2. What is Diabetes?
• The term diabetes mellitus describes a
metabolic disorder of multiple aetiology
characterized by chronic hyperglycaemia with
disturbances of carbohydrate, fat and protein
metabolism resulting from defects in insulin
secretion, insulin action, or both.The effects
of diabetes mellitus include long-term
damage, dysfunction and failure of various
organs.
(K.G.M.M. Alberti et al, 1998)

4. • DM consists of a group
of disorders
characterized by
hyperglycemia; altered
metabolism of Lipids,
carbohydrates, and
proteins and an
increased risk of
complications from
vascular disease.

5. Prevalence of diabetes in
Pakistan
• Cross-sectional survey conducted earlier in
the rural and urban areas of all the four
provinces of Pakistan. Newly diagnosed
diabetes was 5.1% in men and 6.8% in
women in urban areas and 5.0% in men and
4.8% in women in rural areas
( F. Jawad et al,2006)
• Prevalence of diabetes is high ranging from
7.6 to 11% in Pakistan
(R. Hakeem et al ,2010)

6. Global Prevalence
• The prevalence of diabetes for all age-groups
worldwide was estimated to be 2.8% in 2000
and 4.4% in 2030.
(SARAHWILD et,al 2004)

7. Cause:
• Genetic Susceptibility
• Autoimmune Destruction of Beta Cells
(Alexandra E. Butler et al, 2004)
• Environmental Factors
• Viruses and infections
• Obesity and Physical Inactivity
• Insulin Resistance
(NIH Publication No. 09–3873, November 2008)

8. • AbnormalGlucose Production by the Liver
• Metabolic Syndrome Cell Signaling and
Regulation Beta Cell Dysfunction deficit in -cell
mass, increased -cell apoptosis, and impaired
insulin secretion.
• Endocrinopathies.
(AMERICAN DIABETESASSOCIATION,2006)
• Drug- or chemical-induced diabetes.
• Diseases of the exocrine pancreas.

9. • Point mutations in mitochondrial DNA have
been found to be associated with diabetes
mellitus and deafness
• Uncommon forms of immune-mediated
diabetes.
(Expert Committee on the Diagnosis and Classification of
Diabetes,2006)

10. Types of diabetes
The three main types of diabetes are
• Type 1 diabetes
• Type 2 diabetes

11. Type 1 Diabetes
• Type 1 indicates the processes of beta-cell
destruction that may ultimately lead to diabetes
mellitus in which ‘insulin is required for survival’
to prevent the development of ketoacidosis,
coma and death.
• Type 1 is usually characterized by the presence
of anti-GAD, islet cell or insulin antibodies which
identify the autoimmune processes that lead to
beta-cell destruction.
(K.G.M.M. Alberti et al, 1998)

12. Type 1

13. Type 2 Diabetes
• Type 2 is the most common form of diabetes
and is characterized by disorders of insulin
action and insulin secretion, either of which
may be the predominant feature. Both are
usually present at the time that this form of
diabetes is clinically manifest.
(K.G.M.M. Alberti et al, 1998)

15. Pathophysiology
• Several pathogenetic processes are involved
in the development of diabetes.These include
processes which destroy the beta cells of the
pancreas with consequent insulin deficiency,
and others that result in resistance to insulin
action.The abnormalities of carbohydrate, fat
and protein metabolism are due to deficient
action of insulin on target tissues resulting
from insensitivity or lack of insulin.
(KahnSE et al, 2000)

16. • Diabetes mellitus type 2 (formerly noninsulin-
dependent diabetes mellitus (NIDDM) or adult-
onset diabetes) is a metabolic disorder that is
characterized by high blood glucose in the context
of insulin resistance and relative insulin deficiency
Virtually all forms of DM result from a decrease in
the circulating concentration of insulin (insulin
deficiency) and a decrease in the response of
peripheral tissues to insulin (insulin resistance).
• These abnormalities lead to alterations in the
metabolis of carbohydrates, lipids, ketones, and
amino acids , the central feature of the syndrome is
hyperglycemia.

