8/13/2019 Type 2 Diabetes Drugs

1/3

ThiazolidinedionesExamples: troglitazone and rosiglitazone

BNF:pioglitazone reduces peripheral insulin resistance, leading to a reduction in blood

glucose level. Inadequate response to a combination of metformin and sulfonylurea may

indicate failing insulin release, the introduction of pioglitazone has a limited role in these

circumstances, and the initiation of insulin is often more appropriate.

Pioglitazone is associated with increased incidence of heart failure when used with insulin,

especially in patients with predisposing factors, e.g., previous MI. Not to be used in CHF or a

history of CHF; review regularly and monitor for signs of CHF.

Pioglitazone is also linked with a small increase in risk of bladder cancer. However, in

patients who respond adequately to pioglitazone the benefits outweigh the risks. Not to be

used in active bladder cancer or a history of bladder cancer. Caution with elderly who has an

increased risk of bladder cancer due to old age. Before initiating pioglitazone check risk

factors: age, smoking status, exposure to certain occupational or chemotherapy agents, or

previous radiation therapy to the pelvic region.

Rosiglitazone: Avandia, Avandamentthe marketing authorisation of rosiglitazone has been

suspended following a review by the EMA Sept 2010. The EMA concluded that the benefits

of rosiglitazone do not outweigh the cardiovascular risks. Prescribers are not to issue new

prescription or repeat prescriptions for rosiglitazone, and review patients who are taking

rosiglitazone.

Mechanism of action

Thiazolidinediones target nuclear PPAR receptors, as agonists.

PPAR is expressed mainly in adipose tissue and stimulates expression of insulin-sensitive

genes including:

Lipoprotein lipase Fatty acid transporter protein Adipocyte fatty acid binding protein Acyl-CoA synthase GLUT4

PPAR agonists stimulate the uptake of glucose and fatty acids into adipocytes.

More importantly, activation of PPAR in adipose tissues by these agonists potentates the

insulin-stimulated differentiation of preadipocyte cells into insulin-responsive smalladipocytes ready for the storage of fat: adipogenesis.

These agonists also oppose lipolysis, inflammatory cytokine production in large, insulin

resistant adipose cells, thereby reducing the release of FFA and TNF. Thiazolidinedoomes

also promote apoptosis of these insulin resistant fat cells.

The net result will be increased adiposity (increased weight) yet it is thought that itd be safer

to have fatty acid stored away in small adipocytes rather than free in plasma. This

undoubtedly alleviates insulin resistance caused by FFA and reduces blood glucose directly.

Patients need to moderate dietary intake of high fat otherwise obesity will result and T2DM

will recur.

8/13/2019 Type 2 Diabetes Drugs

2/3

Target: PPAR

PPAR is a nuclear receptor and once activated acts as a transcription factor in the adipose

cells. It is involved in adipocyte differentiation and the development of adiposity (the process

of adipogenesis converting preadipocyte to small, insulin-sensitive adipocytes ready to store

fat. A high fat diet promotes adipocyte hypertrophy(conversion of small adipocytes into

large adipocytes) which induces TNF and FFA release and the development of insulinresistance.

Revision: Target: PPAR

Upon binding to their natural ligands (fatty acids or eicosanoids) or fibrates, PPAR is

activated through a conformational change, which promotes dimerization with retinoic acid

receptor (RXR). The PPAR-RXR complex binds to PPAR response elements (PPREs)

which are localised in various gene promoters. PPREs are repeats of an AGGTCA motif

separated by a single nucleotide. Once bound, the complex recruits co-activator proteins to

form a transactivation complex, which in turn activates transcription of the target genes.

These genes code for proteins that help remove lipids from the bloodstream and get rid of

them by oxidation: Lipoprotein lipase which removes TG from chylomicra and VLDLs. Fatty acid transporter which transports fatty acids into cells. Enzymes of peroxisomal and mitochondrial -oxidation and microsomal -oxidation

such as CAT1, acyl-CoA oxidase and CYP450 which are responsible for oxidation of

fatty acid.

ApoA1 and ApoA2, leading to an increase production of HDL to increase removal ofplasma cholesterol via reverse cholesterol transport.

