Future of DM management by Dr Shahjada Selim

1. Dr Shahjada Selim
Associate Professor
Department of Endocrinology, BSMMU
Website: https://shahjadaselim.com/
The Future of Diabetes
Management

2. • The consequences of long-term hyperglycemia
can lead to end stage micro- and macrovascular
damage leading to organ failure such as
neuropathy, nephropathy, retinopathy, peripheral
vascular disease, morbidity and mortality.
• Diabetes mellitus is a devastating disease chat can
present at various ages, in different forms and can
display a myriad of clinical presentations and
features.
Background

3. Background
• The incidence of the disease is increasing
worldwide and the most common diabetes
category in the United States, Canada, Europe and
Australia is type 2 diabetes (T2D), accounting for
more than 80% of diabetes cases."
• Therefore, it is of paramount importance to
prevent DM and if possible, reverse it.

4. Future expectations in Diabetes Care
➢Expanding diabetes care to more
patients
➢Insulin delivery device improvisation
➢Normalization of endogenous insulin
secretion or increasing insulin
producing cells

5. Phillip M et al 2021. DIABETES TECHNOLOGY & THERAPEUTICS Volume 23, Number 2, 2021. DOI: 10.1089/dia.2020.0375
The Digital/Virtual Diabetes Clinic: The Future Is Now—Recommendations from an
International Panel on Diabetes Digital Technologies Introduction

6. Overview of Advanced Diabetes Technology
Continuous Glucose Monitoring
▪ Personal Continuous Glucose Monitoring
▪ Diagnostic/Professional/Blinded Continuous Glucose
Monitoring
Insulin Delivery Systems
▪ Connected Pens
▪ Insulin Pumps
▪ Conventional Pumps
▪ Continuous Subcutaneous Insulin Infusion with Continuous
Glucose Monitoring
▪ Telemedicine Technologies
▪ Smartphone Applications

7. Road Map to Artificial Pancreas

8. What do we need to achieve AP?
• Better accuracy, user
interface, reliability.
• Better algorithm
• One site for CGM &
Insulin
Glucose Sensors
Insulin Delivery Algorithm
Insulin Pumps
Insulin (ultrafast action)

9. Normalization of endogenous insulin
secretion or increasing insulin producing cells
• The cure for IDDM is successful islet cell
transplantation, which will be available in the near
future.
• Gene modulation therapy for susceptible subjects is a
promising preventive measure.

10. Cellular Treatment of DM:
A. Pancreas Transplantation
➢Transplantation of entire pancreatic organ from
immunologically identical donor
➢To prevent rejecting pancreas the patient is kept on
immunosuppressive drugs for life.
➢These patients are susceptible to infections and the
steroid immunosuppressant therapy increases the
metabolic needs of transplanted cells and, ultimately,
their capacity to produce insulin decreases with the
passage of time.
10

11. 11

12. Cellular Treatment:
B. Pancreatic Islets Cells Transplantation
12

13. ➢Cadaveric islets are kept away from recipient's
immune system through the use of
immunosuppressants as sirolimus and tacrolimus.
➢ The islet cells can be encapsulated, allowing the
insulin to exit while protecting the islet cells.
➢Can be performed with steroid-free
immunosuppressive regimen, which was a major
advance in the field.
13

14. ➢By a year after transplantation, about 50 - 68% of
patients were observed off insulin, but by five years
after the procedure, less than 10% of total patients
were seen to be free of daily insulin injections.
➢success depends on the number of transplanted islet
cell grafts received by these individuals.
➢In addition, the need for immunosuppressive therapy
leads to increased insulin resistance in the body and a
decline in insulin production by time.
14

16. General Principle:
• Normalization of blood glucose (not merely control of blood
glucose) will lead to improvements in:
• Survival
• Quality of life
• Protection from heart disease, kidney disease,
retinopathy, and nerve injury
• The only method that normalizes blood glucose in patients
with diabetes is treatment with insulin-producing cells

22. Methods to treat with insulin-producing cells
Pancreas transplant
• Pancreas obtained from
cadaver donors, transplanted
surgically within 12 hours
• Surgical procedure involves
general anesthesia,
abdominal surgery, and a 7-
10 day hospitalization
• Complications:
• Thrombosis of pancreatic
vessels
• Pancreatic leak
• Infection
Islet Cell Transplant
• Islet tissue obtained from
cadaver organs by
collagenase digestion of the
pancreas and purification of
islets via density gradients
• Islets injected into portal vein
for liver implantation,
performed by interventional
radiology, followed by a 1-2
day hospitalization
• Complications:
• Bleeding
• Thrombosis

23. “Insulin independence after solitary islet
transplantation in T1D patients using steroid-free
immunosuppression”
• 7 consecutive patients achieved euglycemia during a mean
follow-up of 11 months, with normal HgbA1c and GTT
• 6/7 patients required >1 donor (>1 transplant) a median of 29
days from the first procedure
• Mean islet equivalents =11,400/kg required to achieve
euglycemia
• Cadaveric pancreas from older donors >45 yo (70% would
have been discarded)
Shapiro AMJ et al, NEJM 2000; 343:230