17. • Insulin lowers the concentration of glucose in
blood by inhibiting hepatic glucose production
and by stimulating the uptake and metabolism of
glucose by muscle and adipose tissue.
• These two important effects occur at different
concentrations of insulin. Glucose production is
inhibited half maximally by an insulin
concentration of about 20 μunits/mL, whereas
glucose utilization is stimulated half maximally at
about 50 μunits/mL.

18. • Lack of GIP amplification of the latephase
plasma insulin response to glucose seems to
be a consequence of diabetes mellitus,
characterizing most, if not all, forms of
diabetes.1 beta-cell dysfunction and insulin
resistance are two central, interrelated
defects in the pathophysiology of type 2
diabetes
(T.VILSBØLL et al, 2003)

19. • Type 2 diabetes is a progressive disease and that
this progression is due to declining beta-cell
function.
(The American Journal of Medicine ,2000)
• Proinsulin is a precursor of mature insulin and C-
peptide. Higher circulating proinsulin levels are
associated with impaired b-cell function, raised
glucose levels, insulin resistance, and type 2
diabetes (T2D). Studies of the insulin processing
pathway could provide new insights aboutT2D
pathophysiology.
(Rona J. Strawbridge et al ,2003)

20. Diabetes Research & Wellness Foundation

21. Role of insulin in glucose
regulation
• Insulin lowers the concentration of glucose in
blood by inhibiting hepatic glucose
production and by stimulating the uptake and
metabolism of glucose by muscle and adipose
tissue
( Goodman and Gillman’s Pharmacology)

23. REGULATION OF GLUCOSE
TRANSPORT
• Stimulation of glucose transport into muscle
and adipose tissue is a key response to insulin.
Glucose enters cells by facilitated diffusion
through one of a family of five glucose
transporters, GLUTs 1–5, that mediate Na+-
independent facilitated diffusion of glucose
into cells

24. • Insulin stimulates glucose transport by
promoting translocation of intracellular
vesicles that contain the GLUT4 and GLUT1
glucose transporters to the plasma
membrane .The transporters return to the
intracellular pool on removal of insulin

25. Symptoms
• Polyuria , polydipsia, and unexplained weight
loss) and a random plasma glucose
concentration of greater than 200 mg/dL , a
fasting plasma glucose concentration of
greater than 126 mL/dL or a plasma glucose
concentration of greater than 200 mg/dL 2
hours after the ingestion of an oral glucose
load.
(K.G.M.M.Alberti et al, 1998)

26. • In its most severe forms, ketoacidosis or a
non-ketotic hyperosmolar state may develop
and lead to stupor, coma and, in absence of
effective treatment, death occur.
(K.G.M.M. Alberti et al, 1998)

27. Complications 5
• Diabetic cardiovascular disease
(Dongjuan wang et al, 2013)
• Insulin resistance
• Beta-cell defect
• Metabolic syndrome
These are the pathologic problems leading to hyperglycemia
• Heart attack
• Stroke
• Cardiovascular death
( Collins FM. Et al, 2013 )

28. • Oxidative stress causes diabetic complications
that are undefined.
• Elevated FFA result in the generation of ROS and
RNS, leading to increased oxidative stress. In the
absence of an appropriate compensatory
response from the endogenous antioxidant
network, the system becomes overwhelmed
(redox imbalance), leading to the activation of
stress-sensitive signaling pathways, such as NF-
B, p38 MAPK, JNK/SAPK, PKC, AGE/RAGE
(JOSEPH L.et al, 2002)

29. Current treatment
• Sulfonylureas
• Insulin secretagogues
• Biguanides
• Alpha-glucosidase inhibitors
• Thiazolidinediones
• Insulin
( Collins FM. Et al, 2013 )

30. Possible targets for diabetes type 2
• Adenosine 58- monophosphate-activated
protein kinase (AMPK) now appears to be a
metabolic master switch, phosphorylating
key target proteins
(W.W.WINDER et al.2013)
• Several G protein-coupled receptors (GPCRs)
expressed in islet β-cells are known to be
involved in the regulation of islet function
(Bo Ahrén et al 2009)

