INSULIN AND ORAL HYPOGLYCEMICSDR. JOHN O’BRYANEmail: [email protected] COMRBDiabetes Mellitus“Diabetes” - to syphonfirst used @250 AD by Greek physician Aretaeusreflected clinical symptoms of increased fluid excretion and wasting“Diabetes mellitus” - mellitus, Latin for honeyCoined 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 actionDiabetes MellitusType 1- selective B cell destructionsevere or absolute insulin deficiencyimmune or idiopathic subtypesType 2- resistance to insulin action combined with a relative deficiency in insulin secretioninsulin produced in B cells but not sufficient to overcome resistanceType 3- other types of causes, ie, pancreatic disease, drug therapy, etcType 4- gestational diabetesfirst occurrence during pregnancyDiabetes & Dentistry-why be concerned?Incidence of Diabetes on the rise in US6% of population (16 million) diabetic1/3 are unaware of their diseaseprevalence is predicted to double by 2010 -32 million!!!Type II diabetes is increasingly common with rise in obesitydiabetics more common as dental patientsmany are unaware of their disease and its complicationsSo what do you, as a future dentist, need to be concerned with?Diabetic Complications1. General complications• neuropathy• vascular disease• increased susceptibility to infection• decreased wound healing• disturbed control of diabetes resulting from Ustress, infection, or surgical procedures2. Specific oral complications• xerostomia (dry mouth)• infection• poor wound healing• incidence and severity of dental caries, candidias, gingivitis, progressive periodontaldisease, and apical abscesses3. Patients may become hypoglycemic• Mild hypoglycemiaHunger, weakness, tachycardia, pallor, sweating• ModerateIncoherence, uncooperative, billigerence, lack of judgement, disorientation• SevereUnconsciousness, comaBe aware of these potentialcomplications patients and preparedto address emergent problems!Insulin productionInsulin secreted from pancreatic Beta cellsGlucose enters through GLUT4Converted to G6PU ATP productionU ATP inhibits K+ channel-depol.Ca+2 channel opens, [Ca+2]UStim. insulin secretion (exocytosis)Take from:Pharmacology, Brennerand Stevens, 2nd ed.Take from: Pharmacology, Brenner and Stevens, 2nd ed.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 indiabetics• Affinity decreased by glucocorticoids• Receptor binding activates intrinsic tyrosine kinase activity resulting in recruitment ofvarious 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 glucoseutilization-decreased formationof glucose fromglycogenFor Type I Diabetes, insulinreplacement is the only therapy!THERAPEUTIC GOAL:faithfully mimic normal insulinlevels throughout dayGlucose levels:-Fasting: <140 mg/dL-2-hr postprandial:<175 mg/dLHbA1c concentration <8%Take from: Pharmacology, Brenner and Stevens, 2nd ed.Types of InsulinA. Rapid-acting with fast onset of action, short durationB. Short-acting with rapid onset of actionC. Intermediate-actingD. Long-acting, slow onsetA. Rapid-acting insulinRapid onset and early peak action more closely mimic endogenous prandial insulin secretinHave low variability of absorptionPreferred for use in subcutaneous infusion devices1. Injectable insulin, modified variants of insulinInsulin lispro (HUMALOG, Lilly)-monomeric, fast absorbing-Lys and Pro at C-tail of B chain are reversed-can be injected just prior to mealsInsulin aspart (NOVOLOG, Novo Nordisk)-monomeric-substitution of B28 Pro with Asp-inhibits self aggregation-absorption/activity similar to lispro-more reproducibly than insulinInsulin glulisine (APIDRA, Aventis)-substitution of B3 Lys with Asn and B29 Lys withGlu-activity/absorption similar to other insulins2. 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 InsulinIdentical to endogenous insulinHas Zinc ion added for stabilityInsulin aggregates into hexamers which slows absorptionRate of absorption varies by site of injectionHighest variability in absorptionCan be administered intravenously since dilution results in rapid solubilization of insulinC. Intermediate-acting1. NPH (neutral protamine Hegadorn) insulincomplexed with protamine (HUMULIN N and NOVOLIN N)protein isolated from rainbow troutdelays absorption of insulin by making it unavailable1 mol protamine binds 6 mol insulinproteolytic enzymes digest protamine to release insulinonset 2-5 hrs4-12 hr durationusually mixed with faster-acting insulins2. Insulin zincD. Long-acting with slow onset of action1. Insulin glargine (LANTUS, Novo Nordisk)-2 Arg attached to B chain C-term and A21 Asn replaced with Gly-less soluble atphysiologic 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 others2. 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 duration3. Ultralente, long acting-crystalline suspension with zinc-lower pH-insulin must re-dissolve at site of injection- delays actionINSULIN MIXTURES-provide tighter glycemic controlcombine rapid- and intermediate-acting insulinsSome combinations can be premixed-insulin lispro, aspart, and glulisine mixed w/ NPH insulin-done acutely, premixed preps unstableStable pre-mixed combinations-use isophane complexes of lispro or aspart insulins andnon-complexed lispro/aspart-NPL, neutral protamine lispro + lispro insulin-NPA,