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Rikako Nakajima Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Mito, Ibaraki, Japan

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Daisuke Sato Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Mito, Ibaraki, Japan

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Ichirota Togashi Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Mito, Ibaraki, Japan

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Hiroto Idesawa Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Mito, Ibaraki, Japan

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Jun Ito Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Mito, Ibaraki, Japan

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Kei Ito Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Mito, Ibaraki, Japan

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Masanao Fujii Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Mito, Ibaraki, Japan

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Hiroaki Yagyu Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Mito, Ibaraki, Japan

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Summary

An 89-year-old woman presented with a 6-year history of occasional episodes of impaired consciousness that were relieved by ingestion of a snack. Three months before presenting to our hospital, she had been hospitalized in a local hospital with subdural hematoma caused by a head contusion, where previously unrecognized hypoglycemia was discovered. Fasting plasma glucose concentration was 37 mg/dL, with a relatively high serum level of insulin (34.9 µU/mL). Computed tomography showed a 14 mm hyperenhancing tumor in the tail of the pancreas and she was referred to our hospital for further investigation. A prolonged fasting test revealed the plasma glucose concentration reduced to 43 mg/dL (2.4 mmol/L) at 8 h after the last meal. Serum insulin, proinsulin, and C-peptide concentrations were 21.1 µU/mL, 16.9 pmol/L, and 2.72 ng/mL, respectively. Subsequent intravenous administration of 1 mg of glucagon increased the plasma glucose concentration to 76 mg/dL (4.2 mmol/L). Moreover, the insulin-to-C-peptide molar ratio was 0.14. These data indicated the presence of insulinoma. Interestingly, serum anti-insulin antibodies were elevated (21.1 U/mL), although she had no history of taking exogenous insulin injection, alpha lipoic acid, or sulfhydryl group-containing agents. Human leukocyte antigen (HLA) typing revealed HLA-DRB1*0407 and HLA-DRB1*1405 alleles. Treatment with diazoxide prevented hypoglycemia, but was discontinued due to weight gain and leg edema. Elevated serum anti-insulin antibodies persisted almost 1 year after the diagnosis of insulinoma. We present a rare case of insulinoma concomitant with serum anti-insulin antibodies.

Learning points

  • Insulinoma presenting with concomitant anti-insulin antibodies appears rare.

  • Insulin/C-peptide molar ratio and serum insulin concentration are useful for differentiating insulinoma and autoimmune syndrome.

  • Flash glucose monitoring systems appear suitable for evaluating treatment outcomes.

Taxonomy:
Clinical Overview, Gland/Organ, Pancreas, Topic, Diabetes, Emergency, Endocrine-related cancer, Condition/ Syndrome, Insulinoma, Patient Demographics, Age, Geriatric, Gender, Female, Ethnicity, Asian - Japanese, Country of Treatment, Japan, Publication Details, Case Report Type, Unique/unexpected symptoms or presentations of a disease
DOI:
https://doi.org/10.1530/EDM-24-0062
Volume/Issue:
Volume 2024: Issue 3
Open access
Rikako Nakajima Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito, Ibaraki, Japan

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Hiroto Idesawa Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito, Ibaraki, Japan

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Daisuke Sato Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito, Ibaraki, Japan

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Jun Ito Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito, Ibaraki, Japan

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Kei Ito Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito, Ibaraki, Japan

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Masanao Fujii Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito, Ibaraki, Japan

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Takamichi Suzuki Department of Gastrointestinal Surgery, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito, Ibaraki, Japan

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Tomoaki Furuta Department of Gastrointestinal Surgery, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito, Ibaraki, Japan

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Hitomi Kawai Department of Pathology, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito, Ibaraki, Japan

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Norio Takayashiki Department of Pathology, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito, Ibaraki, Japan

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Masanao Kurata Department of Gastrointestinal Surgery, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito, Ibaraki, Japan

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Hiroaki Yagyu Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito, Ibaraki, Japan

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Summary

Unawareness of postprandial hypoglycemia for 5 years was identified in a 66-year-old man at a local clinic. The patient was referred to our hospital because of this first awareness of hypoglycemia (i.e. lightheadedness and impaired consciousness) developing after lunch. In a 75 g oral glucose tolerance test, the plasma glucose concentration was decreased to 32 mg/dL (1.8 mmol/L) at 150 min with relatively high concentrations of insulin (8.1 μU/mL), proinsulin (70.3 pmol/L), and C-peptide (4.63 ng/mL). In a prolonged fasting test, the plasma glucose concentration was decreased to 43 mg/dL (2.4 mmol/L) at 66 h with an insulin concentration of 1.4 μU/mL and a C-peptide concentration of 0.49 ng/mL. Computed tomography showed an 18 mm hyperenhancing tumor in the uncinate process of the pancreas. A selective arterial calcium stimulation test showed an elevated serum insulin concentration in the superior mesenteric artery. The patient was then diagnosed with insulinoma and received pancreaticoduodenectomy. Continuous glucose monitoring (CGM) using the Dexcom G6 system showed unawareness of hypoglycemia mainly during the daytime before surgery. When the sensor glucose value was reduced to 55 mg/dL (3.1 mmol/L), the Dexcom G6 system emitted an urgent low glucose alarm to the patient four times for 10 days. Two months after surgery, an overall increase in daily blood glucose concentrations and resolution of hypoglycemia were shown by CGM. We report a case of insulinoma with unawareness of postprandial hypoglycemia in the patient. The Dexcom G6 system was helpful for assessing preoperative hypoglycemia and for evaluating outcomes of treatment by surgery.

