AN UPDATE IN TREATMENT

OF DIABETES MELLITUS

DR.D.ANUSHA
PROFESSOR OF PHARMACOLOGY
OVERVIEW

• Conventional Oral Antidiabetic Drugs

• Newer GLP_1 Agonist,DPP IV inhibitors and SGLT 2 inhibitors
• Future Targets
• Insulin Devices
• Stem cell
• Epigenetics

• Islet cell Trasplantation.

PHARMACOLOGICAL INTERVENTION IN TYPE 2 DIABETES

Carbohydrate
DIGESTIVE ENZYMES

G)I
Glucose
Acarbose e ( G
cos
Glu I
G
Insulin I
Sulphonylureas,

G
G
(I) G

I
G
Meglitinides I G
G
I
I G
G
I
G

I
G
Metformin
GLP-1…
 GLP-1

GLP-1 stands for glucagon-like peptide-1.

This is a metabolic hormone which helps to
regulate blood glucose levels following meals by
 increasing insulin production,
 reducing glucagon release and
 reducing appetite.
• GLP-1 receptor agonists are drugs created to mimic
the effect of GLP-1 ,acts on the allosteric site.
 GLP-1
 Glucagon-like peptide-1 (GLP-1), a member of the incretin
family
 Exendin-4 is a 39 amino acid peptide in salivary secretions
of Gila monster
 Exhibits 53% sequence similarity to GLP-1; protease
resistant
 EXENATIDE/ER

LIRAGLUTIDE

ALBIGLUTIDE

GLP 1 TASPOGLUTIDE

DULAGLUTIDE

SEMAGLUTIDE

PhotoETP
 EXENATIDE

Administered twice daily, (subcutaneously),alone or in

combination with metformin,

Sulfonylurea or both - significantly reduces HbA1c

Side Effects:

Hypoglycemia, when taken in conjunction with a sulfonylurea

GI disturbances – nausea, vomiting, diarrhea

• Improves insulin secretion
• Delays gastric emptying
• Suppresses appetite
• ↓ food intake
• ↓ postprandial glucagon secretion
• Promotes beta cell proliferation
• Reduced weight gain
• ↓ postprandial hyperglycemia
• ↓ HbA1C
 EXENATIDE EXTENDED-RELEASE

• Exenatide ER subcutaneously once weekly,

• In randomized, controlled trials, adjunctive exenatide

ER 2 mg once weekly for 24-30 weeks

• Beneficial effects of exenatide ER were maintained after

up to 6 years of treatment
 LIRAGLUTIDE

• Second GLP-1 agonist

• Lys to Arg substitution

• Pharmacodynamic profile mimics Exenatide

• More potent than Exenatide extended action.

 ALBIGLUTIDE

• Albiglutide is a glucagon-like peptide-1 agonist (GLP-1

agonist)
• It is a dipeptidyl peptidase-4-resistant glucagon-like peptide-
1 dimer fused to human albumin.
• The drug was invented by Human Genome Sciences
• Albiglutide t1/2-4-7 days
 TASPOGLUTIDE

• Taspoglutide is a a glucagon-like peptide-1 agonist (GLP-1

agonist
• Two phase II trials reported it was effective and well tolerated
• In September 2010 Roche halted Phase III clinical trials due to
incidences of serious hypersensitivity reactions and
gastrointestinal side effects.
 CONTRAINDICATIONS

• Hypersensitivity to active principle or any of the product's

components.

• Patients with a personal or family history of medullary

thyroid carcinoma or affected by multiple endocrine
neoplasia syndrome
 DULAGLUTIDE

• Glucagon-like peptide (GLP-1) receptor agonist-- membrane-

bound cell-surface receptor coupled to adenylyl cyclase in
pancreatic beta cells.
• Increases intracellular cyclic AMP (cAMP) in beta cells
leading to glucose-dependent insulin release.
• Decreases glucagon secretion and slows gastric emptying.
• The most common side effects include gastrointestinal disorders,
such as dyspepsia, decreased appetite, nausea, vomiting, abdominal
pain, diarrhea.
• serious adverse reactions: acute pancreatitis ,hypoglycemia, renal
impairment
LIXISENATIDE

• Lixisenatide is a member of the class of Glucagon-like peptide-1

receptor agonist drugs, each of which activates the GLP-1 receptor
• Secrete insulin in response to high blood sugar.

