INSULIN AND ORAL HYPOGLYCEMICS

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1 INSULIN AND ORAL HYPOGLYCEMICS DR. JOHN O BRYAN obryanj@uic.edu 4091 COMRB Diabetes Mellitus Diabetes - to syphon first 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 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?

2 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)

3 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, pm Postprandial, 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, Brenner and Stevens, 2nd ed. Take from: Pharmacology, Brenner and Stevens, 2nd ed.

4 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 HbA 1c concentration <8% Take from: Pharmacology, Brenner and Stevens, 2nd ed.

5 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)

6 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 action

7 INSULIN MIXTURES-provide tighter glycemic control combine rapid- and intermediate-acting insulins Some combinations can be premixed -insulin lispro, aspart, and glulisine mixed w/ NPH insulin -done acutely, premixed preps unstable Stable pre-mixed combinations-use isophane complexes of lispro or aspart insulins and non-complexed lispro/aspart -NPL, neutral protamine lispro + lispro insulin -NPA, neutral protamine aspart + aspart insulin Insulin glargine and determir must be separately injected Mass production of insulin in US utilizes recombinant human insulin expressed in yeast or bacteria-previously purified from pig and cow-allergic reactions Insulin replacement is the only therapy for Type I diabetes!

8 ORAL ANTIDIABETIC DRUGS Used to treat TypeII, no role in TypeI therapy GOAL: maintain normal fasting and postprandial glucose levels Two classes of drugs: 1. Hypoglycemic 2. Antihyperglycemic 1. Hypoglycemic drugs Primarily increase insulin secretion (insulin secretaguoges) Main side effect-hypoglycemia Include sulfonylureas* and meglitinides 2. Antihyperglycemic drugs Prevent or reduce hyperglycemia Do not induce hypoglycemia Includes α-glucosidase inhibitors, thiazolidinediones, and biguanides* *initial treatment choice Sulfonylureas (hypoglycemic) 1 o mechanism of action-stimulate insulin secretion bind co-receptor of B cell K + channel result in depolarization of cell, [Ca +2 ] stim. insulin secretion 2 o serum glucagon levels and closure of extrapancreatic K + channels Tolbutamide, chlorpropamide, and acetohexamide 1st generation (lower potency, higher side effects) Tolazimide, glyburide, glipizide and glimiperide (2nd generation) fewer side effects & drug interaction -use w/ caution in cardiovascular disease and elderly

9 Meglitinides (hypoglycemic) Similar mechanism of action as sulfonylureas-blocks K + channel Relatively new-first approved in 1998 Fast acting, taken just prior to meals hypoglycemia a risk if meals delayed Monotherapy or combined No sulfur so can be used in patients with allergy to sulfur drugs Nateglinide amplifies insulin secretion during Uglucose but less effective at [normoglucose]-less prone to hypoglycemia Biguanides (antihyperglycemic) Functioning Beta cells are not required for glucose lowering effect Mechanism of action unclear; proposed to: glycolysis and glucose removal from blood hepatic and renal gluconeogenesis glucose absorption in GI tract reduce plasma glucagon levels Advantages no reported hypoglycemic effects Useful in combination w. sulfonylureas and thiazolidinediones Efficacious in preventing TypeII diabetes in middle-age, obese patients with impaired glucose tolerance and fasting hyperglycemia-no prevention in older patients Toxicities Mainly GI (nausea, vomiting, diarrhea, discomfort, anorexia) Contraindicated in alcoholics, renal&hepatic disease Increased risk of lactic acidosis

10 Thiazolidinediones (antihyperglycemic) Decrease insulin resistance Major site of action-adipose tissue Mechanism of action : ligand of (PPAR-γ) nuclear receptor family Stimulates expression of genes involved in lipid metabolism, insulin signaling, adipocyte and other tissue differentiation have differing clinical effects goal is to design selective modulators, as with SERMs PPAR-α as well as PPAR-γ activity Overlap of mechanism with fibric acid drugs (hyperlipidemia) that activate PPAR-α Increase sensitivity of peripheral tissues to insulin by 60% Increase # GLUT4 transporters Suppress hepatic glucose production Tend to lower triglyceride levels, increase HDL Adjunct to diet and exercise Slow acting, require 4-6 weeks for max. effectiveness Edema and plasma volume expansion-fluid weight gain contraindicated for persons with heart failure 1. Pioglitazone Monotherapy or combined with metformin, sulfo, and insulin Metabolized by CYP2C8 & CYP3A4-alter bioavailability of other drugs such as oral contraceptives 2. Rosiglitazone Tends to lower triglyceride levels (less so than pioglitazone) Monotherapy or combined with biguanides and sulfo Metabolized by CYP2C8 & CYP2C9-alter bioavailability of other drugs such as oral contraceptives May cause weight gain *troglitazone withdrawn due to hepatic toxicity

