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Type 1 diabetes mellitus etiology
Genetic, Autoimmune destruction of pancreatic beta cells that produce insulin
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Type 2 diabetes mellitus etiology
Genetic, Metabolic abnormalities, environmental factors
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Type 1 diabetes onset
childhood or early childhood before puberty
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Type 2 diabetes onset
any age, usually after age 35
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Type 1 diabetes treatment (general)
insulin, +/- thiazolidine dione
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Type 2 diabetes treatment (general categories)
- 1. oral hypoglycemic agents
- 2.Antihyperglycemic agents
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Agents that promote Insulin Release
sulfonylurea, meglitinide, Incretin Analogues, DPP-IV inhibitors
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Types of Antihyperglycemic agents
metformin, thiazolidinediones, alpha glucosidase inhibitors
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Actions of Insulin
Carbohydrate metabolism, lipid metabolism, protein metabolism
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Adverse effects of insulin
hypoglycemia, visual disturbances, peripheral edema, local or systemic allergic reactions
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Sulfonylurea action
Promote insulin release by binding to and inhibiting K+ conductance by Kir6.2
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Adverse effects of sulfonylureas
hypoglycemia, gastrointestinal disterbances, hematological disturbances, ethanol intolerance, Contraindicated in patients with hepatic renal insufficiency
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Meglitinide actions
Inhibit K+ conductance by Kir 6.2 ----> result in membrane depolarization and insulin release
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Incretin Analog actions and route of administration
- Increase glucose uptake results in closure of the Kir6.2
- (mostly used as adjunct therapy)
- SC injection
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Dipeptidyl Peptidase - IV inhibitor actions
Decreases the inactivation of endogenous incretin hormones ----> Results in a glucose - dependent increase of insulin release and decrease in glucagon levels (used in adjunct therapy)
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Pharmacokinetic issues of Agents that promote insulin release
- Mostly oral administration
- Highly protein bound
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General function of anti hyperglycemic Agents
Lower elevated levels of blood glucose with relatively little potential to produce hypoglycemia. They do not promote insulin release
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Types of Antihyperglycemic Agents
Biguanides, Thiazolidinedione, alpha-Glucosidase inhibitor, Modified amyline peptide
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Biguanides (metformin) function
- decreases the hepatic glucose output
- Inhibits absorption of glucose from the gut
- Increases glucose uptake by muscle and fat cells
- Its mechanism of action appear to involve activation of cAMP dependent protein kinase
- Activation of this kinase in skeletal muscle and adipocytes leads to increase glucose transport by promoting translocation of GLUT4 to the cell surface
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Adverse Effect of metformin
Lactic acidosis and gastrointestinal problems
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Thiazolidinediones action
increases insulin sensitivity by binding ligand activated transcription factor PPAR - y which then activates PPAR - y and increases the expression of mRNAs encoding enzymes and proteins required for optimal insulin sensitivity
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Thiazolidinediones adverse effects
weight gain, edema, possible hepatic toxicity, cardiovascular side effects
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Alpha glucosidase inhibitors
Inhibit alpha - glucosidases, enzymes in the GI tract involved in degradation of complex carbohydrates which stall the rise in blood glucose concentrations after a meal (does not enter the blood stream)
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Adverse effects of alpha glucosidase inhibitors
- abdominal pain
- diarrhea
- flatulence
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Amylin Analog action and route of administration
- acts like insulin to inhibit glucagon secretion
- It also delays gastric emptying
- It also has appetite suppressive properties
- SC administration
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PK issues for anti hyperglycemic agents
- Mostly oral
- TZD are highly protein bound
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Dapagliflozin action
inhibits sodium glucose cotransporter 2 and block resorption of glucose in the kidney, leading to an increase in urinary glucose excretion and lowering of both plasma glucose levels and body weight
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