1. The Future of Pumping Henry Anhalt, DO, CDE
Director, Pediatric Endocrinology and Diabetes
Saint Barnabas Medical Center
Livingston, NJ

2. `In the past we had a light that flickered, in the present, a light that flames, and in the future we will have a light that shines over all the land and the sea’
Winston Churchill

3. DCCT Relationship of HbA1c to Risk of Microvascular Complications
Relative Risk
Retinopathy
Nephropathy
Neuropathy
Microalbuminuria
HbA1c (%) 15 13 11 9 7 5 3 1 6 8 10 12
Skyler. Endocrinol Metab Clin. 1996;25: , with permission.

4. Treatment Goals A1c (%) <7.0 <6.5 FBG (mg/dl) 80-120 <100
ADA
IDF
AACE
A1c (%)
<7.0
<6.5
FBG (mg/dl)
80-120
<100
<110
2 Hr.PP (mg/dl)
<180
<135
<140

5. Limitations/Challenges to Better Glycemic Control
A1c’centric
Hypoglycemic Risk
Glucose excursions above and below what the HbA1c average represents may be more important than HbA1c
Inadequate Postprandial Glucose Control
Weight Gain

6. Obstacles in Glycemic Control
Invasive glucose monitoring devices-owie!!!!!
Limited availability of reliable continuous glucose monitoring
Lack of alternate routes of insulin delivery.

7. 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

8. Alternate Site Glucose Measurements
Over-reads
Under-reads

9. 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

10. APPROACHES TO CURING TYPE 1 DIABETES
in vivo Differentiation of Pancreatic Progenitors
Immune Interventions/
Tolerance Induction
Manipulation
Of non-islet tissue
(Transdifferentiation
Transplantation
Stem Cells
Growth Factors
Islets
Adult
Whole pancreas
Gene Therapy
Modulate Autoimmunity
Islet neogenesis
Fetal
Embryonic

11. TOWARDS CLOSED LOOP DELIVERY
External Closed-Loop
Implanted Closed-Loop
Brad – describe implantable sensor and entire slide…
Gary: ________

12. Glucose Contributions to HbA1c
Postprandial Glucose
Influenced by:
Preprandial glucose
Insulin dose
Glucose load from meal
Insulin sensitivity in peripheral tissues
Fasting Glucose influenced by:
Liver glucose production
Liver sensitivity to insulin +
Lantus, Basal rates,
Humalog, Novalog

13. Are All HbA1c Values Created Equal?
Blood Glucose
Time
HbA1c = 8%
HbA1c = 8%

14. Lesser Known Outcomes from the DCCT
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.”
Diabetes 44: , 1995

15. Actual writing on Hospital charts:Top Ten
She has no rigors or shaking chills, but her husband states she was very hot in bed last night.
Patient has chest pain if she lies on her left side for over a year.
On the second day the knee was better, and on the third day it disappeared.
The patient is tearful and crying constantly. She also appears to be depressed.
The patient has been depressed since she began seeing me in 1993.

16. Why do we need Glucose Sensors?

17. Model of Multihormonal Regulation of Glucose Homeostasis
Brain
Food
Intake* —
Liver
Gastric
Emptying —
Slide Index PH0016
DISCUSSION POINTS:
This diagram shows the key organ systems and hormones known to be involved in glucose regulation
Insulin is a major hormonal regulator of glucose production and disposal.
Glucagon secretion is important to maintain glucose homeostasis under basal (fasting) conditions when endogenous glucose production, primarily by the liver, is necessary. An endogenous source of glucose is no longer needed during and immediately following mealtime. Glucagon is normally suppressed postprandially, leading to a near-total suppression of hepatic glucose output.
Amylin is co-secreted with insulin at meal times. It is a neuroendocrine hormone and its action is mediated by the central nervous system via efferent signals from the brain.
Amylin acts to reduce the rate of glucose inflow to a rate that better matches insulin’s effects on glucose disposal by:
Reducing glucagon excess in the postprandial period.
Regulating the rate of gastric emptying
Amylin also appears to have an effect on satiety in animal studies. Short-term animal studies have shown a reduction in food intake, thereby reducing nutrient load.
GLP-1 is also secreted postprandially from the L-cells in the jejunum and ileum. GLP-1 works to lower glucose by:
Enhancing pancreatic insulin and amylin secretion when glucose concentrations are elevated
Suppressing inappropriately high glucagon secretion (which leads to inhibition of hepatic glucose output)
Regulating gastric emptying
Long-term effects of GLP-1 demonstrated in animals include increased beta-cell mass and maintenance of beta-cell function, improved insulin sensitivity, and reduction of food intake.
SLIDE BACKGROUND:
Stomach
Postprandial Glucagon
Rate of glucose appearance
Plasma Glucose
Rate of glucose disappearance
Gut
Glucose
Disposal
Amylin
Insulin
Pancreas
Tissues
GLP-1
Model derived from animal studies
*Inferred satiety effect
GLP-1 central effect on glucose homeostasis is inferred from animal studies

