Is It Possible to Prevent or Delay Type 1 Diabetes?

What if there was a way to determine exactly who would develop type 1 diabetes (T1D) and doctors could intervene to prevent it altogether or at least delay the onset by years?

JDRF, a leading research advocacy organization, and the Disease Interception Accelerator (DIA) group of Janssen Pharmaceuticals announced a joint venture earlier this year to take on this challenge.¹ The goal is to identify the root cause of T1D and intercept its progression to disease before symptoms arise.

There have been many questions about the actual cause of T1D. Work in recent years suggests there is a window of opportunity to stop or delay the disease before the onset of clinical symptoms of the disease.^2,3 The autoimmune response directed against beta cells is suggested to be secondary to tissue damage and unrelated to disease pathogenesis.⁴ The presence of antibodies against the islets of Langerhans that were detected in the serum of patients diagnosed with T1D, but not in healthy individuals, led to the suggestion of the autoimmune etiology of T1D.⁴

Although T1D has been referred to by many names, such as juvenile diabetes or insulin-dependent diabetes, the treatment has always been the same: insulin. T1D is a pancreatic beta cell specific disease that results in absolute insulin deficiency.^4,5 Data from the United Kingdom suggest life expectancy of adults with T1D is reduced by up to 13 years.^6,7 The symptoms of T1D are similar to type 2 diabetes, including frequent urination and feeling thirsty, hungry, or tired. Additionally, with T1D, there is the possibility of sudden weight loss, nausea and vomiting from the build-up of ketones in the body, and diabetic ketoacidosis.⁸

Although only about 5% of patients with diabetes have T1D,⁹ the effect can be more devastating since children and young adults are the ones most commonly given a diagnosis of T1D. These individuals live with the disease for many more years, thus prolonging the time for cellular damage, which increases the potential for complications of diabetes that include blindness and kidney damage and, in extreme cases, loss of toes or lower limbs.⁸ The goal of intensive insulin therapy is to reduce long-term complications while avoiding acute emergencies, such as hypoglycemia, to optimize quality of life for patients.^2,6

DISEASE PATHOLOGY

T1D is mainly related to an autoimmune response through which the action of T cells and/or T lymphocytes results in destruction of pancreatic cells.¹⁰ The most commonly identified islet autoantibodies associated with progression to T1D are insulin autoantibodies), glutamic acid decarboxylase 65 autoantibodies, insulinoma antigen 2 autoantibodies, and zinc transporter 8 autoantibodies.¹¹However, T1D can also be triggered by different factors such as obesity, viruses, and chronic or acute inflammations that affect the cells of the pancreas that produce insulin.¹⁰ Although there are no physical symptoms, there is data that suggests T1D is commonly preceded by early symptoms including seroconversion to islet autoantibody and metabolic disturbances.¹¹

The mechanism of how metabolic syndrome and autoimmune factors affect the progression of T1D is not yet clear, however.

POTENTIAL PREVENTION STRATEGIES

About 50% of patients with T1D are overweight or obese.¹² Whereas insulin therapy can achieve optimal glucose control, it can also cause patients to gain weight. This makes insulin less effective, which then requires more insulin—and a vicious cycle begins. Traditional treatment options for T1D include pancreas transplantation and transplant of islet and embryonic stem cells.

Pancreas transplantation10 is still a useful treatment for some patients; however, it might not be an optimal option for all patients. Transplant of islet cells is an option, safer than transplantation, but still an invasive procedure.¹⁰ Finally, embryonic stem cells are still in the research phase due to costs and standardization concerns.¹⁰ These options are viable, but they should probably be used in patients with extreme disease progression or reserved as a last resort.

Adjunct therapies may be necessary to help better manage glucose levels and optimize insulin therapy,¹² thereby reducing T1D complications, preserving beta cells, and improving insulin secretion.¹⁰ There is ongoing research for alternative treatments for continuous glycemic control and for slowing down the damage caused by T1D.¹⁰ Studies have looked at the use of immunosuppressive agents, including cyclosporine, prednisone, and azathioprine, for initiating the remission of T1D.⁴ Results suggest the preservation of residual beta cells, with adjunct immunosuppressants, was able to produce sufficient insulin and subsequently improve glycated hemoglobin. However, when treatment ended, T1D rapidly relapsed.^4,10 The big concern with using immunosuppressive agents is the toxicity associated with their use.⁴

JDRF’s chief scientific officer, Richard Insel, MD, and his team are eager to work with Janssen’s DIA group to advance an innovative scientific initiative.¹Insel and JDRF are big advocates for preventive intervention; at the launch of the venture, Insel said it provides an exciting opportunity.¹

“The studies are all still in the research setting,” Insel said in an interview with Evidence-Based Diabetes Management. He shared the 2 main ways of identifying patients at risk of developing T1D. One involves screening relatives of patients with T1D for an autoimmune response, specifically identifying antibodies that would attack islets of pancreas cells. Several antibodies have previously been identified, and individuals who produce 2 or more islet autoantibodies are at a higher risk for developing T1D.¹¹ The progression to T1D, he said, could take years or even decades, however.

