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RECENT ADVANCES IN THE TREATMENT
OF DIABETES MELLITUS AND ITS
COMPLICATIONS
PREPARED BY: SANJAY YADAV
M. PHARM -II YEAR
DE...
INTRODUCTION
 Diabetes mellitus is characterized by chronic hyperglycemia glycosuria,
hyperlipemia, negative nitrogen bal...
ETIOLOGIC CLASSIFICATION
I. Type 1 diabetes (b-cell destruction, usually leading to absolute insulin deficiency)
 A. Immu...
RISK FACTORS OF INSULIN RESISTANCE.
 Obesity/overweight (especially excess visceral adiposity)
 Excess glucorticoids (cu...
PATHOGENESIS OF
DIABETES
DIABETES COMPLICATIONS
DIFFERENT DIABETES COMPLICATIONS
 Macro vascular
 Micro vascular
 Neuropathy
 Infections
MECHANISMS
Hyperglycemia Tissue damage
*Repeated acute changes
in cellular metabolism
**Cumulative long term
changes in st...
MACRO VASCULAR COMPLICATIONS
MACRO-VASCULAR COMPLICATIONS
 Ischemic heart disease
 Cerebrovascular disease
 Peripheral vascular disease
Diabetic pat...
MACRO-VASCULAR COMPLICATIONS
The major cardiovascular risk factors in the
non-diabetic population (smoking,
hypertension a...
MICRO VASCULAR COMPLICATIONS
EYE COMPLICATIONS
 Cataracts
Non enzymatic glycation of lens protein and
subsequent cross linking
 Sorbitol accumulation...
EYE COMPLICATIONS
Retinopathy (stages)
Background
Pre-proliferative
Proliferative
Advanced diabetic eye disease
Maculopath...
DIABETIC RETINOPATHY (DR)
 DR is the leading cause of blindness in the
working population of the Western world
 The prev...
PRE-PROLIFERATIVE RETINOPATHY
 Rapid increase in
amount of micro
aneurisms
 Multiple hemorrhages
 Cotton wool spots
(>5...
ADVANCED DIABETIC EYE DISEASE
 Retinal detachment
with or without retinal
tears
 Rubeosis iridis
 Neovascular
glaucoma
MACULOPATHY
 Macular edema (focal
or diffuse)
 Ischaemic
maculopathy
DIABETIC NEPHROPATHY (DN)
 Diabetes has become the most common
cause of end stage renal failure in the US
and Europe
 Ab...
STAGES OF DN
Stage I
 glomerular filtration and kidney hypertrophy
Stage II
u-albumin excretion < 30mg/24h
Stage III
Micr...
DIABETIC NEUROPATHY
Sensorimotor neuropathy (acute/chronic)
Autonomic neuropathy
Mononeuropathy
Spontaneous
Entrapment
Ext...
SENSORIMOTOR NEUROPATHY
 Patients may be asymptomatic / complain of
numbness, paresthesias, allodynia or pain
 Feet are ...
COMPLICATIONS OF SENSORIMOTOR
NEUROPATHY
 Ulceration (painless)
 Neuropathic edema
 Charcot arthropathy
 Callosities
AUTONOMIC NEUROPATHY
Symptomatic
Postural hypotension
Gastroparesis
Diabetic diarrhea
Neuropathic bladder
Erectile dysfunc...
MONONEUROPATHIES
Cranial nerve palsies
(most common are n.
IV,VI,VII)
Truncal neuropathy
(rare)
ENTRAPMENT NEUROPATHIES
 Carpal tunnel syndrome (median nerve)
 Ulnar compression syndrome
 Meralgia paresthetica (lat ...
PROXIMAL MOTOR NEUROPATHY
Amyotrophy – most common proximal
neuropathy, affects the Quadriceps muscles
with weakness and a...
INFECTIONS
 The association between diabetes and increased
susceptibility to infection in general is not supported
by str...
INFECTIONS (CONT)
 Several aspects of immunity are altered in
patients with diabetes
 There is evidence that improving g...
RHINO-CEREBRAL MUCORMYCOSIS
 RECENT ADVENCES IN ORAL
HYPOGLYCEMIC
AGENTS
ORAL HYPOGYCEMIC DRUGS
 Biguanide
Metformin
 Sulfonylureas
Glimepiride,gliclazide,glipizide,glyburide,glibenclamide
 Me...
SUBCUTANEOUS INJECTION
 Insulin
Rapid, short, intermediate, and long-acting formulations.
 Newer insulins
Insulin detemi...
RECENT DRUGS
Sodium–glucose-cotransporter-2 (SGL2) inhibitors
Dapagliflozin, canagliflozin, ASP1941, LX4211, and BI10773
1...
Glucagon receptor antagonists
Compound 1 (cpd 1)
Atherogenics antioxidant/vascular cell adhesion molecule-1
Succinobucol/A...
49
Muscle/Fat:
• PPARγ
• Protein tyrosine phosphatase-1b
(PTP-1b)
• PPARδ
• IkB Kinase
• AMPK1)
• 11bHSD12)
• Hormone Sens...
1. GLP-1 ANALOGUES
 Glucagon like peptide–1 (GLP-1) is a 30 amino acid gut hormone secreted
in a nutrient dependent manne...
1. GLP-1 ANALOGUES
 Glucagon like peptide–1 (GLP-1) is a 30 amino acid gut hormone secreted
in a nutrient dependent manne...
Time, min
IRInsulin,mU/L
80
60
40
20
0
18060 1200
THE INCRETIN EFFECT IN SUBJECTS
WITHOUT AND WITH TYPE 2 DIABETES
Time, m...
GLP1 EFFECTS IN HUMAN UNDERSTANDING
THE GLUCOREGULATORY ROLE INCRETINS
Promotes satiety and
reduces appetite
Beta cells:
E...
 The incretin effect is mediated by the intestinal secretion of 2
hormones, glucose-dependent insulinotropic polypeptide ...
EXENATIDE
 It is derived from the naturally occurring peptide, exendin- 4, which was
isolated from the salivary secretion...
 Exenatide therapy also caused weight loss in patients with type 2 diabetes,
in addition to its beneficial effects on gly...
LIRAGLUTIDE
 Liraglutide is the first human GLP-1 analogue with two modifications in
the amino acid sequence of native hu...
