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ABSTRACT It is crucial to develop practical and noninvasive methods to assess the functional beta‐cell mass in a donor pancreas, in which monitoring and precise evaluation is challenging. A patient with type 1 diabetes underwent noninvasive imaging following simultaneous kidney–pancreas transplantation with positron emission tomography/computed tomography (PET/CT) using an exendin‐based probe, [18F]FB(ePEG12)12‐exendin‐4. Following transplantation, PET imaging with [18F]FB(ePEG12)12‐exendin‐4 revealed simultaneous and distinct accumulations in the donor and native pancreases. The pancreases were outlined at a reasonable distance from the surrounding organs using [18F]FB(ePEG12)12‐exendin‐4 whole‐body maximum intensity projection and axial PET images. At 1 and 2 h after [18F]FB(ePEG12)12‐exendin‐4 administration, the mean standardized uptake values were 2.96 and 3.08, respectively, in the donor pancreas and 1.97 and 2.25, respectively, in the native pancreas. [18F]FB(ePEG12)12‐exendin‐4 positron emission tomography imaging allowed repeatable and quantitative assessment of beta‐cell mass following simultaneous kidney–pancreas transplantation.

BackgroundInsulinomas are the most common functioning pancreatic neuroendocrine neoplasms, and these tumors induce hypoglycemia due to hyperinsulinemia. Hypoglycemia caused by insulinomas can cause seizures, coma or death due to the delayed diagnosis. The only curative treatment is surgical resection. To perform curative surgical resection of insulinomas, preoperative localization is crucial. However, localization of insulinomas is often challenging using conventional imaging methods such as computed tomography (CT) and magnetic resonance imaging. Although endoscopic ultrasound (EUS) fine-needle aspiration and selective arterial calcium stimulation test, which can reflect the endocrine character of the tumor, are performed in such cases, these modalities are invasive and require operator-dependent techniques. Additionally, somatostatin receptor (SSTR)-targeted imaging has a relatively low sensitivity for detecting insulinomas due to its low SSTR type 2 expression. Thus, there is an urgent need for developing a noninvasive diagnostic technique which is specific for detecting insulinomas. Consequently, glucagon-like peptide-1 receptor-targeted imaging has recently emerged and gained a wide interest. Recently, we have developed a novel 18F-labeled exendin-4-based probe conjugated with polyethylene glycol, [18F]FB(ePEG12)12-exendin-4 (18F-exendin-4), for positron emission tomography (PET) imaging. Here we report a case of insulinoma in which 18F-exendin-4 PET/CT noninvasively provided critical information for localization.Case descriptionThis is a case of a 58-year-old male with symptomatic hypoglycemia for 10 years; however, a preoperative diagnosis of insulinoma was not established due to the difficulty in differentiating it from an accessory spleen using conventional imaging. Moreover, the patient requested to avoid invasive diagnostic procedures including EUS. 18F-exendin-4 PET/CT revealed significant uptakes in the pancreatic tail whereas no apparent uptakes were observed in the spleen; thus, curative laparoscopic enucleation of the pancreatic tail was performed. The diagnosis of insulinoma was confirmed via histopathological examination. This is the first case report of insulinoma diagnosed using 18F-exendin-4 PET/CT.ConclusionIn this case, PET information led to curative resection through enucleation of the pancreas. 18F-exendin-4 PET/CT may serve as a useful noninvasive clinical tool for insulinoma localization.

Abstract Aims/Introduction An efficient screening strategy for identification of cognitive dysfunction remains a clinical issue in the management of elderly adults with diabetes. A magnetic resonance imaging voxel‐based specific regional analysis system for Alzheimer’s disease (VSRAD) has been developed as an automated brain morphometry system that includes the hippocampus. We carried out a multicenter retrospective study to evaluate the utility of VSRAD for screening cognitive dysfunction in diabetes outpatient clinics. Materials and Methods We enrolled patients with diabetes aged >65 years who underwent brain magnetic resonance imaging scans for the purpose of a medical checkup between November 2018 and May 2019. Patients who were already suspected or diagnosed with mild cognitive impairment and/or dementia as well as those with a history of cerebrovascular disease were excluded. Results A total of 67 patients were enrolled. Five patients were diagnosed with mild cognitive impairment or dementia (clinical cognitive dysfunction). Patients with clinical cognitive dysfunction showed a significantly higher z‐score in VSRAD analysis (2.57 ± 0.47 vs 1.15 ± 0.55, P

