3Stem Cell Breakthrough In a breakthrough that signifies a move toward a cure for type 1 diabetes, Australian researchers have identified stem cells in the pancreas that can be turned into insulin-producing cells....Identified and isolated stem cells from the adult pancreas, and then developed a way to coax them into insulin-producing cells that can secrete insulin in response to glucose.2012
4BCGIn the study, six insulin-dependent adults with type 1 diabetes received either two doses of BCG or two fake vaccinations.In the three patients who received the vaccine:"Bad" anti-insulin T cells began dying off.New "good" regulatory T cells increased.There were signs of new, albeit temporary, insulin production from pancreatic beta cells.The vaccine was safe.
5Vitamin D Deficiency Linked to Type 1 Diabetes (Nov, 2012) — A study led by researchers from the University of California, San Diego School of Medicine has found a correlation between vitamin D3 serum levels and subsequent incidence of Type 1 diabetes.The six-year study of blood levels of nearly 2,000 individuals suggests a preventive role for vitamin D3 in this disease.
6Quest to prolong the action of insulin 1930’s-- development of protamine zinc insulinLente, NPH, and ultralente were developed as suspensions to prolong action by delaying absorptionGlargine and detemir were developed to prolong subcutaneous absorption by altering amino acid structure (glargine) or adding fatty acylated side chains (detemir)
7“Ideal” Basal InsulinThe “ideal” longer acting insulin may be expected toReduced variabilityLower risk of hypoglycemia,Reduce the need for twice-daily injectionsProvide minimal peak activityRestore physiologic distribution of the 2-fold portal to systemic insulin levelsSubcutaneous systemic absorption results in similar portal and systemic levelsWith current insulins, reduced hepatic insulin action must be balanced with excess peripheral insulin action to maintain glucose homeostasis.
13Pharmacodynamic Profiles of LY2605541 Heise, et al, Poster ADA 2012
14Better Glycemic Control and Weight Loss with the Novel Long-Acting Basal Insulin LY Compared with Insulin Glargine in Patients with Type 1 Diabetes Julio Rosenstock, Richard M. Bergenstal, Thomas Blevins, Linda A. Morrow, Melvin J. Prince, Yongming Qu,Vikram P. Sinha, Daniel C. Howey, Scott J.JacoberADA, 2012, abstracts/poster session
15Change in A1cADA, 2012, abstracts/poster session
16Change in WeightADA, 2012, abstracts/poster session
19Injected Prandial Insulin Rapid Acting or Very Rapid Acting (Warp Speed?)
20Do We Need Ultrafast Insulin? Current analog insulin is slower than the physiologic prandial insulin response of healthy individualsTypical time to peak insulin concentration is minutes for healthy subjects vs minutes for analog prandial insulinTail of insulin action is longer than physiologic response and leads to 3- 6 hour post meal hypoglycemia (including nocturnal hypoglycemia)Prandial control is elusive for even “well-controlled” patientsMajority of patients fail to achieve Post-Prandial Glucose (PPG) goalsCurrent analog insulin requires approximately minutes meal delay
22rHuPH20 disperses SC administered drugs SC administered drug depot Hyaluronin and HyaluronidaserHuPH20 disperses SC administered drugsSC administered drug depotHyaluronan (hyaluronic acid) Structure/FunctionUntil the late 1970s, hyaluronan was described as a "goo" molecule, a ubiquitous carbohydrate polymer that is part of the extracellular matrixLarge (Mega Dalton), repeating sugar polymer found in interstitial tissuesForms barrier to bulk fluid flow in interstitial spaceHuman body turns over more than 5 grams/day (1/3rd of total body pool)Hyaluronidase Mechanism of ActionCatalyzes the rapid depolymerization of hyaluronanLocally-acting, transient removal of the hyaluronan barrier to enhance the dispersion of coinjected drugsRapid dispersion enhances insulin dissociation kinetics and accelerated absorption into the systemic circulationLAN030408ZXW ZXW
23Pharmacokinetic Results The three marketed rapid acting analog insulins have similar time exposure profilesMorrow et al. ADA oral presentation 2010LAN030408ZXW ZXW
24Pharmacokinetic Results Faster In (Primary Endpoint):With rHuPH20 insulin exposure in the 1st hour was 191%, 229%, and 246% of control for glulisine, lispro and aspart, respectively (all P < )Faster Out:Insulin exposure after 2 hours decreased by 43%, 54%, and 57% for PH20 coinjection with glulisine, lispro and aspart, respectively (all P < )Morrow et al. ADA oral presentation 2010LAN030408ZXW ZXW
