Drugs and Their Targets in Type 2 Diabetes Mellitus

Professor John A. PetersE-mail j.a.peters@dundee.ac.uk

Revise the pathology of type 1 and type 2 diabetes mellitus (T1DM and T2DM, respectively)

List the classes of drug currently employed to treat T2DM noting whether, or not, their action is dependent upon insulin

Understand the action of sulfonylureas upon the KATP channels of pancreatic cells and how closure of this channel causes release of insulin

Outline the mechanism by which glinides (meglitinides) cause insulin release

Explain why GLP-1 analogues and inhibitors of DPP-4 (Gliptins) are used in the treatment of T2DM

Describe the use of metformin as a first line pharmacological intervention in T2DM

Be aware of the use of -glucosidase blockers in T2DM

Comment on the mechanism of action of thiazolidinediones in 2TDM

Describe the novel approach to 2TDM presented by inhibitors of SGLT2

Learning Objectives

Current therapies for type 2 diabetes mellitus (T2DM) act by:

Increasing secretion of insulin (e.g. sulfonylureas, incretin mimetics, glinides (aka meglitinides), DPP-4 inhibitors (gliptins) - insulin dependent action

Decreasing insulin resistance and reducing hepatic glucose output [e.g. biguanides, thiazolidinediones (glitazones)] – insulin dependent action

Slowing glucose absorption from the G.I. tract (e.g. α-glucosidase inhibitors) – insulin independent action

Enhancing glucose excretion by the kidney [sodium glucose type-2 (SGLT2) inhibitors] - insulin independent action

Drugs in Type 2 Diabetes Mellitus

Cellular Energy Status is Linked to Insulin Secretion in the Pancreatic -cell

Elevation of blood glucose concentration

Mechanisms of Disease: advances in diagnosis and treatment of hyperinsulinism in neonates

Diva D De León and Charles A StanleyNature Clinical Practice Endocrinology & Metabolism (2007) 3, 57-68

Increased diffusion of glutamate into the -cell by facilitated

transport (GLUT2)

Phosphorylation of glucose by glucokinase

Increased ATP/ADP ratio within cell closes ATP-sensitive K+ channels causing membrane depolarization

Glycolysis of glucose-6-phosphate in mitochondria yielding ATP

Opening of voltage-activated Ca2+ channels increases intracellular

Ca2+ that triggers insulin secretion

The KATP Channel and its Regulation

ATP binding to each of the Kir6.2 subunits closes the channel causing depolarization of the cell and insulin release (when extracellular glucose is high)

ADP-Mg2+ binding to the SUR1 subunits opens the channel maintaining the resting potential of the cell and inhibits insulin secretion (when extracellular glucose is low)

Sulfonylureas (SUs) used in T2DM bind to SUR1 and close the channel causing depolarization and insulin release independent of plasma glucose concentration

Octomeric complex of 4 potassium inward rectifier 6.2 subunits (Kir6.2) and four sulphonylurea receptor 1 subunits (SUR1)

Tetramer of Kir6.2 subunits form a potassium selective ion channel

SUR1 subunits regulate potassium channel activity

K+

K+

Sulfonylureas Examples are tolbutamide (first generation), glibenclamide (aka

glyburide) and glipizide (second generation)

All incorporate the sulfonylurea moiety (red) with differing R and R2 substituents

Appear to act by displacing the binding of ADP-Mg2+ from the SUR1 subunit (thus closing the KATP channel and stimulating insulin release)

Relative to tolbutamide, glibenclamide and glipazide are more potent and longer acting (but probably have no significant clinical advantage)

Orally active, generally well tolerated, but may cause hypoglycaemia due to excessive insulin secretion (greater risk with long acting agents and in the elderly, or patients with reduced hepatic/renal function)

May be used in conjunction with metformin, or thiazolidinediones Tend to cause undesirable weight gain

Glinides (Meglitinides) Act similarly to the sulfonylureas – bind to SUR1 (at a distinct

benzamido site) to close the KATP channel and trigger insulin release – examples are repaglinide and nateglinide

Have rapid onset/offset kinetics – less likely to cause hypoglycaemia than sulfonylureas

Active orally, taken before meals to reduce postprandial rise in blood glucose

Can be used in conjunction with metformin and thiazolidinediones

Incretin Analogues and DPP-4 Inhibitors (1) Ingestion of food stimulates release of Glucagon Like 1 (GLP-1) and

Glucose Dependent Insulinotropic Peptide (GIP) from enteroendocrine cells in the small intestine (L cells in the ileum and colon and K cells in

the jejunum/duodenum, respectively

GLP-1 and GIP enhance (increment) insulin release

from pancreatic -cells (and delay gastric emptying)

