TOWARDS A BIOLOGICAL CURE OF

TYPE 1 DIABETES..


CHALLENGES AND OPPORTUNITIES

Prediction is very difficult,
especially about the future
Niels Bohr, Danish Physicist Casey Stengel, Yankees Manager
(1885-1962) (1890-1975)
TYPE 1 RESEARCH HIGHLIGHTS
1889 Minkowski & Von Mering show that removal of
pancreas causes diabetes
1915 Urine glucose measurement (Benedicts Solution)
1921 Banting & Best discover insulin
1922 Canadian man given insulin (short acting)
1936 First long acting insulin (protamine zinc) developed
1955 Amino acid sequence of insulin determined
1960 Immunoassay for insulin developed: shows Type 1
patients produce little/no insulin


TYPE 1 RESEARCH HIGHLIGHTS
1964 First kidney transplant in diabetic patient
1966 First human pancreatic transplant
1973-75 ICA, HLA association described
1976 HbA1c
1978 First pump
1980 Genetically engineered human insulin
Home blood glucose monitoring
1983 Islet related autoantibodies predate
development of Type 1 diabetes
1990 First human islet cell transplant
1993 Results of DCCT revealed
1996 Analog insulins
1998 Glucose sensor
MAJOR ADVANCES PAST 30 YRS
Demonstration through the DCCT that tight control can
reduce complications
SIGNIFICANCE: Era of INTENSIVE MANAGEMENT
Technological Advances

Better understanding of beta cell biology leading to
replacement of beta cell function
SIGNIFICANCE: Sets stage for CURE

Type 1 diabetes is a predictable immune mediated
disease using immunological, genetic and metabolic
markers
SIGNIFICANCE: Sets stage for PREVENTION




WHY LIMITED SUCCESS TO DATE?


- Type 1 diabetes is a heterogeneous disease
- Changing face of Type 1 diabetes
- What have we really learned from animal models?
- We know little about mechanism!!
Is Type 1 really a primary autoimmune disease?
- whats actually happening in pancreas?
- no markers in humans other than islet Ab
.of immune dysregulation or cell killing
- lack of correlation of insulitis with islet Ab (nPOD)
- Unable to replace and sustain cell function
- Limited success of immune interventions
Wrong approach? Wrong combination?
- - -
HETEROGENEITY OF TYPE 1 DIABETES
(years)
-CELL
FUNCTION
(%)
10 20 30 40
100
LADA
Adult
Early
childhood
Late
Childhood

PUTATIVE
ENVIRONMENTAL
TRIGGER
TIME
`PRE-T1D IS HETEROGENEOUS


B
E
T
A

C
E
L
L

M
A
S
S

DIABETES
PRE-
DIABETES
GENETIC
PREDISPOSITION
INSULITIS
BETA CELL INJURY
AUTOIMMUNITY
C-PEPTIDE PRESENT IN
LONG-STANDING TYPE 1 DIABETES
Oram et al Diabetologia 57:187-191, 2014
68% + > 30 yrs duration

DISEASE DIVERSITY IN LONG
STANDING TYPE 1 DIABETES
Ki67+Insulin
Amyloid
Insulin+ Medalist (6065)
76 yo T1D for 56 yrs
Insulin- Medalist (6066)
78 yo T1D for 74 yrs
Islets are large and ~100% non-beta
cells
Glucagon
Keenen et al, Diabetes 59: 2846-53, 2010
cells may persist >50 yrs
HETEROGENEITY OF BETA CELL MASS
Saisho et al. Diabetes Care 36:111, 2013
CHANGING FACE OF TYPE 1 DIABETES

WORLDWIDE TRENDS IN INCIDENCE OF T1D*

0
5
10
15
20
25
30
35
40
45
50
1
9
7
3
1
9
7
5
1
9
7
7
1
9
7
9
1
9
8
1
1
9
8
3
1
9
8
5
1
9
8
7
1
9
8
9
1
9
9
1
1
9
9
3
1
9
9
5
1
9
9
7
1
9
9
9
2
0
0
1
2
0
0
3
T
1
D
M

I
n
c
i
d
e
n
c
e

p
e
r

1
0
0
,
0
0
0
Finland
Canada
Australia
Belgium
Slovenia
France
Japan
Chile
United States
Vehik & Dabelea . DMRR 27: 3-13, 2011
* 0-14 years;