24. 600
500
400
300
200
100
2 4 6 8 1
0
1
2
2 4 6 8 10
600
500
400
300
200
100
0
1
2
a.m. p.m.
Post-transplant
Pre-transplant
Time of day
Blood
glucose
(mg/dl)
Blood
glucose
(mg/dl)
Shapiro et al.
N Engl J Med 2000;
343:230-238

25. ITN Multicenter Trial
9 centers enrolled 3-5 patients to replicate Edmonton trial
0
10
20
30
40
50
60
70
80
90
100
1 2 3 4 5 6 7 8 9
%Insulin-
independent
16/36 patients rendered
insulin-independent at one
year following final infusion
Data presented by AMJ Shapiro at the ATC 2004

26. Success rates: pancreas vs. islet transplantation
• Transplant: 1998-00 2001-03
• Kidney/Pancreas (SPK) 82% 86%
• Pancreas after kidney (PAK) 74% 79%
• Pancreas alone (PTA) 76% 76%
• Islet Transplant 1990-96 2000-3
• Combined data 8% 58%*
• *data from 12 participating centers, up to 3 infusions
One-year Graft Survival:
Source: SRTR and CITR

27. 5-year graft survival-all organs
• Kidney 66%
• Pancreas (PTA) 47%
• Liver 66%
• Heart 71%
• Lung 45%
Source: Scientific Registry of Transplant Recipients Annual Report 2004

28. Islets
Possible Reasons for Islet Graft Failure
Allograft rejection
Disease recurrence
Insufficient islet mass Poor quality of islets
Toxicity of anti-
rejection drugs
Failure to engraft
Insulin resistance

29. Obstacles to Successful Islet Transplantation:
Low Engraftment Of Islets
•The transplanted b cell mass is ~50% of the mass present in a
normal individual
•The engrafted b cell mass is ~30% of the transplanted b cell mass
•Islet engraftment takes weeks before revascularization is
completed, rendering islets susceptible to:
• Hypoxic injury
• Nonspecific cell-mediated injury: “IBMIR”,
cytokine release, reactive oxygen intermediates
elaborated during postoperative healing/wound reaction

30. Is islet transplantation safe?
• Acute complications:
• Bleeding ~10-15%
• Thrombosis ~5%
• Transaminitis ~50%
• Long-term complications:
• Renal function
• Hypertension
• Hyperlipidemia
• Mouth ulcers
• Risk of sensitization
• Risk of infection (CMV)

31. Thus, it can be said…
• Successful islet cell transplantation is now possible
• Less invasive but less durable than pancreas transplants
• Innovations in inhibiting early inflammation, reducing toxicity of
meds needed
• Organ allocation, patient selection, and payment for
islet transplantation will remain controversial topics
during the “growth” phase of development of islet
transplant programs

32. Stem Cell in Treatment of
Diabetes
32

33. Stem cells are undifferentiated cells that play a critical role in the
evolution and rebirth of soft tissues and body growth. During the
previous years, many experiments utilized stem cells solely or in
conjunction with other healing methods and revealed the
effectiveness and safety of stem cells in a variety of illnesses such
as diabetes.
The best therapeutic outcome was achieved by transplantation of
BM-HSCs for T1DM and BM-MNCs along with MSCs for T2DM.
However, patients with DKA are not a good candidate for stem cell
transplantation.
Stem Cells Therapy

34. 34
• T1D diabetes could be successfully managed without
the need for the limited supply of donor cells being
treated with stem cell therapy.
• Stem cells can be used in a similar way to treat T2D.
• Although β-cells are still present in T2D, additional b-
cells could supplement the body's supply to overcome
the insulin resistance present in a patient.
• Treatment could aim to continuously maintain β -
cells levels above the required amount to combat a
patient's insulin resistance.
Can stem cell help Diabetes?

35. 35
• Although advances have already been made in the
treatment of diabetes with stem cells, stem cell
research is still ongoing and evolving every day. Stem
cells have been shown to replenish b-cells both in
the body and have been lab-grown for implantation.
• However, the body still retains an autoimmune
response with T1D and insulin resistance with T2D.
Can stem cell help Diabetes?

