INSULIN AND ORAL HYPOGLYCEMICS DR. JOHN O’BRYAN Email: [email protected] 4091 COMRB Diabetes Mellitus “Diabetes” - to syphon first used @250 AD by Greek physician Aretaeus reflected clinical symptoms of increased fluid excretion and wasting “Diabetes mellitus” - mellitus, Latin for honey Coined in 1674 by Thomas Willis, personal physician to King Charles II • Defect in glucose hemostasis • Elevated blood glucose levels • Absent or inadequate pancreatic insulin secretion • May or may not have concurrent impairment in insulin action Diabetes Mellitus Type 1- selective B cell destruction severe or absolute insulin deficiency immune or idiopathic subtypes Type 2- resistance to insulin action combined with a relative deficiency in insulin secretion insulin produced in B cells but not sufficient to overcome resistance Type 3- other types of causes, ie, pancreatic disease, drug therapy, etc Type 4- gestational diabetes first occurrence during pregnancy Diabetes & Dentistry-why be concerned? Incidence of Diabetes on the rise in US 6% of population (16 million) diabetic 1/3 are unaware of their disease prevalence is predicted to double by 2010 -32 million!!! Type II diabetes is increasingly common with rise in obesity diabetics more common as dental patients many are unaware of their disease and its complications So what do you, as a future dentist, need to be concerned with?Diabetic Complications 1. General complications • neuropathy • vascular disease • increased susceptibility to infection • decreased wound healing • disturbed control of diabetes resulting from Ustress, infection, or surgical procedures 2. Specific oral complications • xerostomia (dry mouth) • infection • poor wound healing • incidence and severity of dental caries, candidias, gingivitis, progressive periodontal disease, and apical abscesses 3. Patients may become hypoglycemic • Mild hypoglycemia Hunger, weakness, tachycardia, pallor, sweating • Moderate Incoherence, uncooperative, billigerence, lack of judgement, disorientation • Severe Unconsciousness, coma Be aware of these potential complications patients and prepared to address emergent problems! Insulin production Insulin secreted from pancreatic Beta cells Glucose enters through GLUT2 Converted to G6P ↑ ATP production ↑ ATP inhibits K+ channel-depol. Ca+2 channel opens, [Ca+2] ↑ Stim. insulin secretion (exocytosis)Insulin • Synthesized as proform • Proteolyzed in Golgi (A and B chains, S-S linked) • stored in vesicles (along with equimolar C-peptide) • Binds transmembrane tyrosine kinase receptor (pM affinity) • Basal, 30-90 pM • Postprandial, 360-540 pM • Affinity decreases with pH, ie acidosis will decrease efficacy of exogenous insulin in diabetics • Affinity decreased by glucocorticoids • Receptor binding activates intrinsic tyrosine kinase activity resulting in recruitment of various effectors-IRS proteins major target -recruitment of GLUTs, -endocytosis of insulin-IR complex, activation of Ras, PI3K, -increased glycogen, protein, fat -increased glucose uptake -increased glucose utilization -decreased formation of glucose from glycogen Take from:Pharmacology, Brennerand Stevens, 2nd ed. Take from: Pharmacology, Brenner and Stevens, 2nd ed.For Type I Diabetes, insulin replacement is the only therapy! THERAPEUTIC GOAL: faithfully mimic normal insulin levels throughout day Glucose levels: -Fasting: <140 mg/dL -2-hr postprandial: <175 mg/dL HbA1c concentration <8% Take from: Pharmacology, Brenner and Stevens, 2nd ed.Types of Insulin A. Rapid-acting with fast onset of action, short duration B. Short-acting with rapid onset of action C. Intermediate-acting D. Long-acting, slow onset A. Rapid-acting insulin Rapid onset and early peak action more closely mimic endogenous prandial insulin secretin Have low variability of absorption Preferred for use in subcutaneous infusion devices 1. Injectable insulin, modified variants of insulin Insulin lispro (HUMALOG, Lilly)-monomeric, fast absorbing -Lys and Pro at C-tail of B chain are reversed -can be injected just prior to meals Insulin aspart (NOVOLOG, Novo Nordisk)-monomeric -substitution of B28 Pro with Asp-inhibits self aggregation -absorption/activity similar to lispro -more reproducibly than insulin Insulin glulisine (APIDRA, Aventis)-substitution of B3 Lys with Asn and B29 Lys with Glu -activity/absorption similar to other insulins 2. Inhaled -recently approved by FDA -finely powdered and aerosolized -readily absorbed into bloodstream through alveolar walls -rapid onset and peak insulin levels (by 30 min) -peak effect (2-2.5 hrs) and duration (6-8 hours) -concern about lung safety (pulmonary fibrosis or hypertension, reduced lung volume, excess immune reaction to insulin)B. Short-acting Insulin Identical to endogenous insulin Has Zinc ion added for stability Insulin aggregates into hexamers which slows absorption Rate of absorption varies by site of injection Highest variability in absorption Can be administered intravenously since dilution results in rapid solubilization of insulin C. Intermediate-acting 1. NPH (neutral protamine Hegadorn) insulin complexed with protamine (HUMULIN N and NOVOLIN N) protein isolated from rainbow trout delays absorption of insulin by making it unavailable 1 mol protamine binds 6 mol insulin proteolytic enzymes digest protamine to release insulin onset 2-5 hrs 4-12 hr duration usually mixed with faster-acting insulins 2. Insulin zinc D. Long-acting with slow onset of action 1. Insulin glargine (LANTUS, Novo Nordisk) -2 Arg attached to B chain C-term and A21 Asn replaced with Gly-less soluble at physiologic pH, slowly dissolves -ultra-long-acting -provides background insulin replacement, steady-state -onset 1-1.5hrs, peak 4-6hrs, max. act. maintained 11-24hrs -acidic formulation (pH4.0), can’t be mixed with others 2. Insulin detemir (LEVEMIR, Aventis/Hoechst Marion Roussel) -Thr dropped from B30 and myristic acid added to terminal B29 Lys -increases aggregation and albumin binding -prolongs availability, 1-2 hrs onset,24 hr duration 3. Ultralente, long acting -crystalline suspension with zinc -lower pH -insulin must re-dissolve at site of injection- delays actionINSULIN MIXTURES-provide tighter glycemic control combine rapid- and