FormalPara Key Summary Points

Why carry out this study?

Insulin resistance syndrome and lipodystrophy are rare diseases with limited information and low awareness among the public and healthcare professionals.

This world-first qualitative research study identified the experiences and perceptions of people with insulin resistance syndrome or lipoatrophic diabetes.

What was learned from the study?

Insulin resistance syndrome or lipoatrophic diabetes took a heavy physical and psychological toll, including stigmatisation, on people with these diseases and their families.

Disease information and adequate support from others were limited as a result of low public awareness.

Initiatives to promote understanding of the diseases, educational materials, support consultation services, less burdensome treatment options, and opportunities for peer communication are needed.

Digital Features

This article is published with a Japanese translation, to facilitate understanding of the article. To view digital features for this article, go to https://doi.org/10.6084/m9.figshare.22644598.

Introduction

Insulin resistance syndrome is characterised by attenuation of insulin action due to functional impairment of the insulin receptor or its signalling molecules and is classified into two types as genetic insulin resistance syndrome and type B insulin resistance syndrome [1, 2]. Genetic insulin resistance syndrome is most frequently caused by insulin receptor gene abnormalities [3] and is also attributable to gene abnormalities of downstream signalling molecules. Severe functional impairment of the insulin receptor gene can give rise to Rabson–Mendenhall syndrome or Donohue syndrome in the newborn or during childhood [1, 2]. Genetic insulin resistance syndrome primarily presents with symptoms of hyperinsulinaemia not associated with obesity or other causes of insulin resistance and may be associated with impaired glucose tolerance of juvenile onset, acanthosis nigricans, and hairiness. On the other hands, type B insulin resistance syndrome primarily presents with symptoms and signs of hyperinsulinaemia and may be associated with hyperglycaemia, hypoglycaemia, and autoimmune diseases [1, 2]. No targeted treatment exists for either type of insulin resistance syndrome [4]. While the global prevalence of insulin resistance syndromes has not been reported, an estimated 100 people have this disorder in Japan [3].

Lipodystrophy is characterised by the atrophy-related reduction or loss of fatty tissue throughout or in localised areas of the body. The syndrome may be congenital or acquired and is frequently complicated by metabolic disorders attributable to fatty atrophy, including severe insulin resistance, diabetes, and hypertriglyceridaemia [5]. Diabetes complicated by lipodystrophy is specifically called lipoatrophic diabetes, which is characterised by marked insulin resistance. No targeted treatment has been established for lipodystrophy; however, because a deficiency in leptin secreted by adipocytes accompanies the condition, leptin replacement therapy improves glycolipid metabolism [6]. The prevalence is estimated to be 1–5 per million people in the USA [7, 8] and 1 per 1.3 million people in Japan (approx. 100 people) [6].

Because the prevalence of insulin resistance syndrome and lipodystrophy is low, there is limited information available and low awareness among the general public and healthcare professionals. For these reasons, people with these conditions face various difficulties primarily because others around them lack understanding. Very few reports have been published on their experiences and what they think of their disease, making it difficult to understand their specific burdens, perceptions, needs, and other relevant matters.

This study was designed to identify how people with insulin resistance syndrome or lipoatrophic diabetes perceive their disease, treatment experiences, and treatment-associated burdens—as well as their needs and priorities regarding treatment and activities of daily living—using a qualitative research approach based on individual interviews and meetings. On the basis of their findings, we discuss how to meet participants’ needs and expectations, as well as treatments or support required.

Methods

Study Design

This non-interventional qualitative research study was conducted in accordance with ethical principles based on the Declaration of Helsinki. The protocol, informed consent form, and other written information for participants were approved by the Clinical Research Ethics Committee of the Medical Corporation Kyosokai AMC Nishi-Umeda Clinic. This study is registered at the UMIN Clinical Trials registry (UMIN000043693).

Participants, Recruitment Methods, and Study Process

Eligible participants were aged 20 years or older with physician-diagnosed insulin resistance syndrome or lipoatrophic diabetes. People who were judged as ineligible by physicians or who were participating in clinical trials of empagliflozin for refractory diabetes with insulin resistance (conducted by Kobe University with investigational products and funds provided by Nippon Boehringer Ingelheim Co., Ltd. [jRCT2051190029, jRCT2051190094]) were excluded. Study advisers referred those who met the inclusion criteria to specialist physicians, who recruited those deemed suitable to participate in this study. The target number of participants was set at three to six after taking feasibility into account.

