RESUMEN
BACKGROUND: Both genetic and environmental factors contribute to type 2 diabetes development. We used consomic mice established from an animal type 2 diabetes model to identify susceptibility genes that contribute to type 2 diabetes development under specific environments. We previously established consomic strains (C3H-Chr 11NSY and C3H-Chr 14NSY) that possess diabetogenic Chr 11 or 14 of the Nagoya-Shibata-Yasuda (NSY) mouse, an animal model of spontaneous type 2 diabetes, in the genetic background of C3H mice. To search genes contribute to type 2 diabetes under specific environment, we first investigated whether sucrose administration deteriorates type 2 diabetes-related traits in the consomic strains. We dissected loci on Chr 11 by establishing congenic strains possessing different segments of NSY-derived Chr 11 under sucrose administration. RESULTS: In C3H-Chr 11NSY mice, sucrose administration for 10 weeks deteriorated hyperglycemia, insulin resistance, and impaired insulin secretion, which is comparable to NSY mice with sucrose. In C3H-Chr 14NSY mice, sucrose administration induced glucose intolerance, but not insulin resistance and impaired insulin secretion. To dissect the gene(s) existing on Chr 11 for sucrose-induced type 2 diabetes, we constructed four novel congenic strains (R1, R2, R3, and R4) with different segments of NSY-derived Chr 11 in C3H mice. R2 mice showed marked glucose intolerance and impaired insulin secretion comparable to C3H-Chr 11NSY mice. R3 and R4 mice also showed impaired insulin secretion. R4 mice showed significant decreases in white adipose tissue, which is in the opposite direction from parental C3H-Chr 11NSY and NSY mice. None of the four congenic strains showed insulin resistance. CONCLUSIONS: Genes on mouse Chr 11 could explain glucose intolerance, impaired insulin secretion, insulin resistance in NSY mice under sucrose administration. Congenic mapping with high sucrose environment localized susceptibility genes for type 2 diabetes associated with impaired insulin secretion in the middle segment (26.0-63.4 Mb) of Chr 11. Gene(s) that decrease white adipose tissue were mapped to the distal segment of Chr 11. The identification of diabetogenic gene on Chr 11 in the future study will facilitate precision medicine in type 2 diabetes by controlling specific environments in targeted subjects with susceptible genotypes.
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Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad , Sacarosa/administración & dosificación , Animales , Mapeo Cromosómico , Modelos Animales de Enfermedad , Hiperglucemia/genética , Insulina/metabolismo , Resistencia a la Insulina , Masculino , Ratones , Ratones Congénicos , Ratones Endogámicos C3H , FenotipoRESUMEN
Streptozotocin (STZ) has been widely used to induce diabetes in rodents. Strain-dependent variation in susceptibility to STZ has been reported; however, the gene(s) responsible for STZ susceptibility has not been identified. Here, we utilized the A/J-11SM consomic strain and a set of chromosome 11 (Chr. 11) congenic strains developed from A/J-11SM to identify a candidate STZ-induced diabetes susceptibility gene. The A/J strain exhibited significantly higher susceptibility to STZ-induced diabetes than the A/J-11SM strain, confirming the existence of a susceptibility locus on Chr. 11. We named this locus Stzds1 (STZ-induced diabetes susceptibility 1). Congenic mapping using the Chr. 11 congenic strains indicated that the Stzds1 locus was located between D11Mit163 (27.72 Mb) and D11Mit51 (36.39 Mb). The Mpg gene, which encodes N-methylpurine DNA glycosylase (MPG), a ubiquitous DNA repair enzyme responsible for the removal of alkylated base lesions in DNA, is located within the Stzds1 region. There is a close relationship between DNA alkylation at an early stage of STZ action and the function of MPG. A Sanger sequence analysis of the Mpg gene revealed five polymorphic sites in the A/J genome. One variant, p.Ala132Ser, was located in a highly conserved region among rodent species and in the minimal region for retained enzyme activity of MPG. It is likely that structural alteration of MPG caused by the p.Ala132Ser mutation elicits increased recognition and excision of alkylated base lesions in DNA by STZ.
