1. Type 1 Diabetes Mellitus Gregory E. Peterson, DO, FACP The Diabetes Center Diagnostic & Critical Care Medicine, PC

2. Objectives for Iowa School Nurses l Type 1 Diabetes Mellitus l Ketonuria l Incretin therapy in diabetes management l Types of insulin: Analog insulin in basal and bolus therapy l Strategies to optimize blood glucose levels l Hypoglycemia and Hyperglycemia l Explore tools to management: insulin pens, insulin pump, blood glucose meters, blood glucose sensors

3. Type 1 Diabetes Mellitus Autoimmune destruction of the insulin- producing ß-cells in the islets of Langerhans In the new classification of diabetes, immune mediated type 1 diabetes is called type 1A Some rarer cases in which an autoimmune etiology cannot be determined (type 1B); said to be idiopathic.

4. Diabetes Mellitus in children The clinical diagnosis of diabetes in a previously healthy child requires a high index of suspicion. The earliest symptoms are related to hyperglycemia. Older children and adolescents typically present with polyuria (due to the glucose osmotic diuresis), polydipsia (due to the increased urinary losses), and fatigue. Other findings include weight loss, nocturia (with or without secondary enuresis), daytime enuresis, and vaginal or cutaneous moniliasis

5. Diabetes Mellitus in children l Children with weight loss, anorexia, vomiting, and abdominal pain, which at times can mimic appendicitis or gastroenteritis should be considered l DKA

6. Type 1 Diabetes Mellitus Type 1 diabetes occurs in genetically susceptible subjects. Triggered by one or more environmental agents, and usually progresses over many months or years, during most of which the subject is asymptomatic and euglycemic. A large percentage of the functioning ß-cells must be lost before hyperglycemia appears,

7. Type 1 Diabetes Mellitus Research tools, not for clinical practice: 1. Genetic Markers 2. Immunologic Markers

8. Genetic Markers: Type 1 Diabetes l 6 percent in offspring and 5 percent in siblings (versus 0.4 percent in subjects with no family history) l The risk in siblings is importantly influenced by the degree of genetic similarity, falling from 33 percent in identical twins HLA halotypes: (12.9%) 2 (4.5%) 1 (1.8%) 0

9. Immunologic Markers l islet-cell antibodies (ICA) l insulin autoantibodies (IAA) l antibodies to glutamic acid decarboxylase (GAD)

10. Immunologic Marker for Type 1 DM l 40% within five years versus 3% with single auto-antibodies). l Progression to multiple islet auto-antibodies was fastest in children who developed their first autoantibody by age two years. l Children with the earliest evidence of autoimmunity are at greatest risk for and progress more quickly to the development of type 1 diabetes. l Periodic testing for islet auto-antibodies appears to help assess the risk of diabetes in children of parents with type 1 diabetes.

11. Prevention Recommendations (Research) l Test individuals at risk for type 1 diabetes progression for GAD65 and IA-2 autoantibodies l If they are present and confirmed in a subsequent sample, tests for insulin and islet cell antibodies can be done. l The occurrence of multiple antibodies against islet autoantigens serves as a surrogate marker of disease in primary or secondary intervention strategies aimed at halting the disease process. l Genetic typing for susceptibility or protective HLA alleles can also be performed. This information can be used to ascertain if a high-risk subject is eligible to be entered into an ongoing prevention trial.

12. Ketonuria Always check for ketones in urine with blood glucose over 250mg/dL Presence reflects abnormal metabolism Key feature of DKA: Hyperventilation Life threatening event

13. Ketonuria 1. Children with diabetes will develop ketosis if they omit insulin injections. Untreated ketosis results in nausea, vomiting, abdominal pain, rapid deep breathing, dehydration, lethargy, and ultimately, ketoacidosis. 2. Ketones should be tested if the child has signs of a systemic illness, such as fever and, especially, vomiting, even if the blood glucose is normal. 3. The presence of moderate or large ketones will require extra dosing of insulin to reverse ketosis. 4. Contact parents/medical team. 5. If the child is not vomiting, liberal fluid intake will help prevent dehydration and increase urinary excretion of ketones.