 Significant weight reductions versus placebo were observed with liraglutide
in combination with metformin, metformin plu...
Other Long-Acting GLP-1 Receptor Agonists
ALBIGLUTIDE
 It is a human GLP-1 receptor agonist with two molecules of GLP-1 l...
2. SYNTHETIC AMYLIN ANALOGUES
 Amylin is a peptide neurohormone that is synthesized and secreted by the
b-cells of the pa...
 PRAMLINTIDE
 It is a stable, bioactive analogue that differs from human amylin by three
amino acid substitutions.

 I...
3. NEWER INSULINS
Insulin detemir
 It is a basal insulin analog that provides effective therapeutic options for
patients ...
Insulin Glulisine
 Insulin glulisine is a human insulin analogue altered by replacing asparagine with lysine
at position ...
Insulin degludec (IDeg)
 It is a new generation ultra-long-acting basal insulin acting > 24 hrs.
 The ultra-long effect ...
4. DPP-4 INHIBITORS
 The effects of endogenous incretins are short-lived because Of rapid
degradation and inactivation by...
SITAGLIPTIN
 A selective DPP-4 inhibitor was approved in 2006 by the FDA as the first
oral incretin enhancer for use as m...
VILDAGLIPTIN
 Vildagliptin exhibits higher selectivity for DPP-4 (IC50, 0.1 uM) in vitro
compared with other peptidases.
...
SAXAGLIPTIN
The inhibitory potency of saxagliptin for DPP-4 in vitro is 400-fold
greater than for DPP-8 and 75-fold greate...
Other DPP-IV inhibitors
ALOGLIPTIN
 The quinazoline-based compound alogliptin is a potent (IC50, 6.9 nM)
inhibitor of DPP...
LINAGLIPTIN
 It is the latest DPP-IV inhibitor approved by USFDA.
 It shows highly selective, potent, dose-dependent inh...
5. DOPAMINE D2-RECEPTOR AGONISTS
 Bromocriptine is an ergot alkaloid dopamine-D2- receptor agonist that has
been availabl...
6. SODIUM–GLUCOSE-COTRANSPORTER-2 (SGLT2) INHIBITORS
 The kidneys contribute to glucose homoeostasis through gluconeogene...
7. 11Β-HYDROXYSTEROID-DEHYDROGENASE-1 INHIBITORS
 11β-hydroxysteroid dehydrogenase 1 predominantly converts low-activity
...
8. DUAL PPAR (γ +α) AGONIST
 PPAR-γ agonists (e.g., pioglitazone) improve insulin sensitivity and are an
established trea...
 Aleglitazar reduced HbA1c in a dose-dependent manner.
 The typical side effects of PPAR-γ agonism, oedema and weight ga...
9. GLUCOKINASE ACTIVATOR
 The phosphorylation of glucose by glucokinase after entry into the β cell
affects the rate of g...
10. BILE ACID SEQUESTRANTS
 Bile acid sequestrants are well established for the treatment of dyslipidaemia,
and reduce th...
11. GIPANTAGONISTS
 GIP, like GLP-1, potentiates glucose-dependent insulin secretion, but
unlike GLP-1, it promotes fat d...
12. ANTI-CD3 MONOCLONALANTIBODY
 Otelixizumab is a humanized anti-CD3 monoclonal antibody currently
being evaluated in cl...
13. CANNABINOID RECEPTOR-1 ANTAGONISTS
 An overactive endocannabinoid system in the brain and within adipose
tissue (espe...
14. ADIPOSE TISSUE SIGNALS
 Since the discovery of leptin as an adipocyte satiety signal, adipose tissue
has been recogni...
15. INSULIN ACTION ENHANCERS
 A metabolite from cultures of the fungus Pseudomassaria
(demethylasterriquinone, L-783,281)...
16. HISTAMINE H3 RECEPTOR AGONIST
 Histamine H3 receptors (H3Rs) are located on the presynaptic membranes
of histamine ne...
17. GLUCAGON RECEPTOR ANTAGONISTS
 Glucagon maintains glucose homeostasis during the fasting state by
promoting hepatic g...
18. IL-1 ANTAGONIST
 Interleukin-1 regulates body composition and fat distribution, mainly
through the regulation of feed...
19. SUCCINOBUCOL
 Succinobucol is an oral antioxidant lipid peroxidation inhibitor and
vascular cell adhesion molecule an...
20. TAGATOSE
 Tagatose is a naturally occurring, sweet-tasting, low-calorie
monosaccharide hexoketose found in dairy prod...
21. RECOMBINANT HUMAN GLUTAMIC ACID DECARBOXYLASE-
65 (RHGAD65)
 RHGAD65 is a vaccine that induces immunotolerization and...
CONCLUSION
 A wide range of agents are in development for use in the treatment of type
1 or type 2 diabetes.
 All of the...
REFRENCE:
1. Kamlesh P.Patel, Harsh M. Joshi, Falguni D. Majmudar, Varsha J. Patel. New Approaches in the
treatment of Dia...
Published by JIMSA , SRINAGAR, INDIA. Vol 25; sep 2012; 171-5.