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Mapeo Cromosómico/métodos , Cromosomas de los Mamíferos/genética , Diabetes Mellitus Experimental/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Animales , Glucemia/metabolismo , Diabetes Mellitus Experimental/sangre , Femenino , Sitios Genéticos , Insulina/sangre , Masculino , Ratones Congénicos , Estreptozocina , Factores de TiempoRESUMEN
BACKGROUND: We report a rare case of a juxta-adrenal schwannoma that could not be discriminated from an adrenal tumor before surgical resection and was complicated by bilateral hyperaldosteronism. To the best of our knowledge, this is first case in which both a juxta-adrenal schwannoma and hyperaldosteronism co-existed. CASE PRESENTATION: A 69-year-old male treated for hypertension was found to have a left supra-renal mass (5.8 × 5.2 cm) by abdominal computed tomography. His laboratory data showed that his plasma aldosterone concentration (PAC) was within the normal range, but his plasma renin activity (PRA) was reduced, resulting in an increased aldosterone/renin ratio (ARR). Load tests of captopril or furosemide in the standing position demonstrated autonomous aldosterone secretion and renin suppression. Adrenal venous sampling (AVS) with ACTH stimulation indicated bilateral hypersecretion of aldosterone. A left supra-renal tumor was resected because of the possibility of malignancy and was found to be a benign schwannoma arising from the juxta-adrenal region together with an adrenal gland. The dissected left adrenal gland was morphologically hyperplastic in the zona glomerulosa, but was immunohistochemically negative for CYP11B2 (aldosterone synthase). Multiple CYP11B2-positive adrenocortical micronodules were detected in the adrenal gland, indicating micronodular hyperplasia. Although bilateral aldosteronism was indicated by AVS before the operation, the PRA, PAC and ARR values were within their respective reference ranges after resection of the unilateral tumor, suggesting that the slight increase in hormone secretion from the remaining right-sided lesion could not be detected after resection. CONCLUSION: A clinical and morphologic diagnosis of juxta-adrenal schwannoma is difficult, particularly in a case of hyperaldosteronism, as shown in this case. These data suggest the complexity and difficulty diagnosing adrenal incidentaloma.
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Glándulas Suprarrenales/patología , Adrenalectomía/efectos adversos , Hiperaldosteronismo/complicaciones , Neurilemoma/etiología , Anciano , Humanos , Hiperaldosteronismo/patología , Hiperaldosteronismo/cirugía , Masculino , Neurilemoma/patología , PronósticoRESUMEN
BACKGROUND: A susceptibility locus, Nidd2n, for type 2 diabetes has been mapped to mouse chromosome 14 (Chr 14) and confirmed using the consomic strain (C3H-Chr 14NSY) of the Nagoya-Shibata-Yasuda (NSY) mouse, an animal model of spontaneous type 2 diabetes. The aim of this study was to localize and characterize Nidd2n. RESULTS: We constructed two novel congenic strains homozygous for different segments of NSY-Chr 14 on the control C3H/HeNcrj (C3H) background: R1 (C3H.NSY-(D14Mit206-D14Mit5)) possesses the proximal and middle segment, and R2 (C3H.NSY-(D14Mit206-D14Mit186)) possesses the most proximal segment of NSY-Chr 14. Diabetes-related phenotypes were studied in comparison with those of consomic C3H-Chr 14NSY (R0) and parental NSY and C3H strains. Congenic R1 and R2 showed significantly higher post-challenge glucose than that in C3H mice. Fasting glucose, in contrast, was significantly lower in R1 and R2 than in C3H mice. Insulin sensitivity was significantly impaired in R1 and R2 compared to C3H mice. R2 showed significantly higher body weight and fat-pad weight than those in C3H and R1. Leptin level was significantly higher in R0, R1 and R2 than in C3H mice, with R2 showing the highest level, similar to that in NSY mice. Serum adiponectin level was significantly lower in R0, R1 and R2 than in C3H mice, while it was significantly higher in NSY than in C3H mice. CONCLUSIONS: These data indicate that Chr 14 harbors multiple genes for diabetes-related phenotypes. The original Nidd2n, which is located in the middle region of Chr 14, was divided into two segments; Nidd2.1n in proximal Chr 14 and Nidd2.2n in distal Chr 14. Nidd2.1n contributes to post-challenge hyperglycemia, insulin resistance and adiposity. Nidd2.2n contributes to fasting as well as post-challenge hyperglycemia and insulin resistance. Adp1n, which contributes to decreased adiposity and increased insulin sensitivity, rather than a diabetogenic gene, was mapped in the middle segment.
