Future of DM management- Dr Shahjada Selim

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

2. Background • 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.

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

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? Glucose Sensors • Better accuracy, user interface, reliability. • Better algorithm • One site for CGM & Insulin 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

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12. Cellular Treatment: Cellular Treatment: B. B. Pancreatic Islets Cells Transplantation 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” Shapiro AMJ et al, NEJM 2000; 343:230 • 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)

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

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

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

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

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

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 • Thrombosis ~5% • Transaminitis ~50% • Long-term complications: • Renal function • Hypertension • Hyperlipidemia • Mouth ulcers • Risk of sensitization • Risk of infection (CMV) ~10-15%

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 Therapy 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.

34. Can stem cell help Diabetes? • 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. 34

35. Can stem cell help Diabetes? 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. • 35

36. Possible treatment by stem cells

39. Sources of Stem Cells Used In DM TTT : 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

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42. Stem Cell Transplantation Strategies : 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 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 Topical Stem Cell Therapy For Diabetic Foot Ulcers Diabetic Foot Ulcers 60

45. Stem Cell Therapy: Stem Cell Therapy: Islet Regeneration By Immune Correction 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. Current progress in stem cell therapy for T1D 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

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.