14. RELATIVE RISK HbA 1c Skyler, Endo Met Cl N Am 1996 Relative Risk of Progression of Diabetic Complications by Mean HbA1C Based on DCCT Data

15. HbA1c and Plasma Glucose 26,056 data points (A1c and 7-point glucose profiles) from the DCCT Mean plasma glucose = (A1c x 35.6) – 77.3 Post-lunch, pre-dinner, post-dinner, and bedtime correlated better with A1c than fasting, post-breakfast, or pre-lunch Rohlfing et al, Diabetes Care 25 (2) Feb 2002

16. ADA / AACE Targets for Glycemic Control HbA 1c < 6.5 % Fasting/preprandial glucose< 110 mg/dL Postprandial glucose< 140 mg/dL

17. Incretins l Amylin: Pramlinitide l GLP-1 - Exenatide - Liraglitide

18. Pramlintide Adjunctive Therapy Offers Long-Term Glycemic Control

19. Euglycemia Healthy Subjects (n = 14)   Beta-Cell Workload   Beta-Cell Workload   Beta-Cell Response   Beta-Cell Response   Beta-Cell Workload   Beta-Cell Workload Mean (SE)

20. Insulin and GLP-1 Responses to Meals

21. Glucagon-Like Peptide-1

22. GLP-1 Infusion Improves  -Cell Insulin Secretion

23. GLP-1 and First-Phase Insulin Secretion

24. Exenatide: Proportion of Patients Achieving A1C ≤7%

25. Exenatide: Effect on the  -Cell

26. Exenatide: Clinical Pharmacology

27. ADA/EASD: Glucose-Lowering Interventions as Monotherapy—Step 2 (cont)

29. Euglycemia Healthy Subjects (n = 14)   Beta-Cell Workload   Beta-Cell Workload   Beta-Cell Response   Beta-Cell Response   Beta-Cell Workload   Beta-Cell Workload Hyperglycemia Type 2 Diabetes (n = 12)   Beta-Cell Workload   Beta-Cell Workload   Beta-Cell Response   Beta-Cell Response   Beta-Cell Workload   Beta-Cell Workload Mean (SE) The Pathogenesis of Diabetes Beta-Cell Workload Outpaces Beta-Cell Response

31. Incretin Effect * * * * * * *

34. * * * * * * * * * * * * * * * * * * * GLP-1

35. GEPeterson,DO,FACP Exanetide reduced post prandial glucose and glucagon Exanetide Exanetide and placebo

36. ADA: Clinical Practice Recommendations. 2008. Goals of Intensive Diabetes Management Near-normal glycemia –HbA1c less than 6.5 to 7.0% Avoid short-term crisis –Hypoglycemia –Hyperglycemia –DKA Minimize long-term complications Improve QOL

37. Comparison of Human Insulins / Analogues Insulin Onset ofDuration of preparations action Peak action Regular30–60 min 2–4 h 6–10 h Aspart- Glulisine-Lispro 5–15 min 1–2 h 4–6 h NPH 1–2 h 4–8 h10–20 h Glargine1–2 hFlat ~24 h Detemir 30 min Flat 24h

38. Short-Acting Analogs Aspart-Glulisine-Lispro Convenient administration immediately prior to meals Faster onset of action Limit postprandial hyperglycemic peaks Shorter duration of activity –Reduce late postprandial hypoglycemia –Frequent late postprandial hyperglycemia Need for basal insulin replacement revealed

39. 400 350 300 250 200 150 100 Meal SC injection 50 0 03060 Time (min) 90120180210150240 Regular Lispro 500 450 400 350 300 250 150 50 200 100 0 050100 Time (min) 150200300250 Plasma insulin (pmol/L) Meal SC injection Heinemann, et al. Diabet Med. 1996;13:625–629; Mudaliar, et al. Diabetes Care. 1999;22:1501–1506. Short-Acting Insulin Analogs Regular Aspart

40. Pharmacokinetic Comparison Aspart and Lispro 300 350 250 200 150 100 50 0 7 89101112 13 Aspart Lispro Free Insulin (pmol/L) Time (hours) Hedman, Diabetes Care 2001; 24(6):1120-21

41. 15 10 15202530 1 5101520 Asp Gly Arg Extension Substitution Arg Insulin Glargine A New Long-Acting Insulin Analog Modifications to human insulin chain –Substitution of glycine at position A21 –Addition of 2 arginines at position B30 Gradual release from injection site Peakless, long-lasting insulin profile