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Diabetes Mellitus/genética , Predisposición Genética a la Enfermedad , Proteínas de la Membrana/genética , Fenotipo , Adiposidad/genética , Animales , Glucemia/análisis , Modelos Animales de Enfermedad , Femenino , Hiperglucemia/genética , Resistencia a la Insulina/genética , Masculino , Ratones , Ratones Congénicos , Ratones Endogámicos C3HRESUMEN
Continuous glucose monitoring (CGM) values obtained from CGM systems using the same sensor but with different internal algorithms (the first- and third-generation FreeStyle Libre (1st-gen-libre and 3rd-gen-libre, respectively)) were compared. We used 19,819 paired and simultaneously measured CGM values of 13 patients with diabetes. The average CGM value was significantly higher (P < 0.0001) and the time below range (CGM value < 70 mg/dL) was significantly lower (P < 0.0001) with the 3rd-gen-libre than with the 1st-gen-libre. There was a significant correlation (P < 0.0001) between the CGM values of the 3rd-gen-libre (y-axis, mg/dL) and 1st-gen-libre (x-axis, mg/dL) using the following formula: y = 0.9728x + 10.024. On assessing the association between glycated hemoglobin (HbA1c (%), y-axis) and the average CGM values (x-axis, mg/dL) by applying the obtained equation to previously reported 1st-gen-libre data and converting it to 3rd-gen-libre data, we obtained the equation y = 0.02628x + 3.233, indicating that the glucose management indicator reported in the West may be underestimated compared with the laboratory-measured HbA1c in the Japanese population. Glucose values from the same sensor were found to be significantly different between readers with different algorithms, and the calculation of CGM-related indices may need to be individualized for each device.
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Glucemia , Diabetes Mellitus Tipo 1 , Humanos , Glucosa , Hemoglobina Glucada , Automonitorización de la Glucosa Sanguínea , Monitoreo Continuo de Glucosa , AlgoritmosRESUMEN
CONTEXT: Glucose tolerance worsens after distal pancreatectomy (DP); however, the long-term incidence and factors affecting interindividual variation in this worsening are unclear. OBJECTIVE: To investigate the changes in diabetes-related traits before and after DP and to clarify the incidence of diabetes and its predictors. METHODS: Among 493 registered patients, 117 underwent DP. Among these, 56 patients without diabetes before surgery were included in the study. Glucose and endocrine function were prospectively assessed using a 75-g oral glucose tolerance test preoperatively, 1 month after DP, and every 6 months thereafter for up to 36 months. Pancreatic volumetry was performed using multidetector row computed tomography before and after surgery. RESULTS: Insulin secretion decreased and blood glucose levels worsened after DP. Residual pancreatic volume was significantly associated with the reserve capacity of insulin secretion but not with blood glucose levels or the development of diabetes. Among 56 patients, 33 developed diabetes mellitus. The cumulative incidence of diabetes at 36 months after DP was 74.1%. Multivariate Cox regression analysis showed that impaired glucose tolerance as a preoperative factor as well as a decreased insulinogenic index and impaired glucose tolerance at 1 month postoperatively were identified as risk factors for diabetes following DP. CONCLUSION: Impaired glucose tolerance and reduced early-phase insulin response to glucose are involved in the development of new-onset diabetes after DP; the latter is an additional factor in the development of diabetes and becomes apparent when pancreatic beta cell mass is reduced after DP.
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Diabetes Mellitus , Intolerancia a la Glucosa , Neoplasias Pancreáticas , Humanos , Pancreatectomía/efectos adversos , Pancreatectomía/métodos , Estudios de Seguimiento , Incidencia , Intolerancia a la Glucosa/etiología , Intolerancia a la Glucosa/complicaciones , Glucemia , Diabetes Mellitus/epidemiología , Diabetes Mellitus/etiología , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/complicacionesRESUMEN
Both genetic factors and diabetogenic environmental factors, such as a high-sucrose diet (HSD), are involved in the development of type 2 diabetes. In this study, the Nagoya-Shibata-Yasuda (NSY) mouse, an animal model of type 2 diabetes and C3H mice used as controls, were fed a HSD, a high-fat diet (HFD) or a regular diet (RD) from weaning. In C3H mice, HFD significantly increased body weight gain, but maintained glucose tolerance. In contrast, in NSY mice, HSD resulted in increased body weight gain and liver steatosis and increased glucose intolerance to a greater extent than HFD. Furthermore, we performed DNA microarray analysis to detect differences in hepatic gene expression levels in both strains under HSD. We then performed RT-PCR analysis on selected genes to evaluate basal expression level under RD and changes under HSD conditions. HSD-fed NSY, but not C3H mice, exhibited increased hepatic expression levels of Pparg2, an isoform of Pparg as well as G0s2, a target of Pparg, which are known to be adipocyte-specific genes. Compared to RD-fed C3H mice, hepatic expression levels of Kat2b (transcriptional regulation), Hsd3b5 (steroid hormone metabolism) and Cyp7b1 (bile acid metabolism) were initially lower in RD-fed NSY mice, and were further decreased in HSD-fed NSY mice. Expression of Metallothionein (Mt1) and Metallothionein 2 (Mt2) was significantly lower in NSY mice compared to C3H mice, irrespective of dietary condition. These data suggest that elucidation of this heterogeneity in response to HSD might contribute to further understanding of the gene-environment interactions leading to diabetes in humans.
