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How can ADRs develop from insulin administration?
- Too large a dose administered
- Mismatch between dose and food intake
- increased insulin-independent glucose use (exercise)
- addiditive effects with other physiologic hormones on insulin sensitivity (adrenal insufficiency)
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What are the body responses to low glucose?
- increase of counter regulatory hormones (NE, Epi, GH, glucagon)
- sweating, hunger, palpitations, paresthiesias, tremor, anxiety due to autonomic stimulation
- Neuroglycopenic symptoms- confusion, drowsiness, blurred vision, loss of consciousness (below 30mg/dL)
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What are the ADRs associated with insulin administration?
- Allergy and resistance: w/recombinant if aggregated or denatured
- Lipoatrophy: site of insulin injection
- Insulin edema: severe hyperglycemia/ketoacidosis
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Name the Four classes of Hypoglycemic Agents:
- Sulfonylureas
- Secretagogues
- Biguanides
- Insulin Sensitizers (Thiazolidinediones)
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Effects of Sulfonylureas:
- Stimulate release of insulin from B-islet cells
- promote reduction of blood glucose levels
- decreased liver clearance of insulin
- Acutely: increase insulin levels
- Chronically: levels return to pre-treatment levels with better response of target tissues to insulin
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MOA of Sulfonylureas:
- bind to the SUR1/Kir6.2 proteins on beta-islet cells
- Blocks Inward-Rectifier K ion channel (Kir6.x)
- depolorizing the cell allowing Ca++influx
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Name the (2) 1st Generation and (2) 2nd Generation Sulfonylureas and the major indication:
- 1st Gen: Tolbutamide and Chlorpropamide
- 2nd Gen: Glyburide and Glipizide
- NIDDM: non-insulin dependent diabetes mellitus
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Name the two Secretagogues classes with agents and the MOA:
- Meglitinide- repaglinide
- Phenylalanine derivative- nateglinide
- Block ATP-sensitive K channels, not at SUR
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Which class of hypoglycemic agent is Metform and it's MOA:
- Biguanide-Decreases hepatic glucose production and enhances insulin action in muscle and adipos tissue
- hepatic effect is mediated by activation of AMP-activated protein kinase (AMPK). Which does the following:
- Inhibits HMG-CoA reductase
- Inhibits AcCoA carboxylase
- Increased SIRT1 (silent information regulator two-1)
- Reduces plasma Triglycerideds by ~20%
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What is the side effect of metformin and why does it happen?
- Produces lactic acidosis
- decreases lactate uptake by hepatocytes due to decrease in gluconeogeneis
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What is the major class of insulin sensitizers? What do they bind to get the effect? Name the three drugs with the current status.
- Class: Thiazolidinedione PPAR agonist
- Peroxisone Proliferator-Activated Receptor-gama (PPARy) which are nuclear transcription factors
- Troglitazone- withdrawn due to severe liver toxicity
- Rosiglitazone- Restricted use by FDA
- Pioglitazone- Black Box Warning (Avandia)
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What agents activate PPARgama and what are some of the results?
- Increase transcription factor expression and translocation of GLUT transporter portein
- Decreased inflammation (Reduction COX2, IL1, TNF)
- Adipocyte differentiation- increased lipid storage which
- reduces FFA and allows muscle to respond normally to insulin
- induces expression of adiponectin by adipocytes
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SE and Toxicity issues associated with Insulin Sensitizers
- SE: weight gain, edema and plasma volume expansion
- Toxicity: liver toxicity
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What are the two alpha-Glucosidase Inhibitors and what is the MOA? Effects?
- Acarbose and Miglitol
- targets alpha-Glucosidase on the intestianl brush border to reduce intestinal absorption of starch, dextrin, and disaccharides
- Does not stimulate insulin secretion
- 3--50% reduction of HbA1c levels
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What are the two major incretins with the drugs?
- Glucagon-Like Peptide-1 (GLP-1): Exendin-4, Liraglutide
- Gastric Inhibitory Peptide (GIP):
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What are the effects of GLP-1? Where is it derived from? MOA?
- GLP1- stimulates insulin-released in type 2
- GLP1- natural peptide produced from intestinal L-cells that take proglucagon, cleaved Proconvertase 1/3 to produce a peptide that binds beta islet cell receptors to enhance insulin release, GLP1 is stimulated with food intake
- Degraded rapidly by Dipeptidyl Peptidase IV
- Increases expression of GLUT2 by pancreatic beta cell through cAMP-CREB/PKA/Rap/RAF/MEK/ERK
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What is the agent derived from the Gila Monster with relevant information?
- GLP1 agonist from saliva
- Reduces HbA1c levels by 1-1.3% in Type 2 diabeties
- Mono or Combo therapy
- t1/2: 2-3 hours
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Which agent only reguires 1x daily dosing? Why? Which class?
- Liraglutide
- has a C16 fatty acyl group allows binding to albumin or other plasma proteins
- GLP1 receptor agonist
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