31. • Several mechanisms have been proposed,
including increased non-esterified fatty acids,
inflammatory cytokines, adipokines, and
mitochondrial dysfunction for insulin
resistance, and glucotoxicity, lipotoxicity, and
amyloid formation for β-cell dysfunction
( Michael Stumvoll et al, 2013)

32. • Genes have been identified so far: genes for
calpain 10, potassium inward-rectifier 6·2,
peroxisome proliferator-activated receptor γ,
insulin receptor substrate-1
( Michael Stumvoll et al, 2013)

33. Current targets
(David E. Moller et al, 2001)

34. (David E. Moller et al, 2001)

35. Enhancing glucose-stimulated
insulin secretion
(David E. Moller et al, 2001)

36. Targeting the insulin signalling
pathway
(David E. Moller et al, 2001)

37. AMP-activated kinase and acetyl-
CoA carboxylase
(David E. Moller et al, 2001)

38. Need
• Patients with diabetes have CVD-related
mortality that is 2 to 4 times higher than in non-
diabetics.
• Despite all the new treatments that have
emerged in the last 20 years, diabetes sufferers
remain challenged in effectively managing their
disease over the long term and some drugs lose
efficacy as the disease progresses.Oral drugs
eventually fail to control blood glucose, and
insulin injections become unavoidable.

39. • The challenge will be to advance these agents
while meeting the demands of patients for
better-tolerated drugs, optimal efficacy, and
safety in the face of heightened testing
requirements to assess CV risk.

40. • Metformin was approved by the US food and
drug administration (FDA) in 1994. Preferred
first-line drug for the treatment of type 2
diabetes.
• Additional agents are often prescribed in
combination with metformin.

41. • Alpha-glucosidase inhibitors; various novel
insulins with rapid onset of action or long
duration of effect; thiazolidinediones (tzds);
meglitinides; glucagon-like peptide-1
receptor agonists (GLP-1 RA); and dipeptidyl
peptidase-4 (DPP-4) inhibitors.

42. • Rosiglitazone/avandia published in 2007 raised
concerns about cv safety
• Rosiglitazone had an increased risk of myocardial
infarction and a borderline increased risk of death
from cv events.
• Taking insulin glargine had no effect (negative or
positive) on the risk of a heart attack or stroke.

43. • Treatment of diabetes requires a multi-
faceted approach and there are no “one-size-
fits- all” solutions.
• Some of the newer drugs such as glp-1 ra,
dpp-4 inhibitors, and sodium-glucose
cotransporter 2 (sglt2) inhibitors may have
favourable CV effects.

44. • Novel drug class is oral inhibitors of sglt2, the
protein responsible for at least 90 per cent of
the glucose reabsorption in the kidney.
• Sglt2 compounds have also shown significant
blood pressure-lowering effects, but it
remains uncertain whether these benefits will
reduce CV events.

45. • Dapagliflozin was approved for use in europe,
becoming the first sglt2 entrant to gain regulatory
approval for type 2 diabetes.
• Reductions in weight and blood pressure.
• Dapagliflozin was denied approval by the fda in early
2012 due to concerns over apparent bladder and
breast cancer risks.

46. • Other novel drug classes in development for
type 2 diabetes are G-protein-coupled
receptor (GPCR) agonists and interleukin-1-
receptor (IL-1) antagonists. GPCRs are cell
surface receptors that mediate a variety of
important cellular signals related to control of
blood pressure and blood glucose.

47. New targets
• Aldosterone and MR signaling represent an
ideal candidate pathway linking early
promoters of diabetes, especially
overnutrition and obesity, to vascular insulin
resistance, dysfunction, and disease
(Shawn B. Bender et, al 2013 )

48. • Preserve b-cell function and the impact on
clinical care and outcomes
(Judith E et, al 2013)
• An increased b-cell workload (insulin
resistance) is a risk factor forT2DM, most
individuals adaptively increase insulin and
IAPP expression and secretion without b-cell
failure.
(Safia Costes et, al 2013)

