presented by:

Samir Ahmad
M.Pharm (p’ceutics)

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 What is Diabetes? (Goodman
and Gilman’s)
 Diabetes mellitus (DM) consists of a group of
syndromes characterized by
 Hyperglycemia
 Altered metabolism of lipids,
 Carbohydrates,
 Proteins,
 Increased risk of complications.
 Most common non-communicable diseases
globally

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Types of diabetes?(Goodman
and Gilman’s)
General—genetic and other factors not
precisely defined
 Type 1 diabetes mellitus

• Autoimmune type 1 diabetes mellitus (type

1A)
• Non-autoimmune type 1 diabetes mellitus
(type 1B)
 Type 2 diabetes mellitus

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 Contd..,

 Specific—defined gene mutations

• Maturity-onset diabetes of youth (MODY)
• MODY 1 hepatic nuclear factor 4α (HNF4A)
gene mutations
• MODY 2 glucokinase (GCK) gene mutations
• Maternally inherited diabetes and deafness
(MIDD)
• Insulin gene mutations
• Insulin receptor gene mutations
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 Contd..,

 Diabetes secondary to pancreatic disease

• Chronic pancreatitis
• Surgery
• Tropical diabetes
 Diabetes secondary to other endocrinopathie
• Cushing's disease
• Glucocorticoid administration
• Acromegaly

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Sign n symptom of DM

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Contd..,

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Contd..,

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 Prevalence( diabetes
Atlas.”IDF”)
 At least 171 million people worldwide have diabetes;
 likely to be more than double by 2030;
 Around 3.2 million deaths every year are attributable to
complications of diabetes;
 six deaths every minute (WHO, 2007).
 At least 20 million diabetics in India,

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Risk factors

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complication

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Contd..,

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Type 1DM

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Contd..,

 Virtually all forms of DM are cause by..

• insulin deficiency,
• insulin resistance.
 Usually younger in onset, thin, prone to
kitosis.

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 Insulin (Goodman and
Gilman’s)
 Insulin lowers the concentration of glucose in blood by
• Inhibits hepatic glucose production (liver)
• Stimulates hepatic glucose uptake (liver)
• Stimulates glucose uptake (muscle)
• Inhibits flow of gluconeogenic precursors to the liver
(e.g., alanine, lactate, and pyruvate)
 Inhibits flow of gluconeogenic precursor to liver (glycerol)
and reduces energy substrate for hepatic gluconeogenesis
(nonesterfied fatty acids) (adipose tissue)

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Regulation of Glucose
Transport

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Contd..,

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 Muscle and adipose
tissue( Goodman and Gilman’s)
 Glucose enters cells by facilitated diffusion through
one of a family of glucose transporters (GLUT1
through GLUT5)
 Integral membrane glycoproteins
 Insulin stimulates glucose transport at least in part
by…
• translocation of intracellular vesicles that contain
the GLUT4 and GLUT1
• This effect is reversible
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Contd..,

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Regulation of Glucose
Metabolism

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The Insulin Receptor

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 Insulin Therapy (Goodman
and Gilman’s)
 Insulin is the mainstay for treatment of virtually all type
1 DM and many type 2 DM patients.
 Preparations of insulin can be classified according to
their duration of action into..
• short acting (e.g. Regular soluble (crystalline),
Lispro, Aspart
• Intermediate acting (e.g NPH (isophane), Lente,
• Slow acting (e.g. Ultralente, Protamine zinc

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New Routes of Delivery

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 Factors That Affect Insulin
Absorption (Goodman and
 Gilman’s)
Absorption of insulin after s.c. administration..
• the site of injection,
• the type of insulin,
• subcutaneous blood flow, smoking,
• regional muscular activity
• vol and conc of the injected insulin,
• depth of injection
 (insulin has a more rapid onset of action if delivered
intramuscularly rather than subcutaneously).

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ADR

 Hypoglycemia.
 Insulin Allergy and Resistance
 Lipoatrophy and Lipohypertrophy
 Insulin Edema

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 Beta-cell replacement
(Shimon Efrat)
 Beta-cell replacement is considered the optimal
treatment for type 1 diabetes, however, it is
hindered by a shortage of human organ donors.
 Given the difficulty of expanding adult beta cells in
vitro, stem/progenitor cells, which can be
expanded in tissue culture and induced to
differentiate into multiple cell types, represent an
attractive source for generation of cells with beta-
cell properties.
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 Stem cells for the treatment of
diabetes (Burns CJ et al)
 Bone marrow-derived stem cells could initiate pancreatic
regeneration.
 Pancreatic stem/progenitor cells have been identified, and
the formation of new beta cells from duct, acinar and liver
cells is an active area of investigation.
 Some agents including glucagon-like peptide-1/exendin-4
can stimulate the regeneration of beta cells in vivo .
 Overexpression of embryonic transcription factors in stem
cells could efficiently induce their differentiation into
insulin-expressing cells.

