Hiroki Fujita

Consumption of fat before carbohydrate (preload) attenuates postprandial glucose excursions, although the underlying mechanisms remain unclear. We investigated whether an olive oil preload (OG) reduces glycemia by engaging endocrine and neural regulation of gastric emptying. Wild-type C57BL/6J mice received OG or olive oil after (GO) an oral glucose load, with a water preload (WG) as control. Glucose, insulin, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and gastric emptying were assessed. Studies were also performed in streptozotocin-induced diabetic mice, NSY diabetic mice, Gcg-deficient and Glp1r-deficient mice, mice receiving glucagon and/or GLP-1 receptor blockade, and mice subjected to bilateral subdiaphragmatic vagus nerve ligation (VNL). Compared with WG and GO, OG reduced the early glucose excursion and slowed gastric emptying, accompanied by increased glucagon, GIP, and GLP-1 secretion. Similar effects were evident in diabetic mice. The response was absent in Gcg-deficient mice but largely preserved in Glp1r-deficient mice and following blockade of either receptor alone. Combined receptor blockade attenuated glucose lowering and eliminated detectable gastric slowing, supporting partially redundant signaling. VNL attenuated these effects, despite preserved or enhanced hormone secretion, supporting a contribution of vagal signaling. These findings identify nutrient timing as an integrated endocrine-neural regulator of postchallenge blood glucose homeostasis. Article Highlights: We undertook this study to define how fat consumed before oral glucose attenuates postchallenge glycemia. We asked whether olive oil reduces glycemia by slowing gastric emptying and investigated contributing endocrine and neural pathways. Olive oil increased glucagon, glucose-dependent insulinotropic polypeptide, and glucagon-like peptide-1; slowed gastric emptying; and reduced early glycemia in mice. Glucagon and glucagon-like peptide-1 signaling acted redundantly, with vagal involvement. Nutrient timing integrates endocrine-neural regulation of gastric emptying and glycemia, supporting evaluation of meal sequencing in humans.

Werner syndrome (WS) is a rare autosomal recessive progeroid disorder caused by mutations in the WRN gene and is characterized by distinctive physical features and metabolic complications, including insulin resistance, diabetes, hypertriglyceridemia, and hepatic steatosis. Although lipodystrophy is a recognized component of WS, clinical reports of metreleptin use in this setting remain very limited. We report the case of a 38-year-old woman with WS complicated by partial lipodystrophy, diabetes with suboptimal glycemic levels, hypertriglyceridemia and severe hepatic steatosis. She presented with distal limb lipoatrophy, a bird-like facial appearance, premature hair graying, and cataracts. Genetic testing identified two pathogenic WRN variants (c.1105C>T and c.3446del) resulting in premature protein termination, confirming the diagnosis. At baseline, hemoglobin A1c (HbA1c) was 8.6% despite insulin and oral hypoglycemic agents, and imaging demonstrated hepatomegaly with marked steatosis. Metreleptin therapy was initiated and titrated. Over 26 weeks, HbA1c improved to 7.4% and the visceral-to-subcutaneous fat ratio decreased, accompanied by reduction in liver transaminases, cholestatic enzymes, and imaging-based indices of hepatic steatosis, liver stiffness, and liver volume. To date, only three cases of WS treated with metreleptin, including ours, have been reported. While glycemic improvement is consistent with prior reports, our case additionally demonstrated improvements in hepatic steatosis across biochemical, and imaging parameters. These findings suggest that metreleptin may improve both glucose metabolism and hepatic steatosis in WS-associated lipodystrophy. Further accumulation of cases is essential to clarify its role in the management of WS.

A 67-year-old man with type 1 diabetes, Cronkhite-Canada syndrome, and membranous nephropathy who received insulin therapy was admitted to our hospital with right hemiplegia and dysarthria. Brain magnetic resonance imaging revealed a lesion with a high diffusion-weighted imaging signal and low apparent diffusion coefficient signal in the posterior limb of the left internal capsule. He was hypoglycemic with a blood glucose level of 56 mg/dL (3.1 mmol/L). Following glucose administration, the patient’s symptoms resolved within several hours. The patient experienced similar transient hypoglycemic hemiplegia at midnight, three times within 10 days. In a literature review of 170 cases of hypoglycemic hemiplegia, 26 cases of recurrent hemiplegia were investigated. Recurrent hypoglycemic hemiplegia occurs more frequently on the right side than on the left side, and most recurrences occur within approximately a week, almost exclusively at midnight and in the early morning. We speculate that hypoglycemia-associated autonomic failure may be involved in the nocturnal recurrence of episodes. In our patient, depleted endogenous insulin secretion and lipodystrophy at the injection site, may have acted as additional factors, leading to severe hypoglycemia despite the absence of apparent autonomic neuropathy. Clinically, it is important to recognize hypoglycemia as a cause of hemiplegia to avoid unnecessary intervention and to maintain an appropriate blood glucose level at midnight and early in the morning to prevent recurrent hypoglycemic hemiplegia.