49. • Several nonpeptide, except DPP-4 inhibitors,
binding G protein-coupled receptors (GPCRs)
have been deorphanized recently and are
currently being evaluated as candidate GLP-1
secretagogues forT2DM
(Xiaoyun Zhu et al , 2013)

50. (Xiaoyun Zhu et al , 2013)

51. • A characteristic feature of type 2 diabetes is
delayed wound healing, which increases the
risk of recurrent infections, tissue necrosis,
and limb amputation.
• Diabetes impairs resolution of wound
healingstimulating resolution with
proresolving lipid mediators could be a novel
approach to treating chronic, nonhealing
wounds in patients with diabetes
(YunanTang et, al 2013 )

52. • Damage to mitochondrial DNA (mtDNA),
may result in Glucotoxicity due to metabolic
oversupply
(Martin Picard et al, 2013)

53. (Martin Picard et al, 2013)

54. • Brown adipose tissue (BAT) as therapeutic
strategies for preventing and treating obesity
and type 2 diabetes 20
(Harold Sacks et, al 2013)
• Islet transplantation as a treatment
(R. Paul Robertson et, al 2004)

55. (R. Paul Robertson et, al 2004)

56. • Renoprotective Agents
(Macaulay Onuigbo et al ,2013)

57. • Blood pressure as targets for treatment, the
efficacy of blocking the renin-angiotensin system
(RAS) pathway,
(EBERHARD RITZ et, al 2011)
• Postprandial hyperglycemia is a direct and
independent risk factor for cardiovascular disease
(CVD)Correcting the postprandial hyperglycemia
may form part of the strategy for the prevention
and management of CVDs in diabetes
(Antonio Cerielloet et,al 2005)

58. • The acute phase of insulin release is a major
determinant of the efficiency of glucose
clearance,
• cAMP potentiates both acute-phase and
sustained-phase insulin secretion and
provides a therapeutic target to restore
glucose control.
(Kelly A. Kaihara et,al 2013)

59. • Oleanolic acid (OA), improves insulin response,
preserves functionality and survival of b-cells, and
protects against diabetes complications.
(Jose M. Castellano et,al 2013)
• Vascular endothelial growth factor (VEGF) are
revolutionizing the treatment of diabetic
retinopathy (DR) and diabetic macular edema
(DME).
(Paul M.Titchenell et, al 2013)

60. • Inhibition of hepatic glycogen phosphorylase is
a promising treatment strategy for attenuating
hyperglycemia , glycogen phosphorylase
inhibition aimed at attenuating hyperglycaemia
is unlikely to negatively impact muscle
metabolic and functional capacity.
(David J. Baker et, al 2005)
• Pharmacological inhibition of hepatic glycogen
phosphorylase has the potential to be an
effective therapeutic strategy for the treatment
of type 2 diabetes

61. • A novel peptide has been named ‘irisin’ acts
on the cells of white adipose tissue. Irisin
increases total energy expenditure and, in
certain animal models, prolongs life
expectancy, reduces body weight, and
mitigates diet-induced insulin resistance, thus
reducing obesity and insulin resistance
(Fabian Sanchis et, al 2012)

62. • Use of antioxidants may be very important in
preventing activation of oxidative stress
(JOSEPH L et,al 2012)

63. Molecular targets
• Reducing islet cell oxidative stress is a
potential target of human type 2 diabetes
therapy.
(Silvia Del Guerra et,al 2005)
• Nitrotyrosine and 8-hydroxy-2-
deoxyguanosine concentrations, markers of
oxidative stress, were significantly higher in
type 2 diabetic than control islets, and they
were correlated with the degree of glucose-
stimulated insulin release impairment

64. Plants having hypoglycemic
activity (Nidhi Aggarwal et al , 2011)

65. • Eugenia jambolana (EJ) commonly known as Jaman
• Lawsonia alba Lam commonly known as henna is a
perennial plant of the family Lythraceae, henna leaves
(mehendi)
• Momordica charantia
• Morus alba (synonyms Morus alba Linn) (MA) known
aswhite mulberry
• Nigella sativa Linn. (NS), known as black cumin Kalonji
• Trigonella foenum graecum Linn. (TF) commonly
known as methi (M. SAEEDARAYNEetal, 2007)