42. Lepore, et al. Diabetes. 1999;48(suppl 1):A97. 6 5 4 3 2 1 0 010 Time (h) after SC injection End of observation period 2030 Glargine NPH Glucose utilization rate (mg/kg/h) Glargine vs NPH Insulin in Type 1 Diabetes Action Profiles by Glucose Clamp

43. Glucose Infusion Rate n = 20 T1DM Mean ± SEM SC insulin 4.0 3.0 2.0 1.0 0 24 20 16 12 8 4 0 04812162024 Time (hours) mg/kg/min µmol/kg/min Lepore M, et al. Diabetes. 2000;49:2142–2148. NPH Ultralente CSII Glargine

44. Plasma Glucose Time (hours) 220 200 180 160 140 120 12 11 10 9 8 7 04812162024 mg/dL mmol/L Lepore M, et al. Diabetes. 2000;49:2142–2148. n = 20 T1DM Mean ± SEM SC insulin NPH Ultralente CSII

45. GE Peterson,DO,FACP Detemir: Basal Analog

47. Detemir Clinical Pharmacology Detemir

48. GE Peterson, DO, FACP Detemir Insulin Detemir

49. GEPeterson,DO,FACP Detemir

50. GEPeterson,DO,FACP Insulin Detemir

51. GEPeterson,DO,FACP Insulin Detemir

52. GEPeterson,DO,FACP Treatment with basal insulin detemir is associated Detemir

53. Overall Summary: Basal Insulin Analogs Both insulin detemir and glargine appear to be effective once daily duration. Insulin detemir has less variability Both have comparable glycemic control (FBG) Insulin detemir appears to have lower risk of nocturnal hypoglycemic events Insulin detemir may be associated with less weight gain. Safety profile similar to that of human insulin

54. The Basal/Bolus Insulin Concept Basal insulin –Suppresses glucose production between meals and overnight –40% to 50% of daily needs Bolus insulin (mealtime) –Limits hyperglycemia after meals –Immediate rise and sharp peak at 1 hour –10% to 20% of total daily insulin requirement at each meal

55. Basal vs Mealtime Hyperglycemia in Diabetes Riddle. Diabetes Care. 1990;13:676-686. Plasma Glucose (mg/dL) 200 100 0 06001200 Time of Day 18002400 Type 2 Diabetes 0600 150 250 50 Basal hyperglycemiaMealtime hyperglycemia 6-18 Normal  AUC from normal basal >1875 mgm/dL. hr; Est HbA1 c >8.7%

56. When Basal Corrected Plasma Glucose (mg/dL) 200 100 0 06001200 Time of Day 180024000600 150 250 50 Basal hyperglycemiaMealtime hyperglycemia 6-18 Normal Basal vs Mealtime Hyperglycemia in Diabetes  AUC from normal basal 900 mgm/dL. hr; Est HbA1 c 7.2%

57. When Mealtime Hyperglycemia Corrected Plasma Glucose (mg/dL) 200 100 0 06001200 Time of Day 180024000600 150 250 50 Basal hyperglycemiaMealtime hyperglycemia 6-18 Normal Basal vs Mealtime Hyperglycemia in Diabetes  AUC from normal basal 1425 mgm/dL. hr; Est HbA1 c 7.9

58. When Both Basal & Mealtime Hyperglycemia Corrected Plasma Glucose (mg/dL) 200 100 0 06001200 Time of Day 180024000600 150 250 50 Basal hyperglycemiaMealtime hyperglycemia 6-18 Normal Basal vs Mealtime Hyperglycemia in Diabetes  AUC from normal basal 25 mg/dL. hr; Est HbA1 c 6.4%

59. Glucose Correction Factor 1700 Rule says: John Smith’s Total Insulin Dose 60 units insulin/day 1700/40= 42 So, 1 unit Short Acting Analog will lower BG about 40 mg/dl

60. Correction Bolus Formula Example: –Current BG:220 mg/dl –Ideal BG: 100 mg/dl –Glucose Correction Factor: 40 mg/dl Current BG - Ideal BG Glucose Correction factor 220 - 100 40 =3.0u