11 a-glucosidase inhibitors (antihyperglycemics) Competitive inhibitors of α-glucosidases (sucrase, maltase, glycoamylase, dextranase) block uptake of starch and disaccharides in upper GI Side effect: flatulence, diarrhea, abdominal pain tends to diminish with time Monotherapy or combined with biguanide or sulfonylurea with later combination, hypoglycemia may result-treat with glucose not sucrose (may be blocked!) May be effective inhibitors of TypeII diabetes- STOP-NIDDM trial demonstrated Tin new cases HYPOGLYCEMIC DRUGS Best therapy is a combination of diet, exercise, and oral hypoglycemic treatments for TypeII diabetes! Figure 35-2 Therapeutic effects of diet, exercise, and oral drugs used in the treatment of patients with type II diabetes mellitus. If these treatment measures are not adequate, insulin can be used to control glycemia.

12 Glucagon 29 aa hormone synthesized as proprotein in pancreas Released from A cells Stimulates hepatic glucose output to raise blood glucose Stimulates a Gs coupled receptor in liver raising camp levels Clinical use-treat severe hypoglycemia in Type I diabetics Also stimulates insulin release from B cells Enteroglucagon - incretins glucagon-like peptides secreted in intestine derived from proglucagon glicentin (69 aa) GLP-2 (33 aa) GLP-1 (37 aa) GLP-1(aa7-37) stimulates insulin secretion New antidiabetic drug-exantide (FDA approved 2005) incretin mimetic 39 aa peptide derived from lizard venom GLP-1 like increases insulin secretion acts through GLP-1 receptor may also increase B cell mass Drucker, D. J. Endocrinology 2001;142:

13 IMPORTANT POINTS TO REMEMBER! Type I DM REQUIRES insulin, only available therapy Type II DM managed with diet, exercise, and oral anti-diabetics Insulin increases glucose uptake in muscle and fat, decrease hepatic glucose output Insulin and modified insulins- different onset and duration Type I - intermediate insulin + fast acting at meals or insulin pump Type I Therapies 1. Rapid acting, short duration Trade Insulin lispro Insulin glulisine Insulin aspart Inhaled insulin Lys and Pro at C-term of B chain reversed Lys B3 to Asn; Lys B29-Glu Pro B28 Asp Crystalline, aerosol Name HUMALOG NOVOLOG EXUBERA 2. Short acting, rapid onset Regular insulin+zn +2 Regular human insulin Regular Humulin Velosulin 3. Intermediate NPH insulin Protamine complex w. insulin NPH Humulin Lente insulin Insulin + large amounts of Zn +2 LENTE HUMULIN 4. Long acting Insulin glargine Insulin detemir 2 Arg attached to B chain C-term; Asn A21- Gly ΔThr B30 & replaced with Myr acid LANTUS LEVEMIR

14 IMPORTANT POINTS TO REMEMBER (cont)! Oral antidiabetics 1. hypoglycemic-sufonylureas and meglitinides 2. antihyperglycemic-αglucosidase inhib., biguanide, thiazolidinediones Sulfonylureas (glipizide, glyburide, and glimepimide) meglitinides (repaglinide and nateglinide), and enteroglucagons- insulin secretion, side effect-hypoglycemia Acarbose & miglitol inhibit α-glucosidases, slow digestion and absorption of glucose Metformin (biguanide) and thiazolidinediones (pioglitasone and rosiglitazone) decrease hepatic glucose output & increase insulin sensitivity Metformin and sulfonylureas are 1st line drugs, alone or in combination with each other, α-glucosidase inhibitors, or thiazolidinediones Type II Therapies 1. Hypoglycemic drugs (secretaguoges) A. Sulfonylureas Tolbutamide Tolazamide Chlorpropamide Glyburide Glipizide Glimepiride B. Meglitinides Repaglinide Nataglinide Inhibit pancreatic K+ channel to stimulate insulin secretion Inhibit pancreatic K+ channel to stimulate pancreatic secretion Orinase Tolinase Diabinese Diaβeta Glucotrol Amaryl Prandin Starlix C. Enteroglucagon- incretins Stimulates Insulin secretion Exantide 2. Antihyperglycemics A. Biguanides metformin B. Thiazolidinediones Pioglitozone Roziglitazone C. α-glucosidase inhibitors Acarbose Miglitol Mechanism: unclear Increase glycolysis Decrease hepatic&renal gluconeogenesis Decrease glucose absorption Ligand of PPARγ to stimulate transcription Blocks enzymes which process complex surgar digestion-blocks uptake of starch Actos Avandia Precose Glyset