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Diabetes Mellitus Tipo 2/genética , Sacarosa en la Dieta/administración & dosificación , Hígado/química , Transcriptoma , Animales , Diabetes Mellitus Tipo 2/etiología , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Hígado Graso/etiología , Hígado Graso/genética , Intolerancia a la Glucosa/genética , Prueba de Tolerancia a la Glucosa , Insulina/análisis , Resistencia a la Insulina , Ratones , Ratones Endogámicos C3H , Análisis de Secuencia por Matrices de Oligonucleótidos , Páncreas/química , Reacción en Cadena de la Polimerasa , Aumento de Peso/genéticaRESUMEN
AIMS/INTRODUCTION: In the development of type 1 diabetes, metabolites are significantly altered and might be involved in ß-cell destruction and protection. We aimed to identify new metabolic markers of ß-cell destruction in type 1 diabetes patients. MATERIALS AND METHODS: A total of 33 participants were recruited for this cross-sectional observational study: 23 with type 1 diabetes, seven with type 2 diabetes and three healthy controls. Those with type 1 diabetes were further subdivided into three groups: new-onset, microsecretors and complete lack of endogenous insulin in type 1 diabetes. RESULTS: Metabolomic analysis identified a total of 737 peaks, and partial least square analysis was successful in discriminating between the three groups of type 1 diabetes. Among the factor loadings discriminating type 1 diabetes, 3-phenylpropionic acid (r = 0.80, P = 4.7E-6 ) and hypotaurine (r = -0.484, P = 1.9E-2 ) strongly contributed to identifying new-onset type 1 diabetes, and 5-methylcytosine to identifying complete-lack type 1 diabetes (r = 0.586, P = 6.5E-3 ). Reporter operating characteristics analysis, including all type 1 diabetes, type 2 diabetes and healthy controls, showed that high 3-phenylpropionic acid (Pc <0.0001) and low hypotaurine (Pc <0.0001) were useful for identifying new-onset type 1 diabetes, and high 5-methylcytosine (Pc = 0.002) for the complete-lack type 1 diabetes. CONCLUSIONS: In the present study, metabolic signatures were shown to be useful in identifying type 1 diabetes at different clinical stages, and 3-phenylpropionic acid and hypotaurine are novel biomarkers for identifying new-onset type 1 diabetes, suggesting the involvement of the gut bacterial environment, anti-oxidant mechanisms through the hypotaurine-taurine pathway and methylated deoxyribonucleic acid fragmentation in the process of ß-cell destruction.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Humanos , Metaboloma , 5-Metilcitosina , Estudios Transversales , MetabolómicaRESUMEN
We previously reported that four hyperglycemia loci are located on three chromosomes in the Nagoya-Shibata-Yasuda (NSY) mouse model, commonly used to study type 2 diabetes. However, we did not search for hyperglycemia loci across all chromosomes. In this study, we performed quantitative trait loci (QTLs) mapping of longitudinal phenotypes from crosses between NSY (hyperglycemic) and C3H (normoglycemic) mice. We identified four new QTLs for hyperglycemia, namely Nidd5nsy, Nidd6nsy, Nidd1c3h, and Nidd2c3h, on Chromosome 1, 4, 10, and 13, respectively. These QTLs were associated with hyperglycemia in young mice and had attenuated effects in older mice. Nidd5nsy and Nidd6nsy were hyperglycemic with NSY alleles, and Nidd1c3h and Nidd2c3h were hyperglycemic with C3H alleles. We further bred Nidd5nsy congenic mice and demonstrated that Nidd5nsy has a strong effect on hyperglycemia when young, accompanied by insulin resistance and visceral fat accumulation. These results showed that the effects of individual QTLs strengthened or weakened with age, and that the sum of the effects of QTLs captured the age-related deterioration of glucose tolerance in individuals. Our results support the importance of longitudinal phenotypes in the genetic analysis of polygenic traits and have implications for the genetic basis and pathogenesis of type 2 diabetes in humans.
