Treatment of Diabetes Mellitus

How is blood glucose controlled?
-Pancreas monitors blood glucose
-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.
Diabetes symptoms
Diabetes symptoms
Type 1 diabetes
Type 1 diabetes
Often diagnosed in children
Type 2 diabetes
Diabetes of a form that develops especially in adults and most often obese individuals and that is characterized by high blood glucose resulting from impaired insulin utilization coupled with the body’s inability to compensate with increased insulin production.
Progression to type 2 DM
-Natural progression from prediabetes to diabetes
-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%
Treatment of T1DM
Insulin
Treatment of T2DM
Diet control
Hypoglycaemic drugs

Insulin as a last resort

How is insulin used?
Human insulin is made from recombinant DNA technology

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’

Rapid-acting insulin
Insulin Lispro
Insulin Aspart

-prevent dimer formation allowing more active monomers to be bioavailable and used rapidly.

Intermediate-acting insulin
Neutral protamine Hagedorn insulin
Isophane insulin
Longer-acting insulin
Insulin Glargine

-decreased solubility at neutral pH, which forms aggregates that slowly dissolve.

What kind of insulin formation would you give a person with T1DM?
Intermediate acting
or
Long acting + Short-acting for before meals
Insulin regimens
Insulin regimens
Dosage of insulin
Fixed vs Flexible

Flexible requires more understanding of your blood glucose levels and how meals and activities affect them.

Types of oral Hypoglycaemics
Types of oral Hypoglycaemics
Biguanides (METFORMIN)

Sulphonylureas (TOLBUTAMIDE, ETC)

Thiazolidinediones (Glitazones) (PIOGLITAZONE)

Alpha-Glucosidase inhibitor (ACARBOSE)

Incretin mimetics (EXENATIDE, ETC)

DPP-4 Inhibitors-gliptins (SITAGLIPTIN, ETC)

Metformin
Biguanide drugs
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

Sulphonylureas
Tolbutamide
Chlorpropamide
Glibenclamide
Glipizide

Interferes with beta cell ion channels to potentiate insulin secretion
Well tolerated but can lead to weight gain

Mechanism of action of Sulphonylureas?
-Receptors in B cell membranes
-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.
Repaglinide and Nateglinide
Newer drugs that act in the same way on Katp channels but are not sulphonylureas.
Lead to less weight gain.
Pioglitazone
Thiazolidinedione (glitazone)
-Increased insulin sensitivity and lowers blood glucose in T2D
-PPAR-Gamma agonists
-Normal effects of insulin increase
-Can cause weight gain and fluid retention

Another example is ROSIGLITAZONE

Used as an additive to metformin and sulphonylureas.

Mechanism of action of PIoglitazone
PPAR-gamma ligands promote transcription of genes important in insulin signalling: Liporotein lipase, FA transporters, Glut-4 etc
PPAR -gamma
Peroxisome proliferator activated receptor-gamma
Acarbase
Alpha-Glucosidase inhibitor
-Delays carbohydrate absorption in the small intestine reducing the postprandial spike in glucose.
-T2D

Causes a more even intake of glucose.

Side effects of flatulence and diarrhoea.

What are incretins?
Natural gut peptide hormones

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)

Incretin mimetics
Exenatide (2x daily)
Exenatide LAR (longer acting)
Liraglutide (slows renal clearing)
(analogs of exendin-4/GLP-1)

T2D
Given subcutaneously

DPP-4 inhibitors
Gliptins
SITAGLIPTIN + VILDADIPTIN

Inhibit incretin degradation
Enhance incretin effects by blocking DPP-4

T2D
Sita = well tolerated and weight neutral
Vilda = associated with resp. tract infections, headaches, occaisonal serious pancreatitis

Summary of hypoglycaemics
Summary of hypoglycaemics
Incretin effect
Incretin effect