18. Glucose Concentration (mg/dL)
Excessive 24-Hour Glucose Fluctuations in Type 1 Patients with Mean A1C of 6.7%
400
300
Glucose Concentration (mg/dL)
200
100
12:00 AM
4:00 AM
8:00 AM
12:00 PM
4:00 PM
8:00 PM
12:00 AM
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: mg/dL
Levetan C, et al. Diabetes Care 2003; 26:1-8

19. % Peak Postmeal Glucose Levels Over Target
Intensively-treated T1DM: Diurnal Glucose Fluctuation and Nocturnal Hypoglycemia
Mean A1C = 7.7%
Postprandial Hyperglycemia
Nocturnal Hypoglycemia
100
CH: Still pretty crowded, although I have worked on rearranging text detail to emphasize main point of data.
DISCUSSION POINTS:
Even in intensively treated patients with “reasonable” A1C values (mean of 7.7% for this group), use of continuous glucose monitoring systems (CGMS) can now document excessive hyperglycemic excursions and unrecognized nocturnal hypoglycemia.
The bars on the left illustrate the percentage of peak postprandial glucose concentrations that exceeded target of 180 mg/dL.
Approximately 90% of these peaks exceeded target, even in these patients that were previously thought to be well controlled.
Almost 50% of these peaks were above 300 mg/dL.
The bars on the right illustrate the percentage of patients recording a low overnight sensor glucose concentration in the hypoglycemic range (less than 60 mg/dL).
Nearly 70% of these patients recorded at least one episode of nocturnal hypoglycemia.
Over 30% had glucose concentrations of 40 mg/dL or less recorded at least once.
Over 20% (12 patients) recorded nocturnal hypoglycemia on all 3 nights.
SLIDE BACKGROUND:
Study was conducted at the Yale Children’s Diabetes Clinic. (Tamborlane was senior author for paper)
N=56
All patients were <18 years; mean age= 11 years, 9 months
Most patients used insulin pump (n=42). Others used 2 insulin injections/day (n=12) or 3-4 insulin injections/day (n=2)
Patients were monitored for 3 days using the Medtronic MiniMed Continuous Glucose Monitoring System™ (CGMS)
Nocturnal hypoglycemia
Pre-meal glucose concentrations were in or near target range
Authors describe the mean A1C of 7.7% and the patients’ pre-meal glucose values as “suggestive of good diabetes control” in this pediatric population. Target A1C for these patients was <8%.
CSII: continuous subcutaneous insulin infusions
MDI: multiple daily injections 90
> 300 mg/dL
241–300 mg/dL
181–240 mg/dL
41–60 mg/dL
 40 mg/dL 80 80 70 70 60 60
% Peak Postmeal Glucose Levels Over Target 50 50 40
% Patients 40 30 30 20 20 10 10
Breakfast
Lunch
Supper
1 Night
2 Nights
3 Nights
90% of Postprandial Readings Exceeded ADA Guidelines
Nearly 70% of Patients Had 1 Night With PG < 60 mg/dL
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:

20. Blood Glucose Values (SMBG) Needed to Attain Different HbA1C Values
ATR
33%
ATR
41%
ATR
46%
WTR
45%
WTR
49%
WTR
42%
BTR
18%
BTR
12%
BTR
14%
HbA1c = 7.0%
HbA1c = 8.0%
HbA1c = 8.5%
WTR = within target range ( mg/dl)
BTR = below target range (<70 mg/dl)
ATR = above target range (>150 mg/dl)
Brewer KW, Chase PH, Owen S, Garg SK. Diabetes Care 1998;21(2):