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Diabetes Mellitus Tipo 2 , Hiperglucemia , Ratones , Humanos , Animales , Diabetes Mellitus Tipo 2/genética , Ratones Endogámicos C3H , Hiperglucemia/genética , Mapeo Cromosómico , Fenotipo , Ratones Congénicos , Cruzamientos GenéticosRESUMEN
We herein report a 52-year-old woman with a rare combination of short bowel syndrome due to massive resection of the small intestine and complete loss of endogenous insulin due to type 1 diabetes. To provide nutritional support, she was treated with total parenteral nutrition with co-administration of insulin, requiring careful matching of insulin and glucose levels. This case report provides insights on glycemic excursion and insulin action in type 1 diabetes, even when both insulin and glucose are administered directly into circulation, and the usual obstacles caused by subcutaneous injection of insulin and oral intake of nutrients are eliminated.
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Diabetes Mellitus Tipo 1 , Síndrome del Intestino Corto , Femenino , Humanos , Persona de Mediana Edad , Diabetes Mellitus Tipo 1/complicaciones , Síndrome del Intestino Corto/complicaciones , Insulina/uso terapéutico , Nutrición Parenteral Total , Glucosa , Glucemia , HipoglucemiantesRESUMEN
CONTEXT: The glucose tolerance of patients changes considerably from before to after pancreaticoduodenectomy wherein approximately half of the pancreas is resected. OBJECTIVE: The aim of this prospective study was to investigate the incidence of and risk factors for diabetes after pancreaticoduodenectomy. METHODS: This study is a part of an ongoing prospective study, the Kindai Prospective Study on Metabolism and Endocrinology after Pancreatectomy (KIP-MEP) study. Of the 457 patients enrolled to date, 96 patients without diabetes who underwent pancreaticoduodenectomy were investigated in this study. Preoperatively, 1 month post-pancreaticoduodenectomy, and every 6 months thereafter, the glucose metabolism and endocrine function were evaluated using the 75â g oral glucose tolerance test. Various other metabolic, endocrine, and exocrine indices were also examined over a period of up to 36 months. RESULTS: Of the 96 patients analyzed in this study, 33 were newly diagnosed with diabetes. The cumulative diabetes incidence at 36 months following pancreaticoduodenectomy was 53.8%. The preoperative insulinogenic index and ΔC-peptide in the glucagon stimulation test were significantly lower in the progressors to diabetes than in the nonprogressors. Multivariate Cox regression analysis demonstrated that the insulinogenic index was the only significant risk factor for new-onset diabetes. CONCLUSION: The majority of patients developed new-onset diabetes after pancreaticoduodenectomy, and a low value of the insulinogenic index was suggested to be a risk factor for diabetes. Preoperative assessment for the prediction of the onset of diabetes serves as useful information for patients and is important for postoperative glycemic control and diabetes management in patients who require pancreaticoduodenectomy.
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Diabetes Mellitus , Neoplasias Pancreáticas , Humanos , Pancreaticoduodenectomía/efectos adversos , Pancreatectomía/efectos adversos , Estudios Prospectivos , Japón/epidemiología , Diabetes Mellitus/epidemiología , Glucosa , Glucemia , Neoplasias Pancreáticas/cirugíaRESUMEN
A fundamental question about the pathogenesis of spontaneous autoimmune diabetes is whether there are primary autoantigens. For type 1 diabetes it is clear that multiple islet molecules are the target of autoimmunity in man and animal models. It is not clear whether any of the target molecules are essential for the destruction of islet beta cells. Here we show that the proinsulin/insulin molecules have a sequence that is a primary target of the autoimmunity that causes diabetes of the non-obese diabetic (NOD) mouse. We created insulin 1 and insulin 2 gene knockouts combined with a mutated proinsulin transgene (in which residue 16 on the B chain was changed to alanine) in NOD mice. This mutation abrogated the T-cell stimulation of a series of the major insulin autoreactive NOD T-cell clones. Female mice with only the altered insulin did not develop insulin autoantibodies, insulitis or autoimmune diabetes, in contrast with mice containing at least one copy of the native insulin gene. We suggest that proinsulin is a primary autoantigen of the NOD mouse, and speculate that organ-restricted autoimmune disorders with marked major histocompatibility complex (MHC) restriction of disease are likely to have specific primary autoantigens.