The study process is shown in Fig. 1. Before enrolment, each participant entered into an agreement with the sponsor, Nippon Boehringer Ingelheim Co., Ltd., read the informed consent documents, and gave voluntary written informed consent to participate. The principal investigator verified participants’ eligibility based on their self-reported information. Before conducting individual interviews and advisory board meetings with people living with insulin resistance syndrome or lipoatrophic diabetes, the principal investigator explained the study details to participants, who then completed a pre-study questionnaire about the disease, treatment, and other relevant matters. Individual interviews and advisory board meetings were held online (via Zoom). Three months after the advisory board meetings, each participant was followed up. The study sponsor remunerated participants in accordance with its internal compliance guidelines (JP¥ 10,000 [approx. US $80] per hour, maximum of 6 h); however, remuneration was not used as a stimulus to recruit participants because they were not recruited from the public or widely. Participants could discontinue the study at any time by withdrawing consent.

Fig. 1
figure 1

Process of the present study

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Observation Items

Self-reported background information about participants including sex, age, disease status, age at the time of diagnosis, complications, and treatment was collected. The following information was obtained to gain an understanding of participants’ experiences and perceptions regarding their disease (Table S1 in the supplementary material): physical, psychological, and economic burdens associated with disease and treatment (e.g. impact on daily life, matters causing psychological pain or anxiety, stigma, and burdens on family members and caregivers); understanding and support provided by others including healthcare professionals; and current needs and expectations for the future.

Interview Schedule and Data Collection

Individual interviews were held online for approximately 1 h per participant between 9 and 15 April 2021, with the aim of understanding the participant’s disease status, treatment progress, and burdens associated with disease and treatment. Interviews were conducted by an experienced third-party moderator (index-i Corporation [a market research consulting company], Tokyo, Japan).

Advisory board meetings were held online to collect information about the observation items through interactive discussions among participants in Japanese. The advisory board meetings consisted of a group discussion with three participants (18 April 2021, for 4 h) and an individual discussion meeting with one participant (19 April 2021, for 2 h, using the same agenda as for the group discussion). Each meeting was attended by the participants, a moderator and a transcriptionist (both from index-i Corporation), and two panellists from the study sponsor. The meetings were designed to elicit participants’ feelings and thoughts in their own words.

Individual follow-up activities occurred 3 months after the advisory board meetings, with the objective of confirming anything that was unclear. Participant responses were obtained online or in writing.

The advisory board meetings and individual interviews were recorded with participants’ consent and reproduced verbatim in a report. Information that allowed personal identification, e.g. participants’ names, date of birth, address, phone number, etc., was excluded from the report. Participants’ information was identified only by their registration number. The sponsor created a table to match registration numbers with their personal information and stored it appropriately. Any person involved in this study complied with the ‘Act on the Protection of Personal Information’ and related notifications that apply to the protection of personal information, etc. of study participants.

Methods of Analysis

Information obtained from the advisory board meetings was not quantified but was qualitatively analysed from the verbatim report.

Results

Participants’ Disposition and Demographics

Four women aged 30–41 years, two with genetic insulin resistance syndrome and two with lipoatrophic diabetes, participated in the study (Table 1). For all participants, a confirmed diagnosis took years to obtain. All diagnoses had been made by diabetes specialists.

Table 1 Background information about participants
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Some participants did not remember or know their emotional response to the diagnosis because of their age at diagnosis. Others were psychologically shocked by the diagnosis of diabetes in their youth because they were under the impression that diabetes mellitus (extremely high blood glucose levels and haemoglobin A1c [HbA1c]) was a lifestyle-related disease that develops during middle age.

“I thought that diabetes is a lifestyle-related disease developing in the elderly….” (Participant B)

“I feel that I’ve been living with the disease since I was born.” (Participant C)

Regarding their understanding of the disease and treatment, some expressed no desire to investigate the disease by themselves. Others tried but failed to obtain reliable information about the disease through self-investigation. One participant was concerned that the fundamental question, such as the cause of her symptoms, remained unaddressed.

“I don’t know for sure why insulin in the body does not work. I wish the reason could be known.” (Participant B)

All participants understood that the objective of their current treatment is to continuously stabilise their blood glucose and HbA1c levels. They also understood that taking oral antidiabetic drugs, in addition to insulin and metreleptin, contributes to the control of blood glucose and HbA1c.

