5THE PANCREAS THROUGHOUT HISTORY 1550 BCE-Papyrus describes polyuria and its treatment4th century BCE-Ayur Veda of Susruta (India) described sugarcream urine which attracted ants.7th century CE-Chinese physician Chen Chuan recorded sweet urine in diabetes1869-Langerhans describes islets1909-the name insuline is suggested by Jean de Meyer (Brussels)1921-Banting and Best-report discovering Insulin used in 1922
6BANTING & BESTOrthopod who became a physiologist and died in air crash in Newfoundland while on wartime missionTogether they isolated insulin and Banting won the Nobel Prize in 1923 knighted in 1934
8Prevalence of Diabetes in the US Diagnosed Type 1 Diabetes 1.5 Million(1: children)Diagnosed Type 2 Diabetes 14 millionUndiagnosed Diabetes 6 Million1.5 million new cases of diabetes were diagnosed in people aged 20 years or older in 2005
9Good Glycemic Control (Lower HbA1c) Reduces Incidence of Complications DCCT9 7%63%54%60%41%*Kumamoto9 7%69%70%–UKPDS8 7%17-21%24-33%–16%*HbA1cRetinopathyNephropathyNeuropathyMacrovascular diseaseIn 3 separate studies, good control of blood glucose as measured through HbA1c dramatically lowers the risk of developing comoplications in diabetes. The risk of retinopathy is decreased by 60% with a drop of HbA1c from 9 to 7. Nephropathy decrease by some 50% and neuropathy decreased by 60%.* not statistically significantDCCT Research Group. N Engl J Med. 1993;329: Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28: UKPDS 33: Lancet. 1998;352:
10HbA1c and Microvascular Complications Retinopathy15131197531NephropathyRelative RiskNeuropathy789101112HbA1c, %10
11Incidence of Diabetes- Related Complications (%) Every 1% HbA1c Increase Above Goal Elevates the Risk of Diabetic Complications+37%Incidence of Diabetes- Related Complications (%)+21%+14%+12%It has been shown that with every 1% increase in HbA1c above normal range, the risk of developing cardiovascular complications increases dramatically as well.Increase in AnyDiabetes-RelatedEndpointIncrease in Riskof MyocardialInfarction (MI)Increase in Riskof StrokeIncrease in Riskof MicrovascularComplicationsAdapted from Stratton et al. BMJ. 2000;321:
12Physiology of Insulin and blood glucose secretionBasal InsulinBreakfast Lunch DinnerJust a little background on physiologic secretion of insulin. Normally, insulin is secreted at a basal level with increases during meal time. The increase in insulin during meal time is both a psychological reaction to the anticipation of food and also physiological rise in blood glucose after eating. From this, we can see that one of the biggest disadvantage of traditional insulin therapy is that the insulin injections given in traditional therapy has no correlation to what the patient is doing physiologically.BloodglucoseBasal blood glucose
13Insulin Preparations Action Peak Action Onset of Duration ofAction Peak ActionHumalog/Novalog 5 to 15 min 1 to 2 hr 4 to 6 hrHuman Regular 30 to 60 min 2 to 4 hr 6 to 10 hrHuman NPH 1 to 2 hr 4 to 6 hr 10 to 16 hrHuman Lente 1 to 2 hr 4 to 6 hr 10 to 16 hrHuman Ultralente 2 to 4 hr Unpredictable <24 hrLantus 30minutes none 24hrPatients with diabetes are traditionally treated with an long acting insulin and a short acting insulin. The total daily dose is given as 2/3 in the morning with 2/3 of which in long acting form and 1/3 in short acting form. 1/3 of the total daily dose is given at dinner where ½ is in the form of long acting insulin and the other ½ in short acting form. The intent is to provide coverage throughout the day. However, this method does not correlated with normal physiologic levels of insulin and it does not take into account how much the person really eats in a day. In addition, patients on this treatment are subjected to a rigid diet which makes compliance a problem. In addition, patients are subjected to 3-6 injections a day.