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Autoanticuerpos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Epítopos/inmunología , Insulina/inmunología , Traslado Adoptivo , Animales , Glucemia/análisis , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Diabetes Mellitus Tipo 1/etiología , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Progresión de la Enfermedad , Femenino , Insulina/deficiencia , Insulina/genética , Insulina/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Ratones Transgénicos , Proinsulina/genética , Proinsulina/metabolismo , Bazo/citología , Bazo/inmunologíaRESUMEN
Diabetes mellitus is etiologically classified into type 1, type 2 and other types of diabetes. Despite distinct etiologies and pathogenesis of these subtypes, many studies have suggested the presence of shared susceptibilities and underlying mechanisms in ß-cell failure among different types of diabetes. Understanding these susceptibilities and mechanisms can help in the development of therapeutic strategies regardless of the diabetes subtype. In this review, we discuss recent evidence indicating the shared genetic susceptibilities and common molecular mechanisms between type 1, type 2 and other types of diabetes, and highlight the future prospects as well.
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Apoptosis , Diabetes Mellitus Tipo 1/patología , Diabetes Mellitus Tipo 2/patología , Estrés del Retículo Endoplásmico , Células Secretoras de Insulina/patología , Estrés Oxidativo , Animales , Diabetes Mellitus Tipo 1/etiología , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Células Secretoras de Insulina/metabolismoRESUMEN
Adrenocortical carcinoma (ACC) is a rare tumor, and some histological variants (oncocytic, myxoid, and sarcomatoid ACCs) have been reported in addition to the conventional ACC. Among these subtypes, oncocytic ACC is histologically characterized by the presence of abundant eosinophilic granular cytoplasm in the carcinoma cells owing to the accumulation of mitochondria, which generally yields high 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET). Herein, we report the case of a 21-year-old woman with oncocytic ACC with low FDG uptake on PET scan. Her circulating levels of androgens were high, and androgen-synthesis enzymes were detected in carcinoma cells. The patient also had hypocholesterolemia. However, glucose transporter 1 (GLUT1) was not detected in the tumor, which was considered to account for the low FDG uptake by the tumor. To the best of our knowledge, this is the first case of low FDG uptake by oncocytic ACC without GLUT1 expression. Additionally, since hypocholesterolemia was reported in 3 previous reports of androgen-producing tumors, a possible correlation between androgenicity in adrenal tumors and the development of hypocholesterolemia could be postulated; however, further investigations are needed for clarification. This case highlights important information regarding the diversity of ACC and its impact on hypocholesterolemia.
RESUMEN
AIM: Several genetic loci related to lean mass have been identified in healthy individuals by genome-wide association studies; however, the contribution of these loci to body composition in type 2 diabetes remains to be investigated. Here, we aimed to clarify the genetic determinants of body composition in individuals with type 2 diabetes. METHODS: A total of 176 Japanese outpatients (70 women and 106 men) with type 2 diabetes were studied using a cross-sectional design. Body composition was measured using bioimpedance analysis with a commercially available device (InBody770). Single-nucleotide polymorphisms in IRS1 (rs2943656), HSD17B11 (rs9991501), VCAN (rs2287926), ADAMTSL3 (rs4842924) and FTO (rs9936385) were evaluated by genotyping. The contributions of single-nucleotide polymorphisms to body composition were examined, considering known clinical determinants. RESULTS: Sex, body composition and age were identified as clinical predictors. IRS1 rs2934656 was identified as an independent predictor of skeletal muscle mass (ß = 0.11, P = 0.026), and ADAMTSL3 rs4842924 was an independent predictor of body fat mass (ß = 0.15, P = 0.0095) and appendicular lean mass (ß = -0.13, P = 0.017). CONCLUSIONS: The findings clarified the contribution of genetic factors - IRS1 and ADAMTSL3 - to interindividual variation in body composition, independent of clinical factors, in type 2 diabetes patients. These data will contribute to the establishment of effective methods for the prediction, prevention, and intervention of sarcopenia and frailty in diabetes patients. Geriatr Gerontol Int 2021; 21: 932-938.
