Intensive material on Diabetes, types, new concepts, its existing therapy, recent advances and future prospects

1. Dr Siddhartha Dutta
MAMC, New Delhi

2. Contents
1. Introduction
2. Classification
3. Current therapy of DM
4. Limitations of current therapy
5. Newer Drugs and their status in DM therapy
6. Newer potential targets
7. Future Prospects
8. Summary

3.  250 BC- Apollonius of Memphis coined the name "diabetes”
meaning “siphon- to pass through”
 Thomas Willis in 1675 added "mellitus" to the word "diabetes”
 1869- Paul Langerhans, a German medical student, discovered
islet cells in the pancreas
 1910- Sharpey-Shafer of Edinburgh suggested a single chemical
was missing from the pancreas. He proposed calling this
chemical "insulin.”
 1922, Leonard Thompson became the first human to be
successfully treated for diabetes using insulin

4.  1921- Frederick G. Banting and Charles H. Best
successfully purified insulin from a dog's pancreas
 1923- 1st Nobel prize for insulin


5. World Diabetes Day
 14th November of every year:
to mark the birthday of
Frederick Banting

6. Burden of the Disease
 Around 7% of Indian Adults
 Most of the world’s Diabetics dwell in India
India
51
Million
China
43
Million
USA
26
Million
Rest of
the
World
165
Million
Population of Diabetics-
2010 (285 Million)
PREVALENCE OF DIABETES-
2010
Country Prevalence
India 7.1%
China 4.5%
USA 12.3%
Source: International
Diabetes Federation

7. Etiological Classification
1. Type 1 DM: β-cell destruction
a. Immune-mediated
b. Idiopathic
2. Type 2 DM
3. Other specific types of diabetes:
a. Genetic defects of β cell function: MODY
b. Genetic defects in insulin action
c. Diseases of the exocrine pancreas
d. Endocrinopathies
e. Drug- or chemical-induced
f. Infections
4. Gestational diabetes mellitus (GDM)

8.  IDDM and NIDDM
 Type 1 and type 2
 Age is not a criterion in the classification system
 5 and 10% of individuals who develop DM after age 30 have
type 1 DM
 Type 2 DM more typically develops with increasing age but
is now being diagnosed more frequently in children and
young adults, particularly in obese adolescents.

9. Type 3 diabetes ??

10. Type 3 Diabetes
 Insulin resistance in the brain associated with Alzheimer’s
Disease
 Impaired glucose metabolism in the brain plays a role in the
development of Alzheimer’s by depriving cells of energy
 Evidence
 Tau gene expression and phosphorylation are regulated
through insulin and insulin-like growth factor (IGF) signaling
cascades
 Amyloid beta in pancreas which is similar to the protein
deposits found in the brain tissue of Alzheimer's

11. Type 4 diabetes
• Not associated with insulin deficiency or obesity
• Has been discovered in lean mice
• Abnormally high levels of
immune cells called
T regulatory cells (Tregs) inside their
fat tissue
• Age-related insulin resistance that occurs in lean, elderly
people

12. Diagnostic Criteria
1. Symptoms of hyperglycemia and a Random Plasma
Glucose >200 mg/dl
2. FPG >126 mg/dl
1. <100 mg/dl: Normal fasting glucose
2. 100–125 mg/dl: Impaired fasting glucose (IFG)
3. 2-hour Plasma Glucose >200 mg/dl during an OGTT
1. <140 mg/dl: Normal glucose tolerance
2. 140–199 mg/dl: Impaired glucose tolerance (IGT)
4. HbA1C ≥6.5%
5. Pre-diabetes: IFG and/or IGT(HbA1C ≥5.7% to 6.4%)

13. Treatment Goals for DM
Index Goal
HbA1C <7.0 %
Pre-prandial plasma glucose 90–130 mg/dL
Peak postprandial plasma glucose <180 mg/dL
Blood pressure <130/80 mm of hg
LDL-C <100 mg/dL
HDL-C >40 mg/dL
Triglycerides <150 mg/dL

