飯塚 勝美

(1) Background: Proglucagon-derived peptides (PDGPs) including glucagon (Gcg), GLP-1, and GLP-2 regulate lipid metabolism in the liver, adipocytes, and intestine. However, the mechanism by which PGDPs participate in alterations in lipid metabolism induced by high-fat diet (HFD) feeding has not been elucidated. (2) Methods: Mice deficient in PGDP (GCGKO) and control mice were fed HFD for 7 days and analyzed, and differences in lipid metabolism in the liver, adipose tissue, and duodenum were investigated. (3) Results: GCGKO mice under HFD showed lower expression levels of the genes involved in free fatty acid (FFA) oxidation such as Hsl, Atgl, Cpt1a, Acox1 (p < 0.05), and Pparα (p = 0.05) mRNA in the liver than in control mice, and both FFA and triglycerides content in liver and adipose tissue weight were lower in the GCGKO mice. On the other hand, phosphorylation of hormone-sensitive lipase (HSL) in white adipose tissue did not differ between the two groups. GCGKO mice under HFD exhibited lower expression levels of Pparα and Cd36 mRNA in the duodenum as well as increased fecal cholesterol contents compared to HFD-controls. (4) Conclusions: GCGKO mice fed HFD exhibit a lesser increase in hepatic FFA and triglyceride contents and adipose tissue weight, despite reduced β-oxidation in the liver, than in control mice. Thus, the absence of PGDP prevents dietary-induced fatty liver development due to decreased lipid uptake in the intestinal tract.

AIMS/INTRODUCTION: Glucagon is secreted from pancreatic α-cells and plays an important role in amino acid metabolism in liver. Various animal models deficient in glucagon action show hyper-amino acidemia and α-cell hyperplasia, indicating that glucagon contributes to feedback regulation between the liver and the α-cells. In addition, both insulin and various amino acids, including branched-chain amino acids and alanine, participate in protein synthesis in skeletal muscle. However, the effect of hyperaminoacidemia on skeletal muscle has not been investigated. In the present study, we examined the effect of blockade of glucagon action on skeletal muscle using mice deficient in proglucagon-derived peptides (GCGKO mice). MATERIALS AND METHODS: Muscles isolated from GCGKO and control mice were analyzed for their morphology, gene expression and metabolites. RESULTS: GCGKO mice showed muscle fiber hypertrophy, and a decreased ratio of type IIA and an increased ratio of type IIB fibers in the tibialis anterior. The expression levels of myosin heavy chain (Myh) 7, 2, 1 and myoglobin messenger ribonucleic acid were significantly lower in GCGKO mice than those in control mice in the tibialis anterior. GCGKO mice showed a significantly higher concentration of arginine, asparagine, serine and threonine in the quadriceps femoris muscles, and also alanine, aspartic acid, cysteine, glutamine, glycine and lysine, as well as four amino acids in gastrocnemius muscles. CONCLUSIONS: These results show that hyperaminoacidemia induced by blockade of glucagon action in mice increases skeletal muscle weight and stimulates slow-to-fast transition in type II fibers of skeletal muscle, mimicking the phenotype of a high-protein diet.

Artificial sweeteners have been developed as substitutes for sugar. Sucralose, acesulfame K (ACE K), aspartame, and saccharin are artificial sweeteners. Previously, artificial sweeteners were thought to be effective in treating obesity and diabetes. Human meta-analyses have reported that artificial sweeteners have no effect on body weight or glycemic control. However, recent studies have shown that artificial sweeteners affect glucose absorption in the intestinal tract as well as insulin and incretin secretion in humans and animals. Moreover, artificial sweeteners alter the composition of the microbiota and worsen the glycemic control owing to changes in the gut microbiota. The early intake of ACE K was also shown to suppress the taste response to sugar. Furthermore, a large cohort study showed that high artificial sweetener intake was associated with all-cause mortality, cardiovascular risk, coronary artery disease risk, cerebrovascular risk, and cancer risk. The role of artificial sweeteners in the treatment of diabetes and obesity should be reconsidered, and the replacement of sugar with artificial sweeteners in patients will require the long-term tracking of not only intake but also changes in blood glucose and weight as well as future guidance based on gut bacteria data. To utilize the beneficial properties of artificial sweeteners in treatment, further studies are needed.