61. Intensive Therapy for Type 1 Diabetes Careful balance of food, activity, and insulin Daily self-monitoring BG Patient trained to vary insulin and food Define target BG levels (individualized) Frequent contact of patient and diabetes team Monitoring HbA 1c Basal / Bolus insulin regimen

62. Carbohydrate Counting Most individuals need 1 Unit of insulin for every 15 GM of carbohydrate eaten. Insulin/Carb varies with food eaten Problems with fat content and time of day Individual variation for time of day

63. Options in Insulin Therapy Current –Multiple injections –Insulin pump (CSII) Future –Implant (artificial pancreas) –Transplant (pancreas; islet cells)

64. 1.0 0.8 0.6 0 Insulin Time Multiple Injection Therapy Intermediate & Short-Acting Insulin Pre-Meal

65. Injections 1.0 0.8 0.6 0 Insulin Time Multiple Injection Therapy Intermediate & Short-Acting Insulin Pre-Meal

66. Injections 1.0 0.8 0.6 0 Insulin Time Multiple Injection Therapy Intermediate & Short-Acting Insulin Pre-Meal

67. Case #1: DM 1 on MDI 46 year old white male power line supervisor DM 1 age 40 On MDI: 10 u lispro pre-meal, 20 u NPH HS HbA1c 7.4% SMBG avg 124 mg/dL based on 1.9 tests/day (fasting 171 mg/dL, noon 105 mg/dL, pm 125 mg/dL, HS 75 mg/dL)

68. Case #2: DM 1 on MDI Lantus (glargine) 20 u HS added in place of NPH No change in behavior (diet, SMBG frequency) Seen three months later (8-16-01) HbA1c 6.3% SMBG average 104 mg/dL (fasting BG 91 mg/dL, noon 126 mg/dL, pm 116 mg/dL, HS 126 mg/dL NO HYPOGLYCEMIA HAPPY

69. Insulin Pens

71. Lauritzen. Diabetologia. 1983;24:326–329. Fast (n = 12) Semilente (n = 9) Intermediate (n = 36) Fraction at inj. site 1.00 0.75 0.50 0.25 0 6 121824 36 424830 Hours after single SC injections Femoral region Variability of Insulin Absorption CSII <2.8% Subcutaneous Injectable 10% to 52%

72. Pump Therapy Basal & Bolus Short-Acting Insulin

74. Combined with SMBG, physiologic insulin requirements can be achieved more closely Flexibility in lifestyle

75. History of Pumps

77. Paradigm Pump: Advantages 29% smaller, water resistant Menu driven: bolus, suspend, basal, prime, utilities Reservoir based (easier to fill) Silent motor AAA batteries

78. Paradigm Pump: Advantages Various bolus options normal, square, dual, and “easy bolus” Enhanced memory Enhanced safety features (low reservoir alarm, auto off, etc.)

79. Pump Infusion Sets Softset QRSilhouette

80. Lauritzen. Diabetologia. 1983;24:326–329. Pharmacokinetic Advantages CSII vs MDI Uses only regular or very rapid insulin –More predictable absorption than modified insulins (variation 3% vs 52%) Uses 1 injection site –Reduces variations in absorption due to site rotation Eliminates most of the subcutaneous insulin depot Programmable delivery simulates normal pancreatic function

81. Metabolic Advantages with CSII Improved glycemic control Better pharmacokinetic delivery of insulin –Less hypoglycemia –Less insulin required Improved quality of life

82. Glycemic Control HbA 1c Atlanta Diabetes Associates

83. CSII Reduces HbA 1c 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5.09 9.5 10.0 n = 58n = 107n = 116n = 50n = 25n = 56 Mean dur. = 36 Adolescents Adults Mean dur. = 36Mean dur. = 54Mean dur. = 42Mean dur. = 12 Chantelau E, et al. Diabetologia. 1989;32:421–426; Bode BW, et al. Diabetes Care. 1996;19:324–327; Boland EA, et al. Diabetes Care. 1999;22:1779–1784; Bell DSH, et al. Endocrine Practice. 2000;6:357–360; Chase HP, et al. Pediatrics. 2001;107:351–356. BellRudolphChanteleauBodeBolandChase Pre-pumpPost-pump HbA 1c