25Human Hyaluronidase + Rapid Analog Insulin (RAI) Improves Postprandial Glycemic Control in Type 1 Diabetes Compared to Insulin Lispro AloneIRL B. HIRSCH, JAY S SKYLER, SATISH GARG, THOMAS BLEVINS, DANIEL E VAUGHN, DOUGLAS B MUCHMOREUniversity of Washington, Seattle, WA;University of Miami, Miami, FL;University of Colorado Denver, Aurora, CO;Texas Diabetes and Endocrinology, Austin, TX;Halozyme Therapeutics, San Diego, CAHirsch et al, ADA 2012 Poster
26% Reduction in Glycemic Excursion T1DM: Improved Prandial Control with Analog-PH20 Demonstrated Throughout StudyMeal% Reduction in Glycemic ExcursionBreakfast73% (p=.017)Lunch34% (p=.44)Dinner219% (p=.040)Overall82% (p=.0045)Overall mean PPG change (90 minutes) from pre-meal baseline, routine SMBG monitoring throughout each treatment phase.Confidential
32CSII Reduces Incidents of Severe Hypoglycaemia1/4 23Severe Hypoglycaemic Episodes: CSII vs MDI1 Rudolph JW, Hirsch IB. Endocrine Pract 2002: 8; 401 – 4052 Bode, BW et al., Diabetes Care 1996, 19:325-7.3 Boland, EA et al., Diabetes Care 1999, 22:4 Pickup JC & Sutton, AJ. Diabet Med 2008;25:
33CGM alerts improve glycemic control CGM Alerts Reduce Duration of Hypoglycaemic Excursions171 Type 1 patients wore sensors over a 12-day periodMulti-Center RCT where patients were randomised to:Alert GroupAlerts On 50%Alerts Off 50%Control GroupAlerts OffPeriod 1Period 2Minutes per eventAlertsoffon33.6p=0.004p=0.03CGM alerts improve glycemic control1. Bode et al Diab.Tech & Therapeutics 6(2):
354/11/2017 5:15 AMSensor ReportTake them from top to bottom, quick overview of what report showsSequential Glucose graphs 5 days. If more than 5 days, report will go to 2 pagesSensor Overlays now with color coding, intensity indicates strength of pattern (blow up a part of the 24 hr overlay to illustrate)Clinical time periods (last block)Once you find a problem here you move on to the next report where you can look at more detail to determine cause and effect.35
37The Road to Closing the Loop Low Glucose SuspendPredictive low glucoseHigh glucose bolusPredictive high glucose bolusTrue closed loop
38How Does Low Glucose Suspend Work? User settable: On/OffRange: Trigger at <50 mg/dlFictional illustration of Low Glucose Suspend function in useSuspends insulin infusion for a 2-hour periodAll other sensor functions and alerts remain operational during insulin suspension
39Low Glucose Suspend is the first component of the closed loop Reduces the severity of hypoglycemiaComplements the CGM alertsProvides an additional safety measure for an unresponsive patient
41Introducing the MiniMed Paradigm® Veo™ System A new era in diabetes management Closing the loopFirst device to offer sensor-driven adjustments to insulin deliveryGreater protection from severe hypoglycaemiaAutomatic insulin shut-off mechanism –Low Glucose Suspend (LGS)Greater protection from glycaemic excursionsCGM-ready insulin pumpCombined CSII and CGM offer clinical benefits1CGM alertsGive early warnings of glycaemic excursionsReduce the duration of hypoglycaemic excursions2Improved sensor sensitivity in the hypoglycaemic range1. Pickup JC, Sutton AJ. Severe hypoglycaemia and glycaemic control in Type 1 diabetes: meta-analysis of multiple daily injections compared with continuous subcutaneous insulin infusion. Diabet Med. 2008;25:2. Bode B., et al. Diabetes Technology and Therapeutics. Volume 6, Number 2, 2004
44Effect of LGS on hypoglycemia By means of %SG for individual users**LGS OffLGS OnpMean151.34156.040.050STD60.0754.84 0.028%SG<501.330.920.001%SG<603.582.630.140%SG<706.735.480.433%SG<8011.3910.050.866Reduction in severe hypoglycemic blood glucose levels is observed with LGSFig. Comparison of low sensor BG when LGS is OFF vs. ONPercent time SG <= 50Percent time SG <= 80**”Characterization of the Low Glucose Suspend Feature of the Medtronic Paradigm Veo Insulin Pump and Events Preceding its Activation” . To be presented by Dr. Fran Kaufman at the ADA conference 2011
46Studies Done at Here in Austin at Texas Diabetes and Endocrinology Basal InsulinDegludecBasal insulin lispro (BIL)Rapid, pre-meal insulin (warp speed)HalozymeBiodelInsulin pump-LGS (low glucose suspend)
47Studies- ongoing or coming up for Type 1’s Sanofi U300- Lantus penConcentrated insulin, lower volume3 units for every 1 traditional unitHalozyme- Insulin pump with very rapid acting insulinEli Lily BIL basal insulin flex dosingGiven in the am or pm-flat profileLiraglutide in Type 1’sThe agent that lowers glucose and glucagon with weight loss in Type 2 diabetesNovo DegludecLong acting, basal insulin with flat profile.
48“Smart Insulin” “Smart Insulin” works via competitive binding insulin (orange lines), attached to a sugar group (orange hexagons), binds with a sugar-binding molecule (blue circle) in solution.When glucose (blue hexagons) in the body is high, it competes with insulin to bind to the sugar-binding molecules, displacing insulin and releasing it into the bloodstream as needed