Recent Advances in Therapy of Diabetes Mellitus & Future Prospects

Recent advances in Diabetes Mellitus

Dr Siddhartha DuttaMAMC, New Delhi

ANTIMICROBIAL RESISTANCE & EMERGENCE OF NEWER ANTIMICROBIALS112-Jan-17

Contents IntroductionClassification Current therapy of DMLimitations of current therapyNewer Drugs and their status in DM therapyNewer potential targets Future ProspectsSummary

Classification, Clinical features, Diagnosis and Therapeutic goals of DM

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250 BC- Apollonius of Memphis coined the name "diabetes meaning siphon- to pass through

Thomas Willisin 1675 added "mellitus" to the word "diabetes

1869- Paul Langerhans, a German medical student, discovered islet cells in the pancreas

1910- Sharpey-Shafer of Edinburgh suggested a single chemical was missing from the pancreas. He proposed calling this chemical "insulin.

1922, Leonard Thompson became the first human to be successfully treated for diabetes using insulin

Too much emptying of the urineThomas Williswho in 1675 added "mellitus" to the word "diabetes" as a designation for the disease, when he noticed the urine of a diabetic had a sweet taste (glycosuria)Paul Langerhans, noted that the pancreas contains two distinct groups of cellsthe acinar cells, which secrete digestive enzymes, and cells that are clustered in islands, or islets, which he suggested served a second function.

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1921- Frederick G. Banting and Charles H. Best successfully purified insulin from a dog's pancreas

1923- 1st Nobel prize for insulin

Banting announced that he would share his prize with Best; Macleod did the same with Collip Frederick Sanger established the amino acid sequence Nobel Prize in 1958. Dorothy Hodgkin elucidated insulin's three-dimensional structure. Insulin was the hormone for which Yalow and Berson first developed the radioimmunoassay, which was recognized with the Nobel Prize in 19774

World Diabetes Day14th November of every year: to mark the birthday of Frederick Banting

Burden of the DiseaseAround 7% of Indian AdultsMost of the worlds Diabetics dwell in IndiaPREVALENCE OF DIABETES-2010CountryPrevalenceIndia7.1%China4.5%USA12.3%

Source: International Diabetes Federation

India-7.1%China-4.5%USA-12.3 %

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Etiological ClassificationType 1 DM: -cell destructionImmune-mediatedIdiopathicType 2 DMOther specific types of diabetes:Genetic defects of cell function: MODYGenetic defects in insulin actionDiseases of the exocrine pancreasEndocrinopathiesDrug- or chemical-inducedInfectionsGestational diabetes mellitus (GDM)

3.Other specific Types of DM:a. Genetic defects of beta cell function : MODYb. Genetic defects in insulin action: 1. Type A insulin resistance2. Leprechaunism3. Rabson-Mendenhall syndrome4. Lipodystrophy syndromesc. Diseases of the exocrine pancreaspancreatitis, pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis, fibrocalculous pancreatopathy, mutations in carboxyl ester lipased. Endocrinopathies-acromegaly, Cushing's syndrome, glucagonoma, pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteronomae. Drug or Chemical induced-Vacor, pentamidine, nicotinic acid, glucocorticoids, thyroid hormone, diazoxide, -adrenergic agonists, thiazides, phenytoin, -interferon, protease inhibitors, clozapineF. Infectionscongenital rubella, cytomegalovirus, coxsackie

the terms insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM) are obsolete. Since many individuals with type 2 DM eventually require insulin treatment for control of glycemia, the use of the term NIDDM generated considerable confusion. A second difference is that age is not a criterion in the classification system. Although type 1 DM most commonly develops before the age of 30, an autoimmune beta cell destructive process can develop at any age. It is estimated that between 5 and 10% of individuals who develop DM after age 30 have type 1 DM. Likewise, type 2 DM more typically develops with increasing age but is now being diagnosed more frequently in children and young adults, particularly in obese adolescents.7

IDDM and NIDDM Type 1 and type 2

Age is not a criterion in the classification system

5 and 10% of individuals who develop DM after age 30 have type 1 DM

Type 2 DM more typically develops with increasing age but is now being diagnosed more frequently in children and young adults, particularly in obese adolescents.

2many individuals with type 2 DM eventually require insulin treatment for control of glycemiaAlthough type 1 DM most commonly develops before the age of 30, an autoimmune beta cell destructive process can develop at any age. It is estimated that between 5 and 10% of individuals who develop DM after age 30 have type 1 DM. Likewise, type 2 DM more typically develops with increasing age but is now being diagnosed more frequently in children and young adults, particularly in obese adolescents.

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Type 3 diabetes ??

Type 3 Diabetes Insulin resistance in the brain associated with Alzheimers DiseaseImpaired glucose metabolism in the brain plays a role in the development of Alzheimers by depriving cells of energyEvidence Tau gene expression and phosphorylation are regulated through insulin and insulin-like growth factor (IGF) signaling cascadesAmyloid beta in pancreas which is similar to the protein deposits found in the brain tissue of Alzheimer's

change can occur in the brain in non-diabetics and without any presence of hyperglycemiaPeople that have insulin resistance, in particular those with type 2 diabetes have an increased risk of suffering fromAlzheimer'sdisease estimated to be between 50% and 65% higher.Tau protein is a highly solublemicrotubule-associated proteintau's main functions is to modulate the stability of axonal microtubules.Hyperphosphorylationof the tau protein (tau inclusions, pTau) can result in theself-assemblyoftanglesof paired helical filaments and straight filaments, which are involved in thepathogenesisofAlzheimer's diseaseketogenic diets (which provide the brain with fat instead of glucose as fuel) may be helpful as a therapy.10

Type 4 diabetesNot associated with insulin deficiency or obesity

Has been discovered in lean mice

Abnormally high levels of immune cells called T regulatory cells (Tregs) inside their fat tissue Age-related insulin resistance that occurs in lean, elderly people

lean mice has a different cellular cause than Type 2 diabetes, which results from weight gain. The mice with type 4 diabetes had abnormally high levels of immune cells called T regulatory cells (Tregs) inside their fat tissue. Mice with type 2 diabetes, on the other hand, had abnormally low levels of Tregs within the tissue, despite having more fat tissueTherapeutic intervention that blocks Treg cells from accumulating in the fat reverses age-associated type 4 diabetes. 11

Risk Factors & Clinical Features

ComplicationsAcute:Diabetic KetoacidosisHyperosmolar Hyperglycemic State

Chronic:

Diagnostic CriteriaSymptoms of hyperglycemia and a Random Plasma Glucose >200 mg/dl

FPG >126 mg/dl200 mg/dl during an OGTT