• Slows gastric emptying.

SEMAGLUTIDE

• Semaglutide -- first GLP-1 receptor agonist to be developed that

can be taken orally.

Semaglutide, new way to prevent people with type 2

diabetes from having to take injections.
PHOTOETP

• Dr Hodson -- new method to better understand the allosteric site of

the GLP-1 receptor.
• New drug, PhotoETP, that is activated by blue light and shows that
the drug structure needs to be twisted to fit into the allosteric site
and extended to stimulate insulin secretion.
• novel technique, ---develop and produce more effective drugs with
fewer side effects.
Dipeptidyl Peptidase-4
(DPP-4) Inhibitors
DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS

- DDP-4, a cell surface peptidase that cleaves a wide range of

protein/peptide substrates
• This results in elevated levels of endogenous GLP-1 and GIP. The
• • increases insulin and decreases glucagon secretion,
• leading to better glycemic control.
- It is used as an adjunct monotherapy to diet and exercise, to

• improve glycemic control in patients with type 2 diabetes

mellitus
• May be used in combination with metformin or a
thiazolidinedione (TZD).
 SITAGLIPTIN

SAXAGLIPTIN
DPP IV INHIBITORS

TRELAGLIPTIN
SUCCINATE

OMARIGLIPTIN
 DPP IV INHIBITORS

SITAGLIPTIN:
• orally active in Type II DM

MOA: DPP IV – responsible for inactivation of incretin hormones GLP & GIP;
DPP IV is inhibited by Sitagliptin;

 ↑ insulin secretion to glucose

 ↓ glucagon secretion
 SITAGLIPTIN

Monotherapy or combined with other agents.

PK:
• Orally well absorbed;
• Excreted in urine
• Dose adjustments needed in renal failure;
 .
upper respiratory
principally
tract infection,
hydrolyzed by
UTI,headache,
CYP3A4/5 to major
and
metabolite M2
nasopharyngitis

Substance P
is the
physiologica
" competitive
l substrate
reversible
for DPP-4
inhibitor of DPP-4,
vasodilatory
Saxaglip effect in the
nasal tissue
tin
TRELAGLIPTIN SUCCINATE,

• It is a highly selective dipeptidyl peptidase (DPP-4) inhibitor

• DPP-4 inhibitors activate T-cells and are more commonly known as

• T-cell activation antigens (specifically CD26.

• Chemically, it is a fluorinated derivative of alogliptin.

• DPP-4 inhibitors may increase the risk
of cancer metastasis—Mice

• NRF2– oxidative damage

OMARIGLIPTIN

• Omarigliptin (MK-3102) is a potent, long-acting oral antidiabetic

drug of the DPP-4 inhibitor class used for once-weekly treatment of type
2 diabetes

• Currently under development

• It inhibits DPP-4 to increase incretin levels (GLP-1 and GIP),

• Omarigliptin 25 mg and 12.5 mg tablets were approved by
Japanese Pharmaceuticals and Medical Devices Agency or
PMDA on 28th Sept 2015.

• Japan was the first country to have approved omarigliptin

 ADVERSE EFFECT


Study, effects of the type 2 diabetes drugs sitagliptin and saxagliptin along
with alpha-lipoic acid. Alpha-lipoic acid is a supplement to treat diabetic
neuropathy,

The mice used in the study were engineered to have a high risk of developing
cancer tumours
Drugs did not increase the incidence of tumours developing,there was an
increase in metastasis of existing tumors associated with the DPP-4 inhibitor
drugs.
• DPP-4 inhibitors may increase the risk of cancer metastasis—
Mice

• NRF2– oxidative damage

 SODIUM-GLUCOSE COTRANSPORTER

• . The kidney contributes to glucose balance by:

 Utilizing glucose in the renal medulla

 Reabsorbing up to 100% of the filtered glucose to maintain the normal
circulating glucose pool.
SGLT-2 INHIBITORS
• SGLT2 -- major transporter responsible for renal glucose
reabsorption -useful therapeutic target for the treatment
of diabetes.
• Few studies have indicated that the expression of SGLT2
is up-regulated in diabetes,
 EMPAGLIFLOZIN

SGLT-2 INHIBITORS
DAPAGLIFLOZIN

CANAGLIFLOZIN
EMPAGLIFLOZIN

• SGLT2 inhibitor - kidneys

• lower blood glucose levels.

