Treatment of a case of severe insulin resistance as a result of a <i><scp>PIK</scp>3R1</i> mutation with a sodium–glucose cotransporter 2 inhibitor

Hamaguchi, Tetsushi; Hirota, Yushi; Takeuchi, Tetsushiro; Nakagawa, Yasushi; Matsuoka, Atsuko; Matsumoto, Masaaki; Awano, Hiroyuki; Iijima, Kazumoto; Chieng, Pei; Satake, Wataru; Toda, Tatsushi; Ogawa, Wataru

doi:10.1111/jdi.12825

Cited by 27 publications

(30 citation statements)

References 12 publications

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“…We identified a pathogenic variant of PIK3R1 in a girl who was initially suspected to have SRS or some SRSrelated disorder. PIK3R1 is the sole known causative gene for SHORT syndrome, and the p.(Arg649Trp) variant has been identified most frequently in SHORT syndrome [3][4][5][10][11][12][13]. These findings indicate that this girl had molecularly confirmed SHORT syndrome, an SRSrelated disorder [6].…”

Section: Discussionmentioning

confidence: 67%

Insulin resistant diabetes mellitus in SHORT syndrome: case report and literature review

et al. 2021

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SHORT syndrome is a rare developmental disorder frequently associated with growth failure and insulin resistant diabetes mellitus (IRDM). Since GH has a diabetogenic effect, GH therapy has been regarded as a contraindication. We observed a Brazilian girl with SHORT syndrome who received GH therapy from 4 6/12 years of age for SGA short stature. GH dosage was increased from 0.23 to 0.36 mg/kg/week, but statural response to GH therapy remained poor. Her blood HbA1c level, though it remained 5.5-6.0% in childhood, began to elevate with puberty and increased to 9.2% at 10 6/12 years of age, despite the discontinuation of GH therapy at 9 11/12 years of age. Laboratory studies indicated antibody-negative IRDM. She was treated with metformin and canagliflozin (a sodium glucose co-transporter 2 (SGLT2) inhibitor), which ameliorated overt diurnal hyperglycemia and mild nocturnal hypoglycemia and reduced her blood HbA1c around 7%. Whole exome sequencing revealed a de novo heterozygous pathogenic variant (c.1945C>T:p.(Arg649Trp)) in PIK3R1 known as the sole causative gene for SHORT syndrome. Subsequent literature review for patients with molecularly confirmed SHORT syndrome revealed the development of IRDM in 10 of 15 GH-untreated patients aged ≥12 years but in none of three GHtreated and six GH-untreated patients aged ≤10 years. These findings imply a critical role of pubertal development and/or advanced age rather than GH therapy in the development of IRDM, and a usefulness of SGLT2 inhibitor in the treatment of IRDM.

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Section: Discussionmentioning

confidence: 67%

Insulin resistant diabetes mellitus in SHORT syndrome: case report and literature review

et al. 2021

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“…After we received the questionnaire responses, three patients with type X IRS were shown to harbor mutations in PIK3R1 , which encodes a regulatory subunit of phosphoinositide 3‐kinase (PI 3‐kinase), as a result of analysis carried out independently of the present study. We sequenced PIK3R1 in the remaining five patients with type X IRS, and detected PIK3R1 mutations in two patients.…”

Section: Resultsmentioning

confidence: 88%

Clinical characteristics of insulin resistance syndromes: A nationwide survey in Japan

Takeuchi

Ishigaki

Hirota

et al. 2019

J of Diabetes Invest

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Aims/Introduction: Insulin resistance syndrome (IRS) of type A or B is triggered by gene abnormalities of or autoantibodies to the insulin receptor, respectively. Rabson-Mendenhall/Donohue syndrome is also caused by defects of the insulin receptor gene (INSR), but is more serious than type A IRS. Here, we carried out a nationwide survey of these syndromes in Japan. Materials and Methods:We sent questionnaires to a total of 1,957 academic councilors or responsible individuals at certified facilities of the Japan Diabetes Society, as well as at the department pediatrics or neonatology in medical centers with >300 beds. Results:We received 904 responses with information on 23, 30 and 10 cases of type A or B IRS and Rabson-Mendenhall/Donohue syndrome, respectively. Eight cases with type A IRS-like clinical features, but without an abnormality of INSR, were tentatively designated type X IRS, with five of these cases testing positive for PIK3R1 mutations. Fasting serum insulin levels at diagnosis (meanstandard deviation) were 132.0 -112.4, 1122.1 -3292.5, 2895.5 -3181.5 and 145.0 -141.4 lU/mL for type A IRS, type B IRS, Rabson-Mendenhall/Donohue syndrome and type X IRS, respectively. Type A and type X IRS, as well as Rabson-Mendenhall/Donohue syndrome were associated with low birthweight. Type B IRS was diagnosed most frequently in older individuals, and was often associated with concurrent autoimmune conditions and hypoglycemia. Conclusions: Information yielded by this first nationwide survey should provide epidemiological insight into these rare conditions and inform better healthcare for affected patients.

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“…In that study, SGLT2 inhibitors were used for seven of 71 study participants. However, SGLT2 inhibitor efficacy data for patients with genetically‐determined severe IR are limited. To our knowledge, we are the first to report the long‐term efficacy of an SGLT2 inhibitor for a patient with an INSR mutation.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Just two articles have reported the efficacy of SGLT2 inhibitors in genetically‐induced severe IR. Combining dapagliflozin with insulin and metformin therapy lowered bodyweight and HbA1c levels in a patient with a heterozygous mutation in the phosphatidylinositol 3‐kinase, regulatory subunit 1 gene, which is involved in post‐INSR signaling. Furthermore, combining ipragliflozin with other oral antidiabetic drugs significantly improved severe IR in a patient with a homozygous nonsense mutation of Berardinelli–Seip congenital lipodystrophy 2 gene, which is responsible for adipocyte differentiation, as assessed by a homeostasis model.…”

Section: Discussionmentioning

confidence: 99%

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Long‐term efficacy of the sodium–glucose cotransporter 2 inhibitor, ipragliflozin, in a case of type A insulin resistance syndrome

Nagashima

Wakabayashi

Saito

et al. 2020

J of Diabetes Invest

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Type A insulin resistance (IR) syndrome is a severe IR form caused by insulin receptor (INSR) gene defects. Antidiabetic drugs, including high‐dose insulin and insulin‐sensitizing agents, often fail to control associated hyperglycemia. Therapy with recombinant human insulin‐like growth factor 1 can be more effective, but it is expensive. We report a case of type A IR syndrome with an in‐frame INSR heterozygous deletion (ΔLeu999) that was treated with a combination of conventional therapy and ipragliflozin, a sodium–glucose cotransporter 2 inhibitor. Treatment reduced hemoglobin A1c levels (10.0–7.5%) and induced weight loss (54.4–52.0 kg) within 2 months, and the effects were sustained for >3 years. Sodium–glucose cotransporter 2 inhibitors might be useful to normalize blood glucose in type A IR syndrome by reducing bodyweight and ameliorating glucotoxicity.

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Treatment of a case of severe insulin resistance as a result of a PIK3R1 mutation with a sodium–glucose cotransporter 2 inhibitor

Cited by 27 publications

References 12 publications

Insulin resistant diabetes mellitus in SHORT syndrome: case report and literature review

Insulin resistant diabetes mellitus in SHORT syndrome: case report and literature review

Clinical characteristics of insulin resistance syndromes: A nationwide survey in Japan

Long‐term efficacy of the sodium–glucose cotransporter 2 inhibitor, ipragliflozin, in a case of type A insulin resistance syndrome

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