The expression of ApoC3 is inhibited by the PPAR-RXR complex binding to its PPRE

region of the promoter. ApoC3 normally inhibits lipoprotein lipase and its inhibition leads to

increased clearance of TG from the bloodstream.

Fibrates are agonists acting on nuclear PPAR receptors. They lower TG and increase HDL

levels, while minimally lowering LDL levels.

Sodium-dependent glucose transporter 2 (SGLT2) inhibitorsTarget: SGLT2

SGLT2 is a low-affinity, high capacity glucose transporter located in the proximal tubule of

kidneys and is responsible for 90% of glucose reabsorption from urine back to blood.

SGLT2 inhibitors cause inhibition of reabsorption of glucose and increase glycosuria. Lessglucose is reabsorbed and more is lost in urine. This provides an insulin-independent

mechanism for correction of hyperglycaemia in T2DM.

SGLT1 is involved in glucose uptake in the intestine and is not a target of SGLT2 inhibitors.

Examples: dapagliflozin reversibly inhibits sodium-glucose cotransporter 2 (SGLT2) in the

renal proximal convoluted tubule to reduce glucose reabsorption and increase glucose urinary

excretion. It is licensed as monotherapy or in combination with insulin or other antidiabetic

drugs. Dapagliflozin is not recommended for use with pioglitazone.

Canagliflozin (Invoking) is a new drug recently approved by FDAfirst SGLT2 approved in

the US. It should not be used in T1DM, diabetic ketoacidosis, in those with severe renalimpairment.

8/13/2019 Type 2 Diabetes Drugs

3/3

BiguanidemetforminTarget

During exercise skeletal muscle contraction expends ATP and causes AMP to rise. AMP-

activated protein kinase (AMPK) in skeletal muscles normally respond to increased AMP

levels and reduced ATP levels by stimulating glucose uptake into the muscle and glucose

metabolism to yield more ATP. This mechanism is achieved independently of insulinstimulation of glucose uptake.

NB: two ways to stimulate glucose uptake into muscle: via insulin receptor and AMPK, both

of which increase the expression of GLUT4, and translocation of GLUT4 to plasma

membrane to increase glucose uptake.

AMPK when activated reduce ATP usage and increase ATP production:

Reducing ATP expenditure:

AMPK phosphorylates and inactivates ACC1 and inhibits energy-consuming fattyacid synthesis.

AMPK phosphorylates and inactivates eIF2 inhibits energy-utilising protein synthesis.This is the same as GSK3 whose constitutive activity phosphorylates and inactivateseIF2 and discourages amino acid uptake and protein synthesis.

AMPK phosphorylates and inactivates HMG-CoA and stops energy-consumingcholesterol synthesis.

Increasing ATP production

Like insulin, it activates GLUT4 and stimulates its translocation to the plasmamembrane thus increasing glucose uptake.

AMPK phosphorylates PFK2 and stimulates glycolysis. AMPK phosphorylates and activates transcription factors to increase expression of

GLUT4 and enzymes involved in glucose metabolism. (a bit like activated insulinsignalling)

AMPK phosphorylates and inactivates ACC2 thus decreasing malonyl-CoA, andstimulating uptake and oxidation of fatty acids.

Two mechanisms of activating AMPK:

AMP levels increase; AMP binds to subunit of AMPK and activates it allosterically. AMP

also binds to subunit and makes ita better substrate for AMPK kinase, which

phosphorylates and activates AMPK.

Mechanism of action of metformin:

Metformin acts by activating AMPK in skeletal muscle 5-10 fold higher activity than theusual activation achieved by the effect of exercise which causes ATP depletion and increases

AMP. Metformin-activated AMPK causes an increase in glucose uptake through GLUT4

activation and translocation to the plasma membrane of the muscle. Glucose uptake can still

occur in the absence of insulin or in the presence of insulin resistance. Metformin also

activates AMPK and results in ACC1+2 phosphorylation, which reduces fatty acid synthesis

and increases fatty acid oxidation. This is likely to remove fatty acids that are implicated in

the cause of insulin resistance.