Mobile food records are currently used to determine the nutrition of healthy subjects. To determine the accuracy of such records, we evaluated the nutritional composition of a test meal (noodles and fruit juice) and a hospital meal (Japanese set meal) using two types of mobile food records. Eighteen healthy subjects (2 males and 16 females) were enrolled. Using these diets and validated nutrient-composition information, we evaluated the accuracy of the dietary assessments made by two dietary-record applications, Asken® and Calomeal®, over 5 days. For the test meal, the values provided by the two applications were close to the actual values. In contrast, for the hospital meal, the values provided by the two applications were approximately 1.5 times higher than the actual values. A linear-mixed-model analysis showed that the total energy, carbohydrate, and salt contents were significantly overestimated in the hospital meal. Protein also tended to be overestimated, while the fat content was not significantly overestimated. Furthermore, the total energy and fat contents increased significantly over time. No association with age was observed. A comparison of the coefficients of variation (CVs) for each nutrient in the hospital meal indicated that the fat levels were significantly higher than those in the test meal. In conclusion, the accuracy of mobile food records depends on the type of meal. Our data will provide lessons for the use of meal-recording applications in special cases, such as hospital food.

BACKGROUND: Familial hypocalciuric hypercalcemia (FHH) is a rare autosomal dominant disease, which requires differential diagnosis from relatively common primary hyperparathyroidism (PHPT) in order to avoid unnecessary surgery. CASE PRESENTATION: A 16-year-old female had been followed by the department of psychosomatic medicine at our institution. Throughout the follow-up period, her plasma calcium levels were high, plasma Pi levels were relatively low, and plasma intact PTH was relatively high. She was referred to our department to determine the cause of her hypercalcemia. Her 24 h urinary calcium excretion was as low as 100 mg/day, and calcium creatinine clearance ratio was below 0.01. Moreover, she had a family history of hypercalcemia (proband, her brother, and her father). The genetic testing for her family revealed that she, her brother, and her father were definitively diagnosed with FHH type 1 due to the heterozygous calcium-sensing receptor mutation (NM_00388:4:c.164C > T:p.Pro55Leu). CONCLUSION: We experienced a 16-year-old female with FHH, in whom genetic testing identified the heterozygous calcium-sensing receptor mutation (NM_00388:4:c.164C > T:p.Pro55Leu) as pathogenic, permitting a definitive diagnosis of FHH type 1. The genetic testing for calcium sensing receptor is beneficial to distinguish asymptomatic primary hyperparathyroidism from FHH.

We treated a 22-year-old woman suffering from Graves' disease and thymic hyperplasia. She was referred to our institution for a close investigation of thyrotoxicosis and thymic mass. Thyroid tests and magnetic resonance imaging resulted in a diagnosis of Graves' disease and thymic hyperplasia. The thyroid function and thyroid-stimulating hormone receptor antibody (TRAb) were normalized one and five months after thiamazole initiation, respectively. The thymic size began to decrease after 1 month and was further decreased after 5 months; it was normalized after 12 months. The correlation between TRAb titers and the thymic size (R2=0.99) suggested that the patient's autoimmunity might have contributed to the thymic hyperplasia.

Background: Elderly adults with diabetes are at increased risk of severe hypoglycemia and hypoglycemic coma due to various conditions including decline in cognitive function, reduced activity of daily living (ADL) and reduced renal function; special cautions are, therefore, recommended to avoid these life-threatening events. Case presentation: A 92-year-old female was admitted to our institution because of severe coma. Upon arrival, her serum C-peptide was 1.64 ng/mL despite low plasma glucose (24 mg/dL) and serum glimepiride (40.85 ng/mL). She had past history of compression fracture of her lumbar spine, which substantially affected her ADL. Her score on the dementia assessment sheet for community-based integrated care system-8 items (DASC-8) was 26 points. She had been receiving 12 oral medications for diabetes, essential hypertension, chronic gastritis and constipation from her nearby clinic. Her physician-in-charge had found that she was not taking her medications properly and simplified her prescription regimen to 3 oral medications with vildagliptin 50 mg twice daily replaced by glimepiride 3 mg once daily and asked her son to assist in taking the drugs 6 days before her admission to our hospital. While her consciousness level was improved to some extent, she was transferred to a long-term care bed hospital because it had become too difficult to care for her at home. Conclusions: It is important to note that anti-diabetes drugs should be carefully selected based on each patient's cognitive function and ADL, and that the reasoning should be shared with the general practitioners involved to avoid severe hypoglycemic events. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-021-00510-9.

