This is a 16 slide presentation covering the the classes of drugs used in T2DM and their molecular mechanisms of action. Provided by Professor John A Peters, University of Dundee.

1. Drugs and Their Targets in Type 2
Diabetes Mellitus
Professor John A. Peters
E-mail j.a.peters@dundee.ac.uk

2.  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

3.  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

4. 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 Stanley
Nature 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

5. 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+

6. 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

7. 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

8. 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

9. 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

10. 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

11. -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

12. 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

13. 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)

14. 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

15.  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

16. 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