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Diabetes Mellitus Tipo 2 , Sarcopenia , 17-Hidroxiesteroide Deshidrogenasas/genética , Proteínas ADAMTS/genética , Absorciometría de Fotón , Aldehído Oxidorreductasas/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Composición Corporal/genética , Índice de Masa Corporal , Estudios Transversales , Diabetes Mellitus Tipo 2/genética , Proteínas de la Matriz Extracelular , Femenino , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Proteínas Sustrato del Receptor de Insulina/genética , Masculino , Músculo Esquelético , Sarcopenia/genética , Versicanos/genéticaRESUMEN
CONTEXT: The rate of glucose metabolism changes drastically after partial pancreatectomy. OBJECTIVE: This work aims to analyze changes in patients' glucose metabolism and endocrine and exocrine function before and after partial pancreatectomy relative to different resection types (Kindai Prospective Study on Metabolism and Endocrinology after Pancreatectomy: KIP-MEP study). METHODS: A series of 278 consecutive patients with scheduled pancreatectomy were enrolled into our prospective study. Of them, 109 individuals without diabetes, who underwent partial pancreatectomy, were investigated. Data were compared between patients with pancreaticoduodenectomy (PD, nâ =â 73) and those with distal pancreatectomy (DP, nâ =â 36). RESULTS: Blood glucose levels during the 75-g oral glucose tolerance test (75gOGTT) significantly decreased after pancreatectomy in the PD group (area under the curve [AUC] -9.3%, Pâ <â .01), and significantly increased in the DP population (AUCâ +â 16.8%, Pâ <â .01). Insulin secretion rate during the 75gOGTT and glucagon stimulation test significantly decreased after pancreatectomy both in the PD and DP groups (Pâ <â .001). Both groups showed similar homeostasis model assessment of insulin resistance (HOMA-IR) values after pancreatectomy. Decrease in exocrine function quality after pancreatectomy was more marked in association with PD than DP (Pâ <â .01). Multiple regression analysis indicated that resection type and preoperative HOMA-IR independently influenced glucose tolerance-related postoperative outcomes. CONCLUSIONS: Blood glucose levels after the OGTT differed markedly between PD and DP populations. The observed differences between PD and DP suggest the importance of individualization in the management of metabolism and nutrition after partial pancreatectomy.
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Glucosa/metabolismo , Pancreatectomía , Pancreaticoduodenectomía , Anciano , Glucemia/metabolismo , Estudios de Cohortes , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Secreción de Insulina/fisiología , Japón , Masculino , Persona de Mediana Edad , Páncreas/fisiología , Pancreatectomía/rehabilitación , Pruebas de Función Pancreática , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/cirugía , Pancreaticoduodenectomía/rehabilitación , Periodo Posoperatorio , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
AIMS/INTRODUCTION: Glucosuria is a representative symptom in diabetes patients with poor glycemic control and in those treated with sodium-glucose cotransporter 2 inhibitors. Renal threshold levels of glucose excretion are known to vary among individuals, but factors contributing to glucosuria are not well characterized. The present study aimed to clarify clinical and genetic determinants of glucosuria in individuals with diabetes mellitus. MATERIALS AND METHODS: The 24-h urinary glucose excretion was measured in 135 hospitalized patients on admission, with continuous measurement for five consecutive days in 75 patients. Genetic and clinical factors contributing to glucosuria were studied. As a genetic factor, SLC5A2 polymorphism was genotyped. A total of 476 participants (266 participants with type 2 diabetes and 210 healthy controls) were additionally genotyped for the association study of SLC5A2 with type 2 diabetes. A meta-analysis was carried out with the present study and previous association studies. RESULTS: Multiple regression analysis showed that the independent variables of average blood glucose (ß = 0.41, P = 1.4 × 10-7 ), estimated glomerular filtration rate (ß = 0.28, P = 6.0 × 10-5 ), sex (ß = 0.28, P = 5.7 × 10-5 ) and SLC5A2 rs9934336 polymorphism (ß = 0.17, P = 0.02) were significantly correlated with urinary glucose excretion. The frequency of the A allele of rs9934336 tended to be lower in participants with type 2 diabetes than in controls (odds ratio 0.78, 95% confidence interval 0.53-1.13, not significant), and meta-analysis showed a significant association between the A allele and type 2 diabetes (summary odds ratio for minor allele [A] 0.86, 95% confidence interval 0.78-0.94, P < 0.002). CONCLUSIONS: Blood glucose, estimated glomerular filtration rate, sex and SLC5A2 polymorphism were independent determinants of glucosuria in diabetes mellitus.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/orina , Glucosa/análisis , Glucosuria/genética , Transportador 2 de Sodio-Glucosa/genética , Anciano , Glucemia/análisis , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Genotipo , Tasa de Filtración Glomerular , Glucosuria/sangre , Glucosuria/orina , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo Genético , Análisis de Regresión , Factores SexualesRESUMEN