Progressive loss of β-cell mass (BCM) has a pernicious influence on type 2 diabetes mellitus (T2DM); evaluation of BCM has conventionally required an invasive method that provides only cross-sectional data. However, a noninvasive approach to longitudinal assessment of BCM in living subjects using an indium 111–labeled exendin-4 derivative ([Lys12(111In-BnDTPA-Ahx)]exendin-4) (111In-exendin-4) has been developed recently. Imeglimin is a novel antidiabetic agent that is reported to improve glycemic control and glucose-stimulated insulin secretion (GSIS) via augmentation of mitochondrial function. However, the influence of imeglimin on BCM is not fully understood. We have investigated the effects of imeglimin on BCM in vivo in prediabetic db/db mice using a noninvasive 111In-exendin-4 single-photon emission computed tomography/computed tomography (SPECT/CT) technique. During the 5-week study period, imeglimin treatment attenuated the progression of glucose intolerance, and imeglimin-treated mice retained greater BCM than control, which was consistent with the results of 111In-exendin-4 SPECT/CT scans. Furthermore, immunohistochemical analysis revealed reduced β-cell apoptosis in the imeglimin-treated db/db mice, and also lowered release of cytosolic cytochrome c protein in the β cells. Furthermore, electron microscopy observation and membrane potential measurement revealed improved structural integrity and membrane potential of the mitochondria of imeglimin-treated islets, respectively. These results demonstrate attenuation of progression of BCM loss in prediabetic db/db mice partly via inhibition of mitochondria-mediated apoptosis.

Pancreatic β-cell mass (BCM) has an importance in the pathophysiology of diabetes mellitus. Recently, glucagon-like peptide-1 receptor (GLP-1R)-targeted imaging has emerged as a promising tool for BCM evaluation. While glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP) is known to be involved in high-fat diet (HFD)-induced obesity, the effect of GIP on BCM is still controversial. In this study, we investigated indium 111 (111In)-labeled exendin-4 derivative ([Lys12(111In-BnDTPA-Ahx)]exendin-4) single-photon emission computed tomography/computed tomography (SPECT/CT) as a tool for evaluation of longitudinal BCM changes in HFD-induced obese mice, at the same time we also investigated the effects of GIP on BCM in response to HFD using GIP-knockout (GIP-/-) mice. 111In-exendin-4 SPECT/CT was able to distinguish control-fat diet (CFD)-fed mice from HFD-fed mice and the pancreatic uptake values replicated the BCM measured by conventional histological methods. Furthermore, BCM expansions in HFD-fed mice were demonstrated by time-course changes of the pancreatic uptake values. Additionally, 111In-exendin-4 SPECT/CT demonstrated the distinct changes in BCM between HFD-fed GIP-/- (GIP-/-+HFD) and wild-type (WT+HFD) mice; the pancreatic uptake values of GIP-/-+HFD mice became significantly lower than those of WT+HFD mice. The different changes in the pancreatic uptake values between the two groups preceded those in fat accumulation and insulin resistance. Taken together with the finding of increased β-cell apoptosis in GIP-/-+HFD mice compared with WT+HFD mice, these data indicated that GIP has preferable effects on BCM under HFD. Therefore, 111In-exendin-4 SPECT/CT can be useful for evaluating increasing BCM and the role of GIP in BCM changes under HFD conditions.

Summary: Long-chain triglycerides (LCTs) intake strongly stimulates GIP secretion from enteroendocrine K cells and induces obesity and insulin resistance partly due to GIP hypersecretion. In this study, we found that medium-chain triglycerides (MCTs) inhibit GIP secretion after single LCT ingestion and clarified the mechanism underlying MCT-induced inhibition of GIP secretion. MCTs reduced the CCK effect after single LCT ingestion in wild-type (WT) mice, and a CCK agonist completely reversed MCT-induced inhibition of GIP secretion. In vitro studies showed that medium-chain fatty acids (MCFAs) inhibit long-chain fatty acid (LCFA)-stimulated CCK secretion and increase in intracellular Ca2+ concentrations through inhibition of GPR120 signaling. Long-term administration of MCTs reduced obesity and insulin resistance in high-LCT diet-fed WT mice, but not in high-LCT diet-fed GIP-knockout mice. Thus, MCT-induced inhibition of GIP hypersecretion reduces obesity and insulin resistance under high-LCT diet feeding condition.

