Recent advance T2DM

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RECENT ADVANCES IN THE TREATMENT OF DIABETES MELLITUS:

RECENT ADVANCES IN THE TREATMENT OF DIABETES MELLITUS Dr.KUMARASINGAM.T Department of pharmacology

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Contents….

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IDF

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Insulin structure

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Insulin signaling pathway IRS-1 IRS-1PO-Y IRS-2 IRS-2PO-Y Serine phosphorylation of IRS proieins FFA, PKC,mTOR , stress, TNF PI3-kinase PDK1 PKB PIP2 (AKT) PIP3 FOXO-1 Decreased expression of gluconeogenic Enzymes PEPCK & G6Pase in liver GLUT-4 Glucose p 85,p110 Insulin resistance

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Other Causes & Aggravating Factors of Insulin Resistance PPAR γ co-activator-1 Mitochondrial dysfunction – lipid accumulation Adipokines – TNF, Leptin , Adiponectin & Resistin Combination of genetic and lifestyle factors Heredity Ethnic group Abdominal obesity Lack of exercise Pregnancy-increase in production of placental hormones Insulin resistance

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Newer anti diabetic agents

1. Incretin Effect:

1. Incretin Effect Pancreas Enhanced Insulin secretion Liver Food Suppressed post-prandial glucagon Decreased Glucose Output GLP-1 release Decreased appetite GLP-1 and GIP released in response to food Slowed gastric emptying

Incretin-mimetics - Exenatide:

Incretin-mimetics - Exenatide Synthetic mimetic and agonist of GLP-1 Resistant to DPP4 Obtained from Gila monter S.C twice daily – 30 mins before meals Approved in combination with oral agents HbA1c reduction of 0.5 – 2.0 % A/E Weight loss, nausea, vomiting, diarrhea & necrotising pancretitis .

2. DPP-4 Inhibitors - sitagliptin:

2. DPP-4 Inhibitors - sitagliptin Prevents degradation of endogenous GLP-1 ↑ GLP-1 level and its action was prolong. Longer half life. Oral monotherapy and in combination. A / E – UTI, Nasopharyngitis ( ↑ Substance P ) & Headache. D PP-4 also metabolize – Subtance P, GHRH & Neuropeptide-Y

3. Amylin mimetic - Pramlintide :

3. Amylin mimetic - Pramlintide From long standing T2DM or Insulinoma Co-secreted with insulin Super family – CGRP It modulate the insulin release by Negative feedback mechanism Injectable antihyperglycemic agent Preprandial used in T1DM & T2DM Actions ↓ Glucagon secretion Slow gastric emptying Centrally ↓ appetite A / E – hypoglycemia, GIT symptoms.

4. Sodium Glucose Cotransporter-2 inhibitors:

4. Sodium Glucose Cotransporter-2 inhibitors Orally effective ↓ The amount of glucose reabsorption from the PCT & ↑ excretion in urine Dapagliflozin , Sergliflozin & Remogliflozin . Merits… Weight loss No hypoglycemia Improve insulin resistance Diuretic effects. Demerits… Polyuria UTI Sodium loss

5. Bile acid sequestrants - colesevelam :

5. Bile acid sequestrants - colesevelam Is a cholesterol lowering agent. Exact mechanism is unknown. Interruption of enterohepatic circulation & ↓ farnesoid X receptor (FXR) activation. FXR – cholesterol, glucose & bile acid metabolism. S/E – GIT symptoms Given by oral route – 1875 mg twice daily. Should not used – hypertriglyceridemia & pancreatitis. 6 . Rimonabant - Endocannabinoid system

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Newer insulin

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Not mimicking the physiological insulin release. Onset of action too slow. Duration of action is too long. Leads to post prandial hyperglycemia & late hypoglycemia. These insulin tend to form hexamer in contact with Zinc. Problems with Conventional Insulins

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Better control of sugars Low risk of hypoglycemia Do not inject half an hour before meals Compliance is improved Snacks between meal may be reduced Advantage in term of weight gain Advantage of newer Insulins

Short-Acting Insulin Analogues 1. Insulin Lispro:

Short-Acting Insulin Analogues 1. Insulin Lispro 1 st recommended DNA analogue Inversion proline with lysine. Merits… Block the formation of insulin dimer & hexamer Improving glycemic control at meal time. PP rise of glucose was lower. HbA1C was lower. Hypoglycemia was less. No teratogenicity.

2. Insulin Aspart:

2. Insulin Aspart Created by recombinant DNA technology. Substitution of proline at 28 position with aspartic acid. Prevents the formation of hexamers leading to rapid absorption. Short duration of action. ↓ PPBS & glycosylated Hb level > H uman Insulin Mitogenecity & immunogenecity = Human Insulin

3. Insulin Glulisine:

3. Insulin Glulisine Substitution of Asparagine a t position B3 by Lysine & Lysine at position B29 by Glutamine. Causing Insulin receptor substrate-2 phosphorylation Antiapoptotic activity against cytokine & fatty acid induced cell destruction. It carry the risk of tumorogenecity .

Long-Acting Insulin Analogues 1. Insulin Glargine:

Long-Acting Insulin Analogues 1. Insulin Glargine Less soluble at physiological pH & more soluble at acidic pH Stabilizes the hexamer structure Not mixed with other insulin. Fasting glucose were lower & nocturnal hypoglycemia was less. More affinity to IGF 1 receptor – mitogenic potency.

2. Insulin Detemir:

2. Insulin Detemir Omission of threonine in the 30 position of the B chain and the addition of a C-14 fatty acid chain to the lysine in the 29 position of the B chain. Increasing the half-life and duration of action Increasing its binding to plasma albumin. Given as twice daily Reduction in body weight Fewer incidence of hypoglycemia Less potency for mitogenesis

Inhaled Insulin - Exubera:

Inhaled Insulin - Exubera FDA-2006 Faster onset action More systemic absorption due to large surface area. Bioavailability 10% Problems Loss of drugs Variation in absorption RTI, cough, sore throat & dry mouth.

Albulin:

Albulin Duttaroy – 2005 Single chain – yeast or mammalian cell. Structure – B & A chain linked by dodecapeptide and fused to NH terminal of native human serum albulin . Lower affinity to bind with IR Potent long acting insulin analog - DM

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Needle and Syringe Insulin Pens Insulin Jet Injectors External Insulin Pumps Implantable Pumps Insulin Patches Insulin Inhalers Insulin Spray & oral insulin Islet Cell Transplantation Insulin Nanopump Gene Therapy – SHIP2, PEDF Closed loop insulin delivery Iontophoresis & rectal delivery. Insulin delivery systems

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