14. • Non-Pharmacological
• Insulins
• Oral Hypoglycemic Agents

15. Non-Pharmacological
 Weight Loss
 Regular Physical activity
 Medical Nutrition Therapy
 Lifestyle Changes
Source: ADA Guidelines

16. Type 1 DM

17. Therapy of DM type 1: Insulins
 Rapid Acting:
 Lispro
 Aspart
 Glulisine
 Short Acting:
 Regular
 Intermediate Acting:
 Neutral Protamine Hagedorn (NPH)
 Lente
 Long/Slow Acting:
 Ultralente
 Protamine zinc
 Glargine

22. Why Newer Insulins ??
 Lipodystrophy
 Insulin allergy
 Antibody related insulin resistance
 Hypoglycaemia due to prolonged
circulation of injected insulin
 Immune complex deposition

26. TYPE ONSET PEAK(Hr) DOA (Hr)
Rapid
acting
• Lispro
• Aspart
• Glulisine
5-15 mins
10-15 mins
5-15 mins
1
1
1
3-5
3-5
5-6

27. Insulins Type Onset Peak(Hr) DOA(Hr)
Rapid acting Lispro
Aspart
Glulisine
5-15 mins
10-15 mins
5-15 mins
1
1
1
3-5
3-5
5-6
Long acting Glargine
Detemir
Degludec
1-2 hrs
2-3 hrs
1-2 hrs
No peak
6-8 hrs
No peak
24 hrs
≈ 24 hrs
> 24 hrs

28. Insulin Detemir
 New Long-acting insulin analogue
 Threonine in B30 replaced by Myrsitic acid

29.  Self aggregation in subcutaneous tissue
 Bound to albumin in circulation
 Smooth time action profile with no peak
 Onset of action: 1–2 hrs
 Duration of action: <24 hrs
 Given twice a day

30. Why detemir ??
 Glycaemic control is similar to NPH(1.9% vs 1.8%) after 24
weeks
 Hypoglycaemia less frequent( vs NPH)
 Lesser Nocturnal hypoglycaemia when given as bolus
basal therapy(aspart+detemir)
 Lesser or minimal wt gain as compared to NPH

31. Insulin Degludec
 Newest long acting basal insulin

32. S.C inj- forms multihexamers which forms “S.C depots”

33.  T ½- (25-40 hr)
 In blood it is bound to albumin
 Administered anytime of the day or thrice weekly
 Unlike Glargine, it is effective at physiological pH
 Unlike Glargine & Detemir, it can be mixed with other
insulins
 High incidence of hypoglycaemia in clinical trials

34. NPL and NPA
 “NPL” (Neutral Protamine Lispro) and “NPA” (Neutral
Protamine Aspart): Isophane complexes of protamine with
insulin lispro and insulin aspart
 Intermediate acting insulins
 Detemir vs NPL- achieved similar glycaemic control
 Weight gain and nocturnal hypoglycaemia rate were
statistically higher with NPL
 NPL(75/25) vs NPH(30/70)- Improved glycaemic profile
 Hypoglycaemia rate was low
 FDA has approved NPL/insulin lispro(50-50 and 75-25) and
NPA/insulin aspart(70-30) premixed formulations

35. Hexyl-insulin monoconjugate 2 (HIM2)
 Modified oral human insulin
 Single amphiphilic oligomer is covalently linked to the free
amino acid group on the Lys-β29 residue of recombinant human
insulin via an amide bond.1
 Phase II( type 1 ) & III(type 2) trials
 Has enhanced stability and resistance to intestinal degradation1
 Significantly absorbed from GIT, directly into portal circulation1
 HIM2 insulin v/s Humulin R2
1.Diabetes Care 27:2868–2873, Dec 2004
2.Diabetes Care 26:421–426, Feb 2003

36. Oral Insulin Spray Formulation
 Oral-lyn
 Current Status: Approved in Ecuador, India, Lebanon & under
phase III trials in Europe & USA
 Indicated type 1 and 2
 Effective alternative to prandial insulin injections
 Tasteless liquid aerosol mist formulation
 Efficacy: Dose-related absorption; faster onset and a shorter
duration of action
 Safety: Well tolerated; transient, mild dizziness during dosing.

