Case Report

On November 2, an 85-year-old man was admitted into the Division of Diabetes and
Endocrinology, Kobe University Hospital, Kobe, Japan for the purpose of blood glucose
management. He had been diagnosed with interferon-induced type 1 diabetes mellitus
(T1DM) at the age of 70. He currently has no classic complaints.

Suspected Complications
He complained of numbness in his legs. His physical examination revealed abnormal reflexes,
namely no knee jerk or patellar reflex at all and a weak ankle jerk or achilles reflex. Touch test
with monofilament was also done, where he was not able to perceive monofilaments smaller
than 5.07 normally. Vibration test was also done using the tuning fork, where he was not able
to feel the vibrations properly. From the physical examination, there are signs of peripheral
neuropathy in his feet. He has no complaints regarding his hands. His cardiac autonomic
nerve function was evaluated using the coefficient of variation of R-R interval (CVRR), and it
was found to be within normal range. At rest, his CVRR is 2.47% and when taking a deep
breath, his CVRR is 16.30%. These results indicate that his autonomic nerves are functioning
normally.

He did not complain of anything in his eyes, and did not have a history of retinopathy. There
is also no history of nephropathy. He was tested for microvascular and macrovascular
complications. Based on his resting electrocardiogram results, he had complete right bundle
branch block, and his vascular function test which shows an increase in cardio-ankle vascular
index (CAVI; 11.3/11.4) suggests arteriosclerosis or arterial stiffness. He complained of dull
pain in his left chest.

Current Medical History

His vital signs were within normal range. Complete blood count was done on the patient, of
which there were no abnormal values to note. Laboratory report that was obtained on
November 2 also revealed: blood glucose level: 455 mg/dl, HbA1C: 8.1 mg/dl, glycoalbumin:
30.0%, Glutamic Acid Decarboxylase (GAD): 123 U/ml, C-peptide: 0.17 ng/ml. His high
levels of blood glucose, glycoalbumin, and GAD indicated that he was hyperglycemic, while
low result of C-peptide is an indication of T1DM.

His continuous glucose monitoring (CGM) reported his time-in-range (TIR) as of 16

November for the past 7 days, 14 days, and 30 days. He has a record of 53% TIR for the period
of November 10 – November 16, 55% TIR for the period of November 3 – November 16, and
50% TIR for the period of October 18 – November 16 (target TIR: >50%). It is to be noted
that half of his 30-day TIR is taken outside of his hospitalization period. CGM also reported
his time below range (TBR) for the same periods of time. It is reported that he has a 21%
TBR for the period of November 10 – November 16, 11% TBR for the period of November 3
– November 16, and 9% TBR for the period of October 18 – November 16 (target TBR <1%).

Previous Medical History

Prior to being diagnosed for T1DM, he had a history of liver diseases. He was diagnosed with
hepatitis C in his 50s and was treated with interferon (INF) at the age of 69 to 71. He had also
been diagnosed with hepatocellular carcinoma at the age of 70, which was treated with two
surgeries and three radiofrequency ablation procedures.

Weight History
Recently, he weighed 57.7 kg and had a BMI of 20.5 kg/m 2. However, he used to be 68 kg in
his 20s. His highest weight was 74 kg at the age of 18 years old.

Family History
His mother had a history of diabetes mellitus (DM) [ask age of onset, treatment,
complications, and cause of death]. History of obesity in the family was denied.

Treatment History
He is currently being treated with 4 insulin injections per day: 3 rapid-acting (bolus) insulin
injections before breakfast, lunch, and dinner; as well as 1 long-acting (basal) insulin injection
before sleeping. He takes 5 units for basal injection, while the dosage of his bolus injection
depends on his carbohydrate intake. He takes pregabalin and epalrestat for his peripheral
neuropathy. He also takes vitamin D supplements, as well as medications for osteoporosis and
urinary incontinence.

Lifestyle
The patient takes lessons on how to self-administer insulin and count carbohydrates. The
patient makes a habit of taking photos of his meals to use for carbohydrate count. He eats 3
times a day at 08.00, 12.00, and 18.00. He doesn’t eat snacks. He would occasionally take
walks after meals. He also walks for 60 minutes, 2-3 times a week. He used to work at an
advertising agency but he has retired. He used to drink 3-5 glasses of straight whiskey and 2
large bottles of beer, then stopped drinking at the age of 75. He was a heavy smoker at the age
of 19-45, smoking as much as 40 sticks daily. Currently, he no longer smokes and drinks.