Glucokinase has an important role in regulating glycolysis as a glucose sensor in liver and pancreatic β cells. Glucokinase-maturity onset diabetes in young (GCK-MODY also known as MODY2) is caused by autosomal dominant gene mutation of the GCK gene; it is characterized by mild fasting hyperglycemia and small 2-h glucose increment during 75 g-oral glucose tolerance test (OGTT) as well as near-normal postprandial glucose variabilities. A 10-year-old girl with family history of diabetes visited her physician after being found positive for urinary glucose by school medical checkup. She received a diagnosis of diabetes based on the laboratory data: 75 g-OGTT (mild fasting hyperglycemia and small 2-h glucose increment) and factory-calibrated glucose monitoring (mild elevation of average glucose level and near-normal glycemic variability), which raised suspicion of GCK-MODY. She was then referred to our institution for genetic examination, which revealed a GCK heterozygous mutation (NM_000162: exon10: c.1324G>T: p.E442X) in the proband as well as in her mother and maternal grandmother, who had been receiving anti-diabetes medications without knowing that they had GCK-MODY specifically. GCK-MODY cases show incidence of microvascular and macrovascular diseases similar to that of normal subjects, and their glucose levels are adequately controlled without anti-diabetes drug use. Thus, early and definitive diagnosis of MODY2 by genetic testing is important to avoid unnecessary medication.

INTRODUCTION: Treatments for type 2 diabetes (T2D) targeting baseline glucose levels but not postprandial glucose can result in normalized fasting blood glucose but suboptimal overall glycemic control (high glycated hemoglobin); residual hyperglycemia. In Japanese patients with T2D the predominant pathophysiology is lower insulin secretory capacity, and residual hyperglycemia is common with basal insulin treatment. Single-injection, fixed-ratio combinations of glucagon-like peptide-1 receptor agonists and basal insulin have been developed. iGlarLixi (insulin glargine 100 unit/mL [iGlar]: lixisenatide ratio of 1 U:1 µg) is for specific use in Japan. Post-hoc analysis of the LixiLan JP-L trial (NCT02752412) compared the effect of iGlarLixi with iGlar on this specific subpopulation with residual hyperglycemia. MATERIALS AND METHODS: Outcomes at week 26 (based on last observation carried forward) were assessed in patients in the modified intent-to-treat population with baseline residual hyperglycemia. RESULTS: Overall, 83 (32.5%) patients in the iGlarLixi group and 79 (30.7%) patients in the iGlar group had baseline residual hyperglycemia. The proportion of patients with residual hyperglycemia at week 26 decreased to 15.7% in the iGlarLixi group, and increased to 36.9% in the iGlar group. Patients in the iGlarLixi group had significantly greater reductions in glycated hemoglobin compared with the iGlar group (-0.72% difference between groups; P < 0.0001). CONCLUSIONS: New data from this post-hoc analysis of the JP-L trial show that treatment with fixed-ratio combination iGlarLixi reduced the proportion of Japanese patients with residual hyperglycemia from baseline to week 26 and significantly reduced glycated hemoglobin versus similar doses of iGlar alone.

