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Pharmacotherapy of Type 2 Diabetes Mellitus

Dr. Shamshi Azmi

Junior Resident

Dept. of Pharmacology

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Diabetes mellitus: a group of common metabolic

disorders that share the phenotype of hyperglycemia.

Pathophysiology of type 2 diabetes mellitus. Harrison's Principles Of Internal Medicine. 19th ed.

Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, et al., 2016. Print. page 2404

INTRODUCTION

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• According to International Diabetes Federation 2015 , 1

in 11 adults (415 million) suffer with diabetes

worldwide, projecting that in 2040 this number will

increase to 642 million(1 in 10 adults).

• Studies have shown that India has a potential

epidemic of diabetes and by the year 2040, it will have

maximum increase in incidence of Diabetes mellitus.

"IDF Diabetes Atlas - 2015 Atlas". Diabetesatlas.org. N.p., 2016. Web. 26 Sept. 2016.

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The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert

Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20: 1183–1197, 1997

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GLUCOSE HOMEOSTASIS

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Phases Of InsuIin release

In non diabetic individuals-

50% of the total daily insulin -during basal period

Remainder -postprandial.

“First phase”: promotes peripheral utilization of the prandial

nutrient load, suppresses hepatic glucose production, and limits

postprandial glucose elevation. Begins within 2 min of nutrient

ingestion and continues for 10-15 minutes.

Second phase: follows and is sustained until normoglycemia is

restored.

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PATHOGENESIS OF TYPE 2 DM

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The two metabolic defects that characterize type 2 DM are

(1) Insulin resistance

(2) β-cell dysfunction that is manifested as inadequate insulin

secretion in the face of insulin resistance and hyperglycemia

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Overall goal

Insulin secretagogues

Sulfonylureas

Meglitinide analogues

GLP-1 receptor agonist

DPP-4 inhibitors

Overcome insulin resistance

• Biguanides

• Thiazolidinediones

Misc.

• α- Glucosidase

inhibitors

• Amylin analogue

• SGLT-2 inhibitors

• Dopamine D2

receptor agonist

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Biguanides (AMPK activator)

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β CELL ATP SENSITIVE K+ CHANNEL

Octamer composed of four K+ channel subunits and four sulfonylurea subunits.

Insulin secretagogues

Thiazolidinediones

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Alpha-Glucosidase Inhibitors

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Major transporter of glucose in the kidney

• Nearly exclusively expressed in the kidney

• Responsible for ~90% of renal glucose reabsorption in the proximal tubule

Proximal Tubule

Na+K+

ATPase

Glucose

GLUT2

Glucose

SGLT2

BloodLumen

Na+

Amylin analogue

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ADA 2016 Guidelines

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Criteria for testing for diabetes in asymptomatic adults

Testing should be considered in all adults who are obese and have additional risk factors like:

physical inactivity

first-degree relative with diabetes

high-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander)

women who delivered a baby weighing 9 lb or were diagnosed with GDM

women with PCOD

Hypertension

HDL cholesterol level <35 mg/dL and/or a TG level >250 mg/dL

history of CVD

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thank you

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Target Class

Glycogen synthase kinase-3 Inhibitors

Glucokinase Activators

Protein tyrosine phosphatase-1b Inhibitors

Liver selective glucocorticoid receptors Antagonist

Glucagon receptor Antagonist

α-lipoic acid Agonist

AMP-activated protein kinase Agonist

Protein tyrosine phosphatase-1b inhibitors

Protein tyrosine phosphatase-1b causes: Dephosphorylation of Insulin receptorsDephosphorylation of Januskinase receptors associated with leptin

Negative regulation of insulin signalling and insulin resistanceInhibition of leptin mediated regulation of food intake

Hyperglycemia and obesity

Glycogen synthase kinase-3 (GSK-3) inhibitors

A serine/threonine kinase

Phosphorylates and inhibits

glycogen synthase and

decreases its affinity to

activation by glucose-6-

phosphate

Glycogen phosphorylase inhibitors Glycogen Glycogen phosphorylase Glucose-1-phosphate Phosphoglucomutase Glucose-6-phosphate---------> Glycolytic

pathwayGlycogen phosphorylase can serve a potential

therapeutic target to decrease hepatic glucose production

Phase II trials of GSK-1362885.

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SYNDROMES A few patients with homozygous mutations in the INSR gene have

been described, which causes Donohue syndrome or Leprechaunism. This autosomal recessive disorder results in a totally non-functional insulin receptor. These patients have low-set, often protuberant, ears, flared nostrils, thickened lips, and severe growth retardation.

In most cases, the outlook for these patients is extremely poor, with death occurring within the first year of life.

Other mutations of the same gene cause the less severe Rabson-Mendenhall syndrome, in which patients have characteristically abnormal teeth,hypertrophic gingiva (gums), and enlargement of the pineal gland.

Both diseases present with fluctuations of the glucose level: After a meal the glucose is initially very high, and then falls rapidly to abnormally low levels.

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Drugs causing hyperglycemia Glucocorticoids, Beta blockers (nonselective)Atypical antipsychoticsProtease inhibitorsDiureticsPhenytoinThyroid hormonesPentamidine