Physical Examination

Laboratory Examination

Treatment Plan
Currently, this patient has frequent fluctuations in blood sugar. The goal of this hospitalization
is to stabilize his blood sugar level and prevent incidents of hyperglycemia and hypoglycemia.
He has a much higher TBR compared to the target level. Therefore, a reduction of dose in
basal insulin is being considered. He also often forgets to take his basal insulin before sleep,
which is why a change on his time of basal insulin injection to the evening is also being
considered.

His goal of HbA1c is lower than 8.0% and more than 7.0%. Before hospitalization, his HbA1c
was 8.0%. We are working on the maintenance of this HbA1c level.

Discussion
Interferons (IFN) are signaling molecules produced as part of immune response. Interferon
is used in the therapy of viral infections, tumors, and autoimmune diseases. Despite its diverse
function, there are many side effects of interferon, including the development of several
autoimmune disorders (Khanna and Gerriets, 2023). IFN had been used as the first-line
treatment of chronic hepatitis C before the development of current direct-acting antiviral
tablets. IFN has been proven to have a key role in the pathogenesis of T1DM. T1DM is an
autoimmune disease where pancreatic beta cells are destructed, causing insulin insufficiency.
IFN is able to stimulate an overexpression of HLA class 1 antigen in pancreatic beta cells,
leading to the activation of cytotoxic T-cells and inflammatory response towards the islets
(Lombardi et al., 2018). The percentage of interferon-induced T1DM among T1DM patients
in Japan was estimated to be 1.18%. (Nakamura et al., 2011). Almost all patients who develop
this complication require permanent insulin treatment (Zornitzki et al., 2015).

Diabetes mellitus type 2 often affects small blood vessels, resulting in three common
microvascular complications which are diabetic neuropathy (DN), nephropathy, and
retinopathy. The etiology behind this complication is still unclear, however persistent
hyperglycemia and high glycemic variability have been ascertained as risk factors (Zaino et al.,
2023).
The effect of neuropathy may very easily affect quality of life as it makes daily tasks more
challenging. In the past, the treatment of diabetic neuropathy was focused on managing risk
factors, such as obesity, hyperlipidemia, and hyperglycemia. Antidepressants (e.g. SNRI) and
gabapentinoid (e.g. pregabalin and gabapentin) are used to manage pain caused by DN.
Drugs which are targeting the mechanism preceding the inflammation of neurons itself may
also be used, ranging from antifungals, selective neutrophil elastase inhibitors, and semi-
synthetic antibiotics, as well as TLR-4 inhibitors. Oxidative stress is reduced by drugs
targeting various reactive oxygen series, such as Nrf2 which is targeted by dimethyl fumarate
and epalrestat with different mechanisms (Zaino et al., 2023).

References
Lombardi, A., Tsomos, E., Hammerstad, S.S. and Tomer, Y. (2018). INTERFERON ALPHA:
THE KEY TRIGGER OF TYPE 1 DIABETES. Journal of autoimmunity, [online] 94, pp.7–
15. doi:https://doi.org/10.1016/j.jaut.2018.08.003.

Khanna, N.R. and Gerriets, V. (2020). Interferon. [online] PubMed. Available at:
https://www.ncbi.nlm.nih.gov/books/NBK555932/.

Nakamura, K., Kawasaki, E., Imagawa, A., Awata, T., Ikegami, H., Uchigata, Y., Kobayashi,
T., Shimada, A., Nakanishi, K., Makino, H., Maruyama, T. and Hanafusa, T. (2011). Type 1
Diabetes and Interferon Therapy. Diabetes Care, 34(9), pp.2084–2089.
doi:https://doi.org/10.2337/dc10-2274.
Zornitzki, T., Malnick, S., Lysyy, L., Knobler, H. (2015). Interferon therapy in hepatitis C
leading to chronic type 1 diabetes. World Journal of Gastroenterology, 21(1), p.233.
doi:https://doi.org/10.3748/wjg.v21.i1.233.

Zaino, B., Goel, R., Devaragudi, S., Prakash, A., Vaghamashi, Y., Sethi, Y., Patel, N., & Kaka,
N. (2023). Diabetic neuropathy: Pathogenesis and evolving principles of management.
Disease-a-Month, 69(9), 101582. https://doi.org/10.1016/j.disamonth.2023.101582