Glucose Regulation in the Body: New Understandings for Management

Transcription

1 Glucose Regulation in the Body: New Understandings for Management Curtis Triplitt, PharmD, CDE Texas Diabetes Institute Assistant Professor, Medicine/Diabetes University of Texas Health Science Center at San Antonio San Antonio, TX 1

2 Faculty Information Presenter Curtis Triplitt, PharmD, CDE Texas Diabetes Institute Assistant Professor, Medicine/Diabetes University of Texas Health Science Center at San Antonio San Antonio, TX Q&A Moderator Jeff D. Prescott, PharmD, RPh Vice President, Clinical and Scientific Affairs American Journal of Managed Care This activity is supported by an educational grant from Bristol-Myers Squibb and AstraZeneca LP. 2

3 Disclosures Curtis Triplitt, PharmD, CDE, has disclosed the following commercial financial relationships: Consultant/Advisory Board: Roche, Takeda Pharmaceuticals Speaker s Bureau: Amylin, Eli Lilly, Pfizer The planning staff from Pharmacy Times Office of Continuing Professional Education have no relevant financial relationships to disclose related to this program. The contents of this webinar may include information regarding the use of products that may be inconsistent with or outside the approved labeling for these products in the United States. Physicians should note that the use of these products outside current approved labeling is considered experimental and are advised to consult prescribing information for these products. 3

4 Educational Objectives After completion of this activity, participants should be better able to: Examine pathophysiology of diabetes and different mechanisms involved in maintaining glucose balance Explain new understandings in defects of glucose balance and their role in the pathophysiology of diabetes Review the role of different organ systems in maintaining glucose homeostasis 4

5 Pharmacy Accreditation Pharmacy Times Office of Continuing Professional Education is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. This enduring activity is approved for 1 contact hour (0.1 CEU) under the ACPE universal activity number H01-P. This activity is available for CE credit through October 19, Type of Activity: Knowledge 5

6 Glucose Regulation in the Body: New Understandings for Management Curtis Triplitt, PharmD, CDE Texas Diabetes Institute Assistant Professor, Medicine/Diabetes University of Texas Health Science Center at San Antonio San Antonio, TX 6

7 Glucose Regulation in Diabetes 1. How is glucose tightly regulated in normal healthy people? 2. What are the problems that cause glucose regulation to be abnormal in diabetes? 3. How can each of these 8 key abnormalities be addressed in diabetes? 7

8 The Lingo Gluconeogenesis: making glucose Glycogen: stored glucose Glycogenolysis: breaking down stored glucose FFA: free fatty acid Ra: rate of appearance of glucose Rd: rate of disappearance of glucose NGT: normal glucose tolerance IGT: impaired glucose tolerance T2DM: type 2 diabetes mellitus GLP-1: glucagon-like peptide-1 GIP: glucose-dependent insulinotropic polypeptide 8

9 14-6/2000 Pathogenesis of Type 2 Diabetes: Insulin Resistance and -Cell Dysfunction -Cell Dysfunction GLUCOSE INPUTS 1. Gut (meals) Glucose Insulin Resistance Insulin-Sensitive Pathogenesis BLOOD of Type 2 Diabetes: Tissues Insulin Resistance and -Cell Dysfunction -Cell Dysfunction Insulin Resistance Pancreas Liver Muscle Fat 2. Liver (makes and stores glucose) 3. Muscle (storage) VESSEL Pathogenesis of Type 2 Diabetes: In GLUCOSE Resistance and -Cell Dysfunctio -Cell Dysfunction Insulin Resist Pancreas Liver Muscle Fat The rate of movement of glucose out of the circulation is called the glucose disposal rate (Rd) REASN14-6/2000 The rate of glucose appearance into the blood is called Ra which is mainly from the liver or a meal Pancreas Liver Muscle 9

10 Normal, Hyper-, and Hypoglycemic States Ra 100 mg/dl Ra = the rate of appearance of glucose into the blood Rd = the rate of disappearance of glucose from the blood Rd When Ra = Rd = Euglycemic Ra 200 mg/dl Rd Ra 200 mg/dl Ra > Rd; Ra or Rd HYPERGLYCEMIA Rd Ra 50 mg/dl Rd Ra 50 mg/dl Ra < Rd; Ra or Rd HYPOGLYCEMIA Rd 10