37.  Absorbed through the mucous membranes lining the mouth and
begins lowering blood glucose levels in 5 mins
 Peaks at 30 mins and works till 2 hrs
 Unlike inhaled insulins (Exubera), Oral-lyn does not enter the
lungs, both because of the design of the device used to take it, and
because users are instructed not to inhale as they spray
 An earlier short-term study, in which Oral-Lyn was compared with
short-acting subcutaneously injected pre-prandial insulin
(Humulin) showed similar efficacy

38. Inhalational Insulin
 Inhalable insulin is a powdered form of insulin, delivered
with a nebulizer into the lungs where it is absorbed
 Advantages and Disadvantages of nasal route
 PK:
 Depends hugely on properties of inhaler device, breathing
maneuver & local pathology/physiology
 Bioavailability: 9-22%
 Tmax: 7 to 90 minutes
 High clearance: less incidence of hypoglycemia

39. Inhalational InsulinContd…
 Adverse reactions:
 Insulin acting as a local Growth Factor
 Local alveolar membrane morphological changes
 However much alteration was NOT noted with PFT
 Anti-insulin IgG antibodies
 Contraindications:
 Smokers and ex-smokers (6 months)
 Patients with poorly controlled lung disease
 Allergic patients

40. The Rise and Fall of Exubera
 Exubera-marketed from Sept’06-Pfizer
 Huge hype
 Withdrawal in Oct’07: poor market
Acceptance & poor sales
 Reasons:
 Cost of the inhalant device
 Need for patient training
 Need for PFTs
 Pulmonary fibrosis
 Long-term effects & Risk of Ca Lung in ex-smokers

41. Afrezza
 Approved FDA in 2014
 Meal time insulin
 Rapid-acting inhaled insulin
 Starts to work immediately after inhalation, peaks in about 12
mins, and wanes off by 3 hrs
 Monomeric formulation is reputed to more closely mimic
the natural insulin response of healthy individuals
 Decreases the risk of hypoglycemia and weight gain
 C/I- asthma, active lung cancer or COPD

42. Afrezza vs lispro

43. Controlling PPG is crucial in A1C control

44. Exubera vs Afrezza
 Hexameric form
 Peaks in 50 mins
 Titration in mg
 Size of inhaler
 Needs training
 Starts acting after 12 mins
 Action goes off by 6 hrs
 Needs cleaning every week
 Monomeric form
 Peaks in 12 mins
 Dosage in units
 Easy to use
 Afrezza works instantly
 Fast acting
 Action goes off by 2-3 hrs
 No cleaning needed

45. EXUBERA AFREZZA

46. Inhalational Insulin

47. Newer Insulin delivery systems
 Insulin Pumps: CSII
 Pen devices

48. CONTINUOUS SUBCUTANEOUS INSULIN
INFUSION(CSII)
 Portable infusion devices with S.C cannula
 Only rapid or regular insulins are used
 Programmed to deliver at low basal rates ( 1U/hr) & premeal
bolus (4-10 times of basal rate)
 No definite advantage over multidose S.C inj has been seen in
the trials

49. CSII
INDICATIONS
LIMITATIONS
 Inadequate glycemic control
despite optimized multiple
daily injection (MDI) therapy
 High glucose variability
 Elevated A1C
 Recurrent or unpredictable
hypoglycemia
 Nocturnal hypoglycemia
 Dawn phenomenon
 Pregnancy
 Erratic schedule & Varied work
shifts
 Inconvenience of multi MDI
 Cost
 Strict adherence to diet
 Site infection
 Malfunctioning/ pump
faliure
 Scar
 Allergic reactions