Increasing numbers of children
Decreasing numbers with high-risk HLA alleles
Up to 1/3 may be > 18 years of age at onset
Latent Autoimmune Diabetes of Diabetes (LADA)
new cases/yr doubling every 20 yrs
TRENDS IN INCIDENCE OF T1D
IN NHW YOUTH, 2002-2009
p=0.0008
p=0.0023
p=0.0008
p=0.1862
p=0.0040
Lawrence, et al. Diabetes June 4, 2014, doi: 10.2337/db13-1891

CHANGING HLA GENOTYPE OVER TIME
1978-88 vs 2002-04
44
45
44
28
31
28
0
5
10
15
20
25
30
35
40
45
50
NHW HISP ALL
F
r
e
q
u
e
n
c
y

(
%
)
H
I
G
H

R
I
S
K
Vehik et al Diabetes Care 31: 1392-96, 2008
Conway B et al. Diabet Med. 2010
TEMPORAL PATTERNS IN OVERWEIGHT
AND OBESITY IN TYPE 1 DIABETES
*EDC Study
ACTION LADA (N=6136)
6.3% GAD positive within 5 years post-diagnosis


China LADA (n=5138)
5.9% positive within 5 years post-diagnosis


Hawa et al Diabetes Care 2012
Zhou et al Diabetes 2013
LATENT AUTOIMMUNE DIABETES OF ADULTS

(LADA)
HYPOTHETICAL MODEL OF
IMMUNOPATHOGENESIS OF T1D
Dendritic cell/
Macrophage
nave
T-cell
T CR
CD3
T
eff
IFN-g
TNF-a
I L -12
I L -23
IL -1b
I L -6
IL- -15
T
r eg
Ag
MHC/pep APC