10. BRAIN IRONS. New pharmacotherapies for type 2 Diabetes....
RECENT ADVANCES IN THE TREATMENT OF DIABETES MELLITUS AND ITS COMPLICATIONS
RECENT ADVANCES IN THE TREATMENT OF DIABETES MELLITUS AND ITS COMPLICATIONS
RECENT ADVANCES IN THE TREATMENT OF DIABETES MELLITUS AND ITS COMPLICATIONS
RECENT ADVANCES IN THE TREATMENT OF DIABETES MELLITUS AND ITS COMPLICATIONS
RECENT ADVANCES IN THE TREATMENT OF DIABETES MELLITUS AND ITS COMPLICATIONS
RECENT ADVANCES IN THE TREATMENT OF DIABETES MELLITUS AND ITS COMPLICATIONS
RECENT ADVANCES IN THE TREATMENT OF DIABETES MELLITUS AND ITS COMPLICATIONS
RECENT ADVANCES IN THE TREATMENT OF DIABETES MELLITUS AND ITS COMPLICATIONS
RECENT ADVANCES IN THE TREATMENT OF DIABETES MELLITUS AND ITS COMPLICATIONS
RECENT ADVANCES IN THE TREATMENT OF DIABETES MELLITUS AND ITS COMPLICATIONS
RECENT ADVANCES IN THE TREATMENT OF DIABETES MELLITUS AND ITS COMPLICATIONS
RECENT ADVANCES IN THE TREATMENT OF DIABETES MELLITUS AND ITS COMPLICATIONS
RECENT ADVANCES IN THE TREATMENT OF DIABETES MELLITUS AND ITS COMPLICATIONS
RECENT ADVANCES IN THE TREATMENT OF DIABETES MELLITUS AND ITS COMPLICATIONS
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RECENT ADVANCES IN THE TREATMENT OF DIABETES MELLITUS AND ITS COMPLICATIONS

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RECENT ADVANCES IN THE TREATMENT OF DIABETES MELLITUS AND ITS COMPLICATIONS

  1. 1. RECENT ADVANCES IN THE TREATMENT OF DIABETES MELLITUS AND ITS COMPLICATIONS PREPARED BY: SANJAY YADAV M. PHARM -II YEAR DEPT. OF PHARMACOGY AND TOXICOLOGY KLE UNIVERSITY’S COLLEGE OF PHARMACY , BELGAUM GUIDE : Dr N. A. KHATIB M. PHARM, Ph.D. DEPT. OF PHARMACOLOGY AND TOXICOLOGY KLE UNIVERSITY’S COLLEGE OF PHARMACY, BELGAUM
  2. 2. INTRODUCTION  Diabetes mellitus is characterized by chronic hyperglycemia glycosuria, hyperlipemia, negative nitrogen balance and sometimes ketonemia with disturbances of carbohydrate, fat, and protein metabolism resulting from defects in insulin secretion, insulin action, or both. EPIDIMEOLOGY There is an increase in the prevalence of type 1diabetes also, but main cause of diabetic epidemic is type2 diabetes mellitus, which accounts for more than 90 percent of all diabetes cases. According to World Health Organization (WHO) reports, India had 32 million diabetic people in the year 2001. The International Diabetes Federation (IDF) estimates the total number of diabetic subjects to be around 40.9 million in India and this is further set to rise to 69.9 million by the year 2025. The majority of cases of diabetes fall into two broad etiopathogenetic categories now called type 1 and T2 DM. The etiologic classification of diabetes mellitus currently recommended by WHO and the ADA in 1997.
  3. 3. ETIOLOGIC CLASSIFICATION I. Type 1 diabetes (b-cell destruction, usually leading to absolute insulin deficiency)  A. Immune mediated  B. Idiopathic II. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance) III. TYPE 3.Other specific types A. Genetic defects of b-cell functions B. Genetic defects in insulin action C. Diseases of the exocrine pancreas D. Endocrinopathies E. Drug or chemical induced F. Infections G. Uncommon forms of immune-mediated diabetes III. TYPE IV. Gestational diabetes mellitus
  4. 4. RISK FACTORS OF INSULIN RESISTANCE.  Obesity/overweight (especially excess visceral adiposity)  Excess glucorticoids (cushing’s syndrome or steroid therapy)  Excess growth hormone (acromegaly)  Pregnancy, gestational diabetes  Polycystic ovary disease  Lipodystrophy (acquired or genetic, associated with lipid accumulation in liver)  Autoantibodies to the insulin receptor  Mutations of insulin receptor  Mutations of the peroxisome proliferators’ activator receptor γ  Mutations that cause genetic obesity (e.g., melanocortin receptor mutations)  Hemochromatosis (a hereditary disease that causes tissue iron accumulation).
  5. 5. PATHOGENESIS OF DIABETES
  6. 6. DIABETES COMPLICATIONS
  7. 7. DIFFERENT DIABETES COMPLICATIONS  Macro vascular  Micro vascular  Neuropathy  Infections
  8. 8. MECHANISMS Hyperglycemia Tissue damage *Repeated acute changes in cellular metabolism **Cumulative long term changes in stable macromolecules Genetic susceptibility Independent accelerating factors
  9. 9. MACRO VASCULAR COMPLICATIONS
  10. 10. MACRO-VASCULAR COMPLICATIONS  Ischemic heart disease  Cerebrovascular disease  Peripheral vascular disease Diabetic patients have a 2 to 6 times higher risk for development of these complications than the general population
  11. 11. MACRO-VASCULAR COMPLICATIONS The major cardiovascular risk factors in the non-diabetic population (smoking, hypertension and hyperlipidemia) also operate in diabetes, but the risks are enhanced in the presence of diabetes. Overall life expectancy in diabetic patients is 7 to 10 years shorter than non-diabetic people.