52. Oral Hypoglycemic Agents
1. Insulin Secretogogues:
a. Sulfonylureas:
 1st Gen: Tolazamide, Chlorpropamide, Gliclazide,
Tolbutamide
 2nd generation: Glibenclamide (Glyburide),
Glipizide, Glicazide, Glimepiride
b. Meglitinides/"glinides”
 Nateglinide, Repaglinide

53. Oral Hypoglycemic Agents Contd…
2. Insulin Sensitizers:
a. Biguanides:
 Metformin, Phenformin
b. TZDs (PPAR):
 Pioglitazone, Rosiglitazone
3.α-Glucosidase inhibitors:
Acarbose, Miglitol, Voglibose

55. DRUG MOA ADVANTAGE DISADVANTAGE
SULPHONYL
UREAS
K + ATP channel
blockers
↑ Insulin secretion
inexpensive Hypoglycaemia (at any
glucose conc.)
Wt gain
MEGLITINIDE
S
↑ Insulin secretion Fast onset of action,
Short lasting
lower postprandial
glucose
Hypoglycaemia
Dyspepsia, wt gain
Arthalgia
Need to be administered
before each meal
METFORMIN ↓ Hepatic glucose
production
↑glucose utilization
Weight neutral
No hypoglycaemia
inexpensive
Diarrhoea, nausea
Lactic acidosis(RF)
TZD ↓Insulin resistance,
↑glucose utilization
Lower insulin
requirements
Peripheral edema, CHF,
weight gain, fractures,
macular edema
α-GLUCOSIDASE
INHIBITORS
↓ GI glucose
absorption
Reduce postprandial
glycemia
GI flatulence, loose stools
liver enzymes rises

56. Why need newer drugs?
 Limitations of existing drugs:
 Insulins:
 Repeated injections
 Lipodystrophy, insulin resistance
 Can’t mimic the physiological nature of insulin
release
 OHAs:
 Adverse effect profile-unacceptable: weight
gain;
 abd. distention and flatulence with acarbose
 Basic pathology is left unaltered
 No strategy available to protect beta cells

57. Newer Drugs in DM TYPE 2
 Newer Insulins
 Incretin-based therapy:
 GLP-1 analogues: Exenatide, Liraglutide
 DPP 4 inhibitors: Sitagliptin, Vidagliptin
 Amylin analogue: Pramlintide
 Dual PPAR agonists: Aleglitazar, Muraglitazar, Tesaglitazar
 SGLT2 inhibitors: Dapagliflozin, canagliflozin, empagliflozin
 Others:
 Bromocriptine

58. Newer Drugs in DM 2
 Newer Insulins
Incretin-based therapy:
 GLP-1 analogues: Exenatide, Liraglutide
 DPP 4 inhibitors: Sitagliptin, Vidagliptin
 Amylin analogue: Pramlintide
 Dual PPAR agonists: Aleglitazar, Muraglitazar, Tesaglitazar
 SGLT2 inhibitors: Dapagliflozin, canagliflozin, empagliflozin
 Others:
 Bromocriotine

59. Incretins
 Incretins: GIT Hormones produced in response to
incoming nutrients that contribute to glucose homeostasis
 The Incretin Effect
 Two hormones:
 Gastric inhibitory polypeptide [also known as
Glucose-dependent Insulinotropic Polypeptide] (GIP)
 Glucagon-like peptide-1 (GLP-1)

62. GLP-1
 30-amino acid peptide secreted by L cells in ileum &
colon.
 GLP-1 receptors seen in islets and CNS
 Increases glucose-dependent insulin secretion.
 Inhibits glucagon secretion
 Increases satiety
 Slows gastric emptying.
 In animal studies shown to increase beta-cell mass
Source: Diabetes Care. 2003;26:2929-40.