Signal 1 - TCR
Signal 2
Co-stimulation
B-cell
T-cell B-cell help
-cell
-cell
apoptosis
-cell
regeneration
Activated
Macrophage
I L -10
T GF-b
I L -2
apoptosis
I L -2
CD2
ISLET
CD80/CD86 CD28
a disorder of failed immunoregulation?
T reg
T eff
T reg
Teff
Tolerance Autoimmunity
MANY INTERVENTIONS PREVENT TYPE
1 DIABETES IN NOD MICE
Atkinson et al, 2014
AAV murine IL-10
AAV rat preproinsulin gene (vLP-1)
Adenovirus expressing mIL-4
Aerosol insulin
Allogenic thymic macrophages
Alpha Galactosylceramide
Alpha-interferon (rIFN-alpha)
Alpha/beta T cell receptor thymocytes
Aminoguanidine
Androgens
Anesthesia
Antioxidant MDL 29,311
Antisense GAD mRNA
Azathioprine
Anti-B7-1
Bacille Calmette Guerin (BCG)
Baclofen
Bee venom
Biolistic-mediated IL-4
Blocking peptide of MHC class II
Bone marrow transplantation
Castration
Anti-CD3
Anti-CD4
CD4+CD25+regulatory T cells
Anti-CD8
Anti-CD28 MAb
Cholera toxin B subunit-insulin protein
Class I derived self-I-A beta(g7) (54-76) peptide
Cold exposure
Anti-complement receptor
Complete Freunds adjuvant
Anti-CTLA-4
Cyclic nucleotide phosphodiesterases (PDEs)
Cyclosporin
Cyclosporin A
DC deficient in NF-kappaB
DC from pancreatic lymph node
DC with IL-4
Deflazacort
Deoxysperogualin
Dexamethasone/progesterone/growth hormone/estradiol
Diazoxide
1,25 dihydroxy Vitamin D3, KH1060
1,25 dihydroxycholecalciferol
1,25 dihydroxyl Vitamin D3
Elevated temperature
Emotionality
Encephalomyocarditis virus (ECMV)
Essential fatty acid deficient diets
FK506
FTY720 (myriocin)
GAD 65 peptides in utero
Anti-GAD monoclonal antibody
Galactosylceramide
Glucose (neonatal)
Glutamic acid decarboxylase
(intraperitoneal, intrathymic, intravenous, oral)
Glutamic acid decarboxylase 65 Th2 cell clone
Glutamic acid decarboxylase peptides
(intraperitoneal, intrathymic, intravenous, oral)
Gonadectomy
Guanidinoethyldisulphide
Heat shock protein 65
Heat shock protein peptide (p277)
Hematopoietic stem cells encoding proinsulin
Housing alone
Human IGF-1
I-A beta g7(54-76) peptide
Anti-I-A monoclonal antibodies
Anti-ICAM-1
IgG2a antibodies
Immobilization
Inomide
Anti-integrin alpha 4
Insulin (intraperitoneal, oral, subcutaneous, nasal)
Insulin B chain (plasmid)
Insulin B chain/B chain amino acids 9-23 (intraperitoneal, oral, subcutaneous, nasal)
Insulin-like growth factor I (IGF-I)
Anti-intercellular adhesion molecule-1 (ICAM-1)
Interferon-alpha (oral)
Interferon-gamma
Anti-interferon-gamma
Interferon-gamma receptor/IgG1 fusion protein
Interleukin-1
Interleukin-4
Interleukin-4-Ig fusion protein
Interleukin-4-plasmid
Interleukin-10
Interleukin-10-plasmid DNA
Interleukin-10-viral
Interleukin 11-human
Interleukin-12
Intrathymic administration of mycobacterial heat shock protein 65
Intrathymic administration of mycobacterial heat shock peptide p277
Islet cells-intrathymic
L-Selectin (MEL-14)
Lactate dehydogenase virus (LDH)
Large multilamellar liposome
Lazaroid
Anti-leukocyte function associated antigen (LFA-1)
Anti-LFA-1
Linomide (quinoline-3-carboxamide)
Lipopolysaccharide-activated B cells
Lisofylline
Lymphocyte choriomeningitis virus (LCMV)
Anti-lymphocyte serum
Lymphoctyte vaccination
Lymphocytic choriomeningitis virus
Anti-L-selectin
Lymphotoxin
LZ8
MC1288 (20-epi-1,25-dihydroxyvitamin D3)
MDL 29311
Metabolically inactive insulin analog
Anti-MHC class I
Anti-MHC class II
MHC class II derived cyclic peptide
Mixed allogeneic chimerism
Mixed bone marrow chimeras
Monosodium glutamate
Murine hepatitis virus (MHV)
Mycobacterium avium
Mycobacterium leprae
Natural antibodies
Natural polyreactive autoantibodies
Neuropeptide calcitonin gene-related peptide
Nicotinamide
Nicotine
Ninjin-to (Ren-Shen-Tang), a Kampo (Japanese traditional) formulation
NKT cells
NY4.2 cells
OK432
Overcrowding
Pancreatectomy
Pentoxifylline
Pertussigen
Poly [I:C]
Pregestimil diet
Prenatal stress
Preproinsulin DNA
Probucol
Prolactin
Rampamycin
Recombinant vaccinia virus expressing GAD
Reg protein
Reg protein
Rolipram
Saline (repeated injection)
Schistosoma mansoni
Semi-purified diet (e.g., AIN-76)
Short term chronic stress
Silica
Sirolimus/tacrolimus
Sodium fusidate
Soluble interferon-gamma receptor
Somatostatin
Non-specific pathogen free conditions
Streptococcal enterotoxins
Streptozotocin
Sulfatide (3sulfogalactosylceramide)
Superantigens
Superoxide dismutase-desferrioxamine
Anti-T cell receptor
TGF-beta 1 somatic gene therapy
Th1 clone specific for hsp60 peptide
Anti-thy-1
Thymectomy (neonatal)
Tolbutamide
Tolerogenic dendritic cells induced by vitamin D receptor ligands
Top of the rack
Treatment combined with a 10% w/v sucrose-supplemented drinking water
Tumor necrosis factor-alpha
TX527 (19-nor-14,20-bisepi-23-yne-1,25(OH)(2)D(3))
Vitamin E
Anti-VLA-4



POTENTIAL TARGETS OF IMMUNE MODULATION
Modified from Bluestone et al : 464j29 April 2010jdoi:10.1038/nature08933 with permission

CTLA-4
MAJOR CHALLENGES
Development of new methods for achieving tight control
without hypoglycemia
`artificial pancreas
but insulin is NOT a cure

Development of better methods for replacing beta cell
function (transplantation, regeneration)
`biological cure

