Limitations/Challenges to Better Glycemic Control A1ccentric Hypoglycemic Risk Glucose excursions above and below what the HbA1c average represents may be more important than HbA1c Inadequate Postprandial Glucose Control Weight Gain
Obstacles in Glycemic Control Invasive glucose monitoring devices- owie!!!!! Limited availability of reliable continuous glucose monitoring Lack of alternate routes of insulin delivery.
Alternate Site Glucose Testing (Forearm, Thighs, Abdomen vs. Fingers) Rubbing/exercising/suction does not uniformly increase the blood flow but glucose values may be better correlated to fingers. At extremes of glucose values fingerstick testing is mandatory for confirmation. Rapid changes in glucose values, fingers are the best
Alternate Site Glucose MeasurementsUnder-reads Over-reads
MAJOR RESEARCH CHALLENGES? CLINICALLY Development of new methods for achieving tight control without hypoglycemia RESEARCH Development of methods for replacing beta cell function (islet cell transplantation, artificial pancreas) Enhanced understanding of immunopathogenesis (interaction of genes, environment and immune system) allowing for more effective preventative therapies
APPROACHES TO CURING TYPE 1 DIABETES Immune Interventions/ Tolerance Induction Immune Interventions/ Tolerance Induction Islets Stem Cells Adult Fetal Embryonic in vivo Differentiation of Pancreatic Progenitors Growth Factors Manipulation Of non-islet tissue (Transdifferentiation Manipulation Of non-islet tissue (Transdifferentiation Gene Therapy Modulate Autoimmunity Islet neogenesis Gene Therapy Modulate Autoimmunity Islet neogenesis Whole pancreas Transplantation
Implanted Closed-Loop External Closed-Loop TOWARDS CLOSED LOOP DELIVERY
Glucose Contributions to HbA1c Fasting Glucose influenced by: Liver glucose production Liver sensitivity to insulin Postprandial Glucose Influenced by: Preprandial glucose Insulin dose Glucose load from meal Insulin sensitivity in peripheral tissues HbA1c = + Lantus, Basal rates, Humalog, Novalog
Are All HbA 1c Values Created Equal? Time Blood Glucose HbA 1c = 8%
The DCCT Research Group stated HbA1c is not the entire answer to glycemic control. The Average HbA1c is not the most complete expression of the degree of glycemia and the risk of complications may be more highly dependent on the excursions or influenced by counterregulatory hormonal responses to hypoglycemia. Lesser Known Outcomes from the DCCT Diabetes 44:968-983, 1995
Actual writing on Hospital charts:Top Ten 1.She has no rigors or shaking chills, but her husband states she was very hot in bed last night. 2.Patient has chest pain if she lies on her left side for over a year. 3.On the second day the knee was better, and on the third day it disappeared. 4.The patient is tearful and crying constantly. She also appears to be depressed. 5.The patient has been depressed since she began seeing me in 1993.
Why do we need Glucose Sensors?
Model of Multihormonal Regulation of Glucose Homeostasis Model derived from animal studies *Inferred satiety effect GLP-1 central effect on glucose homeostasis is inferred from animal studies Glucose Disposal GLP-1 Gut Plasma Glucose Postprandial Glucagon Tissues Liver Insulin Pancreas Rate of glucose appearance Rate of glucose disappearance Amylin Gastric Emptying Food Intake* Stomach Brain
Excessive 24-Hour Glucose Fluctuations in Type 1 Patients with Mean A1C of 6.7% Levetan C, et al. Diabetes Care 2003; 26:1-8 N = 9, CSII treated (insulin lispro); A1C average 6.7% (range 5.8%-7.1%) ; 24-hour CGMS glucose sensor data Desired glycemic range in non-diabetic subjects: 80-140 mg/dL 100 200 300 400 12:00 AM4:00 AM8:00 AM12:00 PM4:00 PM8:00 PM12:00 AM Glucose Concentration (mg/dL)
Intensively-treated T1DM: Diurnal Glucose Fluctuation and Nocturnal Hypoglycemia Continuous Glucose Monitoring System (CGMS) data, 56 adolescents, T1DM on CSII or MDI CSII = Continuous subcutaneous insulin infusion; PG = Plasma glucose Boland E, et al. Diabetes Care. 2001;24:1858-1864. % Peak Postmeal Glucose Levels Over Target 100 90 80 70 60 50 40 30 20 10 0 BreakfastLunch Supper % Patients 80 70 60 50 40 30 20 10 0 1 Night2 Nights3 Nights Postprandial HyperglycemiaNocturnal Hypoglycemia > 300 mg/dL 241–300 mg/dL 181–240 mg/dL 41–60 mg/dL 40 mg/dL 90% of Postprandial Readings Exceeded ADA Guidelines Nearly 70% of Patients Had 1 Night With PG < 60 mg/dL Mean A1C = 7.7%