15Disadvantages of NPH/ Regular regimen No flexibility:Required certain amount of calories a daySkipped meal - hypoglycemia (peak of NPH)Exercise - hypoglycemia (excessive glucose use)At night - hypoglycemia (peak of NPH)Overeating- hyperglycemia (not enough)Oversleeping- hyperglycemia (skipped dose)
16Results of conventional therapy Poor control - HbA1C 10% and higherFear of hypoglycemia - worsening of controlInability to exercise - poor fitnessEarly development of complications“OUT OF CONTROL”-Negative reinforcement“Don’t Do This, Don’t Do That”Mauriac syndrome - chronic insulin deficiency - stunted growth, hepatomegaly
17Some causes of hypoglycemia in toddlers and preschoolers: Unpredictable food intake and physical activity.Imprecise administration of low doses of insulin.Frequent viral infections.Inability to convey the symptoms of low blood sugar.Adapted from Litton J et al; J Pediatr 2002;141:
22Humalog/Novolog versus Regular Rapid acting insulins: Start in 10min Peak in 1-2h Gone in 3.5-4hRegular insulin: Starts in 30min Peaks in 3-4h Gone in 6-8h
23Benefits of rapid acting insulins May be given just prior to the meal or after meal in babiesTime of action match rise in sugar caused by most mealsNo action left at the time of next meal - no boluses buildupsLess activity at bedtime - less night “low’s” and no need for bedtime snack
24WHEN WE STARTED TO DABBLE-THREE SHOTS A DAY LisproLisproInsulin EffectNPHNPHBLSHSBMeals
25Twice Daily vs. Three Daily Injections Rationale: Avoid Dawn Phenomenon and Somogyi Effect872 adolescents evaluated over a 3-year period.Either regimen:Increased insulin dose.Deterioration of metabolic control.Increase in BMI.Females faired worse than males.Adapted from Holl R et al; Eur J Pediatr Jan; 162(1): 22-9.
26New Long Acting Insulin (Glargine Insulin) Lantus is a new type of long acting insulin that has no peaksMimics physiological insulin (basal)Newer long acting insulin such as lantus have no peak in blood stream thus mimics more physiological release of insulin.
27INSULIN TACTICS The Basal/Bolus Insulin Concept Basal InsulinInsulin requirement to suppress hepatic glucose production between mealsBolus Insulin (prandial)Insulin requirement to maintain normal glucose disposal after eatingInsulin:CHO Ratio = 500/(total starting dose)Correction Factor = 1500/(total starting dose)Correction factor in young children = 1800/(total starting dose)
28LANTUS AND NOVOLOG-”POOR MANS PUMP” LisproLisproLisproInsulin EffectlANTUSBLSHSBMeals
29Nine Preschool Patients Meticulously Cared For With MDI Switched To CSII: Mean A1c 9.5% reduced to 7.9%.Severe hypoglycemic events 0.52 per month reduced to 0.09 per month.Increased parental confidence and independence.All refused to relinquish pump at completion of study.Adapted from Litton J et al; J Pediatr 2002;141:
30Better Control and Less Hypoglycemia in Young Children Purpose of Study: To determine if glycemic control could be achieved more effectively and safely using CSIIMethods: 9 toddlers with T1DM for a duration of > 6 months Mean age 34 months (range 20 – 58) Infusion sets were change every 2 days, most pts used a flexible set, several used a metal needle Duration of pump therapy: 12.7 1.6 monthsResults: HbA1c decreased from 9.5 to 7.9% (p < 0.001) Severe hypoglycemia decreased from 0.52 to 0.09 episodes per month (p < 0.05) HbA1c HypoglycemiaFrequency of parental contacts with health personnel declined by 80% from once every 5.9 to 46.3 days (p < 0.01) reflecting increasing parental confidence and independence in diabetes care All families preferred the pump to MDI and refused to consider a return to previous modes of insulin administrationConclusions: Our study demonstrates that pump therapy can reduce HbA1c and the frequency of moderate and severe hypoglycemia in poorly controlled preschool children Findings suggest that highly motivated and carefully supervised families can use the insulin pump to provide effective therapy for selected toddlers and preschool children with T1DM.HbA1cHypoglycemiaLitton J., J Pediatr 2002;141:
31Injections Also Fail To Achieve Glycemic Control Randomized, Prospective Trial of CSII vs. MDI with Glargine in ChildrenHypoglycemia:MDI - 5CSII - 2DKA:MDI - 0CSII - 0PreferenceMDI - 4 of 16CSII of 16HbA1c (%)Adapted from Doyle E Diabetes Care July 2004Boland E et al; Diabetes 2003; 52 (Suppl. 1): 192
32195 patients between the ages of 13 and 17 in DCCT: Glycemic Memory: Sustained Beneficial Effect Of Prior Intensive Therapy195 patients between the ages of 13 and 17 in DCCT:Decreased worsening of retinopathy by 74% (p < 0.001).Decreased progression to proliferative or severe non-proliferative retinopathy by 78% (p < 0.007).Adapted from White, N et al, J Pediatr Dec; 139(6):
33Glycemic Memory: Sustained Beneficial Effect Of Prior Intensive Therapy 195 patients between the ages of 13 and 17 in DCCT:Relative risk of hypoglycemia < 1 among prior intensive group.Prevalence of microalbuminuria 48% less.It is vital to achieve the best glycemic control early in the course in diabetes during adolescence and childhood.Adapted from White, N et al, J Pediatr Dec; 139(6):
34“ Less than optimal glycemic control during the early years of diabetes has a lasting detrimental effect on the development and progression of complications, even after better glycemic control is established later in the course of the disease.”Adapted from White, N et al, J Pediatr Dec; 139(6):
35From Preschool to Prom 161 patients with type 1 diabetes: 26 ages 1 to 676 ages 7 to 1159 ages 12 to 1898% remained on CSIIReduced hypoglycemia (events/year)Age 1 to 6: to 0.19Age 7 to 11: to 0.22Age 12 to 18: to 0.27Mean HbA1c levelsAdapted from Ahern J et al; Pediatr Diabetes Mar;3(1): 10-5.