Enhanced understanding of immunopathogenesis
(interaction of genes, environment and immune system)
allowing for more effective preventative therapies
without prevention there cannot be a cure
NO BIOLOGICAL CURE WITHOUT
PREVENTION
Control
Autoimmunity
Beta Cell
Regeneration/
Transplantation
Protect Beta
Cell Mass
Cure
Prevention
IMMUNOMODULATION
CELL THERAPIES
TRANSPLANTATION FOR TYPE 1 DIABETES
6
6.5
7
7.5
8
8.5
9
9.5
0 1 2 3 4 5 6 7 8 9
YEARS
H
b
A
1
c
,

%

CONVENTIONAL GROUP
POST TRANSPLANT
INTENSIVE GROUP
70
80
90
100
0 6 12 18 24 30 36
Months Posttransplant
%
PATIENT SURVIVAL
n = 25,000 : International Pancreas Transplant Registry (IPTR) over 24 yrs
2/09
95%
Gruessner AC. Rev Diabet Stud 8: 6-16, 2011
90%
SPK, PAK, PTA
0
20
40
60
80
100
0 6 12 18 24 30 36
Months Posttransplant
%
PANCREAS GRAFT FUNCTION
USA Primary Pancreas Transplants 1/1/2004
SPK
PAK
PTA
p < 0.0001
3/09
ISLET TRANSPLANTATION
. is improving
Rickels, et al. Diabetes 62:2890, 2013
CURRENT LIMITATIONS OF
TRANSPLANTATION
Availability of cadaveric donors
Quality and quantity of tissues/islets
Limited survival
Immunosuppressive drug toxicity
Rejection (alloimmunity)
Recurrent (autoimmune) b cell destruction

OBTAINING CELLS FROM STEM CELLS

Pancreas
- patient, cadaveric
- ? other human donors (xeno)
Embryonic
Liver
Bone marrow transdifferentiation
Cord blood
? Placenta
? Peripheral blood
Control Insulin C-peptide
I
N
S
-
1

m
B
M
D
S

h
B
M
D
S
C

Yang et al; Diabetes. 2004 ;53:1721-32
OBTAINING CELLS FROM STEM CELLS

Pancreas
- patient, cadaveric
- ? other human donors (xeno)
Embryonic
Liver
Bone marrow transdifferentiation
Cord blood
? Placenta
? Peripheral blood
LIMITED SUCCESS
TO DATE
TIME
INTERVENTION OPPORTUNITIES
AND CHALLENGES
B
E
T
A

C
E
L
L

M
A
S
S

DIABETES
PRE-
DIABETES
GENETIC
PREDISPOSITION
INSULITIS
BETA CELL INJURY
THERAPY MORE LIKELY TO BE EFFECTIVE
PREDICTION LESS ACCURATE
SAFE
PREDICTION MORE ACCURATE
THERAPY LESS LIKELY
TO BE EFFECTIVE
MORE TOXIC

LATE
EARLY
Primary
Secondary
DPT-1 Parenteral Insulin No effect
DPT-1 Oral Insulin ** ??
ENDIT Nicotinamide No effect
DIPP Nasal Insulin No effect
INIT-II Nasal Insulin Ongoing
TRIGR Casein hydrolysate No effect
NIP Docosahexaenoic Acid No effect
Human T1D Prevention Studies
Limited Impact
** Post-hoc analysis identified subgroup with benefit

A Subset with IAA Confirmed > 80 nU/ml
Suggested Potential 4.55 year Delay of T1D

1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
S
u
r
v
i
v
a
l

D
i
s
t
r
i
b
u
t
i
o
n

F
u
n
c
t
i
o
n

0 1 2 3 4 5 6 7
Years Followed
130
133
122
121
104
96
86
69
66
46
40
32
23
12
Number at Risk
P- Value= 0.015
(Log Rank Test)
Oral Insulin
Oral Placebo
STRATA: Oral Insulin
Oral Placebo
Control
Treated
Projected 4.55 year delay
Skyler JS et al. Diabetes Care 2005;28:106876
RECENT NEW-ONSET DIABETES STUDIES
* transient benefit
Published
- * -CD3 (x4)
- * -CD20
- Mycophenolic Mofetil + anti-CD25
- GAD x2
- * CTLA-4
- * DiaPep
- * Autologous non-myeloablative transplantation
- Cord Blood
- IL-2 plus Sirolimus (Phase 1)
- Canakunimab; Anakinra
- Cord Blood Phase 2 (+ Vit D + Omega 3 FA)
- Meticulous Metabolic Control
Completed enrollment
- Mesenchymal Stem Cells
- GCSF
- ATG-GCSF
Enrolling
- T reg - -1 antitrypsin




SUCCESSFUL NEW-ONSET STUDIES..