63. The Problem with GLP-1
 GLP-1 is metabolized rapidly by the enzyme Dipeptidyl Peptidase
4 (DPP 4)
 Very short plasma T1/2: 1-2 mins
 Continuous iv infusion
 Solution:
 Long-acting GLP-1 analogues: Exenatide, Liraglutide
 DPP4 inhibitors: Gliptins

64. GLP-1 Analogues: Exenatide
 Naturally occurring peptide from the saliva of the Gila Monster.
 PK:
 Injectable, SC
 Resistant to DPP4 inactivation
 Plasma T ½ of 10 hrs; Renal clearance
 Therapeutic dose: 5-10 mcg twice daily before meals
 Adverse effects: nausea, vomiting, diarrhea, weight loss;
necrotizing and hemorrhagic pancreatitis.
 Contraindications: severe renal impairment (creatinine
clearance <30 mL/min) or ESRD
 Safety in pregnancy not studied

65. Exenatide: Current Status
 Approved by the FDA on April 2005 as adjunctive therapy
for T2DM pts not well-controlled on other oral medication
(Metformin, Sulfonylurea, TZD, Metformin+SU, Metformin+TZD)
 Not approved as Monotherapy
 Not approved in T1DM
 Exenatide LAR(2013)
 Cost Factor

66. Newer GLP-1 Analogues
 LIRAGLUTIDE:
 Approved by the European Medicines Agency (EMEA) on July
2009; FDA in 2015
 Adjuctive therapy
 Longer T ½ (11 hrs): Once daily, SC
 0.6 mg SC OD for 1 week initially
then increase to 1.2 mg OD &
can increase to 1.8 mg OD

67.  Injection site and time of administration can be
changed without dose adjustment & independent of meals
 Good glycaemic control & wt loss
 S/E- Nausea, Diarrhea, Vomiting, Diarrhea, Constipation
 Hypoglycemia with other therapy
 Black box warning for thyroid cancer
MEN syndrome
 Approved for OBESITY by the FDA December 23, 2014

68. ALBIGLUTIDE
 FDA approved in 2014
 GLP-1 dimer fused with albumin
 T ½ of 6-7 days
 30-50 mg SC once weekly
 No dose adjustments in renal failure
 Black Box Warning– Risk of thyroid C-cell tumors
 Cautions
 MEN-2
 Acute pancreatitis
 Hypersensitivity
 Hypoglycemia

69. DPP 4 Inhibitors
 DPP4 inhibition causes increase in levels of both GIP & GLP-1
 Intrinsic membrane glycoprotein & a serine exopeptidase

70. Sitagliptin
 Approved by FDA as a monotherapy and in combination with
Metformin or TZD
 PK:
 Oral, 87% bioavailable.
 T ½ 8-14 hrs; Hepatic clearance
 Therapeutic dose: 100 mg Once daily
 Weight-neutral
 A/E- Nasopharyngitis, Diarrhea, Headache,
Peripheral edema, Osteoarthritis
 Contraindications: ESRD
 Safety in children<18 yrs & pregnancy not established
 Dose to be reduced in renal failure

71. Vildagliptin
 Less protein bound, less T ½ than Sitagliptin
 Therapeutic dose:
 25-100 mg, twice a day
 Current Status:
 FDA approval pending
 Has been approved by EU in Feb’08 as a combination therapy
with SU, TZD or Metformin
 FDC with Metformin is also EU-approved
 Headache, nasopharyngitis, cough,
constipation & increased sweating
 C/I in liver/ renal failure

72. Other DPP4 inhibitors
 Saxagliptin:
 Therapeutic dose: 2.5-5 mg once a day
 Approved by FDA in July’09 as Monotherapy or in
combination with SU/TZD/Metformin
 Alogliptin: FDA approved in 2013, risk of heart faliure
( FDA 2016)
 Linagliptin: Phase III trials
 Anagliptin- phase III
 Dutogliptin- Phase III trials

