Pharmacology of Type II Diabetic Drugs

What is diabetes and what is its main effect?

- A chronic disease wherein the pancreas does not produce enough insulin or

the body cannot effectively use it

- Hyperglycaemia, the main effect of uncontrolled diabetes, can damage

various systems esp nerve and blood vessels

What are the 4 different types of Diabetes

1. Diabetes Mellitus Type I

2. Diabetes Mellitus Type 2

Less common:

3. Gestational Diabetes - occurs during pregnancy

4. Diabetes Insipidus - diabetes due to other causes

What is type I?

Beta-cell destruction and insulin deficiency

- dependent on insulin

What is type II?

Beta cell dysfunction and insulin resistance

- not dependent on insulin

How does GLP-1 work?

When food is ingested outline the 2 pathways it triggers ? hint. GLP 1 in the intestine release is one of them

-After the consumption of food and digestion is

initiated, glucose levels start to increase and

hormones such as GLP-1 (an incretin - a hormone that helps regulate insulin and glucose levels in the body) which is released in

the intestines

- released in intestines

- triggers insulin (insulin acts to decrease

glucose levels)

- inhibits glucagon

- induces feeling of satiety

- reduce appetite

Note: 2nd pathway

- Food consumption also triggers release of pancreatic hormones like insulin,

amylin and glucagon

- Insulin and amylin work to decrease glucose levels and inhibit glucagon while

glucagon acts on the liver to raise glucose levels

How does glucagon work?

Acts on liver to raise glucose

Outline the goal of Diabetes management, diet suggestions and main treatments for Type I and Type II Diabetes

- Goal of management: keep blood glucose levels as close to normal as safely

possible

- Diet: decrease carbohydrate intake

- Type I: insulin (IDDM)

- Type II: Biguanides, Incretins, DPP4, SGLT2I, amylin analogues, insulin

What is the main agent for type I?

Insulin

What are the main agents for type II?

Biguanides

Incretins

DPP4-I

SGLT2-I

Amylin analogues

What is the main biguanide? How does it work?

- Metformin

- Absorbed from small intestine- half-life is 3 hours, unbound to plasma protein

and excreted unchanged in the urine

It decreased blood glucose concentration by:

- inhibit genes involved in gluconeogenesis in liver

- enhances insulin action on muscle and adipose

- stimulate glycolysis and uptake in tissue

- Decreases carbohydrate absorption

Generally as a drug combinations: given with incretins, DPP4 inhibitors,

SGLT2 inhibitors, sulphonylureas, thiazolidinediones and/or insulin

Why is Metformin preferred?

It does not cause:

- hypoglycaemia

- stimulate appetite

-Cause weight gain

- It reduces microvascular complications

What are Metformin SEs?

diarrhoea, nausea, metallic taste, reduced folate and B12 absorption (may need to take

supplements)

What is a complication of metformin?

Lactic acidosis (rare)

Which anti-type II drugs cause hypoglycaemia?

Sulphonylureas

Thioazolidiones

Insulin

What is the mechanism of action of Metformin?

- Does NOT directly affect insulin, glucagon, GH, cortisol, somatostatin

- Activates AMP-activated protein

kinase (AMPK) which inhibits anabolic gluconeogenesis and promotes catabolic lipid oxidation which prevents insulin resistance

- AMPK activation enhances insulin sensitivity

- Increases intestinal GLP-1 release which enhances glucose induced insulin secretion and glucagon inhibition

- Main way it is thought to act is inhibiting complex-1 in mitochondria which

alters ATP-ADP ratio = activation of AMPK

What formulation of insulin causes more insulin release tabs or IV and why?

- Oral glucose causes more insulin release compared to IV due to orally drug goes quickly through the gut where secretion of

gut factors called incretins are

What are incretins?

- GLP-1: glucagon-like peptide 1 (made by L-cells in distal ileum)

- GIP: gastric inhibitory peptide / glucose-dependent insulinotropic peptide (made by K- cells in duodenum)

- stimulate insulin release and preserve beta cells

What are the types of pancreatic cells and what do they secrete?

- Islets secrete insulin and amylin

- Alpha cells secrete incretins GLP-1/2 and GIP as well as glucagon

- Delta cells secrete somatostatin which inhibits both insulin and glucagon

-Pancreatic polypeptide cells - secrete pancreatic polypeptide which inhibits insulin

Cell types in islets of Langerhans summary

How are Incretins and Glucagons made in the body?

-Glucagons and incretins are made from the same pre-cursor

- Posttranslational processing of preproglucagon

- The preproglucagon gene encodes proglucagon, a peptide that is differentially

processed based on the relative activities of the prohormone convertases 1/3

and 2. In the α-cells of the pancreatic islet, prohormone convertase 2 (Psck2 - peptidase that cuts the precursor)

predominates and glucagon, glicentin-related pancreatic polypeptide (GRPP),

intervening peptide 1 (IP1), and a proglucagon fragment are the more

prevalent products.

- In the intestinal L-cell and specific CNS neurons, prohormone convertase 1

(Psck1) action is relatively greater and proglucagon is cleaved to GLP-1,

GLP-2, oxyntomodulin, glicentin, and IP2.

- Most recent evidence indicates that α-cells have some Prohormone Convertase 1/3 activity, and it

is likely that neurons and L-cells also have Prohormone Convertase 2.

What are incretin mimetics (drug), what is a weakness of it and suggest a solution?