The targets for continuous glucose monitoring (CGM)-derived metrics were recently set; however, studies on CGM data over a long period with stable glycemic control are limited. We analyzed 194,279 CGM values obtained from 19 adult Japanese patients with type 1 diabetes. CGM data obtained during stable glycemic control over four months were analyzed. CGM-related metrics of different durations "within 120, 90, 60, 30, and 7 days" were calculated from baseline. Time in range (TIR; glucose 70-180 mg/dL), time above range (TAR; glucose ≥ 181 mg/dL), and average glucose levels, but not time below range (TBR; glucose ≤ 69 mg/dL), strongly correlated with glycated hemoglobin (HbA1c) values (P < 0.0001). TBR correlated with glucose coefficient of variation (CV) (P < 0.01). Fasting serum C-peptide levels negatively correlated with glucose CV (P < 0.01). HbA1c of approximately 7% corresponded to TIR of 74% and TAR of 20%. The shorter the CGM period, the weaker was the relationship between HbA1c and CGM-related metrics. TIR, TAR, and average glucose levels accurately reflected HbA1c values in Japanese patients with type 1 diabetes with stable glycemic control. Glucose CV and TBR complemented the limitation of HbA1c to detect glucose variability and hypoglycemia. Stable glycemic control with minimal hypoglycemia depended on residual ß-cell function.
Asunto(s)
Automonitorización de la Glucosa Sanguínea/métodos , Glucemia/análisis , Hemoglobina Glucada/análisis , Adulto , Anciano , Glucemia/química , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/metabolismo , Femenino , Glucosa/metabolismo , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemia/metabolismo , Hipoglucemia/fisiopatología , Hipoglucemiantes , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/fisiología , Japón/epidemiología , Masculino , Persona de Mediana EdadRESUMEN
Mixed corticomedullary tumors (MCMTs) are rare and comprise medullary and cortical cells in a single adrenal tumor. The mechanisms underlying their development have not been fully elucidated. Here, we report a case of MCMT in a 42-year-old woman. Based on the preoperative clinical findings, the patient was diagnosed as having a pheochromocytoma with subclinical Cushing syndrome. Postoperative pathological diagnosis revealed that the tumor demonstrated morphologically distinct medullary and cortical components, which produced catecholamines and cortisol, respectively. Hybrid tumor cells producing both catecholamines and cortisol were not detected. Adrenocorticotropin (ACTH)-positive tumor cells were identified to be present in the pheochromocytoma. This ectopic production of ACTH can contribute to an autonomous cortisol production in a paracrine manner. In addition, micronodules producing aldosterone were detected in the adrenal tissue adjacent to the tumor. The simultaneous development of these 2 lesions may not be correlated with each other; however, this case confirms the importance of a detailed histopathological examination of the adrenal lesions harboring complicated hormonal abnormalities by providing pivotal and indispensable information on their pathogenesis and the possible interaction of the hormones produced in the adrenal gland.
RESUMEN
Characterization of adrenocortical disorders is challenging because of varying origins, laterality, the presence or absence of hormone production, and unclarity about the benign or malignant nature of the lesion. Histopathological examination in conjunction with immunohistochemistry is generally considered mandatory in this characterization. We report a rare case of bilateral adrenocortical adenomas associated with unilateral adrenal endothelial cysts in a 65-year-old woman whose condition was not diagnosed before surgery. Detailed histological examination of the resected adrenal glands revealed hyperplasia in the zona glomerulosa. Despite hyperplasia, the patient had normal serum aldosterone levels and renin activity without clinical evidence of hypertension. The patient was treated with a sodium-glucose cotransporter protein 2 (SGLT2) inhibitor. This may have stimulated the renin-angiotensin-aldosterone system. To the best of our knowledge, this is the first case in which both relatively large bilateral adrenocortical adenomas and unilateral adrenal endothelial cysts were detected. This case also highlights the complexity and difficulty of preoperative diagnosis. Furthermore, this case reports the first detailed histopathological examination of adrenal lesions with SGLT2 treatment and the possibility of SGLT2 inhibitor treatment resulting in histological hyperplasia in the zona glomerulosa; however, it is difficult to prove a causative relationship between SGLT2 inhibitors and hyperplasia of the zona glomerulosa based on the data of this case. It can be confirmed only under limited conditions; therefore, further studies on adrenal gland histology employing SGLT2 inhibition are warranted.