Carbohydrates are macronutrients that serve as energy sources. Many studies have shown that carbohydrate intake is nonlinearly associated with mortality. Moreover, high-fructose corn syrup (HFCS) consumption is positively associated with obesity, cardiovascular disease, and type 2 diabetes mellitus (T2DM). Accordingly, products with equal amounts of glucose and fructose have the worst effects on caloric intake, body weight gain, and glucose intolerance, suggesting that carbohydrate amount, kind, and form determine mortality. Understanding the role of carbohydrate response element binding protein (ChREBP) in glucose and lipid metabolism will be beneficial for elucidating the harmful effects of high-fructose corn syrup (HFCS), as this glucose-activated transcription factor regulates glycolytic and lipogenic gene expression. Glucose and fructose coordinately supply the metabolites necessary for ChREBP activation and de novo lipogenesis. Chrebp overexpression causes fatty liver and lower plasma glucose levels, and ChREBP deletion prevents obesity and fatty liver. Intestinal ChREBP regulates fructose absorption and catabolism, and adipose-specific Chrebp-knockout mice show insulin resistance. ChREBP also regulates the appetite for sweets by controlling fibroblast growth factor 21, which promotes energy expenditure. Thus, ChREBP partly mimics the effects of carbohydrate, especially HFCS. The relationship between carbohydrate intake and diseases partly resembles those between ChREBP activity and diseases.

Diet composition determines the risk of obesity, cardiovascular disease, malignant tumors, and type 2 diabetes mellitus [...].

Carbohydrates, otherwise known as saccharides, are a macronutrient that is found in a wide variety of natural and processed foods. Carbohydrates include sugars, starch, and cellulose (insoluble dietary fiber), and can be categorized as monosaccharides, disaccharides, oligosaccharides, and polysaccharides. Monosaccharides such as glucose and fructose, and disaccharides such as sucrose, are together referred to as sugars.

Heterozygous RFX6 mutation has emerged as a potential cause of maturity-onset diabetes mellitus of the young (MODY). A 16-year-old female was diagnosed with diabetes by her family doctor and was referred to our institution for genetic examination. Genetic testing revealed a novel RFX6 heterozygous mutation (NM_173560: exon17: c.1954C>T: p.R652X) in the patient and in her mother and brother. She had no islet-specific autoantibodies and showed a reduced meal-induced response of insulin, glucose-dependent insulinotropic polypeptide, and glucagon-like peptide-1, which is consistent with the phenotype of MODY due to heterozygous RFX6 mutation. In conclusion, we report a case of MODY due to a novel heterozygous mutation, p.R652X.

AIMS: To compare the benefits of iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL and lixisenatide (iGlarLixi), over insulin glargine (iGlar) for reducing residual hyperglycaemia (defined as glycated haemoglobin [HbA1c] ≥7% despite fasting plasma glucose [FPG] <130 mg/dL) in Japanese people with type 2 diabetes (T2D) inadequately controlled on oral antidiabetic drugs. MATERIALS AND METHODS: The open-label LixiLan JP-O2 study compared iGlarLixi with iGlar over 26 weeks in 521 people with T2D. This post-hoc analysis assessed the proportions of participants with residual hyperglycaemia in the overall population, and in subgroups defined by age and dipeptidyl-peptidase 4 inhibitor (DPP4i) use at screening. RESULTS: At 26 weeks, significantly fewer participants had residual hyperglycaemia in the iGlarLixi versus the iGlar arm (8.1% vs. 19.6%; P = 0.0002). There was also less residual hyperglycaemia with iGlarLixi than iGlar in all subgroup analyses: 9.0% versus 16.8% in participants aged <65 years (P = 0.0369); 6.5% versus 24.2% in participants aged ≥65 years (P = 0.0008); 10.1% versus 20.5% (P = 0.0202) in participants with DPP4i use; and 6.2% versus 18.8% in those without DPP4i use (P = 0.0024). The proportion reaching both HbA1c <7% and FPG <130 mg/dL was higher with iGlarLixi versus iGlar in the overall population (50.8% vs. 31.5%; P < 0.0001), and in all studied subgroups. CONCLUSIONS: iGlarLixi reduced the prevalence of residual hyperglycaemia in Japanese people with uncontrolled T2D compared with iGlar, both in the overall population and in subgroups defined by age and DPP4i use at screening. This article is protected by copyright. All rights reserved.