11 Glucose Regulation Is Tightly Controlled 11

12 DEFN75-3/99 Impaired Insulin Secretion ETIOLOGY OF T2DM Hyperglycemia HGP Lipolysis Decreased Glucose Uptake Decreased Insulin Secretion Ominous Octet Decreased Incretin Effect Lipolysis Islet α cell Glucagon Secretion Hepatic Glucose Production HYPERGLYCEMIA Neurotransmitter Dysfunction Glucose Reabsorption Decreased Glucose Uptake 12 Adapted from DeFronzo RA. Med Clin N Am. 2004;88(4):

13 DEFN75-3/99 Impaired Insulin Secretion ETIOLOGY OF T2DM Hyperglycemia HGP Lipolysis Decreased Glucose Uptake Decreased Insulin Secretion Ominous Octet Decreased Incretin Effect Lipolysis Islet α cell Glucagon Secretion Hepatic Glucose Production HYPERGLYCEMIA DRUG? Neurotransmitter Dysfunction Glucose Reabsorption Decreased Glucose Uptake 13 Adapted from DeFronzo RA. Med Clin N Am. 2004;88(4):

14 Overflow Hypothesis Adipocytes represent a storage depot for energy (ie, fat). When the capacity of adipocytes to store fat is exceed, there is an overflow of fat to: Muscle Liver Pancreas Fat cell insulin resistance HGP (gluconeogenesis) insulin secretion sick HGP indicates hepatic glucose production. 14

15 Lipotoxicity Insulin Secretion Gluconeogenesis Glucose Oxidation FFA FFA FFA Send discussion questions to FFA indicates free fatty acid. 15

16 Insulin Sensitivity (Clamp Log 10 M) (mg/min kg FFM ) Relationship Between Insulin Sensitivity and Intramyocellular Triglyceride Concentration in Pima Indians With NGT r = P < FFM indicates fat-free mass; NGT, normal glucose tolerance Skeletal Muscle Associated Triglyceride ( mol/g wet weight of tissue) Reprinted with permission from Pan DA, Lillioja S, Kriketos AD, et al. Diabetes. 1997;46(6):

17 Suppression of HGP (mg/m 2 min) Impact of Hepatic Fat Content on Ability to Decrease Hepatic Glucose Production 125 FPI (pm) 100 Baseline Baseline Lo Fat 32±4 Hi Fat 44±3 b a P <.05; b P < With Insulin Low Liver Fat (1.7%) FPI indicates fasting plasma insulin; HGP, hepatic glucose production. a With Insulin High Liver Fat (10.5%) LEAN MEN WITHOUT DIABETES Seppälä-Lindroos A, Vehkavaara S, Häkkinen AM, et al. J Clin Endocrinol Metab. 2002;87(7):

18 % Suppression of EGP by Insulin Liver Fat Content and Suppression of Glucose Production From Liver Insulin Dose (U/day) Liver fat (%) 0 T2DM Patients Treated With Bedtime Insulin + Metformin r = 0.72 P < r = 0.76 P < r = 0.73 P < Liver fat (%) Liver fat (%) Fat mass (kg) EGP indicates endogenous glucose production; T2DM, type 2 diabetes mellitus. 18 Adapted from Ryysy L, Häkkinen AM, Goto T, et al. Diabetes. 2000;49(5):

19 Sick, Dysfunctional Fat Cell ASP & Adipsin MIF FFA IL-6 Leptin PAI-1 ADIPOCYTE Adiponectin TNF Resistin Angiotensinogen ASP indicates acylation-stimulating protein; FFA, free fatty acid; IL-6, interleukin 6; MIF, macrophage migration inhibitory factor; PAI-1, plasminogen activator inhibitor-1; TNF, tumor necrosis factor-alpha. 19

20 DEFN75-3/99 Impaired Insulin Secretion ETIOLOGY OF T2DM Hyperglycemia HGP Lipolysis Decreased Glucose Uptake Decreased Insulin Secretion Islet α cell Ominous Octet Decreased Incretin Effect DRUG? Lipolysis Glucagon Secretion Hepatic Glucose Production HYPERGLYCEMIA Neurotransmitter Dysfunction Glucose Reabsorption Decreased Glucose Uptake 20 Adapted from DeFronzo RA. Med Clin N Am. 2004;88(4):