- Act on GLP-1 receptor

- stimulate insulin release

- suppress glucagon

- reduce appetite and weight

- slow gastric emptying

- stimulate beta cell proliferation

Weakness: It is very unstable - rapidly cleaved by DPP4 is part of the reason for this

Solution: Structural changes of amino acids in GLP-1 analogues cause peptide to be

more stable and useful

Example: Exendin-4 isolated from saliva of Glia monster and then Exenatide was

formulated as the synthetic version

What are DPP-4 inhibitors?

- DPP-4 rapidly degrade incretins within minutes

- DPP4- inhibitors block this degradation

- no effect on weight and no hypoglycaemia

- Possible SE: increase in incidence of some cancers

Examples: Sitagliptin and Linagliptin

What are SGLT-2 inhibitors?

- Glucose reabsorbed in SGLT-2 and SGLT-1 in distal/proximal tubules

- Ideally want a drug that is better at inhibiting SGLT-2 than SGLT-1 (as more

reabsorbed at SGLT-2 receptor)

- Inhibits SGLT-2 so glucose not reabsorbed

Example: Dapagliflozin and Canagliflozin

How do sulphonylureas work?

- hypoglycaemic agent - acutely increase insulin release, increase plasma insulin concentration

and decrease hepatic insulin clearance

MOA:

- inhibitor binds to sulphonylurea receptor and closes ATP-K channel = depolarisation

= insulin secretion

- receptor can be desensitised in chronic use

- largely protein bound increased interactions with NSAIDs/MAOIs/anitbiotics

-This happens regardless of having high or low glucose

- Excreted in urine with enhanced effect in elderly and renal impairment

- Main adverse effect is hypoglycaemia but also causes neuroglycopenia (lack

of glucose supply to top part of brain), confusion/coma ->solution is to take

oral glucose

- If severe give: IV glucose, glucagon, adrenaline

Examples:

1st generation:

Carbutamide and tolbutamide

2nd generation Glizlazide, Glimepiride and Gliplizide

What are the effects of chronic exposure of sulphonylureas to patients

Chronic exposure to this drug effects:

o No acute increase in insulin release BUT a decreased plasma glucose

concentration still remains

o Chronic hyperglycaemia as it decreases insulin release

o Down-regulation of sulphonylurea receptor

o Largely protein bound ~90-99% increases likelihood of drug

interactions with NSAIDS, MAOIs, some antibiotics

o Receptor desensitisation in chronic use

How is the MOA of sulphonylureas and ATP generation similar?

Inhibitors have same effect as ATP generation- bind to a site of

sulphonylureas receptor and close ATP-sensitive K channel = depolarises

eventually secretes insulin

- When glucose is taken up by the cell it goes into mitochondria where it is

oxidised and ATP is generated

- ATP closes an ATP-sensitive K channel which has sulphonylureas as a co-

factor

- When ATP closes channel = depolarises beta cell = opens calcium channel =

calcium ion influx = stimulates exocytosis of secretory granules = insulin

secreted out from beta cells

How do meglitinides work? compare them to sulphonylureas

- close ATP-K channel on beta cells (Same MOA as sulphonylureas )

-share two binding sites

with sulphonylureas but have their own distinct binding site

- more selective for beta cells than cardiac ATP-K

- more rapid, less sustained release than sulphonylureas

- less potent than sulphonylureas

- Cause less hypoglycaemia

-Taken before a meal

How do Thiazolidinediones (glitazones) work?

- selective agonists for PPAR-gamma (a transcription factor) in adipose, muscle and liver

-PPAR-gamma Dimerises with RXR (retinoid X receptor)

MOA :

- Thiazolidinediones activate insulin responsive genes that control carbohydrate and lipid metabolism; they need insulin to be effective

- reduce insulin resistance in peripheral tissues

- reduce liver glucose production

-Enhances actions of insulin

- increase glucose uptake in muscle/adipose

- increase adipocytes and lipogenesis

- weight gain - due to increased differentiation of adipocytes, fluid retention by stimulating amiloride sensitive Na-absorption

Example : Pioglitazone

Extra info:

-Half-life of 7 hours and takes 6-12 weeks for maximum effects

-Given with metformin, insulin or other hypoglycaemic drugs

What are the effects of PPAR-gamma activation?

How do a-GLUCOSIDASE INHIBITORS (AGIs) work

•AGIs inhibit the absorption of carbohydrates from the small intestine

•Inhibit enzymes that convert complex non-absorbable carbohydrates into absorbable ones (effective in Type I and Type 2).

•Reduce postprandial hyperglycaemia.

Side effects

flatulence and diarrhoea

How do AMYLIN ANALOGUES work

-Amylin (37aa) main component of pancreatic amyloid

related to calcitonin/CGRP:

- Decreases gastric emptying

Inhibits glucagon release

-Promotes satiety, decreases food intake

-Related to b-amyloid, which forms aggregates in neurodegenerative diseases

Example: Pramlintide - analogue of human amylin with Pro replacement as in rat amylin - does not aggregate

-Can be used in both TYPE I and II

INSULIN

-See insulin quizlet

Decision cycle for management of Type 2 diabetes

What are the agents for obesity?

- lipase inhibitor e.g. Orlistat

- GLP-1 agonist e.g. Buproprione, Naltrexone, Saxenda

-5HT-2C agonist e.g., Lorcaserin