Background: Insulinomas are the most common functioning pancreatic neuroendocrine neoplasms, and these tumors induce hypoglycemia due to hyperinsulinemia. Hypoglycemia caused by insulinomas can cause seizures, coma or death due to the delayed diagnosis. The only curative treatment is surgical resection. To perform curative surgical resection of insulinomas, preoperative localization is crucial. However, localization of insulinomas is often challenging using conventional imaging methods such as computed tomography (CT) and magnetic resonance imaging. Although endoscopic ultrasound (EUS) fine-needle aspiration and selective arterial calcium stimulation test, which can reflect the endocrine character of the tumor, are performed in such cases, these modalities are invasive and require operatordependent techniques. Additionally, somatostatin receptor (SSTR)-targeted imaging has a relatively low sensitivity for detecting insulinomas due to its low SSTR type 2 expression. Thus, there is an urgent need for developing a noninvasive diagnostic technique which is specific for detecting insulinomas. Consequently, glucagon-like peptide-1 receptor-targeted imaging has recently emerged and gained a wide interest. Recently, we have developed a novel 18Flabeled exendin-4-based probe conjugated with polyethylene glycol, [18F]FB (ePEG12)12-exendin-4 (18F-exendin-4), for positron emission tomography (PET) imaging. Here we report a case of insulinoma in which 18F-exendin-4 PET/CT noninvasively provided critical information for localization. Case description: This is a case of a 58-year-old male with symptomatic hypoglycemia for 10 years; however, a preoperative diagnosis of insulinoma was not established due to the difficulty in differentiating it from an accessory spleen using conventional imaging. Moreover, the patient requested to avoid invasive diagnostic procedures including EUS. 18F-exendin-4 PET/CT revealed significant uptakes in the pancreatic tail whereas no apparent uptakes were observed in the spleen; thus, curative laparoscopic enucleation of the pancreatic tail was performed. The diagnosis of insulinoma was confirmed via histopathological examination. This is the first case report of insulinoma diagnosed using 18F-exendin-4 PET/CT. Conclusion: In this case, PET information led to curative resection through enucleation of the pancreas. 18F-exendin-4 PET/CT may serve as a useful noninvasive clinical tool for insulinoma localization. [ABSTRACT FROM AUTHOR]

Progressive loss of β-cell mass (BCM) has a pernicious influence on type 2 diabetes mellitus (T2DM); evaluation of BCM has conventionally required an invasive method that provides only cross-sectional data. However, a noninvasive approach to longitudinal assessment of BCM in living subjects using an indium 111-labeled exendin-4 derivative ([Lys12(111In-BnDTPA-Ahx)] exendin-4) (111In-exendin-4) has been developed recently. Imeglimin is a novel antidiabetic agent that is reported to improve glycemic control and glucosestimulated insulin secretion (GSIS) via augmentation of mitochondrial function. However, the influence of imeglimin on BCM is not fully understood. We have investigated the effects of imeglimin on BCM in vivo in prediabetic db/db mice using a noninvasive 111In-exendin-4 single-photon emission computed tomography/computed tomography (SPECT/CT) technique. During the 5-week study period, imeglimin treatment attenuated the progression of glucose intolerance, and imeglimin-treated mice retained greater BCM than control, which was consistent with the results of 111In-exendin-4 SPECT/CT scans. Furthermore, immunohistochemical analysis revealed reduced β-cell apoptosis in the imeglimin-treated db/db mice, and also lowered release of cytosolic cytochrome c protein in the β cells. Furthermore, electron microscopy observation and membrane potential measurement revealed improved structural integrity and membrane potential of the mitochondria of imeglimin-treated islets, respectively. These results demonstrate attenuation of progression of BCM loss in prediabetic db/db mice partly via inhibition of mitochondria-mediated apoptosis. [ABSTRACT FROM AUTHOR]

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin secreted from enteroendocine K cells after nutrient ingestion. Fat strongly induces GIP secretion, and GIP hypersecretion is involved in high-fat diet-induced obesity and insulin resistance. Aging also induces GIP hypersecretion, but its effect on body we ight gain and insulin sensitivity remains unclear. In the present study, we investiga ted the effect of GIP on age-related body weight gain and insulin resistance using GIP-k nockout homozygous (GIP-/-) and heterozygous (GIP+/-) mice, which have entirely absent and 50% reduced GIP secretion compared to wild-type (WT) mice, respectively. Un der 12% fat-containing normal diet feeding condition, body weight was significantly low er in GIP-/- mice compared to that in WT and GIP+/- mice from 38 weeks of age, while there was no significant difference between WT and GIP+/- mice. Visceral and s.c. fat mass were also significantly lower in GIP-/- mice compared to those in WT and GIP +/- mice. During oral glucose tolerance test, blood glucose levels did not differ amon g the three groups. Insulin levels were significantly lower in GIP-/- mice than those in WT and GIP +/- mice. During insulin tolerance test, GIP-/- mice showed higher insulin sensitivity than that of WT and GIP+/- mice. Adiponectin mRNA levels were increased and leptin mRNA l evels tended to be decreased in adipose tissue of GIP-/- mice. These results demonstrate that GIP is involved in age-related obesity and insulin resistance and that inhibition of GIP secretion alleviates age-related fat mass gain and insulin resistance under carbohydratebased diet feeding condition. [ABSTRACT FROM AUTHOR]