21 Liver and Kidney Major source of net endogenous glucose production (kidney maybe 10%-15% fasting) Accomplished by gluconeogenesis and glycogenolysis when glucose is low and glycogen synthesis when glucose is high Can oxidize glucose for energy and convert it to fat which can be incorporated into VLDL for transport In T2DM, there is increased gluconeogenesis Send discussion questions to T2DM indicates type 2 diabetes mellitus; VLDL, very low density lipoprotein. 21

22 Regulation of Hepatic Glucose Production DECREASE INCREASE Insulin Hyperglycemia Parasympathetic 0 FFA Cortisol Glucagon Epinephrine Growth Hormone Sympathetic FFA indicates free fatty acid. 22

23 Regulation of Hepatic Glucose Production DECREASE INCREASE Insulin Hyperglycemia Parasympathetic 0 FFA Cortisol Glucagon Epinephrine Growth Hormone Sympathetic FFA indicates free fatty acid. 23

24 Regulation of Hepatic Glucose Production Insulin Hyperglycemia Parasympathetic DECREASE 0 INCREASE FFA Cortisol Glucagon Epinephrine Growth Hormone Sympathetic FFA indicates free fatty acid. 24

25 Direct Versus Indirect Effect of Insulin on Hepatic Glucose Production Direct effect: 60%-70% Indirect effect: 30%-40% FFA (adipocyte) Glucagon (alpha cell) Gluconeogenic precursors Amino acids (muscle) Glycerol (adipocyte) FFA indicates free fatty acid. 25

26 Basal HGP (mg/kg min) Basal Hepatic Glucose Production in T2DM: Relationship With Fasting Plasma Glucose P <.001 Control T2DM r = 0.85, P < Basal HGP (mg/kg min) CONTROL T2DM FPG indicates fasting plasma glucose; HGP, hepatic glucose production; T2DM, type 2 diabetes mellitus FPG (mg/dl) 26 DeFronzo RA, Ferrannini E, Simonson DC. Metabolism. 1989;38(4):

27 Muscle Can convert glucose to glycogen (storage) Can convert glucose to pyruvate through glycolysis; pyruvate is further metabolized to lactate, transaminated to alanine, or channeled into the TCA cycle (energy) In the fasting state, can utilize FFA for fuel and mobilize amino acids by proteolysis for transport to the liver for gluconeogenesis Can break down glycogen (mobilization of stored glucose) FFA indicates free fatty acid; TCA, tricarboxylic acid. 27

28 Insulin Signaling System in Humans Insulin Receptor Plasma Membrane GLUT4 Glucose IRS-1 p85 p110 Akt PI-3-Kinase Protein Synthesis Lipid Synthesis Glycogen Synthesis + Artery GLUT4 indicates glucose transporter type 4; IRS-1, insulin receptor substrate-1; NOS, nitric oxide synthase; PI-3, phosphatidylinositol-3. Adapted from DeFronzo RA. Med Clin N Am. 2004;88(4): Cusi K, Maezono K, Osman A, et al. J Clin Invest. 2000;105(3): ; Miyazaki Y, He H, Mandarino LJ, DeFronzo RA. Diabetes. 2003;52(8):

29 Insulin Receptor Insulin Signaling System in Humans Plasma Membrane IRS-1 p85 p110 Akt GLUT4 PI-3-Kinase Shc + Artery Inflammation Atherosclerosis GLUT4 indicates glucose transporter type 4; IRS-1, insulin receptor substrate-1; MAP, mitogen-activated protein; NOS, nitric oxide synthase; PI- 3, phosphatidylinositol-3. Adapted from DeFronzo RA. Med Clin N Am. 2004;88(4): Cusi K, Maezono K, Osman A, et al. J Clin Invest. 2000;105(3): ; Miyazaki Y, He H, Mandarino LJ, DeFronzo RA. Diabetes. 2003;52(8):

30 DEFN75-3/99 Impaired Insulin Secretion ETIOLOGY OF T2DM Hyperglycemia HGP Lipolysis Decreased Glucose Uptake Decreased Insulin Secretion Ominous Octet Decreased Incretin Effect Lipolysis Islet α cell Glucagon Secretion DRUG? Hepatic Glucose Production HYPERGLYCEMIA Neurotransmitter Dysfunction DRUG? Glucose Reabsorption Decreased Glucose Uptake 30 Adapted from DeFronzo RA. Med Clin N Am. 2004;88(4):