21. Need for Continuous glucose monitoring
Direction
Magnitude
Duration
Frequency
Cause of fluctuation
Alerts/Alarms
Improve therapeutics decisions

22. Glucose Sensors Continuous Glucose Monitoring System (CGMS)
GlucoWatch Automatic Biographer
Navigator
Near-InfraRed (NIR)
Implantable glucose sensors-Dexcom
Optical sensors
Ultrasonic sensors

23. DexCom Implantable Sensors
Glucose Sensors
DexCom Implantable Sensors
Pendra®
GlucoWatch
FreeStyle Navigator
Sensys Medical NIR
CH: Is this a problem to mention name brands for all these devices? Check with Maryland Academy of Family Physicians.
Re-sized images for better fit.
Deleted references to lessen “busyness” of slide.
GlucoWatch Garg SK, et al. Diabetes Care 1999
Tamada & Garg SK, et al. JAMA, 1999
Pendra Caduff et al. ADA, IDF, 03
DexCom Garg SK, et al. Diabetes Care. 2004
MiniMed Tamborlane, Saudek and and Bode Diabetes Care
Freestyle Feldman et al. ADA and DT&T, 2003
Sensys Monfre and Garg SK, et al. Diabetes, 2000
MiniMed

24. MiniMed® Continuous Glucose Monitoring System (CGMS)

25. GlucoWatch® Biographer

26. Schematics of the Autosensor & Biographer
Mask
Hydrogel Pads
Ionto
Sensor
Electrode
Assembly
AAA Battery
Electronic
Components
Garg et al. Diabetes Care 1999;22:

27. Device Evaluation Advantages Disadvantages 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

28. 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)

29. 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

30. Role of Frequent Glucose Monitoring

31. More Frequent Testing Improves HbA1c in Type 1 Patients11
< 2
< 2 10
HbA1c (%) 9 8
> 4
> 4
> 4 7 6
Initial
No Contact
Cross-Over
Intensify
Schiffrin A, Belmonte M. Diabetes Care 1982;(5):

32. Current Medical Practice
Repeated finger-sticks are required to obtain glucose readings periodically
Testing is generally performed before meals
Occasional measurements provide limited information about glucose levels 80
121 40
120
160
200
240
280
320
360
400
11:00 AM
1:00 PM
3:00
5:00
7:00
9:00
Glucose (mg/dL)
Pre Lunch
Pre Dinner
This slide has been previously shown to you by Dr. Pitzer. He shows you two time points where the blood sugars are incredibly normal. A pre-lunch and pre-dinner blood sugar that are in the normal range. Now a clinician would look at this glucose diary and tell the patient that the patient was doing excellently. Not to come back for several months and continue to do everything the patient was doing at that moment.
Garg et al Diabetes Care ; 22; , 1999

33. 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
400
360
Biographer
Blood Glucose
320
Calibration Point
280
240
Glucose (mg/dL)
200
160
120 80
Pre Dinner
He then showed you what the GlucoWatch Biographer would have shown us had we had the opportunity to know the glucose patterns in between the pre-lunch and pre-dinner numbers. You can see the long periods of time the patient is sustained in the hyperglycemic levels. With this new information, we would not have concluded the patient was doing excellently, and could have counseled them on ways to improve their glucose control. 40
Pre Lunch
11:00
1:00
3:00
5:00
7:00
9:00
11:00
1:00 AM PM PM PM PM PM PM AM
Garg SK et al Diabetes Care ; 22; , 1999

34. Measurement of Blood Glucose Conventional Blood Glucose Meters
400
360
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.
320
280
240
Glucose (mg/dL)
200
121
160 80
120 80
Pre Dinner 40
Pre Lunch
11:00
1:00
3:00
5:00
7:00
9:00
11:00
1:00 AM PM PM PM PM PM PM AM
Garg et al Diabetes Care ; 22; , 1999