  12. 12. MICRO VASCULAR COMPLICATIONS
  13. 13. EYE COMPLICATIONS  Cataracts Non enzymatic glycation of lens protein and subsequent cross linking  Sorbitol accumulation could also lead to osmotic swelling of the lens but evidence of involvement in cataract formation is less strong
  14. 14. EYE COMPLICATIONS Retinopathy (stages) Background Pre-proliferative Proliferative Advanced diabetic eye disease Maculopathy Glaucoma
  15. 15. DIABETIC RETINOPATHY (DR)  DR is the leading cause of blindness in the working population of the Western world  The prevalence increase with the duration of the disease (few within 5 years, 80 – 100% will have some form of DR after 20 years)  Maculopathy is most common in type 2 patients and can cause severe visual loss
  16. 16. PRE-PROLIFERATIVE RETINOPATHY  Rapid increase in amount of micro aneurisms  Multiple hemorrhages  Cotton wool spots (>5)  Venous beading, looping and duplication Proliferative retinopathy
  17. 17. ADVANCED DIABETIC EYE DISEASE  Retinal detachment with or without retinal tears  Rubeosis iridis  Neovascular glaucoma
  18. 18. MACULOPATHY  Macular edema (focal or diffuse)  Ischaemic maculopathy
  19. 19. DIABETIC NEPHROPATHY (DN)  Diabetes has become the most common cause of end stage renal failure in the US and Europe  About 20 – 30% of patients with diabetes develop evidence of nephropathy  The prevalence of DN is higher in Black Americans than in Whites (Figures for South Africa is not available)
  20. 20. STAGES OF DN Stage I  glomerular filtration and kidney hypertrophy Stage II u-albumin excretion < 30mg/24h Stage III Microalbuminuria (30 – 300 mg/24h)
  21. 21. DIABETIC NEUROPATHY Sensorimotor neuropathy (acute/chronic) Autonomic neuropathy Mononeuropathy Spontaneous Entrapment External pressure palsies Proximal motor neuropathy
  22. 22. SENSORIMOTOR NEUROPATHY  Patients may be asymptomatic / complain of numbness, paresthesias, allodynia or pain  Feet are mostly affected, hands are seldom affected  In Diabetic patients sensory neuropathy usually predominates
  23. 23. COMPLICATIONS OF SENSORIMOTOR NEUROPATHY  Ulceration (painless)  Neuropathic edema  Charcot arthropathy  Callosities
  24. 24. AUTONOMIC NEUROPATHY Symptomatic Postural hypotension Gastroparesis Diabetic diarrhea Neuropathic bladder Erectile dysfunction Neuropathic edema Charcot arthropathy Gustatatory sweating Subclinical abnormalities Abnormal pupillary reflexes Esophageal dysfunction Abnormal cardiovascular reflexes Blunted counter-regulatory responses to hypoglycemia Increased peripheral blood flow
  25. 25. MONONEUROPATHIES Cranial nerve palsies (most common are n. IV,VI,VII) Truncal neuropathy (rare)
  26. 26. ENTRAPMENT NEUROPATHIES  Carpal tunnel syndrome (median nerve)  Ulnar compression syndrome  Meralgia paresthetica (lat cut nerve to the thigh)  Lat Popliteal nerve compression (drop foot) All the above are more common in diabetic patients
  27. 27. PROXIMAL MOTOR NEUROPATHY Amyotrophy – most common proximal neuropathy, affects the Quadriceps muscles with weakness and atrophy (synonym: Diabetic Femoral radiculo- neuropathy)
  28. 28. INFECTIONS  The association between diabetes and increased susceptibility to infection in general is not supported by strong evidence  However, many specific infections are more common in diabetic patients and some occur almost exclusively in them  Other infections occur with increased severity and are associated with an increased risk of complications
  29. 29. INFECTIONS (CONT)  Several aspects of immunity are altered in patients with diabetes  There is evidence that improving glycemic control patients improves immune function
  30. 30. RHINO-CEREBRAL MUCORMYCOSIS
  31. 31.  RECENT ADVENCES IN ORAL HYPOGLYCEMIC AGENTS
  32. 32. ORAL HYPOGYCEMIC DRUGS  Biguanide Metformin  Sulfonylureas Glimepiride,gliclazide,glipizide,glyburide,glibenclamide  Meglitinides Repaglinide,nateglinide  Gliptins (DPP-4 inhibitors) Sitagliptin,vildagliptin,saxagliptin,alogliptin,linagliptin  Thiazolidinediones (PPAR-γ agonists) Pioglitazone,rosiglitazone  α-Glucosidase inhibitors Acarbose,miglitol,voglibose  Dopamine D2-receptor agonists Bromocriptine
  33. 33. SUBCUTANEOUS INJECTION  Insulin Rapid, short, intermediate, and long-acting formulations.  Newer insulins Insulin detemir, insulin glulisine, insulin degludec  GLP-1 agonists Exenatide, liraglutide,albiglutide,lixisenatide,taspoglutide  Amylin analogue Pramlintide
  34. 34. RECENT DRUGS Sodium–glucose-cotransporter-2 (SGL2) inhibitors Dapagliflozin, canagliflozin, ASP1941, LX4211, and BI10773 11β-hydroxysteroid-dehydrogenase-1 inhibitors INCB13739 (200 mg) DUAL PPAR (γ +α) AGONIST Aleglitazar Glucokinase activator Piragliatin, compound 14, R1511, AZD1656, AZD6370, compound 6 Bile acid sequestrants Colesevelam Anti-CD3 monoclonal antibody Otelixizumab, teplizumab Cannabinoid receptor-1 antagonists Rimonabant Histamine H3 receptor agonist Proxyfan
  35. 35. Glucagon receptor antagonists Compound 1 (cpd 1) Atherogenics antioxidant/vascular cell adhesion molecule-1 Succinobucol/AGI 1067 Recombinant human glutamic acid decarboxylase-65 (rhgad65) Vaccine, induces immunotolerization IL-1 antagonist Anakinra Insulin action enhancers Gip antagonists Sirtuins Adipose tissue signals
  36. 36. 49 Muscle/Fat: • PPARγ • Protein tyrosine phosphatase-1b (PTP-1b) • PPARδ • IkB Kinase • AMPK1) • 11bHSD12) • Hormone Sensitive Lipase • Adiponectin3) ß-cell: • GLP-1 Brain: • GLP-1 • Appetite regulators Liver: • Hepatic enzyme inhibitors • PPARα • Glukokinase • Glucagon antagonists • PPARδ Gut: • DPP-IV 1) AMPK: Adenosine 5’-MonoPhosphate activated protein Kinase 2) 11bHSD1: 11b-hydroxysteroid dehydrogenase-1 3) Adiponectin: One of the adipocyte-expressed proteins that function in the homeostatic control of glucose, lipid, and energy metabolism. Potential future targets for Type 2 diabetes Cure Disease prevention Stop disease progression Symptomatic treatment Possible targets Treatment aspiration Kidney (SGLT2 inhibitors)
  37. 37. 1. GLP-1 ANALOGUES  Glucagon like peptide–1 (GLP-1) is a 30 amino acid gut hormone secreted in a nutrient dependent manner that stimulates insulin secretion and inhibits glucagon secretion and gastric emptying, resulting in reduced postprandial glycemia.  GLP-1 is a member of the proglucagon incretin family and has insulinomimetic, insulinotropic, and antiapoptotic properties.  In individuals with normal glucose tolerance, the ingestion of glucose involves a much larger insulin response than observed after an isoglycemic intravenous glucose infusion.  This enhancement in insulin secretion called the “incretin” effect is markedly reduced to >50% in patients with diabetes compared with individuals with normal blood glucose.
