presented by: Samir Ahmad M.

Pharm (p’ceutics)

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What is Diabetes? (Goodman and Gilman’s)
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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..,
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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..,
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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”)
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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..,
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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)
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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)

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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)

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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
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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 betacell properties.
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Stem cells for the treatment of diabetes (Burns CJ et al)
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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..,

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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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The basic defects in Type 2 diabetes consist of Insulin deficiency Insulin resistance increased hepatic glucose production beta cell exhaustion finally beta cell failure.

NEWER ANTIDIABETIC DRUGS 2 DM (A. sundaram et al)

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Treatment strategies
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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..,
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Alpha glucosidase inhibitors, eg. Acarbose Insulin Sensitizer, eg. Troglitazone. Insulin secretoguogues, eg. Glimepiride and Repaglinide.

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ALPHA-GLUCOSIDASE INHIBITORS

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In human salivary amylase, pancreatic amylase and alphaglucosidase 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
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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..,

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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
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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 )
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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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Diabetes Education (Diabetes atlas “IDF”
Goal of DE
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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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