38I WAS A NON-BELEIVER TOO HARD/TIME CONSUMING I WAS UNINFORMED ON HOW TO USE THEMNOT FOR THE VERY YOUNG OR THE UNMOTIVATEDONLY AFTER HONEYMOONYOU HAVE TO TEST FOR ME TO PUT YOU ON PUMPYOU WILL SUFFER PSYCHOLOGICALLY
40Purpose and Method of Study Purpose: compare two algorithms of management for newly diagnosed kids with diabetes in our clinic.Method: A study of HbA1c level and total daily insulin dose in 2 groups of patients with new onset diabetes type 1 at diagnosis, 6 months, and 12th months after diagnosis.The purpose of our study is to compare our newly diagnosed type 1 patients who are placed on pump therapy versus patients who were not placed on pump therapy in our clinic.To determine how well these 2 groups respond to our therapy, HbA1c level and total daily insulin dose in the 2 groups were examined at diagnosis, at 6 months, and at 12th month after diagnosis.Total number in study is 35, ages 15 month to 16 years.All patient were confirmed with GAD or islet cell antibodies to be afflicted with type 1 diabetes.
41Hypothesis Our hypothesis are: Patients on pump have better control of their blood glucose levelBetter control allows extension of the “honey moon” periodOur hypothesis are:Patients on pump have better control of their blood glucose level which is reflected in their HbA1cBetter control allows extension of the “honey moon” period which is a period where the patient still has some insulin secretion from their pancreas. We hypothesize that this extension is the result of better control which lessen number of hyperglycemic insults to the pancreatic parenchyma thus allowing the beta cells to survive longer.
42Treatment Algorithm Algorithm #1 Algorithm #2 Treatment algorithm Group 1 (number of patients = 24)Treatment algorithm Group 2 (number of patients = 11)All patients with new onset diabetes were discharged within 3-5 days.All patients with new onset diabetes were discharged within 24 hours.Patients and parents were taught within 3 to 5 days in-hospital how to manage diabetes by pediatric endocrinology team.Patients and parents were taught within first 24 hours in-hospital how to manage diabetes by pediatric endocrinology team.Patients were started on Humalog and NPH in the hospital after correction of diabetic ketoacidosis.Patients were started on Humalog and Lantus after correction of diabetic ketoacidosis and regiment was continued for the first 1-2 weeks.CSII was started within first 14 days after diagnosis.A pediatric endocrinologist was available 24 hours a day 7 days a week to support insulin dose adjustment and education over the phone for the patients and parents.This is a comparison of our treatment algorithm.Algorithm 1 is our old method. Patients in this algorithm stay in the hospital for 3-5 days. During this period patients are taught how to use NPH and insulin. Patient are reevaluated at 3mo, 6mo, and 1 year and have their HbA1c drawn at those periods.Algorithm 2 is our new pump method. Patients in this algorithm stay in the hospital for 24hours where the patient receive intensive teaching on how to use humalog and lantus. Pt are also taught on how to count carbohydrates and how to use the injection pens. Patients return to clinic at 2nd week to have their blood glucose followed up and at this time patient’s pump therapy is initiated.A pediatric endocrinologist was available 24 hours a day 7 days a week to support insulin dose adjustment and education over the phone for the patients and parents in both algorithms.
43HbA1cThis is a bar graph of our results. Y-axis is HbA1c and X-axis is time. From this you can see that HbA1c is significantly lower in individuals being treated on the pump (shown in dark purple) relative to individuals without a pump (shown in light blue) at the 12th month period. Interestly, there seems to be no difference in HbA1c level between the 2 groups at 6months.