  38. 38. 1. GLP-1 ANALOGUES  Glucagon like peptide–1 (GLP-1) is a 30 amino acid gut hormone secreted in a nutrient dependent manner that stimulates insulin secretion and inhibits glucagon secretion and gastric emptying, resulting in reduced postprandial glycemia.  GLP-1 is a member of the proglucagon incretin family and has insulinomimetic, insulinotropic, and antiapoptotic properties.  In individuals with normal glucose tolerance, the ingestion of glucose involves a much larger insulin response than observed after an isoglycemic intravenous glucose infusion.  This enhancement in insulin secretion called the “incretin” effect is markedly reduced to >50% in patients with diabetes compared with individuals with normal blood glucose.
  39. 39. Time, min IRInsulin,mU/L 80 60 40 20 0 18060 1200 THE INCRETIN EFFECT IN SUBJECTS WITHOUT AND WITH TYPE 2 DIABETES Time, min IRInsulin,mU/L 80 60 40 20 0 18060 1200 Oral glucose load Intravenous (IV) glucose infusion Incretin Effect The incretin effect is diminished in type 2 diabetes. Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.
  40. 40. GLP1 EFFECTS IN HUMAN UNDERSTANDING THE GLUCOREGULATORY ROLE INCRETINS Promotes satiety and reduces appetite Beta cells: Enhances glucose- dependent insulin secretion Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520.; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.; Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553.; Adapted from Drucker DJ. Diabetes. 1998;47:159-169. Liver: ↓ Glucagon reduces hepatic glucose output Alpha cells: ↓ Postprandial glucagon secretion Stomach: Helps regulate gastric emptying GLP-1 secreted upon the ingestion of food
  41. 41.  The incretin effect is mediated by the intestinal secretion of 2 hormones, glucose-dependent insulinotropic polypeptide (GIP) and GLP-1.  GLP-1 concentrations are often reduced in type 2 diabetes, but biological potency is mostly retained, making GLP-1 an attractive target for development of treatment.  But, circulating GLP-1 is rapidly (1 to 2 minutes) inactivated by the dipeptidyl peptidase IV enzyme (DPP-IV).  GLP-1 agonists (exenatide and liraglutide) are a class of drugs approved for the treatment of diabetes which are resistant to DPP IV enzyme.
  42. 42. EXENATIDE  It is derived from the naturally occurring peptide, exendin- 4, which was isolated from the salivary secretions of the lizard Heloderma suspectum (Gila monster).  Exenatide is a agonist at the GLP-1 receptor, is resistant to DPP-4 degradation, and is cleared by the kidneys.  It is usually administered twice daily as injections and provides adequate daily replacement of GLP-1.  It is currently approved in combination with metformin and/or a sulfonylurea in patients failing to reach the therapeutic goals with their current oral medication.
  43. 43.  Exenatide therapy also caused weight loss in patients with type 2 diabetes, in addition to its beneficial effects on glycaemic parameters.  Side-effects of exenatide include nausea and less commonly vomiting or diarrhoea, particularly when starting therapy.  Exenatide has no intrinsic risk for increasing the incidence of hypoglycaemia.  It is recommended that treatment is initiated with a dose of 5 mg twice daily which may be increased to 10 mg twice daily approximately 1 month later.
  44. 44. LIRAGLUTIDE  Liraglutide is the first human GLP-1 analogue with two modifications in the amino acid sequence of native human GLP-1 and an attachment of a fatty acid side chain to the peptide.  It is not excreted by the kidneys, and is not subjected to DPP-4 degradation.  It provides greater improvements in glycaemic control, induces weight loss and improves obesity-related risk factors.  It is also associated with reductions in HbA1c and blood pressure.  In a direct head-to-head comparison with the DPP-4 inhibitor sitagliptin, liraglutide was superior in lowering glycaemic parameters and body weight at both doses of 1.2 mg/day and 1.8 mg/day.
  45. 45.  Significant weight reductions versus placebo were observed with liraglutide in combination with metformin, metformin plus rosiglitazone, and metformin plus a sulfonylurea.  Gastrointestinal adverse effects were also common in clinical studies with liraglutide; however, in a direct head-to-head study, nausea and vomiting were less frequent with liraglutide and presented for a shorter period at the beginning of therapy than with exenatide.  Animal studies have shown an increased occurrence of thyroid medullary cancer with high doses of liraglutide but the clinical relevance of this work is unclear.  Early clinical trials of liraglutide suggested an increased incidence of pancreatitis.
  46. 46. Other Long-Acting GLP-1 Receptor Agonists ALBIGLUTIDE  It is a human GLP-1 receptor agonist with two molecules of GLP-1 linked to albumin.  The biological half life is around 5 days, which makes once-weekly dosing feasible for albiglutide. LIXISENATIDE  A GLP-1 agonist, as a once-daily monotherapy is being assessed in the GetGoal-M-As phase 3 clinical trial program, which started in May 2008 and has enrolled 4,500 patients.  Lixisenatide had been demonstrated to improve glycemic control and promote weight loss in 361 patients with type 2 diabetes during a 12-week, randomized, double-blind, multicenter phase 3 trial. TASPOGLUTIDE  It has 93% homology to endogenous GLP-1.  A long-acting profile was obtained by making 2 amino acid substitutions and using of a sustained-release formulation.
  47. 47. 2. SYNTHETIC AMYLIN ANALOGUES  Amylin is a peptide neurohormone that is synthesized and secreted by the b-cells of the pancreas with insulin.  Amylin secretion, like GLP-1, is stimulated by the presence of food in the gut.  The physiological effects of amylin are also similar to those of GLP-1. Amylin suppresses glucagon secretion, delays gastric-emptying, and acts centrally in the area postrema of the hindbrain to induce satiety.
  48. 48.  PRAMLINTIDE  It is a stable, bioactive analogue that differs from human amylin by three amino acid substitutions.   It is given as a subcutaneous injection two to three times daily and is administered before meals.  It has a rapid onset of action and duration of action of 2–4 h.  It is currently used in patients with type 1 DM and in those type 2 diabetics using meal time insulin or insulin in combination with a sulphonylurea or metformin.  Hypoglycaemia can occur particularly in the first 4 weeks of treatment.  Pramlintide also causes some weight loss, reduces HbA1c by 0.3–0.6%, and significantly lowers postprandial glucose.
  49. 49. 3. NEWER INSULINS Insulin detemir  It is a basal insulin analog that provides effective therapeutic options for patients with type 1 and type 2 diabetes.  Insulin detemir is a soluble derivative of human insulin in which the threonine residue at position B30 of the human insulin molecule has been removed and a 14-carbon fatty acid side-chain has been attached to position B29.  Insulin detemir has consistently been shown in randomized, controlled trials to have a weight- sparing effect in both type 1 DM and type 2 DM.