Background: Intramuscular adipose tissue (IMAT) formation derived from muscle fibro‐adipogenic progenitors (FAPs) has been recognized as a pathological feature of sarcopenia. This study aimed to explore whether genetic and pharmacological gastric inhibitory polypeptide (GIP) receptor antagonism suppresses IMAT accumulation and ameliorates sarcopenia in mice.Methods: Whole body composition, grip strength, skeletal muscle weight, tibialis anterior (TA) muscle fibre cross‐sectional area (CSA) and TA muscle IMAT area were measured in young and aged male C57BL/6 strain GIP receptor (Gipr)‐knockout (Gipr^−/−) and wild‐type (Gipr^+/+) mice. FAPs isolated from lower limb muscles of 12‐week‐old Gipr^+/+ mice were cultured with GIP, and their differentiation into mature adipocytes was examined. Furthermore, TA muscle IMAT area and fibre CSA were measured in untreated Gipr^−/− mice and GIP receptor antagonist‐treated Gipr^+/+ mice after glycerol injection into the TA muscles.Results: Body composition analysis revealed that 104‐week‐old Gipr^−/− mice had a greater proportion of lean tissue mass (73.7 ± 1.2% vs. 66.5 ± 2.7%, P < 0.05 vs. 104‐week‐old Gipr^+/+ mice) and less adipose tissue mass (13.1 ± 1.3% vs. 19.4 ± 2.6%, P < 0.05 vs. 104‐week‐old Gipr^+/+ mice). Eighty‐four‐week‐old Gipr^−/− mice exhibited increases in grip strength (P < 0.05), weights of TA (P < 0.05), soleus (P < 0.01), gastrocnemius (P < 0.05) and quadriceps femoris (P < 0.01) muscles, and average TA muscle fibre CSA (P < 0.05) along with a reduction in TA muscle IMAT area assessed by the number of perilipin‐positive cells (P < 0.0001) compared with 84‐week‐old Gipr^+/+ mice. Oil Red O staining analysis revealed 1.6‐ and 1.7‐fold increased adipogenesis in muscle FAPs cultured with 10 and 100 nM of GIP (P < 0.01 and P < 0.001 vs. 0 nM of GIP, respectively). Furthermore, both untreated Gipr^−/− mice and GIP receptor antagonist‐treated Gipr^+/+ mice for 14 days after glycerol injection into the TA muscles at 12 weeks of age showed reduced TA muscle IMAT area (1.39 ± 0.38% and 2.65 ± 0.36% vs. 6.54 ± 1.30%, P < 0.001 and P < 0.01 vs. untreated Gipr^+/+ mice, respectively) and increased average TA muscle fibre CSA (P < 0.01 and P < 0.05 vs. untreated Gipr^+/+ mice, respectively).Conclusions: GIP promotes the differentiation of muscle FAPs into adipocytes and its receptor antagonism suppresses IMAT accumulation and promotes muscle regeneration. Pharmacological GIP receptor antagonism may serve as a novel therapeutic approach for sarcopenia.

