Diabetes Mellitus, Lipoatrophic

Insulin resistance syndrome and lipoatrophic diabetes are characterized by severe insulin resistance and are often refractory to treatment. Trials assessing the efficacy of antidiabetes drugs for these rare conditions have been limited, however. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which lower glycemia independently of insulin action, have shown efficacy for type 2 diabetes with insulin resistance. We here investigated the efficacy and safety of the SGLT2 inhibitor empagliflozin for treatment of insulin resistance syndrome and lipoatrophic diabetes.

The trial was conducted at five academic centers in Japan and included seven patients with insulin resistance syndrome and one patient with lipoatrophic diabetes. Participants received 10 mg of empagliflozin daily. If the hemoglobin A_1c (HbA_1c) level was ≥ 7.0% (52 mmol/mol) after 12 weeks, the dose was adjusted to 25 mg. The study duration was 24 weeks, and the primary outcome was the change in HbA_1c level by the end of the treatment period. Safety evaluations were performed for all participants.

By the end of the 24-week treatment period, the mean HbA_1c level for all eight patients had decreased by 0.99 percentage points (10.8 mmol/mol) (95% confidence interval [CI], 0.59 to 1.38 percentage points, 6.6 to 14.9 mmol/mol) and the mean fasting plasma glucose concentration had declined by 63.9 mg/dL (3.55 mmol/L) (95% CI 25.5 to 102.3 mg/dL, 1.42 to 5.68 mmol/L). Continuous glucose monitoring revealed a reduction in mean glucose levels from 164.3 ± 76.1 to 137.6 ± 46.6 mg/dL (9.13 ± 4.23 to 7.65 ± 2.59 mmol/L) as well as an increase in the time in range (70-180 mg/dL) from 58.9 ± 36.1% to 70.8 ± 18.3%. Seventeen mild adverse events were recorded in five individuals throughout the study period. No severe events were reported. The mean body mass showed a slight decrease and the mean serum ketone body concentration showed a slight increase during treatment.

Our results demonstrate that empagliflozin shows a certain level of efficacy and safety for treatment of insulin resistance syndrome and lipoatrophic diabetes.

jRCTs2051190029 and NCT04018365.

Long-term ad libitum dietary restrictions, such as low-protein diets (LPDs), improve metabolic health and extend the life span of mice and humans. However, most studies conducted thus far have focused on the preventive effects of LPDs on metabolic syndromes. To test the therapeutic potential of LPD, we treated a lipodystrophy mouse model IR^FKO (adipose-specific insulin receptor knockout) in this study. We have previously shown that IR^FKO mice have profound insulin resistance, hyperglycemia, and whitening of interscapular brown adipose tissue (BAT), closely mimicking the phenotypes in lipoatrophic diabetic patients. Here, we demonstrate that 14-day of LPD (5.1% kcal from protein) feeding is sufficient to reduce postprandial blood glucose, improve insulin resistance, and normalize glucose tolerance in the IR^FKO mice. This profound metabolic improvement is associated with BAT activation and increase in whole body energy expenditure. To confirm, we showed that surgical denervation of BAT attenuated the beneficial metabolic effects of LPD feeding in IR^FKO mice, including the 'browning' effects on BAT and the glucose-ameliorating results. However, BAT denervation failed to affect the body weight-lowering effects of LPD. Together, our results imply a therapeutic potential to use LPD for the treatment of lipoatrophic diabetes.

There are few reports on the experiences and perceptions of people living with the rare diseases of insulin resistance syndrome or lipodystrophy. This study was designed to identify treatment experiences and perceptions of disease-related burdens among affected people, as well as their needs and priorities. We discussed how to meet identified needs and expectations, in addition to the types of therapeutic drugs and support required.

Qualitative data regarding participants' experiences and perceptions of the diseases were collected through individual interviews, advisory board meetings, and individual follow-up activities. Verbatim transcripts from recorded participants' statements were qualitatively analysed.

Four women aged 30-41 years participated in the study, two with insulin resistance syndrome and two with lipoatrophic diabetes. The diseases not only took a heavy physical toll on these women, but they and their families were also affected psychologically, with some experiencing stigmatisation. There was a lack of information for participants about their disease and little public awareness of the disease. The needs identified include initiatives to promote an accurate understanding of these diseases, information booklets, consultation service for those affected by the diseases, less burdensome treatment options, and opportunities for peer communication.

People living with insulin resistance syndrome or lipoatrophic diabetes have significant physical/psychological burdens and unmet needs. The following are highly desirable to alleviate the burdens: promoting proper understanding of the diseases; establishing a framework for dissemination of disease and treatment information to those living with the diseases; development of therapeutic drugs for these diseases; educational materials that raise public awareness; and opportunities for peer communication.

UMIN Clinical Trials Registry (UMIN000043693). A Japanese translation is available for this article.