• Improve glycemic control and HbA1c.

• Approved by the European Commission in May 2014

• In 2015, reduce the risk of heart attack, stroke and death in
a three-year clinical trial.

• Fainting, yeast infections, low blood sugar with insulin or

insulin secretagogues, elevation in LDL cholesterol, and
impaired kidney function.
 DAPAGLIFLOZIN

In phase 3 clinical Decrease in both Increase in blood urea

trials HbA1c-lowering Fasting and nitrogen and
effect ranged from Postprandial hematocrit
0.35% to 0.90% andsystolic BP (3–6 higher risk for
mm Hg),and body reversible
weight (0.46–4.5 kg). genitourinary
infections
CANAGLIFLOZIN ,ADVERSE EFFECTS
increases
serum
creatinine
"Bone and
fractures decreases
have been eGFR dangerous
seen in [glomerular low blood
filtration pressure
patients rate.] and
taking the hyperalke
type 2 mia
diabetes
medicine
 SYNTHETIC AMYLIN ANALOG

• Islet amyloid polypeptide produced in the Pancreatic

Betacell secreted along with Insulin.

• Synthetic form—Aminoacid modifications to improve

bioavailability
• Bind to amylin receptor in specific regions of hind brain.
 SYNTHETIC AMYLIN ANALOG
PRAMLINTIDE:
• Adjunct to mealtime insulin in Type I & II Diabetes mellitus;
• Amylinomimetic;
• Delays gastric emptying
• ↓ glucagon secretion pp
• Improves satiety;

Administered s.c. prior to meals.

Insulin dose can be decreased by 50%
ADR: nausea, vomiting, anorexia
CI: gastroparesis, unaware hypoglycemia
 PANCRELIPASE

• Ultresa (pancrelipase) delayed-release capsules is a

pancreatic enzyme preparation consisting of pancrelipase,
an extract derived from porcine pancreatic glands.

• Digestive enzymes physiologically secreted by the

pancreas.
 MIFEPRISTONE

 Korlym (mifepristone)-- progesterone and glucocorticoid antagonist. It

blocks the binding of cortisol to its receptor.

 Blocks only the glucocorticoid receptor (GR-II) at higher doses

 Control hyperglycemia secondary to hypercortisolism in adults with

endogenous Cushing's syndrome who have type II diabetes mellitus or
glucose intolerance .
• The recommended initial dose is a single dose of 300
mg orally once daily.

• The dose of Korlym may be increased to a maximum

of 1200 mg once daily but should not exceed 20
mg/kg per day.
• The FDA approval was based on an open-label, 24-week, multicenter
clinical study. The study enrolled 50 subjects with clinical and
biochemical evidence of hypercortisolemia despite prior surgical
treatment and radiotherapy.
 NEUROPATHY

 The research team, led by Sandra Rieger, Ph.D, exposed

zebrafish to paclitaxel, a chemotherapeutic agent ,

 Paclitaxel induced the degeneration of sensory nerve endings by

damaging the epidermis, which is supplied by free sensory nerve
endings that establish direct contact with skin cells.
 This degeneration was found to be caused by an increase in matrix-
metalloproteinase 13 (MMP-13), an enzyme which degrades the collagen between
the cells

 The researchers now plan to study the effect of MMP-13 on peripheral neuropathy in
mammalian animals,
 MSDC-0602
• A new study, led by Washington University School of Medicine in St.
Louis
• Working with mice, found that shutting down a liver protein
that controls glucose production led to lower levels of blood
sugar.
• The investigational drug MSDC-0602.
insulin sensitizer - the drug is currently undergoing trials .
 PYRUVATE TRANSPORT BLOCKERS

Interfere pyruvate - Inhibiting a

a building block of Mitochondrial
glucose - from the pyruvate carrier 2 To treat
bloodstream into (MPC2) in the
the mitochondria of liver of mice
nonalcoholic
liver cells may blocked pyruvate fatty liver
reduce glucose transport and cut disease.
production in the glucose
liver. production.
 XANTHOHUMOL

• xanthohumol, a naturally occurring prenylated flavonoid

found in hops and beer significantly improves certain
biologic markers of metabolic syndrome in mice.