36. Possible treatment by stem cells

39. Sources of Stem Cells Used In DM TTT :
1) Embryonic stem cells
2) Induced pluripotent stem cells
3) Pancreatic stem cells
4) Mesenchymal stem cells
5) Other sources
39

40. Other Sources
➢Recent reports suggest that pancreatic duct cells,
liver cells, spleen cells can be used to produce IPC.
➢ In fact, the gallbladder develops from the ventral
pancreatic bud.
➢Thus understanding the development of
gallbladder-derived hormone producing immature
islet cells will help us in generating an alternate
source of pancreatic stem cells for replacement
therapy in diabetes
53

41. 54

42. Stem Cell Transplantation Strategies :
1) Transplantation methods
2) Stem cell transplantation
3) Transplantation of differentiated stem
cells
4) Stem cell gene therapy
5) Transplantation of immuno-isolated
IPCs
55

43. Transplantation Methods
➢Cells can be grafted underneath the kidney
capsule; intra-peritoneal injection ; or intra-
portally ; into the liver or injected into the tail vein.
➢Although DM is caused by destruction of the beta
cells within the pancreatic islets, no studies have
attempted transplantation directly into the
pancreas, because the pancreas is very sensitive
organ and vulnerable to mechanical intervention
(pancreatitis).
56

44. Topical Stem Cell Therapy For
Diabetic Foot Ulcers
60

45. Stem Cell Therapy:
Islet Regeneration By Immune Correction
➢There is increasing evidence that both autoimmune
and autoinflammatory mechanisms are involved in the
development of type 1 and type-2 DM.
➢Type 1 DM is currently treated with anti-
inflammatory drugs, immunosuppressive and
immunomodulatory agents. However, despite their
profound effects on immune responses, these drugs
do not induce clinically significant remission in
certain patients.
61

46. Attempts to cure T1DM. The discovery of insulin has enhanced the life span of T1DM
patients, and successes in islet/pancreas transplantation have provided direct evidence
for the feasibility of reestablishing β cells in vivo to treat T1DM. However, the restriction
of a pancreas shortage has driven scientists to generate IPCs, and even whole pancreas, in
vitro from hESCs, iPSCs, and adult stem cells. Studies focusing on the immune
mechanism of T/B cell destruction in T1DM have made breakthroughs. Gene therapy has
shown great promise as a potential therapeutic to treat T1DM, although its safety still
needs to be confirmed in humans
Current progress in stem cell therapy for T1D

47. GENE THERAPY FOR DIABETES
Generic engineering can occur by one of two possible
methods• germ line and somatic manipulation.
• Genes from germ line genetic manipulation are
transferred to the individual's offspring whereas
somatic genetic manipulation will only affect the
individual to which the transgene is introduced.

48. GENE THERAPY FOR DIABETES
• Gene transfer can be divided into in vivo or in
vitro transfer. For successful in vivo delivery, the
vehicle for the transgene must be appropriately
directed to the target cells and the gene product
must be protected from immune attack.
• Manipulating cells genetically in vitro is less
invasive than in vivo techniques however target
cells are required to be easily removed and
transplanted back into the host.

49. Gene therapy.
In Tl D, islets are the target for autoreactive T cell
destruction. The absence of islets leads to insulin
deficiencies and resultant hyperglycemia. Gene
therapy is a useful technique to treat TID as it can
be applied from many different angles. The insulin
gene can be replaced in a host or the autoreactive T
cells suppressed.

50. Genetic Engineering
Genetic engineering can occur by one of two possible methods—
germ line and somatic manipulation. Genes from germ line
genetic manipulation are transferred to the individual's offspring
whereas somatic genetic manipulation will only affect the
individual to which the transgene is introduced. Gene transfer
can be divided into in vivo or in vitro transfer.
For successful in vivo delivery, the vehicle for the transgene must
be appropriately directed to the target cells and the gene product
must be protected from immune attack. Manipulating cells
genetically in vitro is less invasive than in vivo techniques
however target cells are required to be easily removed and
transplanted back into the host.

51. Stem Cell Gene Therapy
Due to their properties of
self-renewal and capacity
for multipotent
differentiation, stem cells
are thought to be the best
vector for delivering
genes and therapeutic
gene-coded proteins into
the body.
68

52. The future of diabetes gene therapy
AAV vectors are currently being researched in human
gene therapy trials and could be delivered to the
pancreas through a non-surgical endoscopic
procedure, eventually. However, the researchers
caution that the protection observed in the mice was
not permanent, and 4 months of restored glucose
levels in a mouse model “might translate to several
years in humans.”

53. The future of diabetes gene therapy
➢Primary prevention by a vaccine or
drug will be offered to at risk subjects
identified by genetic studies.
Yet to grasp those

54. • Both T1D and T2D are among the most amenable
diseases for treatment. Functional restoration of
existing beta-cells, transplantation of stem cells or stem
cell-derived beta-like cells might provide new
opportunities for treatment.
• Regenerative medicine remains a new and exciting field
of research that holds much promise into the treatment
of patients with endocrine diseases of all ages.
• Evidence based clinical treatment of diabetic symptoms
only adds to the disease burden.
Summary

55. • With the advent of stem cell therapy, the potential to
eradicate diabetes seems to be on the horizon.
• However, the use of stem cells to generate a renewable
source of beta-cells for diabetes treatment remains
challenging, largely due to safety concerns.
• Larger studies are needed to advance the field and
understand the best way to realize its potential.
Summary

56. 73
Conclusion