  50. 50. Insulin Glulisine  Insulin glulisine is a human insulin analogue altered by replacing asparagine with lysine at position B3 and by replacing lysine with glutamic acid at position B29, forming 3B- lysine-29Bglutamic acid-human insulin.  It is a rapid acting insulin analogue.  It has similar binding properties, and is associated with a faster onset but similar level of glucose disposal, to regular human insulin (RHI).  Several well designed trials have investigated the efficacy of insulin glulisine (with and without basal insulin) versus other agents (with and without basal insulin) in patients with type 1 and type 2 diabetes.  In patients with type 1 diabetes, insulin glulisine was non inferior to insulin lispro(in both adult and paediatric patients) and to RHI (in adult patients).  In adult patients with type 2 diabetes, insulin glulisine was noninferior (and superior in one study) to RHI and (with basal insulin glargine) more effective than premixed insulin.
  51. 51. Insulin degludec (IDeg)  It is a new generation ultra-long-acting basal insulin acting > 24 hrs.  The ultra-long effect of IDeg is primarily a result of the slow release of IDeg monomers from soluble multihexamers that form after subcutaneous injection, resulting in a long half-life and a smooth and stable pharmacokinetic profile at steady state.  These attributes are expected to provide improved glycemic control and to lower the risk of hypoglycemia, relative to currently available basal insulin analogs.
  52. 52. 4. DPP-4 INHIBITORS  The effects of endogenous incretins are short-lived because Of rapid degradation and inactivation by the enzyme Dpp-4.  Inhibitors of dpp-4 have been developed To prevent the inactivation of glp- 1 and prolong the activity Of the endogenously released hormone.  In contrast To glp-1 receptor agonists, these drugs are available Orally and have a longer duration of action, requiring Only once daily dosing.  They are effective at controlling Hyperglycaemia, reducing Hba1c concentrations By around 1%, improving pancreatic b-cell function And can be used as monotherapy or in combination with Other agents.
  53. 53. SITAGLIPTIN  A selective DPP-4 inhibitor was approved in 2006 by the FDA as the first oral incretin enhancer for use as monotherapy or in combination with metformin or thiazolidinedione.  In clinical trials of sitagliptin, reductions in HbA1c were seen with combination therapy with metformin and with monotherapy. Cleared primarily renally; reduce dosage in patients with moderate or severe renal impairment (CrCl _50 mL/min).
  54. 54. VILDAGLIPTIN  Vildagliptin exhibits higher selectivity for DPP-4 (IC50, 0.1 uM) in vitro compared with other peptidases.  The adverse events with vildagliptin are rare cases of hepatic dysfunction (including hepatitis).
  55. 55. SAXAGLIPTIN The inhibitory potency of saxagliptin for DPP-4 in vitro is 400-fold greater than for DPP-8 and 75-fold greater than for DPP-9. Common adverse events with saxagliptin are: Headache (7%), Sinusitis (3%), Abdominal pain, gastroenteritis, vomiting (2%), and UTI (7%).
  56. 56. Other DPP-IV inhibitors ALOGLIPTIN  The quinazoline-based compound alogliptin is a potent (IC50, 6.9 nM) inhibitor of DPP-4 in vitro.  In a randomized, double-blind study in 500 patients with inadequate glycemic control while receiving sulfonylurea monotherapy, treatment with alogliptin 12.5 mg, alogliptin 25 mg, or placebo was added for 26 weeks.
  57. 57. LINAGLIPTIN  It is the latest DPP-IV inhibitor approved by USFDA.  It shows highly selective, potent, dose-dependent inhibition of DPP-4, with >80% inhibition of DPP-4 throughout the 24-hour dosing interval.  Its recommended dose is 5 mg once a day.  Linagliptin 5 or 10mg once daily was also significantly more efficacious than voglibose 0.2 mg three times daily in terms of improving glycaemic control in a 26-week, double-blind, multicentre trial.
  58. 58. 5. DOPAMINE D2-RECEPTOR AGONISTS  Bromocriptine is an ergot alkaloid dopamine-D2- receptor agonist that has been available since 1978 to treat patients with prolactinomas and Parkinson’s disease.  Although bromocriptine quick release has only been licensed since 2010 by the US Food and Drug Administration (FDA) for the treatment of type 2 diabetes as an adjunct to lifestyle changes, its effects on glycaemic variables have been noted since 1980.  Bromocriptine produces its effects without increasing insulin concentrations, possibly by altering the activity of hypothalamic neurons to reduce hepatic gluconeogenesis through a vagally mediated route.
  59. 59. 6. SODIUM–GLUCOSE-COTRANSPORTER-2 (SGLT2) INHIBITORS  The kidneys contribute to glucose homoeostasis through gluconeogenesis, glucose use, and glucose reabsorption from the glomerular filtrate.  Renal gluconeogenesis might contribute 20–25% of total glucose production in the fasting state, most of which can be used immediately by the kidney.  About 180 L of plasma is normally filtered daily through the kidneys, and represents about 180 g of glucose if the average plasma glucose concentration is 5.5 mmol/L.  All of this glucose is normally reabsorbed, mostly through SGLT2, a low- affinity high capacity transporter, located predominantly in the brush border membrane of the proximal tubule.  Several SGLT2 inhibitors are recent drugs, including dapagliflozin, canagliflozin, ASP1941, LX4211, and BI10773.
  60. 60. 7. 11Β-HYDROXYSTEROID-DEHYDROGENASE-1 INHIBITORS  11β-hydroxysteroid dehydrogenase 1 predominantly converts low-activity cortisone to the more active cortisol.  11β-hydroxysteroid dehydrogenase 2 converts cortisol to cortisone.  It is mainly expressed in tissues that also express the mineralocorticoid receptor (especially the kidneys), allowing aldosterone to bind to this receptor.  The phenotypic and metabolic similarities between metabolic syndrome and Cushing’s syndrome have sparked interest in the therapeutic potential of inhibiting 11β-hydroxysteroid dehydrogenase 1 to reduce cortisol formation in the liver and adipose tissue. .  Reductions were also noted in concentrations of total cholesterol, LDL cholesterol, and triglycerides in patients with hyperlipidaemia, offering possible additional cardiovascular benefits.