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 Contd..,

 New technology, known as protein transduction

technology, facilitates the differentiation of stem cells
into insulin-producing cells.
 Recent progress in the search for new sources of
beta cells has opened up several possibilities for the
development of new treatments for diabetes.
 Potential role of leptin in diabetes.
 Regulating appetite control and energy metabolism,
plays a major role in islet cell growth and insulin
secretion
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 NEWER ANTIDIABETIC
DRUGS 2 DM
(A. sundaram et al)
 The basic defects in Type 2 diabetes consist of
• Insulin deficiency
• Insulin resistance
• increased hepatic glucose production
• beta cell exhaustion
• finally beta cell failure.

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 Treatment strategies

 Modified meal Plan

 Exercise
 Blood glucose lowering drugs and
 Insulin
 The current oral blood glucose lowering agents and dietary
measures only partially correct the multiple metabolic defects
in NIDDM with insulin resistance.
 the need for newer blood glucose lowering drugs.

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Contd..,

 Alpha glucosidase inhibitors, eg. Acarbose

 Insulin Sensitizer, eg. Troglitazone.
 Insulin secretoguogues, eg. Glimepiride and
Repaglinide.

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 ALPHA-GLUCOSIDASE
INHIBITORS
 In human salivary amylase, pancreatic amylase and alpha-
glucosidase are the enzymes involved in the digestion of starch.
 Glucosidase inhibitors are three types:
 Reversible competitive inhibitors of α-glucosidase.eg: a.
Acarbose; b. Meglital
 Irreversible glucosidase inhibitor eg. Gasternospermine.
 Powerful Sucrose inhibitor eg: Veglibose.

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 Acarbose

 Acarbose is a psuedotetrasaccharide
 Reversible competitive inhibitor of the brush border alpha
glucosidases.
 binds to alpha-glucosidase with high affinity.
 Blocks the digestion of starch, sucrose and maltose.
 Absorption of glucose and other monosaccharides in not
affected.
 Decrease in post prandial rise in blood glu..

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 Contd..,

 Decreases meal stimulated secretion of gastric

inhibitory polypeptide and other gastrointenstinal
peptide (inhibitors) hormones.
 Does not cause weight gain.
 Side Effects:
• Abdominal fullness, borborygmi, increased
• intestinal flatulence and diarrhoea.

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 INSULIN SENSITIZERS

 Mechanism of Action of Troglitazone:

 In Adipose Tissue
 increase glucose oxidation,
 Lipogenesis,
 increase the expression of GLUT-4,
 Bind with the PPAR-Y (Peroxidase Proliferator
 Activated receptor –Y) nuclear receptor of adipocytes. improving insulin sensitivity.
 decreased production of TNF alpha, leptin, and FFA levels in adipose tissue,
 reducing white adipose tissue mass

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 In Muscle:
increases GLUT-4 and increases the activity of glycogen
synthase.
 In Liver:Reduce hepatic glucose Production, by

suppressing neoglucognesis. (phosphoenolpyruvate

carboxykinase).
 Reduces TG level,NEFA increase.

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 INSULIN SECRETAGOGUES

 Loss of sensitivity of insulin secretion to a rise in blood glucose concentration,

 Impaired processing of pro-insulin.
 An ideal insulin secretagogue would restore beta cell sensitivity to glucose
 Insulin secretagogues can be divided into
• Initiators of Insulin secretion eg. Glimepiride
• Potentiator of insulin secretion eg. GIP and GLP –1 (Gastric Inhibitory
polypeptide,Glucagon Like Peptide).

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 Contd..,
 GLIMEPIRIDE:
 The mechanism of insulin secretion,

• the closure of ATP dependent potassium channel and opening up

of voltage dependent calcium channel and increase of intracellular

calcuim concentration leading to exocytosis of insulin.
 Insulin-independent blood glucose decreasing

activity of Glimepiride: (Extra-pancreatication):

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Potentiator of insulin
secretion

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Contd..,

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Elucidation of the genome for
diabetics (Medicineworld.org )
 New genes conferring a predisposition to
DT2 have been identified.
 They include the zinc transporter of
pancreatic insulin-secreting cells (ZnT8),
which is a potential target for therapy.
 The recent sequencing of the human genome
and the establishment of a complete map of
DNA variations in the human species have
finally made it possible to explore genetic
predisposition to DT2 in its entirety.
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How is diabetes managed?

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Contd..,

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Diabetes Education
(Diabetes atlas “IDF”
Goal of DE
 understand the nature of their illness and its treatment;
 identify emerging health problems in early, reversible
stages;
 adhere to self-care practices; and
 make needed changes in their health habits.

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