MiniMed ® Continuous Glucose Monitoring System (CGMS)
GlucoWatch ® Biographer
Schematics of the Autosensor & Biographer Mask Hydrogel Pads Ionto Sensor Electrode Assembly Electronic Components Garg et al. Diabetes Care 1999;22:1708-1714 AAA Battery
Device Evaluation Advantages –Real-time measurement –Non-invasive (no-biological fluids) –Calibration stability –71% of patients calibrate –Trending capability Disadvantages –Not portable –Skin temperature control –Sampling site critical –Failure modes not all identified –Requires daily finger stick
Near Infrared Ray (NIR) Large desk-like apparatus Skin temperature and hydration Calibration is too cumbersome Patient intervention required Real Need! Need a small wearable, patient- friendly continuous glucose monitor with alarms and remote displays and feed the information to insulin pumps (closed-loop system)
Sensors in Development DexCom and Vascular Sensors NIR, Nostix, Therasense The Pendra, Pendragon Medica Sensys Glucose Tracking System, Sensys Glucon Solution, Glucon Sugartrac, Lifetrac Systems GlucoNIR, CME Telemetrix ReSense, MedOptix Pindi, Pindi Products Head-Mounted Goggles, NASA
Role of Frequent Glucose Monitoring
6 7 8 9 10 11 InitialNo ContactCross-OverIntensify Schiffrin A, Belmonte M. Diabetes Care 1982;(5):479-84. More Frequent Testing Improves HbA 1c in Type 1 Patients > 4 < 2 HbA 1c (%)
Current Medical Practice Repeated finger- sticks are required to obtain glucose readings periodicallyRepeated finger- sticks are required to obtain glucose readings periodically Testing is generally performed before mealsTesting is generally performed before meals Occasional measurements provide limited information about glucose levelsOccasional measurements provide limited information about glucose levels Repeated finger- sticks are required to obtain glucose readings periodicallyRepeated finger- sticks are required to obtain glucose readings periodically Testing is generally performed before mealsTesting is generally performed before meals Occasional measurements provide limited information about glucose levelsOccasional measurements provide limited information about glucose levels 80 121 0 0 40 80 120 160 200 240 280 320 360 400 11:00 AM 1:00 PM 3:00 PM 5:00 PM 7:00 PM 9:00 PM 11:00 PM 1:00 AM Glucose (mg/dL) Pre Lunch Pre Dinner Garg et al Diabetes Care ; 22; 1708-1714, 1999
0 0 40 80 120 160 200 240 280 320 360 400 11:00 AM 1:00 PM 3:00 PM 5:00 PM 7:00 PM 9:00 PM 11:00 PM 1:00 AM Glucose (mg/dL) Biographer Blood Glucose Calibration Point With the GlucoWatch® Biographer After one fingerstick for calibration, glucose readings are available automatically Frequent readings provide more information about glucose levels Trend information helps to identify opportunities for improved glucose control After one fingerstick for calibration, glucose readings are available automatically Frequent readings provide more information about glucose levels Trend information helps to identify opportunities for improved glucose control Pre Lunch Pre Dinner Garg SK et al Diabetes Care ; 22; 1708-1714, 1999
Measurement of Blood Glucose Conventional Blood Glucose Meters 80 121 0 0 40 80 120 160 200 240 280 320 360 400 11:00 AM 1:00 PM 3:00 PM 5:00 PM 7:00 PM 9:00 PM 11:00 PM 1:00 AM Glucose (mg/dL) Pre Lunch Pre Dinner Biographer Blood Glucose Calibration Point Based on significant postprandial hyperglycemia, the dose of pre-meal boluses on insulin lispro were adjusted and HbA1c values have remained consistently below 6.5% during the subsequent year. Garg et al Diabetes Care ; 22; 1708-1714, 1999
Continuous Subcutaneous Glucose Monitoring in a Subject with Type 1 Diabetes 0 50 100 150 200 250 300 350 400 450 12 MN 1:30 AM3:00 AM4:30 AM6:00 AM7:30 AM9:00 AM 10:30 AM 12 NOON 1:30 PM3:00 PM4:30 PM6:00 PM 7:30 PM9:00 PM 10:30 PM 12 MN Time Glucose Concentration (mg/dL) Meter Value Sensor Value Insulin Meal Chase and Garg, Pediatrics:107; 222-226, 2001
Technical Aspects of Continuous Glucose Monitoring Interstitial vs. Blood glucose –reported Lag of few seconds to 15 minutes High frequency of measurements Signal Stability –Quick and over time Calibration Issues Duration of Sensor application
Limitations with Current Technologies SMBG –Solitary Data points with no trend information CGMS –No real time feedback, 4T/day calibration –Unreliable data, size of the needle GlucoWatch - Prospective data but too many skips,12 hr.sensor - Skin irritation, Sweating,Temperature changes * HbA1c and Fructosamine Assay –Purely retrospective –No immediate Feedback