GLP-1 decreases glucagon release from pancreatic α-

cells

Enhanced glucose uptake and utilization

GLP-1 and GIP enter portal blood

Decreased glucose

production

Decreased blood glucose

Incretin Analogues Incretin analogues (i.e. extenatide) mimic the

action of GLP-1 but are longer lasting Extenatide is a synthetic version of extendin-4,

peptide found in the saliva of the Gila monster

Increases insulin secretion, suppresses glucagon secretion, slows gastric emptying, decreases appetite

Causes modest weight loss, reduces hepatic fat accumulation

Administered subcutaneously (s.c.) twice daily

May cause nausea, hypoglycaemia, far more rarely pancreatitis

Binds to GPCR GLP-1 receptors that increase intracellular cAMP concentration

Liraglutide is a longer acting agent, suitable for once daily s.c. administration

DPP-4 Inhibitors (Gliptins) Actions of GLP-1 and GIP are very rapidly terminated (within

minutes) by the enzyme dipeptidyl peptidase-4 (DPP-4)

Gliptins competitively inhibit DPP-4, prolonging the actions of GLP-1 and GIP

Sitagliptin, orally active administered once daily, is generally well tolerated – no hypoglycaemia (when used as monotherapy), weight neutral

Usually used in combination with thiazolidinediones, or metformin, but can be employed as monotherapy

Other agents in the class include saxigliptin and vildagliptin

-Glucosidase Inhibitors (Acarbose) Dietary carbohydrate require digestion to monosaccharides in

order to be absorbed in the small intestine

-Glucosidase is a brush border enzyme that breaks down starch and disaccharides to absorbable glucose

Inhibitors of -glucosidase (i.e. acarbose) delay absorption of glucose thus reducing postprandial increase in blood glucose

Used in 2TDM patients inadequately controlled by life style measures or other drugs

Adverse effects occur in the G.I. tract – flatulence, loose stools, diarrhoea, abdominal pain, bloating – undigested carbohydrate is welcomed by colonic bacteria!

Pose no risk of hypoglycaemia

Biguanides

The only therapeutic agent in this class is metformin (originally found in French lilac)

Metformin (biguanide moiety ringed) French lilac

Metformin

• First line agent in the treatment of T2DM in obese patients (with normal hepatic and renal function)

• Reduces hepatic gluoconeogenesis [by stimulating AMP-activated protein kinase (AMPK)]

• Increases glucose uptake and utilization by skeletal muscle (increases insulin signalling)

• Reduces carbohydrate absorption

• Increases fatty acid oxidation

Metformin – Clinical Aspects

• Prevents hyperglycaemia but does not cause hypoglycaemia

Desirable

• Causes weight loss (unlike insulin and agents that promote insulin release)

• Suitable for oral administration

• May be combined with other agents (e.g. insulin, thiazolidinediones, sulfonylureas)

• Rarely lactic acidosis (avoid routine use in patients with hepatic, or renal, disease)

Adverse• Gastrointestinal upsets (diarrhoea, nausea, anorexia)

Thiazolidinediones (TZDs, Glitazones) Enhance the action of insulin at target tissues, but do not directly

affect insulin secretion – reduce the amount of insulin required to maintain a given blood level of glucose

Act as exogenous agonists of the nuclear receptor peroxyisome profilerator-activated receptor- (PPAR) which associates with retinoid receptor X (RXR) - PPAR is largely confined to adipocytes

Activated PPAR-RXR complex acts as a transcription factor that binds to DNA to promote the expression of genes encoding several proteins involved in insulin signalling, among others Lipoprotein lipase Fatty acid transport protein GLUT4

Desirable effects Promote fatty acid uptake and storage in adipocytes, rather than

skeletal muscle and liver Reduced hepatic glucose output

Adverse effects Weight gain – differentiation of adipocytes contributes along

with… Fluid retention – TZDs promote Na+ reabsorption by the kidney Several members of the class (e.g. ciglitazone, troglitazone)

cause serious hepatotoxicity – only pioglitazone (which does not cause liver dysfunction is now used

Increased incidence of bone fractures

Thiazolidinediones (TZDs, Glitazones)

Pioglitazone may be used in combination with either metformin, or SUs, to achieve adequate control of blood glucose

Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors Represent a novel approach to treatment of T2DM that is not

dependent upon insulin

Act to selectively block the reabsorption of glucose by SGLT2 in the proximal tubule of the kidney nephron to deliberately cause glucosuria

Cause decrease in blood glucose with little risk of hypoglycaemia

Calorific loss (i.e. glucose voided) and water accompanying glucose (i.e. osmotic diuresis) contributes to weight loss

Currently licensed agent is dapagliflozin