• Metabolic rate of mice fed a high-fat diet supplemented

with varying levels of Xanthohumol.,
 80 per cent in LDL cholesterol
 78 per cent decrease in levels of inflammation marker IL-6.
 42 per cent insulin production
 xanthohumol experienced 22 per cent less weight gain than the control group and
decreased fasting plasma glucose as well as improving mitochondrial beta
oxidation and lipid homeostasis.

 The synthesis of xanthohumol analogues for the development of very low-

cost treatment for metabolic syndrome and protection against oxidative damage
 GLYCOGEN PHOSPHORYLASE INHIBITORS

• The liver is central to glucose handling and

homeostasis.

• Inhibition of hepatic glucose production.

• Cleavage of Glycogen

• Targeting glycogen phosphorylase --decrease the amount of

glucose produced by the liver.
• Martin and colleagues --oral CP-91149 indirectly inhibits
gluconeogenesis by inhibiting liver glycogen phosphorylase to
improve glucose levels in animal studies.

• The development of glycogen phosphorylase inhibitors is

promising;
 GLUCOKINASE

• Glucokinase -rate of glucose metabolism

• Glucokinase act more in type 2 diabetes

• Glucokinase in the liver is regulated by a glucokinase regulatory

protein,
 GLUCOKINASE ACTIVATORS (GKAS)

 Increase the enzymatic activity of glucokinase.

 GKAs bind to the allosteric site of glucokinase, which increases the maximum
velocity or glucose affinity of glucokinase .

 Active role in glucose homeostasis and, as a glucose sensor.

 Development looks promising for treating type 2 diabetes.

G PROTEIN-COUPLED RECEPTOR 119 AGONISTS

GPR119 expressed in pancreatic beta cells increases cyclic AMP

(cAMP) and induces insulin release

Stimulates the release of incretins glucagon-like peptide (GLP)-1

and gastric inhibitory peptide.

Potential target for glycemic control -- direct insulinotropic

effects
• Chu and colleagues showed that oral treatment with a GPR119
agonist AR231453 provided better glycemic control than
intravenous treatment, which suggests possible incretin
involvement.

• Yoshida and colleagues confirmed that the GPR119 agonist

AS1907417 is effective in preserving beta-cells and controlling
glucose levels.
PROTEIN TYROSINE PHOSPHATASE (PTP) 1B
INHIBITORS
• Acts on Insulin
cascade downstream of the • Increase in
leptin receptor
• removal of a insulin and
phosphate group
from the tyrosine • downregulation of leptin
phosphate leptin signaling by sensitivity
dephosphorylating
receptor.
Janus kinase2 and
improving
glucose
type 2
homeostasis,
• Oral diabetes
agent
negatively controls
with
insulin release functioning
beta-cells.
 A study with PTP1B-knockout mice demonstrated resistance to obesity
and increased insulin sensitivity.
 In a recent study in monkeys, inhibition of PTP1B with antisense
oligonucleotides led to improved insulin.
 The drawbacks of PTP1B inhibitors include their low affinity to and
selectivity for the enzyme and their difficulty with membrane
permeability.
GLUCAGON RECEPTOR BLOCKERS
Glucagon
alphacells in the pancreas

glycogenolysis and gluconeogenesis through the

activation of cAMP-dependent protein kinase
cascade in the liver.

excess--Increase in fasting and postprandial

hyperglycemia
 competitive
blockade of the
interaction of Stabilize
Bay 27–9955, a glucagon with plasma glucose
non-peptide the human concentrations
compound glucagon and the rate of
receptor glucose
production
(200mg single
dose)
 INSULIN PUMP

• OpT2mise study—RCT compared Insulin pump to MDI

• 6 month cross over study

• Reduction in HbA1c (1.2%) in both the group

• Significant advantage with a safe and consistent effect

 SMART’ INSULINS

• ‘Smart’ insulins or glucose-responsive insulins are being

designed to only turn on when they’re needed and off
when they’re not.
• smart insulin would circulate in the body, inactive, until
blood glucose levels start to rise. As glucose levels rise, the
insulin would go to work to bring these levels back down.
• When blood glucose levels are low, a ‘binding
element’ stays attached to the insulin
 PEGYLATED INSULIN LISPRO