Background: We previously conducted a pilot randomized controlled trial “the MASTER study” and demonstrated that alpha-glucosidase inhibitor miglitol and a dipeptidyl peptidase-4 inhibitor sitagliptin modified postprandial plasma excursions of active glucagon-like peptide-1 (aGLP-1) and active gastric inhibitory polypeptide (aGIP), and miglitol treatment decreased body fat mass in patients with type 2 diabetes (T2D). However, the details regarding the relationships among postprandial plasma aGLP-1 and aGIP excursions, skeletal muscle mass, and body fat mass are unclear. Methods: We conducted a secondary analysis of the relationships among skeletal muscle mass index (SMI), total body fat mass index (TBFMI), and the incremental area under the curves (iAUC) of plasma aGLP-1 and aGIP excursions following mixed meal ingestion at baseline and after 24-week add-on treatment with either miglitol alone, sitagliptin alone, or their combination in T2D patients. Results: SMI was not changed after the 24-week treatment with miglitol and/or sitagliptin. TBFMI was reduced and the rates of aGIP-iAUC change were lowered in the two groups treated with miglitol, although their correlations did not reach statistical significance. We observed a positive correlation between the rates of aGIP-iAUC and TBFMI changes and a negative correlation between the rates of TBFMI and SMI changes in T2D patients treated with sitagliptin alone whose rates of aGIP-iAUC change were elevated. Conclusions: Collectively, although T2D patients treated with miglitol and/or sitagliptin did not show altered SMI after 24-week treatment, the current study suggests that there are possible interrelationships among postprandial plasma aGIP excursion modified by sitagliptin, skeletal muscle mass, and body fat mass.

The aim of this study was to investigate the effects of increased dietary protein in daily-life settings in Japan for 6 months on the activities of daily living (ADL) in adults aged 75 or older at nutritional risk. The study was an open-label, exploratory, randomized controlled trial conducted at seven hospitals in Japan. The study participants were adults aged 75 or older who were hospitalized for treatable cancer, pneumonia, fractures, and/or urinary-tract infection at nutritional risk. The primary outcome was change in grip strength, skeletal muscle, and ADL indices (Barthel index, Lawton score). One hundred sixty-nine patients were randomly assigned to the intensive care (IC) or standard care (SC) group; the protein intake goals (g/kgw/day) were 1.5 for IC and 1.0 for SC. There was a significant improvement in grip strength only in the IC group (1.1 kg: 95% CI 0.1 to 2.1) (p = 0.02). While the skeletal muscle index and ADL indices were not significantly improved in either group, the improvement ratio tended to be greater in the IC group. There was no decrease in renal function in either group. Thus, intervention of increased dietary protein in daily-life settings for 6 months in adults aged 75 or older with treatable cancer, pneumonia, fractures, and/or urinary-tract infection and at nutritional risk may be effective in ameliorating loss of muscle strength.

Introduction A newly developed resistant starch (RS) rice line with double mutation of starch synthase IIIa and branching enzyme IIb (ss3a/be2b) exhibits a tenfold greater percentage RS value than the wild-type rice line. Currently, the effects of cooked rice with such high RS content on secretion and action of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are unclear. Therefore, we conducted a pilot study to assess postprandial responses of GLP-1 and GIP along with glucose and insulin and also gastric emptying after ingestion of the high-RS cooked rice with ss3a/be2b in healthy subjects. Methods In a non-randomized crossover design, five healthy men ingested two test foods, control (low-RS) and high-RS cooked rice, with at least 1-week washout period between testing days. Plasma glucose, serum insulin, plasma total GLP-1, plasma total GIP, and also gastric emptying rate were measured after ingestion of each test food, and the incremental area under the curves (iAUC) was calculated for each biochemical parameter using the values from 0 to 180 min after ingestion. Results The high-RS cooked rice ingestion tended to reduce iAUC-glucose (p = 0.06) and significantly reduced iAUC-insulin (p < 0.01) and iAUC-GLP-1 (p < 0.05) but not iAUC-GIP (p = 0.21) relative to control cooked rice ingestion. In addition, the high-RS cooked rice ingestion did not affect gastric emptying. Conclusions The present results indicate that the suppressive effects of the high-RS cooked rice ingestion on postprandial responses of glucose and insulin may be provided through attenuation in GLP-1 secretion along with its low digestibility into glucose. We suggest that the high-RS rice with ss3a/be2b may serve as a better carbohydrate source and also as a novel functional food for dietary interventions to improve postprandial hyperglycemia and hyperinsulinemia without both enhancing GLP-1 secretion and affecting gastric emptying in patients with diabetes.

Isthmin‐1 is an adipokine that has a potent glucose‐lowering effect by stimulating a common intracellular signaling pathway with insulin through a distinct receptor and has an inhibitory effect on lipogenesis in the liver, whereas insulin has the opposite effect. Isthmin‐1 is expected to have clinical benefits in the treatment of diabetes.