73. Newer Drugs in DM
 Newer Insulins
 Incretin-based therapy:
 GLP-1 analogues: Exenatide, Liraglutide
 DPP 4 inhibitors: Sitagliptin, Vidagliptin
Amylin analogue: Pramlintide
 Dual PPAR agonists: Aleglitazar, Muraglitazar, Tesaglitazar
 SGLT2 inhibitors: Dapagliflozin, Remogliflozin,
Sergliflozin
 Others:
 Rimonabant
 Bromocriotine

74. Amylin
 Also known as IAPP
 Secreted from Beta cells in response to meals
 Actions:
 Suppresses endogenous glucagon production
 Reduces postprandial hepatic glucose production
 Delays gastric emptying
 Induces satiety: Centrally mediated
 Amylin secretion is diminished (or even absent) in patients
with Diabetes

76. Pramlintide
 Synthetic Analogue of Amylin
 FDA approved 2005
 PK:
 SC, T ½ around 50 min
 Metabolised in kidney: active metabolite
 Therapeutic dose:
 T2DM: 60-120 mcg
 T1DM: 15-60 mcg
 To be given immediately prior to meals
 Adverse effects:
 Nausea
 Hypoglycemia

77. Pramlintide
 Adjuvant: to decrease the
insulin dose
 Not to be mixed with insulin in
the same syringe
 Can also be used in pts on
SU/Metformin
 Contraindications:
Gastroparesis, Hypersensitivity
300
250
200
150
100
PlasmaGlucose(pM) -30 0 30 60 90 120 150 180
Meal
Insulin only
Insulin + Pramlintide (30 µg)
Plasma Glucose
Kolterman O, et al.
Diabetologia 1996;39:492-499

78. Newer Drugs in DM
 Newer Insulins
 Incretin-based therapy:
 GLP-1 analogues: Exenatide, Liraglutide
 DPP 4 inhibitors: Sitagliptin, Vidagliptin
 Amylin analogue: Pramlintide
Dual PPAR agonists: Aleglitazar,
Muraglitazar, Tesaglitazar
 SGLT2 inhibitors: Dapagliflozin, Remogliflozin,
Sergliflozin
 Others:
 Rimonabant
 Bromocriotine

79. Dual PPAR agonists: Rationale
Dual PPAR
Agonists
Dyslipidemia
Glucose intolerance
and
Type 2 diabetes
PPARa
(liver, vascular wall)
 Increases circulating HDL
 Reduced triglycerides
 Improved LDL buoyancy
PPARg
(fat, muscle)
 Modulates glucose
metabolism & insulin
sensitivity
TZDs : Rosiglitazone;
Pioglitazone
Fibrates
Metabolic
Syndrome
???

80. Dual PPAR agonists: Current Status
• Saroglitazar –
• Only drug approved till date for DIABETIC DYSLIPIDAEMIA
• Indigenously developed NCE by any Indian company
• Approved for use in India by the DCGI in 2013
• Phase II trials for NASH in US ( june,2016)
• Diabetic dyslipidemia and hypertriglyceridemia
in T2DM not controlled by statin therapy
• 2 mg & 4 mg OD orally before meals
• Phase III trials- NASH in India.
• A/E- weight gain, edema & gastritis

81. Newer agents
Muraglitazar
Meta-analysis of the phase 2 and 3 clinical trials revealed
that it was associated with a greater incidence
of MI, stroke, TIA and CHF
when compared to placebo or pioglitazone
Aleglitazar: currently in phase II
Tesaglitazar: no longer studied, discontinued: renal toxicity

82. Newer Drugs in DM
 Newer Insulins
 Incretin-based therapy:
 GLP-1 analogues: Exenatide, Liraglutide
 DPP 4 inhibitors: Sitagliptin, Vidagliptin
 Amylin analogue: Pramlintide
 Dual PPAR agonists: Aleglitazar, Muraglitazar,
Tesaglitazar
SGLT2 inhibitors: Dapagliflozin,
canagliflozin, empagliflozin

83. From Victim to Ally: Kidney in DM
• Role of SGLT-2 in renal tubules
• SGLT 2 is expressed almost exclusively in the
proximal tubule of the kidney
 An adjunct to diet and exercise to
improve glycemic control in adults with
Type 2 DM
• Canagliflozin
• Dapagliflozin
• Empagliflozin

84.  Inhibition of SGLT2, and thus inhibition of renal glucose
reabsorption, has the potential to reduce hyperglycemia in
patients with DM.