インクレチンと総称されるglucagon-like peptide-1(GLP-1)、glucose-dependent insulinotropic polypeptide(GIP)は、栄養素摂取に応答し消化管から分泌され、全身の糖・脂質代謝を制御することから、糖尿病や肥満に代表される生活習慣病の発症・重症化予防の標的として注目される。GLP-1、GIPは、膵β細胞に作用して血糖依存的にインスリン分泌を促進する。さらに、GLP-1は膵α細胞からのグルカゴン分泌を抑制するとともに、胃内容物排出時間を遅延させることで食後高血糖を是正する。また、GLP-1は消化管からの脂質吸収を抑制するとともに、肝臓の脂肪酸代謝を制御することで脂肪肝を是正する。加えて、GLP-1は中枢に作用して食欲を抑制し、減量効果を発揮する。GIPは、低血糖時に膵α細胞からのグルカゴン分泌を促進し、血糖値を正常範囲に保つ。また、GIPは骨形成を促進することから、骨折やサルコペニア、フレイルの観点からも注目されている。一方、GIPは、高脂肪食に対して脂肪組織へのエネルギー蓄積を促進するため、インスリン抵抗性を惹起し、耐糖能を悪化させうる。GLP-1、GIP共に、食事に含まれるさまざまな栄養素の量や内容、さらには摂取の順番により分泌量が変化することから、糖尿病や肥満に代表される生活習慣病の発症・重症化予防に資する食事療法を考える上で、インクレチンが注目される。(著者抄録)

Carbohydrate response element binding protein (ChREBP) is critical in the regulation of fatty acid and triglyceride synthesis in the liver. Interestingly, Chrebp-/- mice show reduced levels of plasma cholesterol, which is critical for steroid hormone synthesis in adrenal glands. Furthermore, Chrebp mRNA expression was previously reported in human adrenal glands. Thus, it remains to be investigated whether ChREBP plays a role directly or indirectly in steroid hormone synthesis and release in adrenal glands. In the present study, we find that Chrebp mRNA is expressed in mouse adrenal glands and that ChREBP binds to carbohydrate response elements. Histological analysis of Chrebp-/- mice shows no adrenal hyperplasia and less oil red O staining compared with that in wild-type mice. In adrenal glands of Chrebp-/- mice, expression of Fasn and Scd1, two enzymes critical for fatty acid synthesis, was substantially lower and triglyceride content was reduced. Expression of Srebf2, a key transcription factor controlling synthesis and uptake of cholesterol and the target genes was upregulated, while cholesterol content was not significantly altered in the adrenal glands of Chrebp-/- mice. Adrenal corticosterone content and plasma adrenocorticotropic hormone and corticosterone levels were not significantly altered in Chrebp-/- mice. Consistently, expression of genes related to steroid hormone synthesis was not altered. Corticosterone secretion in response to two different stimuli, namely 24-h starvation and cosyntropin administration, were also not altered in Chrebp-/- mice. Taking these results together, corticosterone synthesis and release were not affected in Chrebp-/- mice despite reduced plasma cholesterol levels.

BACKGROUND: Primary central nervous system lymphoma is a rare extra-nodal lymphoma of the central nervous system. Primary central nervous system lymphoma lesions usually appear in the vicinity of the ventricle, and there are few reports of primary central nervous system lymphoma with hypothalamic-pituitary lesions. CASE PRESENTATION: We treated a 56-year-old male with primary central nervous system lymphoma with the primary lesion in the hypothalamus, which was found by magnetic resonance imaging after sudden onset of endocrinological abnormalities. Initially, he was hospitalized to our department for hyponatremia. Endocrinological examination in conjunction with head magnetic resonance imaging and endoscopic biopsy revealed hypothalamic hypopituitarism and tertiary hypoadrenocorticism caused by a rapidly growing, diffuse large B-cell lymphoma in the hypothalamus. Remission of the tumor was achieved by high-dose methotrexate with whole brain radiotherapy, and some of the hormone responses were normalized. CONCLUSIONS: While primary central nervous system lymphoma is rare, it is important to note that hypopituitarism can result and that the endocrinological abnormalities can be partially restored by its remission.