DexCom G1 Sensor –Subcutaneous implant in the abdominal wall –Multi-layer membrane system –Measures glucose every 30 seconds –Wireless transmission to receiver Device Description: Sensor Garg et al., Diabetes Care, 27:734-38, 2004
Receives and processes data from sensor Updates and displays glucose values every 5 minutes Displays 1, 3 and 9 hour trends High and low glucose alerts Device Description: DEXCOM Receiver Long Or Short Term Use Garg et al., Diabetes Care, 27:734-38, 2004
Profile With Continuous Glucose Sensor in Patients With Insulin-requiring Diabetes Time Spent (hours/day) *P < 0.05, Students t test Garg SK, et al. Diabetes Care. 2004;27:734-738. 2.462.136.37 6.46 6.581.533.00 8.746.164.57 0 2 4 6 8 10 40–5556–7980–140141–239240–400 Glucose Range (mg/dL) Blinded period Unblinded period 38%* decrease Mean A1C = 7.2% 37%* increase 4%* decrease 31%* decrease 41%* increase
Slicing the Pie from DCGM Sensor Downloads Blinded vs. Unblinded phases (n=14) WTR = within target range (60-150 mg/dl) BTR = below target range (<60 mg/dl) ATR = above target range (>150 mg/dl) WTR 51% ATR 41% BTR 8% WTR 37% BTR 12% ATR 51% Blinded phase Unblinded phase
Results (G2) Excursion Duration (min)*Excursion Amplitude (mg/dl)* BlindedUnblinded Change BlindedUnblinded Change Hyperglycemic ( 200 mg/dl) 307 62 215 29 -30%** 352 12 332 14 -13%** Hypoglycemic ( 80 mg/dl) 181 15 138 10 -24%** 50 351 4 +3% * Expressed as Mean SEM ** Two-sided paired t-Test, p 0.05 Scott and Garg. ADA (LB5), o4 and EASD 2004
Results (G2) Hyperglycemia Exposure (mg/dl*hrs)* BlindedUnblinded Change 573 123340 64 -40%** * Expressed as Mean SEM ** Two-sided paired t-Test, p 0.05 Scott and Garg. ADA (LB5)and EASD 2004
Closing the Loop: The Artificial Pancreas Accurate, reliable continuous glucose monitoring systems, in progress Algorithms to incorporate glucose trend data into proper dose adjustments External or internal insulin pump systems
Pardigm Link & Bolus Wizard Paradigm 512 ONLY Medtronic MiniMeds Family of Insulin Pumps MiniMed 508 Paradigm 511 Paradigm Link Meter Paradigm 512 Remote Control B 102 mg/dL
Actual writing on Hospital charts:Top Ten (cont.) 6.Discharge status: Alive but without my permission. 7.Healthy appearing decrepit 69 year old male, mentally alert but forgetful. 8.Patient has left white blood cells at another hospital. 9.The patient has no previous history of suicides. 10.The patient refused autopsy.
Until the Cure-The Realities: Learn to manage glucose TRENDS rather than isolated numbers Minimize the moodiness associated with wide glucose excursions Understand glucose profiles over extended time Improve implementation of new regimens Knowledge and acceptance of inaccuracies and data interpretation
Conclusions Continuous glucose monitoring promises the goal of normalization of blood sugars while minimizing risk of hypoglycemia The result of full implementation will be normal HbA1c with further reduction in complications of diabetes A closed loop, artificial pancreas either externally or internally based is now on the horizon
Implantable pump Implanted under the skin of the abdomen through a minor surgical procedure. Controlled today by hand-held radio frequency telemetry. Delivers short, frequent pulses of insulin into the peritoneal cavity. Designed to be refilled in a physicians office every 3 months. Projected 10 year battery life. Hypoglycemic events reduced 400%.
Out-takes from a Web Blog Of RT User Now, I never look at a single reading. I check my NOW number and then quickly scroll back in time using the down arrow button. Five minutes per click. I usually glance at half an hour…I think about what Im looking at. Direction? Is the BG going up or down? Or is it fairly stable? Speed? Speed Im not always so good at, because that takes mental mathematics, which is my weak spot. That said I can get a rough idea of how fast things are moving.
THE RUB Even if the continuous sensors are refined, reimbursement for the devices as well as for providers time to help analyze data remains a problem. As things now stand, relatively few doctors and nurses have the time or expertise to assess the log records of individual glucose readings.
Predictions are difficult - particularly when youre talking about the future! Casey Stengel Adapted from Niels Bohr - Nobel Prize (Physics) 1922