Learning points

  • Insulinoma occasionally leads to postprandial hypoglycemia.

  • The CGM system is useful for revealing the presence of unnoticed hypoglycemia and for evaluating treatment outcomes after surgical resection.

  • The Dexcom G6 system has an urgent low glucose alarm, making it particularly suitable for patients who are unaware of hypoglycemia.

Taxonomy:
Clinical Overview, Gland/Organ, Pancreas, Topic, Diabetes, Endocrine-related cancer, Tumours and neoplasia, Patient Demographics, Age, Adult, Gender, Male, Ethnicity, Asian - Japanese, Country of Treatment, Japan, Publication Details, Case Report Type, Insight into disease pathogenesis or mechanism of therapy
DOI:
https://doi.org/10.1530/EDM-23-0056
Volume/Issue:
Volume 2023: Issue 3
Open access
Kei Ito Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito-shi, Ibaraki, Japan

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Jun Ito Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito-shi, Ibaraki, Japan

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Yuki Yamamoto Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito-shi, Ibaraki, Japan

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Rikako Nakajima Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito-shi, Ibaraki, Japan

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Masanao Fujii Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito-shi, Ibaraki, Japan

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Yukino Katakura Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito-shi, Ibaraki, Japan

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Aiko Muramatsu Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito-shi, Ibaraki, Japan

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Norio Takayashiki Department of Pathology, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito-shi, Ibaraki, Japan

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Kazuhiro Toyama Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

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Mineo Kurokawa Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

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Hiroaki Yagyu Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito-shi, Ibaraki, Japan

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Summary

A 61-year-old man developed central diabetes insipidus caused by mixed histiocytosis (MH) representing Langerhans cell histiocytosis overlapping with Erdheim–Chester disease. Bone, skin, vascular, and retroperitoneal involvements were also observed. Dynamic hormonal testing showed normal responses for anterior pituitary hormones, except for impaired secretion of growth hormone (GH). MRI of the brain showed thickening of the pituitary stalk with slightly reduced signal hyperintensity in the posterior pituitary lobe on T1-weighted imaging. During 2 years of follow-up without radical treatment for MH, imaging studies suggested extension of vascular and retroperitoneal involvements. In contrast, brain MRI did not show any particular interval changes, except for the disappearance of hyperintense signalling in the posterior pituitary lobe. Moreover, no other anterior pituitary dysfunctions beyond GH deficiency emerged during the 2 years of follow-up. The natural history of MH in this case is described, focusing on serial assessments of pituitary functions using dynamic tests.

Learning points

  • Erdheim–Chester disease and Langerhans cell histiocytosis overlapping as MH was described, focusing on pituitary functions.

  • MH caused both GH deficiency and central diabetes insipidus.

  • Despite a lack of radical therapy for MH, no other anterior pituitary dysfunctions emerged for 2 years.

  • Radiological images showed no particular interval changes in pituitary stalk lesions, while vascular and retroperitoneal involvements extended.

Taxonomy:
Clinical Overview, Gland/Organ, Pituitary, Topic, Pituitary, Patient Demographics, Age, Adult, Gender, Male, Ethnicity, Asian - Japanese, Country of Treatment, Japan, Publication Details, Case Report Type, Insight into disease pathogenesis or mechanism of therapy
DOI:
https://doi.org/10.1530/EDM-21-0030
Volume/Issue:
Volume 2021: Issue 1
Open access
Motohiro Sekiya Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

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Mikiko Yuhara Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

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Yuki Murayama Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

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Mariko Ohyama Osawa Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

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Rikako Nakajima Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

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Nami Ohuchi Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

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Nako Matsumoto Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

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Daichi Yamazaki Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

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Sayuri Mori Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

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Takaaki Matsuda Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

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Yoko Sugano Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

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Yoshinori Osaki Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

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Hitoshi Iwasaki Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

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Hiroaki Suzuki Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

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Hitoshi Shimano Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