• LY2605541, or PEGylated insulin Lispro, has a

large hydrodynamic size while still exerting the
metabolic effects of insulin.
• Preclinical, phase I and phase II studies LY2605541
had a non-inferior glucose-lowering efficacy compared
to insulin glargine in people with type 1 and type 2
diabetes and may afford a weight-loss advantage.
• Pre-clinical studies indicate that LY2605541 has low
mitogenic potency, exerting a preferential hepatic
effect on glucose homeostasis.
 VIT.D
• An American trial finds a high percentage of vitamin D
deficiency in a large population of children with type 1 diabetes.

Researchers at the University of Pennsylvania School of Nursing

showed association of 25-hydroxyvitamin D and blood glucose
levels among children and adolescents with type 1 diabetes.
 NASAL INSULIN
• Size of a flashlight has a thumb-sized, (Technospore
technique) compact inhaler device including the
insertion of insulin blisters into a small slot in the
inhaler
Exubera ® (2
[
• Noninferior HbA1c lowering cough, hypoglycaemia
006–2007 and throat pain/irritation,pharyngitis,pulmonary
fibrosis,Antibody formation.

Afrezza • Afrezza ultrashort to lower blood sugar (A1c)

• Afrezza, bronchospasm in patients with asthma or chronic
: June obstructive pulmonary disease (COPD),

2014
 STEM CELLS

• At ENDO2016 stem cells that

successfully mature into
insulin producing cells when implanted into mice.

A protein that activates a process

which overcomes a longstanding
obstacle in generating fully functional
pancreatic beta cells.
 TRANSCRIPTOMES

Development
(ERR-gamma),
points between a differences
occurred in much
stem cell and a between fetal and
larger amounts in
fully-grown cell adult beta cells
adult beta cells.
type.
• Beta cells produce a high level of this regulator-
induces greater mitochondrial growth .
• Promotes oxidative use of sugars and lipids to
generate energy intensive process to release insulin.
• Mice that lacked ERR-gamma, the animals' beta
cells could not produce insulin in response to blood
glucose spikes.
• Human beta-like cells grown in the lab to produce more
ERR-gamma, "Voilà,“ . The cells in culture began to
respond to glucose and release insulin.
• To further test the dish-matured cells, transplanted
them into mice that lacked beta cells.

• From the first day of transplantation, the cells

produced insulin in response to glucose spikes in the
mice's blood, alleviating the modeled diabetes.
 ISLET CELL TRANSPLANTATION

• Pig islet cell transplantation could soon be used to help

treat type 1 diabetes in Japan.

Insulin(insulin from pigs) --- free from virus

Researchers from the National Center for Global Health and Medicine
plan to conduct the first transplant on people with type 1 diabetes in
2019.

Pigs islet cells are considered as being suitable for use in humans
because of the structural similarity between human insulin and porcine
• The transplants also give control of sugar levels back
to the body which often means a greatly reduced risk
of severe hypoglycemia occurring.
• The downside of islet cell transplantation is that
immunosuppressant drugs need to be taken for life to
prevent the autoimmune attack of type 1 diabetes
destroying the transplanted cells.
 EPIGENETICS

• The Scripps Research Institute (TSRI) have discovered cells which

resemble conventional T cells, but can transform into T regulatory cells
(Tregs).

• Treg cells are known to be able to control the body's immune response
and protect the body from autoimmune disease.
 SOMATIC CELL NUCLEAR TRANSFER (SCNT)

• Researchers isolated an individual Treg from a mouse

model of type 1 diabetes,
• Inserted its nucleus - which contained the unique
genetic immune receptor information - into a mouse
egg that had its own nucleus removed.
• Cloning method
• Researchers from Sweden's Lund University To measure the
presence of DNA methylations -chemical changes that control
gene activity –
Dr. Karl Bacos, a specialist in epigenetics at Lund University,
said: "This could motivate a person at risk to change their
lifestyle. The hope is that this will be developed into a better
way to predict the disease."
THANK
YOU