Cardiovascular disease (CVD) is one of the most serious health-related problems in patients with type 2 diabetes, especially in western countries. Basic and clinical research on how to prevent CVD onset and progression in patients with type 2 diabetes have been an urgent task for decades. Glucagon-like peptide-1 (GLP-1) is one of two incretins that are responsible for ≥50% of postprandial insulin secretion and subsequent glucose excursion, and has been intensively investigated from the perspective of CVD due to its cardiovascular benefits in preclinical studies1, 2 .

Pancreatic tail hypoplasia is a common manifestation of maturity onset diabetes of the young (MODY) 5 that can cause reno-genito-urinary malformations such as renal cysts and bicornuate uterus. A 69-year-old female was admitted to our hospital for consultation on her relatively high HbA1c value. At age 20, she was diagnosed with uterus bicornis. At age 68, she was diagnosed with pancreas tail hypoplasia, renal cysts and non-functioning pancreatic neuroendocrine tumor (NET) in addition to right hydronephrosis due to multiple ureteral bladder carcinomas. She received total right nephrectomy, ureterectomy and partial cystectomy for multiple ureteral bladder carcinomas [non-invasive papillary urothelial carcinoma, low grade (G1), pTa, LV10, u-rtx, RM0, and pN0 (0/8)]. She also received distal pancreatomy for pancreatic NET [NET G1]. She then was referred to our department at age 69 due to increase in her HbA1c value from 6.2 to 7.2%; 75 g oral glucose tolerance test revealed impaired glucose tolerance. Her clinical characteristics (uterus bicornis, pancreas hypoplasia, and renal cysts) closely resembled the phenotype of MODY5, in which mutations in the HNF1B gene have been reported. Our genetic testing failed to detect any mutation or microdeletion in the coding or minimal promoter regions of the HNF1B gene. Although there remains a possibility that genetic mutations in introns and regulatory regions of the HNF1B gene might cause the MODY5-like manifestations in this patient, these results might suggest involvement of genes other than HNF1B in the pathogenesis of our patient's disease.

While adjustment of total energy and nutritional balance is critically important, meal sequence, a relatively simple method of correcting postprandial hyperglycemia, is becoming established as a practical dietary approach for prevention and management of diabetes and obesity. Meal sequence, i.e., consumption of protein and/or fat before carbohydrate, promotes secretion of glucagon-like peptide-1 (GLP-1) from the gut and ameliorates secretions of insulin and glucagon and delays gastric emptying, thereby improving postprandial glucose excursion. GLP-1 is known to suppress appetite by acting on the hypothalamus via the afferent vagus nerve. Thus, enhancement of GLP-1 secretion by meal sequence is expected to reduce body weight. Importantly, consumption of a diet rich in saturated fatty acids such as meat dishes before carbohydrate increases secretions of not only GLP-1 but also glucose-dependent insulinotropic polypeptide (GIP), which promotes energy storage in adipose tissue and may lead to weight gain in the long term. Dietary fiber intake before carbohydrate intake significantly reduces postprandial glucose elevation and may have a weight loss effect, but this dietary strategy does not enhance the secretion of GLP-1. Thus, it is suggested that their combination may have additive effects on postprandial glucose excursion and body weight. Indeed, results of some clinical research supports the idea that ingesting dietary fiber together with meal sequence of protein and/or fat before carbohydrate benefits metabolic conditions of individuals with diabetes and obesity.

A 72-year-old man had type 2 diabetes (T2D) that had been diagnosed at 54 years old. Macroalbuminuria was first detected at age 64. While his HbA1c had been kept below 7%, his estimated glomerular filtration rate (eGFR) was declining rapidly. At 70 years old, his eGFR dropped below 50 ml/min/1.73 m2. A renal biopsy revealed diabetic nephropathy. sodium glucose transporter 2 inhibitors (SGLT2i)/glucagon-like peptide-1 receptor agonists (GLP-1RA) combination therapy substantially improved his eGFR and urinary albumin level, and the renoprotective effect persisted for the two-year study period. These findings suggest that SGLT2i and GLP-1RA can additively improve the renal function in patients with T2D.

Conventional recommendations for dietary intervention have been generally based on population groups divided by gender and age [...]