulence and diarrhoea.
Glucagon like peptide-1 (GLP-1) + Glucose-dependent insulinotrophic peptide (GIP) are secreted after meals to coordinate the digestive process.
Incretins stimulate insulin secretion, inhibit glucagon secretion, delay gastric emptying and increase satiety signals to the brain.
Incretins are rapidly degraded by an enzyme called dipeptidyl peptidase-4 (DPP-4)
Exenatide LAR (longer acting)
Liraglutide (slows renal clearing)
(analogs of exendin-4/GLP-1)
SITAGLIPTIN + VILDADIPTIN
Inhibit incretin degradation
Enhance incretin effects by blocking DPP-4
Sita = well tolerated and weight neutral
Vilda = associated with resp. tract infections, headaches, occaisonal serious pancreatitis