84. Episodes/month/patient 0 2 4 6 8 10 12 insulin asparthuman insulininsulin lispro p < 0.05 Symptomatic or Confirmed Hypoglycaemia 30% relative reduction Bode et al: Diabetes Care, March 2002

85. 7.19 7.57 9.2 5.00 6.00 7.00 8.00 9.00 10.00 Baseline6 months18 months P = 0.026P = 0.040 N = 11 CSII Usage in Type 2 Patients The Diabetes Center Mean HbA 1c (%)

86. Glycemic Control in Type 2 DM: CSII vs MDI in 127 patients A1C 7.0 7.2 7.4 7.6 7.8 8.0 8.2 8.4 CSIIMDI Baseline End of Study (24 wks) Raskin, Diabetes 2001; 50(S2):A106

87. DM 2 Study: CSII vs MDI Overall treatment satisfaction improved in the CSII group: 59% pre to 79% at 24 weeks 93% in the CSII group preferred the pump to their prior regiment (insulin +/- OHA) CSII group had less hyperglycemic episodes (3 subjects, 6 episodes vs. 11 subjects, 26 episodes in the MDI group)

88. CSII Reduces Hypoglycemia 0 20 40 60 80 100 120 140 160 n = 55 Mean age 42 n = 107 Mean age 36 n = 116 Mean age 29 n = 25 Mean age 14 n = 56 Mean age 17 Events per hundred patient years Chantelau E, et al. Diabetologia. 1989;32:421–426; Bode BW, et al. Diabetes Care. 1996;19:324–327; Boland EA, et al. Diabetes Care. 1999;22:1779–1784; Chase HP, et al. Pediatrics. 2001;107:351–356. BodeRudolphChanteleauBoland Chase Pre-pumpPost-pump

89. -28%-18%-16%-17% * P <0.001 * * * * n = 389n = 389n = 298n = 246n = 187 Insulin Reduction Following CSII

90. Normalization of Lifestyle Liberalization of diet — timing & amount Increased control with exercise Able to work shifts & through lunch Less hassle with travel — time zones Weight control Less anxiety in trying to keep on schedule

91. N = 165 Average Duration = 3.6 years Average Discontinuation <1%/yr Continued 97% Discontinued 3% Current Continuation Rate Continuous Subcutaneous Insulin Infusion (CSII) Bode BW, et al. Diabetes. 1998;47(suppl 1):392.

92. Pump Therapy Indications HbA 1c >7.0% Frequent hypoglycemia Dawn phenomenon Exercise Pediatrics Pregnancy Gastroparesis Hectic lifestyle Shift work Type 2 Marcus. Postgrad Med. 1995.

93. Poor Candidates for CSII Unwilling to comply with medical follow-up Unwilling to perform self blood glucose monitoring 4 times daily Unwilling to quantitate food intake

94. Current Candidate Selection Patient Requirements –Willing to monitor and record BG –Motivated to take insulin –Willing to quantify food intake –Willing to follow-up –Interested in extending life

95. What Type of Bolus Should You Give? 9 DM 1 patients on CSII ate pizza and coke on four consecutive Saturdays Dual wave bolus (70% at meal, 30% as 2-h square): 9 mg/dl glucose rise Single bolus: 33 mg/dl rise Double bolus at -10 and 90 min: 66 mg/dl rise Square wave bolus over 2 hours: 80 mg/dl rise Chase et al, Diabetes June 2001 #365

96. Treatment of Hypoglycemia Education –Glucose tablets –Glucagon Call healthcare team –Any hypoglycemic events requiring assistance

97. Treatment of Hyperglycemia If blood glucose is above 250 mg/dl –Take a correction bolus by pump –Check BG again in 1 hr If still above 250 mg/dl –Take correction bolus by syringe –Change infusion set and reservoir –Check BG again in 1 hr If BG has not decreased –Increase correction bolus by syringe –CALL PHYSICIAN

98. If HbA 1c is Not to Goal SMBG frequency and recording Diet practiced –Do they know what they are eating? –Do they bolus for all food and snacks? Infusion site areas –Are they in areas of lipohypertrophy? Other factors: –Fear of low BG –Overtreatment of low BG Must look at:

99. Evolution of Diabetes Management Technologies Insulin Injections Urine Test Strips Glucose Sensor Artificial Pancreas 19991978 19221900s 1977 Urine Tasting 1776 BG Meters Insulin Pump Therapy

100. Continuous Glucose Monitoring System CGMS

101. Pilot Study: CGMS in Young Children with Type 1 Diabetes Evaluate the functionality of the MiniMed CGMS in children less than 7 years of age Evaluate hypoglycemic patterns in young children using the MiniMed CGMS Adjust insulin/dietary regimens based on sensor patterns to prevent hypoglycemia and hyperglycemia

102. Study Design: Timeline Clinic Visit 1Clinic Visit 2Clinic Visit 3Clinic Visit 4 0 Months2 Months4 Months6 Months Sensor 1A Sensor 1B Two weeks later Sensor 2A Sensor 2B Two weeks later Sensor 3A Sensor 3B Two weeks later Third pair of runs is optional

103. Results 19 children enrolled between 12/02 and 7/03 102 runs, (99 were successful, >24 hours of data) 422 days and 319 nights of data collected Each sensor worn for on average 75.1 ± 25 hours and provided on average 916 ± 306 glucose values per run Total of 88,865 glucose values collected, of which 45,310 were between 8 pm and 8 am

104. Results: Adverse Events Adverse events included mild irritation and rash at the insertion site, which did not require therapy. No infections occurred. The sensor was removed before 48 hours on 11 of 102 runs. Reasons for removal included –fell out (5) –serial alarms due to low signal (5) –parents’ preference (1) Fructose. Micro.magnet.fsu.edu

105. Post-breakfast excursion Nocturnal lows Glucose Trends: CT

106. Glucose Trends: NB(1) NPH “run-out” NPH

107. Glucose Trends: NB(2) NPH

115. CGMS data on Jackson Pollack

118. Hypoglycemia Duration and Frequency Duration of hypoglycemia did not differ based on age (<5, ≥5yr), pump v. MDI, or HbA1c (<8, ≥8.0%) Frequency of mild hypoglycemia was higher in children on the pump (1.1 v. 1.8 episodes per day of monitoring, p<0.05) Frequency of severe hypoglycemia did not differ based on insulin regimen Frequency of mild or severe hypoglycemia did not differ based on age or HbA1c

119. Results: Timing of Hypoglycemia Time of Day No. of Episodes

120. Conclusions CGMS can be used successfully in young children: –Well tolerated without significant adverse effects –Accuracy is acceptable –Defines consistent patterns Nocturnal hypoglycemia in young children with diabetes is common –Severe hypoglycemia most frequently occurs between 4a-8a –Duration of hypoglycemia is longer at night

121. Conclusions Post-prandial hyperglycemia is common, especially after breakfast HbA1c is positively correlated with severity of glucose rise after breakfast and lunch; a similar association is not seen at dinner CGMS can be used to define and assess algorithms which address typical glycemic excursions Glucose. Micro.magnet.fsu.edu

122. NEED FOR A CONTINUOUS GLUCOSE SENSOR Prevent nocturnal hypoglycemia Improved diabetes management –Post prandial highs –Dawn phenomenon “Close the loop” and allow for an “artificial pancreas” With 4 blood tests/day –14,600 finger pokes in 10 years –Yet only 0.2% of minutes each day are measured

123. GLUCOSE MONITORING SYSTEMS - EXTERNAL Physician downloads data for retrospective analysis Com-Station and software packages combine data from: –Sensor –Models 508 and 507C insulin pumps –Traditional glucose meters Physician Product

124. Role of the School Nurse Developmental, cognitive, and physical status of the student within his/her family structure to determine the ability of the student to independently manage diabetes care at school. Identifying and coordinating the medical interventions the student requires at school, based on orders from the health care provider and the nursing assessment of the student; Determining the nursing interventions and school accommodations needed for all school activities based on the developmental cognitive, and physical status of the student;Identifying and coordinating the interventions for school activities, which may include blood glucose monitoring, insulin administration, dietary intake, and instruction in identifying signs of and response to hypoglycemia/hyperglycemia; Assisting the student in determining realistic and achievable personal goals for attaining self-care and independence in the management of her/his health.