85. DRUG APPROVAL DOSE ADVERSE
EFFECTS
COMMENTS
CANAGLIFLOZIN 2013 100-300 mg
OD
UTI
Hypotension
LDL ↑
↑ risk of DKA
↑ risk of Stroke
↓bone density and ↑
fracture
Amputation of toe??
DAPAGLIFLOZIN 2014 5-10 mg OD UTI
Candidiasis
Rapid wt loss
Tiredness
Rash
Sore throat
Not used in moderate
renal faliure or ESRD
Bladder cancer ??
EMPAGLIFLOZIN 2014 10-25 mg
OD
UTI, Candidiasis
Dizziness
Not used in moderate
renal faliure or ESRD
Reduces cvs mortality
??
Remogliflozin Phase II 1000 mg T2DM, NASH
Tofogliflozin Phase III,
approved in
japan
20-40 mg T2DM

86.  From March 2013 to October 2015
 FDA received reports of 101 confirmable cases* of AKI
some requiring hospitalization and
dialysis, with canagliflozin or
dapagliflozin use

87. SGLT2 Inhibitors: CAUTIONS !!
 Pregnant or are breast-feeding
 Renal problems, low or high blood pressure, or high
cholesterol
 History of UTI, candidiasis
 Dehydrated or have low blood volume
 Drug interactions:
 Insulin or other insulin secretagogues- risk of hypoglycaemia
 Diuretics
 Possible challenge:
 Increase in incidence of UTI
 Hypotension
 Bladder cancer, amputations, fractures

88. Hypothalamus and Insulin Resistance
 Migrating birds developed seasonal insulin resistance;
dopamine????
 Seasonal circadian rhythm
 non-existant in humans
 Decreased hypothalamic dopaminergic tone involved in the
pathogenesis of insulin resistance
 Effect of Dopaminergic stimulation of Hypothalamus

90. Bromocriptine
 Centrally acting D2 agonist
 FDA approved in May’09 for T2DM
 PK:
 Oral, Extensive first-pass metabolism in the liver.
 T ½ : 2 - 8 hours
 Dose in T2DM:
 0.8 mg daily
 Increased in 0.8 mg increments weekly until the target range (1.6 - 4.8 mg)
or till maximal tolerance is reached
 Once daily dosing within two hours of waking and with food

91. Newer potential targets
in Insulin signaling
Pathway

92. Newer targets in DM: PTP-1b inhibitors
 Insulin binds to receptor-
IRTK phosphorylates IRS-1
 Protein Tyrosine
Phosphatase(PTP)-1b
dephosphorylates IRS-1
 Inhibitors of PTP-1b are
potential therapeutic targets
in DM

93. Insulin Receptor Tyrosine Kinase
(IRTK) and Insulin Mimetics

94. 1.ACTIVATION DOWNSTREAM OF IRTK
Activation of IRS-1, Akt, and GSK-3, which was independent of
IRTK phosphorylation
Vanadate analogues
Phase II trial for AKP-020

95. 2. Protein Tyrosine Phosphatase 1B (PTP1B)
Inhibitors
Endoplasmic reticulum protein - negative regulator of insulin and
leptin (dephosphorylating activated IRTK and IRS, JAK2)
Mice lacking PTP1B have enhanced insulin sensitivity,
did not gain weight
synergistic effects on glucose/lipid
levels and food intake
Potential targets : Anti-obesity, DM II

96. 3. Glycogen Synthase Kinase-3 (GSK3b)
Inhibitors
GS is the rate-limiting step in glycogen synthesis and is
inactivated by phosphorylation by GSK3b
Two isoforms
GSK3b favors IR by its proinflammatory and GS inhibitory
effects
Pre- clinical stages