  61. 61. 8. DUAL PPAR (γ +α) AGONIST  PPAR-γ agonists (e.g., pioglitazone) improve insulin sensitivity and are an established treatment for type 2 diabetes, whereas PPAR-α agonists (fibrates) are for dyslipidaemia, particularly high triglyceride and low HDL concentrations.  The effects of PPAR-γ and PPAR-α agonists are fully retained when used together.  Thus, dual PPAR-α and PPAR-γ agonists (glitazars) were developed to achieve a combined effect on lipids and glucose.  Development of previous dual agonists, such as tesaglitazar and muraglitazar, was stopped because of adverse events, but aleglitazar (a newer dual PPAR-α and PPAR-γ agonism) seems to have a better side- effect profile.  Administration of aleglitazar (300–900 μg once a day for 6 weeks) to patients with type 2 diabetes resulted in dose-dependent improvements in fasting and postprandial glucose concentrations, reduced insulin resistance, and improved lipid variables.
  62. 62.  Aleglitazar reduced HbA1c in a dose-dependent manner.  The typical side effects of PPAR-γ agonism, oedema and weight gain, were less severe with doses that were smaller than 300 μg aleglitazar than with pioglitazone.
  63. 63. 9. GLUCOKINASE ACTIVATOR  The phosphorylation of glucose by glucokinase after entry into the β cell affects the rate of glucose metabolism and subsequent ATP production, which closes potassium– ATP channels and initiates insulin secretion.  To enhance glucokinase action in β cells, several glucokinase activators have been developed, including piragliatin, compound 14, compound 6, .  Glucokinase activators increased insulin concentrations and reduced glucose concentrations in animal models of diabetes and patients with type 2 diabetes.  Glucokinase activators can additionally reduce glucose concentrations through effects on hepatic glucose metabolism.  Glucokinase activation is associated with increased concentrations of triglycerides and risk of hypoglycaemia.
  64. 64. 10. BILE ACID SEQUESTRANTS  Bile acid sequestrants are well established for the treatment of dyslipidaemia, and reduce the risk of cardiovascular disease.  They also reduce glucose concentrations in patients with type 2 diabetes.  The mechanism of action is not known, but is possibly mediated by activation of liver farnesoid receptors.  In 2009, the FDA licensed colesevelam to improve glycaemic control in patients with type 2 diabetes as an adjunct to lifestyle changes.  Colesevelam reduced HbA1c concentrations by 0.50– 0.54% when used in combination with metformin, sulphonylureas, or insulin, without increasing the risk of hypoglycaemia.
  65. 65. 11. GIPANTAGONISTS  GIP, like GLP-1, potentiates glucose-dependent insulin secretion, but unlike GLP-1, it promotes fat deposition in the adipocytes, does not inhibit glucagon secretion, and has little effect on food intake, satiety, gastric emptying, or bodyweight.  Studies of animal models of diabetes have shown that blocking GIP action increases energy expenditure.  This inhibition has a favourable effect on glucose homoeostasis, enhancing muscle glucose uptake, reducing hepatic glucose output, and improving β- cell function  Hence, GIP-receptor antagonists are potential treatments for patients with type 2 diabetes.  Orally active insulin releasing GIP agonists have also been reported.
  66. 66. 12. ANTI-CD3 MONOCLONALANTIBODY  Otelixizumab is a humanized anti-CD3 monoclonal antibody currently being evaluated in clinical studies in patients with new-onset type 1 diabetes.  Otelixizumab binds to the CD3/TCR complex and blocks full T-cell activation, proliferation, and cytokine release.   It has been hypothesized that otelixizumab’s downregulation of T effector cells via binding of the T-cell receptors will result in inhibition of the autoimmune attack on β-cells in the pancreatic islets and establishment of long lasting operational tolerance by the generation and expansion of regulatory T-cells, which prevent further autoimmune destruction.
  67. 67. 13. CANNABINOID RECEPTOR-1 ANTAGONISTS  An overactive endocannabinoid system in the brain and within adipose tissue (especially intra-abdominal depots) appears to contribute to increased appetite and excess adipose deposition in obese individuals.  Inhibitors of the cannabinoid receptor-1 (CB1) reduce obesity, and the CB1 antagonist rimonabant was introduced in Europe (in 2006)  Development of most other CB1 antagonists has since been discontinued, although experimental studies continue to explore the possibility that novel CB1 antagonists might specifically target adipose tissue without crossing the blood–brain barrier.
  68. 68. 14. ADIPOSE TISSUE SIGNALS  Since the discovery of leptin as an adipocyte satiety signal, adipose tissue has been recognized as a rich source of peptides that affect hunger/satiety and nutrient metabolism.  Adipose tissue produces a large amount of adiponectin (Acrp30), and the amount decreases as the adipose mass increases.  Adiponectin exerts many potentially advantageous effects, such as improved insulin sensitivity, antiinflammatory activity, and improved vascular reactivity.  From a therapeutic perspective, adiponectin stimulants, analogues, and nonpeptide receptor agonists are being considered for treatment of type 2 diabetes.
  69. 69. 15. INSULIN ACTION ENHANCERS  A metabolite from cultures of the fungus Pseudomassaria (demethylasterriquinone, L-783,281) has been identified as a nonpeptide activator of the insulin receptor.  It can initiate phosphorylation and tyrosine kinase activity of the β subunit of the insulin receptor, and lower blood glucose in insulin-resistant obese- diabetic mice.  Although this particular molecule is not suited to clinical application, it does demonstrate proof of concept for activation of insulin action independently of insulin.  Extending the tyrosine kinase activity of the preactivated insulin receptor has been demonstrated with substances that inhibit receptor dephosphorylation, notably inhibitors of protein tyrosine phosphatase-1B.  Vanadium salts may act, in part, through this mechanism to enhance insulin action.  Inhibitors of certain isoforms of protein kinase C also can prolong insulin receptor tyrosine kinase activity.