No remarkable treatment-induced symptoms were reported except for excessively decreased appetite due to metreleptin. Self-management of diet and exercise, in addition to pharmacotherapy, was recognised by all participants as important to prevent the rapid rise in blood glucose. Dietary self-management was initiated with support from registered dieticians during a previous hospitalisation, including educational hospitalisation, and was not excessive (i.e. only fried foods were prohibited). Three participants experienced hypoglycaemia and were concerned about the risk of hypoglycaemia caused by insulin or other treatments. Some participants shared that injecting insulin at the appropriate time (i.e. immediately before a meal) to avoid hypoglycaemia could be difficult in some situations.

Perceptions of Burdens Associated with Disease

Physical Burden

Physical burdens were those associated with injectable drugs, such as pain and lumps at injection sites, the inconvenience of self-injection, handling (such as refrigerated storage and portability), and visiting physicians. Conversely, some participants reported that self-injection actually reduced their burden. Before regulatory approval of self-injection in Japan, the participants had been required to visit physicians daily to receive injections, which limited their other activities. Self-injection alleviated these burdens. Switching to treatment with oral drugs alone also reduced their physical burden.

“I felt so much better after my treatment was switched to oral drugs.” (Participant C)

Psychological Burden

Participants were burdened by the long disease duration, concern about the decline in their physical function, and the increase in complications due to ageing.

“As I am getting older, will I be able to continue to control the disease adequately?” (Participant B)

There was also concern about the potential future burden on family members.

“Having my own family to take care of, I take my disease more seriously than ever.” (Participant C)

Emotional and psychological stresses and their stigma were also caused by the participants’ concerns about how others perceive their physical appearance, prejudice against long-term hospitalisation, and lack of understanding of the disease.

“Wearing a face mask was the only way I felt protected.” (Participant A)

A stigma associated with their appearance affected not only the participants but also their family members (especially mothers).

“… when I went shopping with my mother, I felt like I was being stared at by people around me, thinking why I was so thin. I think my mother had a harder time than I did.” (Participant D)

Having insulin resistance syndrome or lipoatrophic diabetes was a major concern and obstacle in decisions of marriage, pregnancy, and childbearing. The possibility that their child(ren) may inherit the same genetic abnormality and develop the disease requiring treatment caused them anxiety. Support and understanding from others close to the participants helped them to eventually make decisions.

“I want to marry and have a child. But I am afraid that my partner’s family would disagree.” (Participant A)

“We eventually decided to have a child and had to be prepared for the possibility that they would inherit the disease.” (Participant C)

Their stress was also exacerbated by their daily burden of dietary management, i.e. restrictions on frequency and timing of food intake.

Socioeconomic Burden

Medical expenses imposed varying degrees of economic burden on participants who were treated with oral antidiabetic drugs in addition to insulin. Conversely, the economic burden was significantly reduced by switching to oral antidiabetic drugs alone. The designation of lipodystrophy as an intractable disease [5] and subsequent provision of a medical expense subsidy for prescribed antidiabetic drugs also reduced the economic burden.

Perceptions of Communication with Physicians, and Understanding and Support from Others

Communication with Physicians

All participants have been treated by diabetes specialists. While the participants felt they communicated well with their current physician, issues related to communication with healthcare professionals were also mentioned. For example, in medical institutions and specialties other than where participants regularly received treatment, some healthcare professionals had little understanding of the disease, which caused an additional burden for participants who had to provide relevant disease information by way of explanation. To reduce the communication-related burden faced by participants, some proposed setting up an online portal where they can talk about or ask for advice on minor questions and concerns, such as unexpected changes in their physical condition and daily activities.

Understanding and Support from Others

Participants felt that their family members and friends understood their diseases, although not perfectly, and provided support to some extent. However, as awareness of the disease is still low among the general public, they felt that understanding from others was limited.

“My colleagues know I have diabetes. But I haven’t told them that I suffer from lipodystrophy. Perhaps they won’t be able to understand lipodystrophy even if I explain it to them.” (Participant D)

Peer Communication

Participants understood that they have a lifelong disease. However, as the currently attending physician is the only person with whom they can talk about the disease and ask for advice, information about treatment options is limited. In Japan, there is no patient association for insulin resistance syndrome or lipoatrophic diabetes like there is for other diseases. Most participants expressed their desire to participate in an event or occasion in which they can share information and communicate with people with the same disease or concerns.