66. Plant having hypoglycemic
activity
Botanical name : Allium cepa
Family : (Liliaceae)
Common name :Onion
• Allium cepa has some anti-diabetic that b may
be due to the antioxidant properties of its
essential oil components, which can signify its
anti-diabetic and antihyperlipidaemic activity
(DK Patel et,al 2012)

67. Why this plant…!!!
• Hypoglycaemic and hypolipidaemic activity
• Antioxidative activity
(Ozougwu et al , 2011)

68. Methods
1. Streptozotocin-induceddiabetes
2. Alloxan-induced diabetes
3. Virus-induced diabetes
4. Pancreatectomy in dogs
5. Growth hormone-induced diabetes
6. Corticosteroid-induced diabetes
7. Insulin deficiency due to insulin antibodies
HansGerhard Vogel
3rd edition

69. Streptozotocin Induced
Diabetic
Aim :
This is apropos to investigate the
antioxidative effect of allium cepa essential
oil in streptozotocin induced diabetic albino
rats
(Neveen Abou El-Soud et,al 2010)

70. Materials
• Essential oil of red onion (0.05%) will be
prepared and isolate it according to Harborne
(Harborne JB et, al 1984)
• Streptozotocin (STZ) will be purchased from
ABC company Pakistan
• Chloroform, Methyl alcohol, ether will be
purchased from GHK chemicals

71. Animals:
• Thirty male albino rats weighing 150-200g will
be obtained from UOS animal house
• Rats will be caged under controlled
temperature 20-24°C and 12 h light/dark
cycle.They will be fed with standard
laboratory chow and water ad libitum.

72. Induction of Diabetes
• Rats will be kept on fasting prior to
streptozotocin injection.
• On the day of administration, STZ will be freshly
dissolved in 50 Mm sodium citrate (pH 4.5)
solution containing 150 mM NaCl and
subcutaneous injection will be given at the
dosage of 60 mg/kg b.w.
• Blood glucose concentration will be checked by
the glucose oxidase method (Trinder P. Et, al
1969) after 3 days of STZ injection.The animals
with glucose concentration exceeding 200 mg /dl
will be considered diabetic.

73. Rats will be divided into 3 groups 10 rats in each
• Group: group I: normal control rats
• Group II: diabetic control rats
• Group III: diabetic rats received onion
essential oil (100 mg/kg b.W. Orally)
• The dose will be chosen according to its LD50
(the medium 50 lethal doses after acute
toxicity).

74. Groups FBG (mg/dl) Serum insulin
(µu/ml)
I Normal
control
II Diabetic
control
III Onion
essential oil
control
(100 mg/kg
b.W. Orally)

75. Samples Collection
• After 21 days from the beginning of the
experiment
• Rats will be fasted for 12 hours
• Then blood samples will collected
• Blood will be collected retro-orbitally from the
inner canthus of the eye under ether anaesthesia
using capillary tubes containing sodium fluoride
(MadwayW et, al 1969)

76. • Serum and plasma will be separated and
centrifuged at 3000 rpm for 5 minutes.
• The serum and plasma will be separated for
measurement of glucose, insulin,
cholesterol, triglycerides, HDL, LDL, nitric
oxide and tbars in different study groups.

77. ALLOXAN-INDUCED
DIABETES
(Ozougwu et al ,2011)

78. Animal Model
• Sixty three (63) adult white wistar strain albino
rats (R. norvegicus) weighing 200 to 250g, bred in
the animal house of the Faculty of Pharmacology
UOS will be used for the study.
• They will be fed ad labium with 30% crude protein
(Guinea feed) commercial feed.
• They will be allowed to acclimatize under
standard photoperiodic condition in a clean rat
cage Research Laboratory.
• All animals will be maintained under the standard
laboratory condition for temperature (26 ± 20C)
and light (12 hours day length) and allowed free
access to food and water.