  70. 70. 16. HISTAMINE H3 RECEPTOR AGONIST  Histamine H3 receptors (H3Rs) are located on the presynaptic membranes of histamine neurons, where they negatively regulate the synthesis and release of histamine.  Proxyfan is a histamine H3 receptor agonist  Central histamine H3 receptor agonism by proxyfan can significantly improve glucose excursion by increasing plasma insulin levels via a glucose-independent mechanism.  Proxyfan reduced glucose excursion by significantly increasing plasma insulin levels.  Various study results provide roles of H3Rs in energy homeostasis and suggest a therapeutic potential for H3R agonists in the treatment of obesity and diabetes mellitus.  Chronic dosing with an H3R agonist reduces body weight, fat mass, hyperleptinemia, and hyperinsulinemia.
  71. 71. 17. GLUCAGON RECEPTOR ANTAGONISTS  Glucagon maintains glucose homeostasis during the fasting state by promoting hepatic gluconeogenesis and glycogenolysis.  Hyperglucagonemia and/or an elevated glucagon-to-insulin ratio have been reported in diabetic patients and animals.  Antagonizing the glucagon receptor is expected to result in reduced hepatic glucose overproduction, leading to overall glycemic control.  Compound 1 (Cpd 1), a compound that inhibits binding of glucagon to the human glucagon receptor.  Cpd 1 represents a novel class of compound that functions to block glucagon binding and antagonize biological responses elicited by glucagon in human hepatocytes.  Results indicate that GCGR antagonists can be derived and efficient blockade of glucagon action is an effective means to control fasting and postprandial hyperglycemia in type 2 diabetes.
  72. 72. 18. IL-1 ANTAGONIST  Interleukin-1 regulates body composition and fat distribution, mainly through the regulation of feeding behavior, satiety regulation, and energy metabolism, including thermogenesis.  The blockade of interleukin-1 with anakinra improved glycemia and beta- cell secretory function and reduced markers of systemic inflammation in patients with type 2 diabetes.
  73. 73. 19. SUCCINOBUCOL  Succinobucol is an oral antioxidant lipid peroxidation inhibitor and vascular cell adhesion molecule antagonist that is in phase 3 development for the treatment of atherosclerosis and type 2 diabetes.
  74. 74. 20. TAGATOSE  Tagatose is a naturally occurring, sweet-tasting, low-calorie monosaccharide hexoketose found in dairy products.  Tagatose was originally developed as a sugar substitute for calorie and weight control.  Oral administration of this product decreases the postprandial glucose peaks seen in patients with type 2 diabetes when it is administered before meals.  Administration three times a day with meals in patients with type 2 diabetes has been associated with weight loss, reduced A1C, and increased HDL cholesterol levels.  It is believed to exert its effect on postprandial glucose by attenuating glucose absorption in the intestine, as well as increasing glycogen synthesis and decreasing glycogen utilization.  Adverse effects have primarily included diarrhea, nausea, and flatulence.
  75. 75. 21. RECOMBINANT HUMAN GLUTAMIC ACID DECARBOXYLASE- 65 (RHGAD65)  RHGAD65 is a vaccine that induces immunotolerization and may thereby slow or prevent autoimmune destruction of pancreatic islet cells.  Antibodies against GAD are present at the time of diagnosis in 80–90% of patients with type 1 diabetes.  In patients with adult-onset autoimmune diabetes and the presence of antibodies against GAD, administration of rhGAD65 has been associated with reduced A1C and increased fasting and stimulated C-peptide levels for 2 years.  Two phase 3 studies were recently initiated to assess whether rhGAD65 formulated in alum preserves the body’s own insulin-producing capacity in patients recently diagnosed with type 1 diabetes.
  76. 76. CONCLUSION  A wide range of agents are in development for use in the treatment of type 1 or type 2 diabetes.  All of these agents appear to be effective in improving glycemic control, but it is unknown whether they will have an impact on the course of the disease or alter the micro- and macrovascular consequences of uncontrolled diabetes.  Although the newer therapies will excite the physicians with their novel mechanisms of action, these agents are very expensive and may reveal serious side effects in long term use.
  77. 77. REFRENCE: 1. Kamlesh P.Patel, Harsh M. Joshi, Falguni D. Majmudar, Varsha J. Patel. New Approaches in the treatment of Diabetes Melittus. Department of Pharmacology ; Published by NHL Journal of Medical sciences ; AHEMDABAD. 2(1); jan 2013 2. Ozougwv J.C., Obimba K.C., Belonwu C.D. , and Unakalamba C.B. The Pathogenesis and Pathophisiology of type 1 and type 2 Diabetes Mellitus. Published by Journal of Physiology and Pathophisiology 4:4; sep 2013; 46-57. 3. Kathleen Dungan, and John B. Base. Glucagon like Peptide-1 based therapies for type 2 –diabetes. Feature article, 23:2; 2005 4. Michael J. Fowler. Microvascular and Macrovascular Complications of Diabetes. Published by Clinical Diabetes Journals.org . vol. 26; number 2; 2008; http://clinical diabetes Journals.org. 5. Diagnosis and Classification of Diabetes Mellitus. American Diabetes Association. vol. 26 supplement 1; jan 2013; http://care.diabetes journals.org . 6. Juveline Diabetes Foundation International 120 Wall street. NEWYORK; www.jdf.org. 7. Maralitharan Nair. Diabetes Mellitus 1: Physiology and complications. Published by British Journal of Nursing. Vol . 16 no. 3; 2007; 184-8. 8. Nora Hosszu Faluri. Complication of Diabetes Mellitus . 03:29; 2011 9. Mohhamad Ashraf Ganie, Suman Kotwal. Recent advances in Management of Diabetes Melittus. Department of Endocrinology
  78. 78. Published by JIMSA , SRINAGAR, INDIA. Vol 25; sep 2012; 171-5. 10. BRAIN IRONS. New pharmacotherapies for type 2 Diabetes. Published by PSAP; Cardiology/Endocrinology;2013 11. Muhammad Akram. Diabetes and metabolism. Department of eastern medicine and surgery. Faculty of medical and health sciences.published by The university of poonch; Review article; 4:9;2013. 12. Management of Diabetes Mellitus. Standards of Diabetes care and clinical practice Guidelines. http://WHO-EM/DING/E/G 13. S. chauhan Nitesh, Chauhan Sanjeev, Handa Vandana, Arora Alka and Singh Vijender. Recent advances in insulin delivery systems. Department of pharmaceutics KIET school of Pharmacy, Ghaziabad, INDIA; IDOSHI publications. World applied sciences journal ; 11:22; 2010 ; 1552-6.

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