46Total daily doseThis bar graph compares the amount of total daily dose between people on pump and patient who are not on pump. Y-axis represent units of insulin per kg per day. X-axis represent time. As you can see, people who are on the pump (shown in dark purple) uses a significantly smaller amount of insulin per day in comparison with patients who are not on the pump (shown in light blue).
48Conclusion:Intensive teaching, 24 hour support, and CSII within 2 weeks of diagnosis improved patient’s HbA1c levels and decreased total daily dosage of insulin over traditional therapy.CSII was beneficial for newly diagnosed diabetes patients at the onset of disease.Thus, it is our conclusion that:Intensive teaching, 24 hour support, and CSII within 2 weeks of diagnosis improved patient’s HbA1c levels and decreased total daily dosage of insulin over traditional therapy.CSII was beneficial for newly diagnosed diabetes patients at the onset of disease.
49Candidates for pump therapy My CriteriaAny patient who is willing to start and has abilities to learnMay improve complianceAny age adults and children of any age (independent users 7-80 y old)Particularly “non-compliant” patientsTypical CriteriaOnly motivated patientsonly patients who showed good compliance on previous regimenAdults and children > 6y old
52The Yale Experience > 200 children started on pumps over last 5 yrs No difference in severe hypoglycemiaParents report less mild hypoglycemiaHbA1cAge (yr)pre3 mos post< 77.66.77-127.87.313-187.97.5Ahern presented Yale’s experience with kids and pumps at the 2000 ISPAD meetings and noted improvements in HbA1c with no increase in hypoglycemia. The data from the youngest children was most significant. Children less than 7 years of age had the greatest improvement in HbA1c levels.Ahern et al., Journal of Pediatric Endocrinology and Metabolism 2000, 13(suppl 4):1220.
53Additional Evidence From Yale Decreased hypoglycemiaNo change in BMI or TDD98% remained on CSIIInsulin Pump Therapy in Pediatrics: A Therapeutic Alternative to Safely Lower HbA1c Levels Across All Age GroupsAhern JAH, Boland EA, Doane R, Ahern JJ, Rose P, Vincent M, Tamborlane WVYale School of Medicine, New Haven, CTBackground: While some of the initial pump patients of the 1970’s were pediatric patients, this therapy was initially used primarily with just adults. Over the last five years there has been increased interest in using pumps in children, however, some clinicians remain skeptical, despite many reports suggesting its usefulness in this population.Purpose of Study: The purpose of this paper was to describe the outcomes of a large group of children successfully using CSII at one center.Methods:Number of patients: Total: 161 with type 1 diabetesPreschoolers (1-6 yrs) 26Schoolagers (7-11 yrs) 76Adolescents (12-18) 59Treatment: Pump therapy was offered to parents and patients who were performing 4 BG tests day, were motivated to achieve intensive treatment goals, or if the child had repeated episodes of hypoglycemia. A retrospective chart review was done on patients with at least 12 months on pump therapy.Results:Pump UseAverage of months (range 19-57)All children experienced a decreased in HbA1c (p <0.02, see figure).98% patients (158 of the 161) remained on CSII.No significant change in BMITDD pre vs post pump had no statistical changePreschoolers: 0.7 vs 0.8 u/kgSchoolagers: 1.0 vs 0.9 u/kgAdolescents: 1.3 vs 0.9 u/kgSevere hypoglycemia decreased (events/year)Preschoolers: vs 0.19Schoolagers: vs 0.22Adolescents: vs 0.27Total : vs 0.24 (p <0.05)Conclusions:· Insulin pump therapy can result in an improvement in metabolic control with a simultaneous decrease in severe hypoglycemia in children of all ages with type 1 diabetes.· This improvement can occur without any deleterious effects on weight gain.· Insulin pump therapy should be offered and encouraged for children of all ages with type 1 diabetes to achieve the best outcomes.Ahern, JAH, et.al. Pediatric Diabetes 2002;3:10-15.