0
50
100
0 6 12 18 24
Months
A
U
C

c
-
p
e
p
t
i
d
e

Control
Treated
Long term benefit ??Lon
?? Proof of concept for prevention vs C-peptide preservation
THE CONCEPT FOR COMBINATION
Monotherapy transiently effective
Combo may allow lower dose of riskier agents
Rational combinations assist in complex disease
Efficacy in other disorders (cancer, HIV,
transplantation)
To speed translation, can choose agents with
FDA approval for other indications


Diabetes Care, 2002
`EXTREME COMBO THERAPY:
BRAZIL APPROACH
Voltarelli et al JAMA, 297:1568-76, 2007
Couri et al JAMA, 301:1573-9, 2009

1 Hematopoetic stem cell mobilization -
- Cyclophosphamide 2 g/m
2
- G-CSF 10 g/kg daily
- CD34+ cells harvested (3x10
6
CD34+ cells/kg)
2. Non-myeloablation
- Cyclophosphamide 50 mg/kg x 4 days
- ATG 0.5-1 mg/kg x 5 days
3. Transplantation / Mobilization
- G-CSF 5g/kg till ANC >1,000
4. Intensive supportive care
- Pre: Cipro/Cefepime, Acyclovir, Amphotericin
- Post: Fluconazole, Septra or Dapsone
Couri, C. E. B. et al. JAMA 2009;301:1573-1579.
C-PEPTIDE LEVELS
12 Patients Continuously Insulin Free
8 Patients Transiently Insulin Free
CRITIQUE
? ethical
Mortality 1-17%
Morbidity:
Hospitalization 28 days; pneumonia
Long term complications
Malignancy (leukemia, lymphoma, solid tumors), infertility
No randomized and matching control group
?? Mechanism
insulin discontinued in 12/14 after immunosuppression but before
infusion had time to take effect

LOGICAL to study lower risk components of therapy
BRAZIL-LITE.low dose ATG+GCSF Combination

SEARCHING FOR THE RIGHT
COMBINATION..




ATG+G-CSF
REVERSAL IN NOD MICE




G-CSF rescues reversal rate of 1/3 ATG dose from 35% back to 80%
GCSF allows reversal at higher initial glucose
BRAZIL `Lite ATG/GCSF Combo
Established Type 1 Diabetes (Helmsley)













Established Diabetes (4 months 2 years)
Thymo - 2.5 mg/kg over 2 days (low dose)
Neulasta - 6 mg q 2 weeks for 12 weeks
n=25
Single Blinded
2:1 combo: placebo randomization
2 Sub cohorts, 12 years 45 years
- 4 months to year post Dx
- 1-2 years post Dx


UF/BDC/UCSF (2013)
ATG/GCSF Combo
Preliminary Data Summary
CONFIDENTIAL UF/BDC/UCSF 2013
CHALLENGES & OPPORTUNITIES(1)
Current treatment quite good butinsulin not a biological cure
Primum non nocere (safety)

Define clinical significance (efficacy)
- superiority/ease over current treatment
- only do if translatable
- define responders

Develop more robust endpoints

Re-evaluate study design (smaller, shorter
mechanistic studies)
CHALLENGES & OPPORTUNITIES(2)

Study more homogeneous populations

Institute multiple concurrent innovative
strategies in multiple populations
(At-risk Established)

Use a `cocktail approach

Pursue an endless supply of
immunoprotected islets

Better understand triggers, mechanisms


Anti-CD3 Trials Negative, but
Responders and Non-Responders
0 10 20 30
0.0
0.3
0.6
0.9
1.2
Control
Drug Responder
Drug Non-Responder
*** *** *** ***
Months
C
-
p
e
p
t
i
d
e

A
U
C
(
p
m
o
l
/
m
L
/
m
i
n
)
Diabetes 2013; 62: 3766-3774
PUTATIVE
ENVIRONMENTAL
TRIGGER
TIME
FUTURE PREVENTION OF TYPE 1 DIABETES
TriaNet and other Networks
B
E
T
A