99. 1. Glucokinase (GK) Activators
 Enzymes of the glycolytic
pathway that converts glucose
to glucose-6-phosphate
 Glucose sensor
 Upregulating insulin (from
pancreas)
 Promoting glucose storage as
glycogen

101. Piragliatin - Phase 2
Possible concern –
Increased hepatic glycogen, lipid deposition in liver and
muscle

102. 2. Fructose-1,6-Bisphosphatase (FBP) Inhibitors
(FBP) is the Gluconeogenesis
enzyme that catalyzes the
reverse conversion (F1,6P to
F6P)
FBPi - decrease Hepatic
Glucose Production
Efficacy has been an issue
Phase 2 - MB07803

103. 3. Glycogen Phosphorylase (GP) Inhibitors
Glycogenolysis is a substantial
contributor to hyperglycemia
GP produces glucose-1-
phosphate converted to glucose-
6-phosphate which feeds into
glycolysis
GP(a) inhibition of the liver
isoform in a selective fashion is
important
Ingliforib - phase 1

105. 1. Beta3-Adrenergic Receptor (β3-AR) Agonists
Activate the uncoupling protein (UCP) which causes the
expenditure of metabolic calories as heat
Preclinical stages
Lipolysis & β oxidation
Low bioavailability
Efficacy is less
Is it suitable?? β3AR stimulated thermogenesis to expend
excess energy in human diabetic patients is still undefined

106. 2. Hormone Sensitive Lipase (HSL) Inhibitors
Rate-limiting step in adipose tissue lipolysis
FFA’s - inhibits glucose uptake and utilization by muscle,
increasing HGP
HSLi improved lipid profiles and elevated insulin sensitivity
(reduced plasma glucose levels)
Preclinical stages

107. 3. GPR40 /(Free Fatty Acid Receptor 1 (FFAR1)) Ligands
 FFAR1 facilitates glucose-stimulated insulin secretion from
pancreatic β-cells
GPR 40 regulates the secretion of glucagon-like peptide-1 in
the intestine, as well as increases insulin sensitivity
Potential therapeutic targets for type 2 DM
Chronic exposure impairs β-cell function (lipotoxicity)
Phase II : TAK-875

108. Otelixizumab
Humanized Anti-CD3 Monoclonal Antibody
Inhibition of autoimmune attack on β-cells
Phase 3- DEFEND (Durable-response therapy Evaluation For Early or New-
onset type 1 Diabetes)
 Evaluate whether a single course of otelixizumab, administered within
90 days after the initial diagnosis, would reduce the amount of
administered insulin required to control blood glucose levels by
inhibiting the destruction of beta cells
Falied to show efficacy
Orphan drug status by FDA
S/E- infusion reactions, headache, vomiting

109. Teplizumab
Anti-CD3 monoclonal antibody
New-onset type 1 diabetes
Minimize cytokine release and prevent the progressive
destruction of β-cells
Phase 3

110. Recombinant Human Glutamic Acid Decarboxylase-65
(rhGAD65)
Vaccine
Phase 3
Antibodies against GAD - 80–90% type 1 DM
Induces immunotolerance and may thereby slow or
prevent autoimmune destruction of pancreatic islet cells

111. Future Prospects:
Pancreatic Transplantation
 Specially in T1DM
 Can be:
 Isolated pancreas transplantation
 Pancreas-Kidney transplantation
 Islet cells transplantation
 Limited success rate at present

112. Future Prospects: Artificial Pancreas
 FDA approved it on 30 sept 2016
 Components:
 Continuous Glucose Sensor
 Insulin Infusion Pump
 An Algorithm to determine amount of insulin to be
delivered
 Barricades:
 Sensor: needle site infections
 Pumps: Need for changing the pump often; INSULIN
 Algorithm: complexity
 Cost
 Patient Compliance, understanding