The second method of identifying patients at risk for developing T1D requires screening all children younger than 18 years. This would include a genetic-risk screening of children once a year, perhaps at the annual medical visit. This is already being done in Germany for all 3- and 4-year-olds. Insel referred to TrialNet, a T1D study conducted by an international network of researchers who are exploring ways to prevent, delay, and reverse the progression of disease.¹³The study presented by Alberto Pugliese, MD, in June 2014 at the 74th Scientific Sessions of the American Diabetes Association, was a 5-year study that followed relatives of patients who have T1D. In the study, researcher looked at the risk of developing T1D with human leukocyte antigen influence, in addition to having positive autoantibodies. The results showed that having several high-risk haplotypes/genotypes indicated a high risk for 5-year T1D incidence. Relatives with a single antibody had an increased risk of developing additional autoantibodies, without progression to T1D.¹⁴

Another article pooled data from several prospective cohort studies that examined children who were genetically at risk for developing T1D. The results showed an almost 70% risk of progression to T1D at a 10-year follow-up when patients had multiple islet autoantibodies compared with 15% for patients with a single autoantibody. Children who lacked islet autoantibodies had a less than 1% risk to progression.¹⁵

The Pre-POINT study, funded by JDRF, was conducted in Germany, Austria, the United States, and the United Kingdom. The study enrolled 25 children aged 2 to 7 years with a family history of T1D and who were islet autoantibodies—negative. The children were randomized to receive either oral insulin or placebo once daily. The study results showed there was an immune response without hypoglycemia at high doses; however, there were almost twice as many adverse events—67 versus 35, respectively—in the insulin-treated compared with the placebo group.3 This might be an interesting treatment option, but larger trials are necessary for further study.

“Currently, there are multiple ongoing studies and over 150,000 patients have been screened to determine predisposition of developing T1D,” said Insel. JDRF is funding multiple trials along with National Institutes of Health’s TrialNet trials. “Some of the trials are looking to arrest the progression to T1D.” Although this is currently in the research setting, there are high expectations from the results of these studies.

SUMMARY

Postponing or preventing T1D is an exciting concept. Although extensive groundwork is necessary to identify the right precursors, determine the correct agents, and maintain optimal glucose control, the focus on this patient population will have a huge impact. Additionally, looking at adjunct therapy to help optimize insulin therapy in patients with T1D needs ongoing research.

There is some excitement in the identification of the mechanism and management of T1D, which is long overdue. Ongoing trials are evaluating ways to arrest progression, perhaps using some of the newer agents to help improve the response to insulin or to prevent the rapid breakdown of insulin. References

1. Janssen sets a course to intercept type 1 diabetes together with JDRF [press release]. Raritan, NJ: Janssen Research and Development; February 11, 2015.

https://www.jnj.com/news/all/Janssen-Sets-A-Course-To-Intercept-Type-1-Diabetes-Together-With-JDRF. Accessed September 25, 2015.

2. Beauchamp G, Haller MJ. Can we prevent type 1 diabetes? Curr Diab Rep. 2015;15(11):86.

3. Bonifacio E, Ziegler AG, Klingensmith G, et al; Pre-POINT Study Group. Effects of high-dose oral insulin on immune responses in children at high risk for type 1 diabetes: the Pre-POINT randomized clinical trial. JAMA. 2015;313(15):1541-1549.

4. Mannering SI, Pathiraja V, Kay TWH. The case for an autoimmune etiology of type 1 diabetes [published online August 27, 2015]. Clin Exp Immunol. doi:10.1111/cei.12699.

5. Campbell-Thompson M, Rodriques-Calvo T, Battaglia M. Abnormalities of the exocrine pancreas in type 1 diabetes. Curr Diab Rep. 2015;15(10):653.

6. Amiel SA, Pursey N, Higgins B, Dawoud D; Guideline Development Group. Diagnosis and management of type 1 diabetes in adults: summary of updated NICE guidance. BMJ.2015;351:h4188.

7. Livingstone SJ, Levin D, Looker HC, et al; Scottish Diabetes Research Network epidemiology group; Scottish Renal Registry. Estimated life expectancy in a Scottish cohort with type 1 diabetes, 2008-2010. JAMA. 2015;313(1)37-44.

8. The diabetes advisor. American Diabetes Association website. http://professional.diabetes.org/PatientEducationLibraryDetail. aspx?pmlPath=Symptoms_18afd79d-5335-430b-a951-87c547003035&pmlName=Symptoms.pdf&pmlId=270&pmlTitle=Diabetes%20Symptoms. Accessed September 25, 2015.

9. Type 1 diabetes. American Diabetes Association website. http://www.diabetes.org/diabetes-basics/type-1/?loc=utilheader_type1. Accessed September 25, 2015.

10. Mancio RD, Minatel E, de Almeida Cardoso M, Ali Khan B, José Caldeira E. The immunomodulation to diabetes control:new proposals for the reversion of this disease. Diab Metab Syndr. 2015; 9(4):210-212.

11. Marinkovic T, Oresic M. Modeling strategies to study metabolic pathways in progression to type 1 diabetes — challenges and opportunities [published online August 24, 2015]. Arch Biochem Biophys. 2015; pii: S0003-9861(15)30037-0. doi: 10.1016/j.abb.2015.08.011.

12. Schechter R, Reutrakul S. Management of severe insulin resistance in patients with type 1 diabetes. Curr Diab Rep 2015;15(77):1-12.

13. TrialNet studies. Type 1 Diabetes TrialNet website. http://www.diabetestrialnet.org/studies/. Accessed September 29, 2015.

14. Pugliese A. HLA influence progression to type 1 diabetes (T1D) in autoantibody-positive relatives. Presented at: the 74th Scientific Sessions of the American Diabetes Association; San Francisco, CA; June 13-17, 2014. Accessed September 25, 2015.

15. Ziegler AG, Rewers MD, Simell O, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA 2013;309(23):2473-2479.