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Summary

A paired homeodomain transcription factor, PAX6 (paired-box 6), is essential for the development and differentiation of pancreatic endocrine cells as well as ocular cells. Despite the impairment of insulin secretion observed in PAX6-deficient mice, evidence implicating causal association between PAX6 gene mutations and monogenic forms of human diabetes is limited. We herein describe a 33-year-old Japanese woman with congenital aniridia who was referred to our hospital because of her uncontrolled diabetes with elevated hemoglobin A1c (13.1%) and blood glucose (32.5 mmol/L) levels. Our biochemical analysis revealed that her insulin secretory capacity was modestly impaired as represented by decreased 24-h urinary C-peptide levels (38.0 μg/day), primarily explaining her diabetes. Intriguingly, there was a trend toward a reduction in her serum glucagon levels as well. Based on the well-recognized association of PAX6 gene mutations with congenital aniridia, we screened the whole PAX6 coding sequence, leading to an identification of a heterozygous Gln135* mutation. We tested our idea that this mutation may at least in part explain the impaired insulin secretion observed in this patient. In cultured pancreatic β-cells, exogenous expression of the PAX6 Gln135* mutant produced a truncated protein that lacked the transcriptional activity to induce insulin gene expression. Our observation together with preceding reports support the recent attempt to include PAX6 in the growing list of genes causally responsible for monogenic diabetes. In addition, since most cases of congenital aniridia carry PAX6 mutations, we may need to pay more attention to blood glucose levels in these patients.

Learning points

  • PAX6 Gln135* mutation may be causally associated not only with congenital aniridia but also with diabetes.

  • Blood glucose levels may deserve more attention in cases of congenital aniridia with PAX6 mutations.

  • Our case supports the recent attempt to include PAX6 in the list of MODY genes, and Gln135* may be pathogenic.

Taxonomy:
Clinical Overview, Gland/Organ, Pancreas, Topic, Genetics and mutation, Tumours and neoplasia, Patient Demographics, Age, Adult, Gender, Female, Ethnicity, Asian - Japanese, Country of Treatment, Japan, Related Disciplines, Gastroenterology, Radiology/Rheumatology, Publication Details, Case Report Type, Insight into disease pathogenesis or mechanism of therapy
DOI:
https://doi.org/10.1530/EDM-22-0271
Volume/Issue:
Volume 2022: Issue 1
Open access
Rikako Nakajima Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Motohiro Sekiya Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Yasuhisa Furuta Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Takafumi Miyamoto Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Masashi Sato Department of Gastroenterology, Faculty of Medicine, University of Tsukuba

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Kuniaki Fukuda Department of Gastroenterology, Faculty of Medicine, University of Tsukuba
Department of Gastroenterology, Kasumigaura Medical Center, 2-7-14 Shimotakatsu, Tsuchiura, Ibaraki, Japan

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Keiichiro Hattori Department of Hematology, Faculty of Medicine, University of Tsukuba

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Yasuhito Suehara Department of Hematology, Faculty of Medicine, University of Tsukuba

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Mamiko Sakata-Yanagimoto Department of Hematology, Faculty of Medicine, University of Tsukuba

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Shigeru Chiba Department of Hematology, Faculty of Medicine, University of Tsukuba

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Yuka Okajima Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Takashi Matsuzaka Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan
Transborder Medical Research Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Satoru Takase Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, the University of Tokyo, Bunkyo, Tokyo, Japan

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Mikio Takanashi Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, the University of Tokyo, Bunkyo, Tokyo, Japan

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Hiroaki Okazaki Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, the University of Tokyo, Bunkyo, Tokyo, Japan

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Yusuke Takashima Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Mikiko Yuhara Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Yuta Mitani Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Nako Matsumoto Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Yuki Murayama Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Mariko Ohyama Osawa Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Nami Ohuchi Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Daichi Yamazaki Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Sayuri Mori Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Yoko Sugano Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Yoshinori Osaki Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Hitoshi Iwasaki Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Hiroaki Suzuki Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Hitoshi Shimano Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Summary

In this study, we herein describe a 47-year-old Japanese woman who manifested inheritable non-alcoholic steatohepatitis (NASH) and severe dyslipidemia. Interestingly, her NASH progression was ameliorated by treatment with a sodium–glucose co-transporter 2 (SGLT2) inhibitor. This inheritability prompted us to comprehensively decode her genomic information using whole-exome sequencing. We found the well-established I148M mutation in PNPLA3 as well as mutations in LGALS3 and PEMT for her NASH. Mutations in GCKR may contribute to both NASH and dyslipidemia. We further mined gene mutations potentially responsible for her manifestations that led to the identification of a novel M188fs mutation in MUL1 that may be causally associated with her mitochondrial dysfunction. Our case may provide some clues to better understand this spectrum of disease as well as the rationale for selecting medications.

Learning points

  • While the PNPLA3 I148M mutation is well-established, accumulation of other mutations may accelerate susceptibility to non-alcoholic steatohepatitis (NASH).

  • NASH and dyslipidemia may be intertwined biochemically and genetically through several key genes.

  • SGLT2 inhibitors emerge as promising treatment for NASH albeit with interindividual variation in efficacy. Genetic background may explain the mechanisms behind the variation.

  • A novel dysfunctional mutation in MUL1 may lead to metabolic inflexibilities through impaired mitochondrial dynamics and function.

Taxonomy:
Clinical Overview, Gland/Organ, Liver, Topic, Diabetes, Patient Demographics, Age, Adult, Gender, Female, Ethnicity, Asian - Japanese, Country of Treatment, Japan, Publication Details, Case Report Type, Insight into disease pathogenesis or mechanism of therapy
DOI:
https://doi.org/10.1530/EDM-22-0368
Volume/Issue:
Volume 2022: Issue 1
Open access