79. Preparation of Plant Extracts
• The methods of Habib MY et al 2005 and Battu
GR et al, 2005 will be used.
• Fresh health plant of A. cepa (2000 g) will be
washed, cut into small pieces and homogenized
in a warring blender.
• The resulting mixture will be soaked in 2L of
distilled water.
• The mixture will be allowed to stand for twenty
four hours with intermittent shaking.

80. • Following filtration, the filtrates will be
heated to dryness in a water bath and the
weight of the crude extract will be
determined.
• The extract will be kept in refrigerator (40 C)
thereafter.
• The extract will be reconstituted in normal
saline (0.85% NaCl) at a concentration of
1g/ml before administration.

81. Induction of Diabetes Mellitus
• The methods of Osinubi AA et al , 2006 and Battu GR et
al , 2007 will be used to induce diabetes in the rats.
• 150 mg of alloxan per kg body weight of rat will be
administered intraperitoneally after overnight fast
(access to only water) of twelve hours to make them
more susceptible to developing diabetes.
• Rats with serum glucose levels between (250 – 400
mg/dl) after two weeks will be considered diabetic and
used for the experiment.

82. Experimental Design
• The study will be carried out on alloxan- induced
diabetic rats for six weeks.
• The animals will be fasted for sixteen hours before
each experiment and blood sample collected from
the eye of the rats.
• All parameters assessed will be determined before
the extract treatments of the animals (initials) and
subsequently will be evaluated weekly for six weeks.
• The experimental design will be three by three Latin
square design using 63 rats divided into two major
groups

83. • Group I: nine non diabetic rats (non diabetic
control)
• Group II: fifty four alloxan induced diabetic rats.
• Group I rats were divided into 3 subgroups (Ia, Ib,
Ic) of 3 rats each in different cages and receives
1.0ml of normal saline intraperitoneally daily.
• Group II (fifty - four alloxan induced diabetic rats)
will be divided into 2 subgroups (IIa , IIb).
Subgroups IIa, (twenty seven rats) will be divided
into 3 replicates (IIa1, IIa2, IIa3).

84. • Each replicate will have three rats and received
200 mg/kg, 250 mg/kg or 300 mg/kg of A. cepa
aqueous extracts intraperitoneally daily
respectively.
• The subgroups IIb will be diabetic control (twenty-
seven rats) and will be divided into 3 replicates
(IId1, IId2 and IId3) each replicate will have three
rats and will be administered 2.5mg/kg/, 3.8mg/kg
and 5.0mg/kg of standard antidiabetic drug
(glibenclamide) daily for six weeks

85. Parameters
• Determination of Blood Glucose
• Determinations ofTotal Serum
• Cholesterolose Level Determination
• Determination ofTotal Lipids in Serum

86. INSULIN DEFICIENCY DUETO
INSULIN ANTIBODIES:
• Bovine insulin, will be dissolved in acidified water
(pH 3.0) and incorporated in a water-oil emulsion
based on complete Freund’s adjuvant or a
mixture of paraffin oil and lanolin.
• A dose of 1 mg insulin will be injected in divided
doses subcutaneously to male guinea pigs
weighing 300–400 gm.

87. • Injections will be given at monthly intervals and
the guinea pigs will be bled by cardiac puncture
twoWeeks after the second and subsequent
doses of antigen.
• It is possible to get 10 ml blood from every
animal once a month. Intravenous injection of
0.25–1.0 ml guinea pig antiinsulin serum to rats
will induce a dose-dependent increase of blood
glucose reaching values up to 300 mg%.

88. • This effect is unique to guinea pig anti-insulin serum
and is due to neutralization by insulin antibodies of
endogenous insulin secreted by the injected animal. In
this way a state of insulin deficiency will be induced.
• It persists as long as antibodies capable of reacting
with insulin remain in the circulation. Slow rate
intravenous infusion or intraperitoneal injection
prolongs the effect for more than a few hours.
• However, large doses and prolonged administration
accompanied by ketonemia, ketonuria, glucosuria, and
acidosis will proove to be fatal to the animals.
• After lower doses, the diabetic syndrome will be
reversible after a few hours (Moloney and Coval 1955;
Wright 1968).

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