C
E
L
L

M
A
S
S

M
DIABETES
PRE-
DIABETES
GENETIC
PREDISPOSITION
INSULITIS
BETA CELL INJURY
Early Monotherapy
Late Combinations
SAFE
MORE TOXIC ?
Anti-CD3 or
ATG and/or
Anti-CD20 and/or
CTLA4-Ig
GLP-1 Receptor Agonists
Oral Insulin
GAD
GAD GAD
T-regs

POTENTIAL COMBINATION THERAPY APPROACH
GCSF GCSF GCSF
Anti-CD3 or
ATG and/or
Anti-CD20 and/or
CTLA4-Ig
Possible
retreatment
GRAS Therapies

RE-WRITING THE TEXTBOOKS ON
HOW TYPE 1 DIABETES DEVELOPS



Lessons to be learned from the Network for
Pancreatic Organ Donors with Diabetes (nPOD)

TEDDY

Type 1 diabetes is a disorder of beta
cells.

One marked with diversity and
likely, contribute to their self-demise
PANCREAS WEIGHT IN DIABETES
INSULIN PRESERVED IN A SUBSET OF T1D PATIENTS
WHY DO THEY STOP SECRETING INSULIN?
! !
GLUT2
Glucose
P
Pyruvate
ATP/ADP !!
K
+
! !
!

Ca
2+
Ca
2+
!!
Insulin
Secretory
Granules
K
+
GCK
ATP
Synthase
nPOD 6051
(13 yrs with T1D)
nPOD 6113
(1 yr with T1D)
Courtesy Clayton Mathews
Courtesy, Clayton Mathews
Control New Onset AA +
BETA CELLS DOWNREGULATE
METABOLIC ACTIVITIES IN PRE-DIABETES
5 YEAR PREDICTIONS
Incidence and prevalence will stabilize
Greater awareness of diabetes, cost, morbidity and
mortality
With improvements in glucose control, rates of
retinopathy and nephropathy will continue to decrease
Heart disease will continue to be reduced due to use
of statins, ACE inhibitors, and better screening
Severe hypoglycemia will be reduced due to more and
better use of CGM
More agents approved for T2D will be used in T1D
Socio-economic barriers, inequities and cost will be
challenging.


LESSONS FOR FUTURE
..find solutions rather than spouting
theory.
not an optimist but a great believer in
hope..
.always seems impossible till it is done

Nelson Mandela (1918-2013)
ACKNOWLEDGEMENTS
Mike Haller
Mark Atkinson
Maigan Hulme
Clive Wasserfall
Todd Brusko
Clay Mathews
Amanda Posgai PATIENTS
Martha Campbell-Thompson
Mary Alice Dennis
Miriam Cintron
Matt Parker
Kieran McGrail
Sean McGrail
Theresa Sumrall


Barbara Davis Center:
Peter Gottleib
Aaron Michels
Jenna Lungaro

UCSF:
Steve Gitelman
Marcia Wertz
Rebecca Wesch



ITN:
Jerry Nepom
Mario Ehlers

Engineering a Multi-functional Device
for Insulin Producing Cells
Modulating the Local Environment
Co-delivery of
Helper Cells
Mechanical
Protection
Bioactive
Surfaces
Vascular
Infiltration
Localized
Drug
Delivery
In situ
Oxygen
Generation
Multi-functional Platform
Encapsulation
Insulin Effect Most Evident in Subjects
with Baseline IAA 300
N=63 (Ins.) and 69
(Plac.)
P
r
o
p
o
r
t
i
o
n

F
r
e
e

o
f

D
i
a
b
e
t
e
s

0 1 2 3 4 5 6
0.0
0.2
0.4
0.6
0.8
1.0
Oral Insulin
Placebo
Log-rank P=0.01
Peto Pr. P=0.01
Hazard Ratio: 0.41 (0.21, 0.80)
Projected 10 year
delay
Years Followed
Control
Treated
CLOSING THE LOOP
will precede the biological cure....butbarriers
Technological
? need for frequent and accurate BG monitoring
Need faster acting insulin
Tough routine!
Motivation and support
family
healthcare team
Fear of/actual hypoglycemia/DKA
Weight gain
Cost

NEED FASTER ACTING INSULIN
Less hypoglycemia
Insulin on quickly, then off so better
separation with basal insulin
IMPORTANT: development of all insulin
analogues, no matter if basal or prandial, have
shown reductions in hypoglycemia but no
improvements in HbA1c

Solve one of our biggest problems with the
artificial pancreas projects