35. Continuous Subcutaneous Glucose Monitoring in a Subject with Type 1 Diabetes
Meter Value
Sensor Value
Insulin
Meal
450
400
350
300
250
Glucose Concentration (mg/dL)
200
150
100 50
12 MN
12 MN
1:30 AM
3:00 AM
4:30 AM
6:00 AM
7:30 AM
9:00 AM
1:30 PM
3:00 PM
4:30 PM
6:00 PM
10:30 AM
12 NOON
7:30 PM
9:00 PM
10:30 PM
Time
Chase and Garg , Pediatrics:107; , 2001

36. 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

37. 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

38. Device Description: Sensor
DexCom G1 Sensor
Subcutaneous implant in the
abdominal wall
Multi-layer membrane system
Measures glucose every 30 seconds
Wireless transmission to receiver
Garg et al., Diabetes Care, 27:734-38, 2004

39. Device Description: DEXCOM Receiver Long Or Short Term Use
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
Garg et al., Diabetes Care, 27:734-38, 2004

40. Profile With Continuous Glucose Sensor in Patients With Insulin-requiring Diabetes
Blinded period
Unblinded period 10
37%* increase
Mean A1C = 7.2%
4%* decrease
31%* decrease 8 6
41%* increase
Time Spent (hours/day)
38%* decrease 4 2
CH: Shortened title and re-arranged some elements of figure to try to lessen “busyness.” Needs more work in graphic design to make he graph smaller.
As you can see, this patient had a 74% drop in glucose levels under 55 mg/dL once the real-time values were displayed to him. In addition, this patient saw a 110% increase in values in the target range while he spent 4.4 hours less per day above 240 mg/dL.
2.46
1.53
2.13
3.00
6.37
8.74
6.46
6.16
6.58
4.57
40–55
56–79
80–140
141–239
240–400
Glucose Range (mg/dL)
*P < 0.05, Student’s t test
Garg SK, et al. Diabetes Care. 2004;27:

41. Slicing the Pie from DCGM Sensor Downloads Blinded vs
Slicing the Pie from DCGM Sensor Downloads Blinded vs. Unblinded phases (n=14)
Unblinded phase
Blinded phase
WTR
37%
WTR
51%
ATR
41%
ATR
51%
BTR
12%
BTR 8%
WTR = within target range ( mg/dl)
BTR = below target range (<60 mg/dl)
ATR = above target range (>150 mg/dl)

42. Results (G2) 307  62 215  29 -30%** 352  12 332  14 -13%**
Excursion Duration (min)*
Excursion Amplitude (mg/dl)*
Blinded
Unblinded
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  3
51  4
+3%
* Expressed as Mean  SEM
** Two-sided paired t-Test, p  0.05
Scott and Garg. ADA (LB5), o4 and EASD 2004

43. Hyperglycemia Exposure (mg/dl*hrs)*
Results (G2)
Hyperglycemia Exposure (mg/dl*hrs)*
Blinded
Unblinded
Change
573  123
340  64
-40%**
* Expressed as Mean  SEM
** Two-sided paired t-Test, p  0.05
Scott and Garg. ADA (LB5)and EASD 2004

44. 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

45. Family of Insulin Pumps Pardigm Link & Bolus Wizard Paradigm 512 ONLY
Medtronic MiniMed’s
Family of Insulin Pumps
Remote Control
Paradigm 511
MiniMed 508
Paradigm 512
Paradigm Link Meter B
102 mg/dL
Pardigm Link & Bolus Wizard Paradigm 512 ONLY

46. Actual writing on Hospital charts:Top Ten (cont.)
Discharge status: Alive but without my permission.
Healthy appearing decrepit 69 year old male, mentally alert but forgetful.
Patient has left white blood cells at another hospital.
The patient has no previous history of suicides.
The patient refused autopsy.

47. 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

48. 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

49. 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 physician’s office every 3 months.
Projected 10 year battery life.
Hypoglycemic events reduced 400%.

50. 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 I’m looking at. Direction? Is the BG going up or down? Or is it fairly stable? Speed? Speed I’m 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.”

51. 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.

52. Predictions are difficult - particularly when you’re talking about the future!
Casey Stengel
Adapted from Niels Bohr - Nobel Prize (Physics) 1922