31 Insulin Secretion AIR (µu/ml) Early Insulin Secretion Increases With Decreasing Insulin Action DIA IGT NGT NGT NGT NGT Progressors Insulin Sensitivity M-low (mg/kg EMBS per minute) Non-Progressors AIR indicates acute insulin secretory response; DIA, diabetes; EBMS, estimated metabolic body size; IGT, impaired glucose tolerance; NGT, normal glucose tolerance. Reprinted with permission from Weyer C, Bogardus C, Mott DM, Pratley RE. J Clin Invest. 1999;104(6):

32 FPG (mg/dl) ß-cell Volume (%) Beta Cell Volume Is Related to Fasting Plasma Glucose Levels P < P < NGT IFG T2DM P <.01 P < NGT IFG T2DM FPG indicates fasting plasma glucose; IFG, impaired fasting glucose; NGT, normal glucose tolerance; T2DM, type 2 diabetes mellitus. Adapted from Butler AE, Janson J, Bonner-Weir S, et al. Diabetes. 2003;52(1):

33 INSULIN/ GLUCOSE IR 40 Ability to Release Insulin in Response to a Glucose Load Lean CALCULATED VIA OGTT 10 0 Obese 2-Hour PG (mg/dl) NGT IGT T2DM IGT indicates impaired glucose tolerance; IR, insulin resistance; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; PG, plasma glucose; T2DM, type 2 diabetes mellitus. 33 Gastaldelli A, Ferrannini E, Miyazaki Y, et al. Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study. Diabetologia. 2004;47(1):31-39.

34 Median HBA1c (%) UKPDS: Effect of SU & Metformin Rx on HbA1c 9 Conventional Glibenclamide 8 7 Metformin 6 0 Time (years) HbA1c indicates glycosylated hemoglobin; Rx, prescription; SU, sulfonylurea; UKPDS, United Kingdom Prospective Diabetes Study. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131): ; UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):

35 Etiology of Beta Cell Failure in T2DM Incretin Effect Age Genetics (TCF7L2) Amyloid (IAPP) Deposition β Cell Failure Insulin Resistance Glucose Toxicity Lipotoxicity FFA FFA indicates free fatty acid; IAPP, islet amyloid polypeptide; TCF7L2, transcription factor 7-like 2; T2DM, type 2 diabetes mellitis. 35

36 Plasma Amylin, pmol/l Amylin Is Co-Secreted With Insulin and Deficient in Diabetes Plasma Insulin, pmol/l Plasma Amylin, pmol/l Meal Meal Meal Meal Amylin Insulin Healthy male adults (n = 6) Without diabetes (n = 12) Insulin-using T2DM (n = 27) T1DM (n = 190) 5 7 AM 12 Noon 5 PM Midnight Time, 24-h Time After Sustacal Meal, min Central satiety; decreases glucagon; slows gastric emptying T1DM indicates type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus. Reprinted with permission from Kruger DF, Gatcomb PM, Owen SK. Diabetes Educ. 1999;25(3):

37 DEFN75-3/99 Impaired Insulin Secretion ETIOLOGY OF T2DM Hyperglycemia HGP Lipolysis Decreased Glucose Uptake Ominous Octet Decreased Insulin Secretion Islet α cell DRUG? Decreased Incretin Effect Lipolysis Glucagon Secretion DRUG? Hepatic Glucose Production HYPERGLYCEMIA Neurotransmitter Dysfunction Glucose Reabsorption Decreased Glucose Uptake 37 Adapted from DeFronzo RA. Med Clin N Am. 2004;88(4):

38 The Incretin Effect Is Reduced in Patients With T2DM In diabetic patients vs. healthy subjects challenged with an oral 50 g glucose load and IV glucose: o Differences between responses to oral and IV glucose were attributed to factors other than glucose itself (incretin effect) o After oral glucose, immunoreactive insulin and connecting peptide responses were delayed in diabetic vs. healthy subjects o After IV glucose, insulin and connecting peptide responses were greater in diabetic patients vs. healthy subjects (as consequence of higher glycemic stimulus) Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. Diabetologia. 1986;29(1):46-52.