54CSII vs. MDI With Glargine in Children Randomized, Parallel-group, 16 week studySubjects at baseline Age: 8-19 yr (mean 12.7 ± 2.7) Type 1 DM > 1 yr duration Standard insulin therapy (2-3 injections/day)CSII (aspart) n=12Randomized, Prospective Trial of CSII vs MDI with Glargine in Children: A Preliminary ReportElizabeth A. Boland, Stuart A. Weinzimer, Jo Ann H. Ahern, Amy T. Steffen, William V. TamborlaneDepartment of Pediatrics, School of Medicine, Yale University, New Haven, CTPurpose: To compare CSII and MDI with glargine in youth with T1DM.Injection therapyMDI (aspart/glargine) n=14Boland et al., Diabetes 2003, 52:S1, A45, 192-OR
55Pump Group Achieved Better Control Overall Changes in HbA1c Levels8.5p=.30(NS)p=.15 (NS)p=.001p = .0387.5 HbA1c was significantly lowered in the pump group and remained unchanged in the glargine-based MDI group (p = 0.03) 7PumpMDI6.5Baseline4 wks8 wks12 wks16 wksBoland, E. Diabetes 52,(Suppl 1), 2003 Abstract 192.
56More Pump Wearers Achieved HbA1c 6.9% _<% Patients AchievingHbA1c<6.9%1020304050The percent of patients able to achieve a HbA1c below 6.9% was higher in the pump treated group than the glargine-based MDI group (43% vs 12%).In addition:The pump group used 37% less insulin than the glargine-based MDI group (p < 0.05)The pump group had less hypoglycemiaNo DKA in either groupPost study: all pumpers continued on pumps and 86% of MDIs switched to pumps Conclusion: Patients randomized to Glargine-based MDI therapy were able to achieve as good as control as they did on conventional injection regimens using the same total daily dose of insulin. Pump treated patients were able to significantly lower their HbA1c levels compared to both baseline values and the glargine group with a lower total daily dose of insulin. Insulin pump treatment is a more effective means to obtain strict metabolic control than glargine-based MDI therapy, in children with type 1 diabetes.Pump GlargineBoland, E. Diabetes 52,(Suppl 1), 2003 Abstract 192.
57Sweden’s Experience 89 children 3-21 y.o Diabetes duration 6.1 years 30% using CSIIHbA1c decreased from 9.2% to 8.4% after CSII startSevere hyposPump: 11.1/100 pt yearsMDI: 40.3/100 pt yearsSweden investigators presented their pediatric data at the 2000 ADA meeting and showed an improvement in HbA1c when pump therapy was used and much less severe hypoglycemia (approximately 25% of that experienced with MDI).Hanas, Diabetes, 2000, 49 (Suppl 1):A133.
58Patient Characteristics of Successful Pediatric Pumpers Able to maintain follow up appointments with health care providerWilling to record blood glucose valuesAble to count carbohydratesGood family/social support system
59Pump therapy benefitsImproved control - more physiological basal rates (“dawn phenomenon” match), different boluses for food, less absorption variabilityLess hypoglycemiaMore flexible lifestyle and possibility to exercisePrecise dosing u u increments for basal rate and bolusesLess injections - improved quality of lifeLess possibility of overdoseAdapted from Plotnick L et al; Diabetes Care 2003; 26(4):
60Pump Use in Children Is Increasing 200,000 users (adults and kids in the US). 10,000 are adults with type 2 diabetes~ 20,000 children using pump therapy10% of all children with diabetesPenetration as high as 90% in some pediatric clinics (ours)Increasing use in younger children (as young as 10 months)Current outcomes indicate CSII is safe and effective in childrenIncreasing acceptance likely due to DCCT findings as well as the introduction of smaller, safer insulin pumpsThere are approximately 400,000 insulin pump users worldwide
61Avoiding DKA Give a pen with the pump Instruct that any time the patient feels nauseated or has abdominal pain -- change the siteBlood sugar is greater than 250 mg/dlTake correction doseCheck for ketonesRecheck in 60 minutesIf coming down, leave aloneIf not, take a shot and change the sitePatients should leave insulin pens (or syringe and vial of fast-acting insulin) at home, in school, in parents’ handbag, at grandma’s or anywhere else they spend a lot of time
62SummaryPump therapy is an intensive process for pediatric patients and their families and the diabetes education team.Successful pumpers are motivated and willing to maintain follow-up, carbohydrate count, and check blood glucose frequently.Benefits of pump therapy for pediatric patients include: improved lifestyle, decrease in hypoglycemia, accurate dosing , ability to review history to see if doses were actually given.
63SummaryChildren with diabetes should be intensively treated to avoid short and long term complicationsInsulin pumps can provide better control and less hypoglycemia than MDIWith good support and a standardized process, insulin pump therapy can help to improve diabetes management in childrenInsulin pump therapy should be the only form of therapy offered to children with diabetes
64When meditating over a disease, I never think of finding a remedy for it, but rather, a means of preventing it. Louis Pasteur, 1884