“…I like talking to people, so I want to go [to a gathering].” (Participant A)

“…because I have no opportunity to talk to people suffering from the same disease. …It would be nice if we could exchange various types of information.” (Participant B)

Participants found information about self-directed efforts, e.g. lifestyle modification, relevant to their daily activities and valued it more than information about the disease and treatment.

“Information about how to make improvements is more important than information about the disease. Information on what to do in our daily life is most helpful.” (Participant C)

There were no specific statements from participants regarding support provided by organisations such as patient groups.

Needs and Priorities for People with Insulin Resistance Syndrome and Lipoatrophic Diabetes

Several needs were identified that would help to promote a better understanding of the disease among the general public and reduce the burden of those with the disease. These include the following: addressing the fundamental question, i.e. the cause of the disease; information on the future course of the disease; and a support programme that people with the disease can access on a casual basis with concerns and questions such as unexpected changes in their conditions and daily activities. Participants were also seeking peer-to-peer communication opportunities in which they can encourage one another, and initiatives to facilitate a better understanding of the disease among the general public (e.g. a disease awareness event during a diabetes awareness month in collaboration with those living with the disease, and information booklets that they can use to explain the disease to people closely associated with them).

Some expressed opinions that the development of drugs indicated for insulin resistance syndrome or lipoatrophic diabetes would promote an accurate understanding of the disease among others and give participants a sense of relief (due to reduced psychological burdens).

“Diabetes and lipodystrophy are things I really want to be differently described.” (Participant A)

“Only because I receive treatment for diabetes, others think that I have diabetes. So, I think it would be good if people no longer thought that I have diabetes; this would make me happy.” (Participant B)

“A drug not for diabetes in general but for insulin resistance syndrome would give me a sense of relief.” (Participant C)

Participants’ unmet needs regarding current treatment included reduction of the burden associated with injectable drugs, such as pain, self-administration, storage, and portability. They also suggested that development of more effective treatments was a priority.

“It would be nice if treatment with oral drugs alone could stabilise blood glucose and HbA1c levels.” (Participant B)

“Even if I need to take drugs, it would be nice if I could easily take them or could inject them anywhere.” (Participant C)

Discussion

The study findings obtained through individual interviews and advisory board meetings clearly indicated that people living with insulin resistance syndrome or lipoatrophic diabetes had considerable physical and psychological burden.

Treatment for insulin resistance syndrome or lipoatrophic diabetes is associated with pain due to frequent injection, drug management, psychological burden caused by the time and effort required for drug administration, and glycaemic control, all of which have a considerable impact on daily life. The unmet medical needs identified in this study include the need for treatments with less frequent and less burdensome injectable and oral drugs. Previous studies have reported that people with diabetes receiving insulin treatment experience anxiety or fear in relation to frequency of injections and pain associated with the injection, which may cause poor compliance, impaired blood glucose control, and lower quality of life (QOL) [9, 10]. A regimen with fewer injections and simplified timing has been reported to greatly improve health-related QOL of people with diabetes [11]. Therefore, addressing issues around reducing treatment-related burden should be prioritised.

Participants in this study were concerned that the mechanism of onset of insulin resistance syndrome or lipoatrophic diabetes has not been sufficiently clarified, and that targeted treatments for the disease are not available. In addition, as a result of the limited availability of disease information for those living with the diseases, the participants felt it was difficult to explain the disease to others. Because they need to control blood glucose levels, participants felt that others may misunderstand that they have type 2 diabetes despite their diseases being refractory genetic diseases, which causes emotional distress. On the other hand, it was suggested that the participants in this study may not have an adequate understanding of type 2 diabetes. Ensuring that those close to people living with the diseases and their family members have a better understanding of the disease might lessen such burdens. Limited information about rare diseases leads to a lower awareness of the diseases among not only the general public but also healthcare professionals, and there is a need to create more opportunities to educate healthcare professionals on rare diseases [12]. It is therefore important to establish a framework that increases access to information about insulin resistance syndrome and lipoatrophic diabetes and their treatments for those living with these diseases, and provides more opportunities for healthcare professionals to learn about these diseases.