39 GLP-1 and GIP Responses in T2DM Postprandial GLP-1 levels are decreased in patients with IGT and T2DM, compared to controls with normal glucose tolerance o Most pronounced GLP-1 decreases seen in T2DM Glucose-dependent insulinotrophic polypeptide (GIP) levels are increased in T2DM, compared to controls with normal glucose tolerance Toft-Nielsen MB, Damholt MB, Madsbad S, et al. J Clin Endocrinol Metab. 2001;86(8): Jones IR, Owens DR, Luzio S, Williams S, Hayes TM. Diabetologia. 1989;32(9):

40 GLP-1 Modulates Numerous Functions in Humans GLP-1: Secreted upon the ingestion of food Exenatide: IV infusion Promotes satiety and reduces appetite α cells: Postprandial glucagon secretion β cells: Enhances glucose-dependent insulin secretion Liver: Glucagon reduces hepatic glucose output (glycogenolysis) Stomach: Helps regulate gastric emptying GLP-1 indicates glucagon-like peptide-1; IV, intravenous. Flint A, Raben A, Astrup A, Holst JJ. J Clin Invest. 1998;101(3): ; Larsson H, Holst JJ, Ahrén B. Acta Physiol Scand. 1997;160(4): ; Nauck MA, Wollschläger D, Werner J, et al. Diabetologia. 1996;39(12): ; Drucker DJ. Diabetes. 1998;47(2):

41 DEFN75-3/99 Impaired Insulin Secretion ETIOLOGY OF T2DM Hyperglycemia HGP Lipolysis Decreased Glucose Uptake Decreased Insulin Secretion Islet α cell Ominous Octet Decreased Incretin Effect DRUG? Lipolysis Glucagon Secretion Hepatic Glucose Production HYPERGLYCEMIA Neurotransmitter Dysfunction Glucose Reabsorption Decreased Glucose Uptake 41 Adapted from DeFronzo RA. Med Clin N Am. 2004;88(4):

42 Renal Handling of Glucose (180 L/day) (900 mg/l) = 162 g/day Glucose SGLT-2 90% S1 10% S3 S G L T 1 Send discussion questions to CEINFO@pharmacytimes.com SGLT indicates sodium glucose cotransporter. NO GLUCOSE 42

43 Fold Increase Normalized Glucose Transporter Levels CPM SGLT-2 Glucose Transporter mrna IN HUMAN RENAL PROXIMAL TUBULAR CELLS 5 SGLT-2 mrna a 6 SGLT-2 PROTEIN AMG UPTAKE a a CON T2DM 0 CON T2DM CON T2DM 0 a P <.05 - P <.01. AMG indicates methyl-α-d-[u14c]-glucopyranoside; CON, control; CPM, counts per minute; mrna, messenger ribonucleic acid; SGLT, sodium glucose cotransporter; T2DM, type 2 diabetes mellitus. 43 Adapted from Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J. Diabetes. 2005;54(12):

44 Multiple drugs are likely necessary in type 2 diabetes mellitus to address the underlying abnormalities Brain: amylinomimetics, GLP-1 agonists, dopamine agonists Fat: thiazolidinediones (TZDs) Summary Liver and muscle: metformin and TZDs, but HGP can be reduced by mass action through increased insulin (insulin, SU, etc) Glucagon: GLP-1 agonists, DPP-4 inhibitors, amylinomimetics Insulin: insulin, sulfonylureas, meglitinides, DPP-4 inhibitors, and GLP-1 agonists Incretins: GLP-1 agonists, DPP-4 inhibitors, alpha glucosidase inhibitors (?), bile acid sequestrants (?) Renal glucose absorption: SGLT-2 inhibitors (not currently on the market) DPP-4 indicates dipeptidyl peptidase 4; GLP-1, glucagon-like peptide-1; HGP, hepatic glucose production; SGLT, sodium glucose cotransporter; SU, sulfonylurea; TZD, thiazolidinedione. 44

45 Summary Glucose is tightly regulated in our bodies Regulation can be disrupted through many different pathways At least 8 different pathways or abnormalities have been identified in diabetes None of the pathways have been proved to fully correct all of the abnormalities associated with type 2 diabetes mellitus Affecting multiple pathways is likely advantageous 45

46 Glucose Regulation in the Body: New Understandings for Management THANK YOU! For any questions regarding this activity, contact: 46