There is more going on than just the immune system attacking.
Type 1 diabetes is a disease in which the patient’s immune system is known to destroy the body’s own beta cells. But a previous study has demonstrated that not all the beta cells are completely eliminated. The Diabetes Control and Complications Trial (DCCT) showed “that 11% of adult participants with type 1 diabetes for more than 5 years had measurable C-peptide in the fasting state and following mixed-meal stimulation.” They also found that a decline in C-peptide was less in volunteers who were intensely treated with insulin after a year. And just two weeks of intensive insulin therapy in teenagers actually improved their beta cell function after a year (glucose levels were lowered as well).
C-peptide aside, proinsulin (prohormone precursor to insulin) was found to still be circulating in patients with type 1 diabetes as well, even after 30 months (since diagnosis). So, this is proof that in patients with type 1 diabetes, beta cells are still able to produce proinsulin. In many people with type 1 diabetes, proinsulin is also capable of being further processed into C-peptide and insulin.
In this Diabetes Care study, three groups of volunteers had their C-peptide responses tested. The three different C-peptide responses were “absent,” “intermediate,” and “high” responses. The “high” C-peptide response was still not as high as in healthy individuals (it was only named “high” as a differentiating category). In the absent group, C-peptide responses were undetectable. Only the intermediate and high groups were tested (with mixed-meal tests) at years 1, 2, and 4 after their initial test because these two categories had measurable C-peptide responses. The high-response category had C-peptide response levels (both fasting and stimulated) that were seven times that of the intermediate-response group. Glucose management was better in the high-response group as well.
Even though both the high-response and intermediate response groups were diagnosed for type 1 diabetes around the same time, “those in the high-response group were markedly older (mean of 29 years of age) at the time of diagnosis than were those with intermediate responses (19 years of age),” researchers found. So, it seems that those who were diagnosed later in life may have had more functioning beta cells. The levels of proinsulin versus C-peptide were abnormally increased in both groups at their initial visit, which demonstrated beta-cell dysfunction. “Further, the proinsulin–to–C-peptide ratio was greater in those with the lowest C-peptide responses, compatible with them having poorer b-cell function.” Hence, the patients in the high C-peptide response group had better beta-cell function than the intermediate-response group.
It is known that type 1 diabetes is heterogeneous. This can include involvement of HLA genotype, age of onset, number of autoantibodies, and the differences in beta-cell mass and beta-cell survival. Also, some people with type 2 diabetes have genes that contributed to the disease (antibodies and/or T-cell activation). Most people with chronic type 1 diabetes have proinsulin present in the blood, whereas it is more difficult to detect C-peptide in the majority of type 1 diabetes patients. So, we know that they still have beta-cells. We don’t know whether they are old cells (before the diabetes disease) or new cells. Therefore, we don’t know the extent of function of these lingering beta-cells in processing proinsulin, but we know that there are more functional beta-cells in patients who were diagnosed when they were older in age.
In conclusion, the duration of type 1 diabetes disease is not the main factor in the worsening of beta-cell function, given the age of the study’s volunteers and their better proinsulin processing ability. But research is still necessary, for example, in determining the amount of insulin required to achieve a lower hemoglobin A1c, and in identifying what factors affect beta-cell function, such as if the beta-cells have been affected by the body’s immune system if they are from before the diabetes disease onset or not, or if they are new beta cells. Changes in expression of proinsulin was suggested in previous studies. It would be helpful to learn if there are differences in proinsulin processing in type 1 and type 2 diabetes. Another hypothesis on which to continue research is if prohormone convertase expression or action has been lost in type 1 diabetes people. Amyloid deposits may also play a role. The “location of the amyloid deposits is in keeping with IAPP (islet amyloid polypeptide), their unique peptide component, being a secretory product of the b-cell that typically has to be exocytosed for amyloid to form,” according to researchers. Amyloid build-up should be looked into as well. There must be so much more than simple destruction occurring in type 1 diabetes.
- Genetics and the immune system are very involved in type 1 diabetes, but not all beta cells are destroyed in the disease. Not all functioning may be lost either. C-peptide and proinsulin are still being processed in many of these patients.
- A longer duration of the disease does not lead to progression of beta cell dysfunction.
- People diagnosed with type 1 diabetes when they were older had more functioning beta cells than people diagnosed when they were younger.
Hull, Rebecca L.; Kahn, Steven E.; Templin, Andrew T.; Verchere, C. Bruce. “Probing the Meaning of Persistent Propeptide Release in Type 1 Diabetes.” Diabetes Care 2019. http://care.diabetesjournals.org/content/42/2/183. 31 January 2019.
Annahita Forghan, Pharm.D. Candidate 2019, LECOM College of Pharmacy