The psychological burdens experienced by people living with the disease may also cause their family members to be stigmatised. The concerns and feelings of parents at the time their child(ren) is(are) diagnosed are often left uncommunicated to healthcare professionals in the early phase of diagnosis and treatment. Stigma in family members is recognised as a common challenge in research involving people living with a rare disease [12, 13]. Discrimination against people who are overweight or obese (weight stigma) has been reported to negatively affect parents (especially mothers) and caregivers who have children with paediatric obesity: they report feelings of isolation, a sense of being blamed for their child’s weight struggles, and anxiety about their child’s health [14]. A survey on the need for mental health support for parents and family members who have a child with a rare disease reported that early diagnosis screening and training of healthcare professionals to raise awareness of rare diseases may lead to an accurate and rapid diagnosis and lessen parental anxiety [15]. The study also suggested that providing parents with information about their child’s disease soon after diagnosis, together with an explanation of the expected difficulties, might help to reduce anxiety in parents (especially mothers) [15]. These findings highlight the need for enhanced awareness among healthcare professionals of proactively including family members in their communication in the early post-diagnosis stage.

Participants in this study expressed their desire to participate in occasions to share information and communicate with others who are affected by the same disease. Peer communication opportunities should be actively pursued through not only disease-specific patient groups or support organisations but also groups for patients with other types of diabetes. Such interactions will facilitate better understanding of various type of diabetes and address these needs, with the aim of sharing psychological concerns, providing support, and improving the QOL of those living with the diseases.

This study has suggested that initiatives to promote an accurate understanding of insulin resistance syndrome and lipoatrophic diabetes may contribute to reducing the burdens on people living with the diseases and their family members. As an effective means of raising public awareness of the diseases, some participants proposed using mass media, such as television, and an information booklet for people living with the diseases to explain the disease to others. We suggest that not only information about the disease but also other types of diabetes should be included in the booklet to clarify the difference between them. Also, the diagnostic criteria of the disease will be helpful for health professionals. Hosting educational events during Diabetes Week was also suggested. In Japan, insulin resistance syndrome is not currently registered as a designated intractable disease. Some participants expected registration to be a driver for raising public awareness of the disease and reducing the burden on people living with the diseases in explaining the disease to others, in addition to alleviating financial burden through a medical expense subsidy. When providing disease information, it is important to ensure that educational materials are created in a form readily understandable by people with diabetes and their family members, with close attention to terminology, length of sentences, and structure of the content [16]. In addition, development of therapeutic drugs indicated for these diseases may contribute to promoting an accurate understanding of the diseases among the general public. As such, clinical trials to evaluate the effect of the sodium-glucose cotransporter 2 inhibitor empagliflozin on these diseases are ongoing (NCT04018365, NCT04221152).

To our knowledge, this is the first report anywhere to examine the experiences and perceptions of people living with insulin resistance syndrome or lipoatrophic diabetes. The findings provide new knowledge and insights about these diseases, as well as a better understanding of the associated burdens, and the treatment experiences, needs, and priorities of those living with the diseases, of which there are only about 100 people in Japan for each disease type. Furthermore, one of the study participants, an individual with the disease, contributed as an author, which is another strength of this report.

The limitations of this study include the small number of participants, all of whom were Japanese women, who are not representative of all people with the diseases. The generalisability of the study findings may therefore be limited. Moreover, the views and opinions expressed in the study may be biased because all the participants had participated in clinical trials regarding the diseases concerned, which might suggest that they were well aware of their own health and diseases. In response to participants’ availability, advisory board meetings were held on two separate occasions: one meeting was a group session with three participants, and the other was an individual session with one participant. These meetings were not consistent because in the group session, constructive statements might have been based on the other participants’ opinions, whereas such interaction was not possible in the individual session. Finally, although validated questionnaires to evaluate participant burden were not used in the current qualitative study, such questionnaires could provide additional insights in future studies involving a greater number of participants.

Conclusions

Using individual interviews and advisory board meetings, the authors performed a qualitative research study to identify disease- and treatment-related experiences and difficulties faced by people with insulin resistance syndrome and lipoatrophic diabetes, as well as their needs and priorities related to activities of daily living. Using the insights gained from the participants, the authors then discussed how to meet the identified needs and expectations, as well as what types of therapeutic drugs are required. The diseases and their treatment take a heavy physical and psychological toll on participants. Disease information targeting affected people is limited and those around them lack understanding. This study shed light on the fact that psychological burdens are experienced not only by those directly affected but also by their family members because of the stigma associated with the disease. Current, pressing needs include promoting a proper understanding of insulin resistance syndrome and lipoatrophic diabetes; establishing a framework for providing disease and treatment information targeting people living with the diseases; developing therapeutic drugs indicated for the diseases; providing educational materials to explain and raise public awareness of the diseases; and setting up opportunities for facilitating peer communication.