👤 Toshikazu Yabe

Future directions in incretin research: Three major directions currently shape therapeutic innovation in incretin research: multi-receptor agonism, oral drug development, and mechanistic reappraisal of glucose-dependent insulinotropic polypeptide (GIP) physiology. These advances indicate that incretin-based therapies should be understood within an integrated enteroinsular network rather than through isolated hormone actions. DPP-4, dipeptidyl peptidase-4; GCGR, glucagon receptor; GIPR, GIP receptor; GLP-1, glucagon-like peptide-1; GLP-1R, GLP-1 receptor; T2D, type 2 diabetes. Show less

Dipeptidyl peptidase-4 (DPP-4) inhibitors enhance circulating levels of biologically intact incretins, yet the relative contribution of glucose-dependent insulinotropic polypeptide (GIP) to their metabolic effects remains incompletely understood. While glucagon-like peptide-1 (GLP-1) has long been emphasized in incretin biology, emerging evidence suggests important physiological roles for GIP. This study investigated whether endogenous GIP signaling is indispensable for the glucose-lowering and anti-obesity effects of DPP-4 inhibition. Male Gipr DPP-4 inhibition significantly improved glucose tolerance and attenuated body-weight gain in HFD-fed Gipr Endogenous GIP signaling is essential for both glucose-lowering and anti-obesity actions of DPP-4 inhibitors in mice. GLP-1 elevation alone is insufficient to compensate for GIP receptor deficiency. These findings refined the mechanistic understanding of DPP-4 inhibitors, highlighted the physiological importance of GIP, and suggested context-dependent metabolic actions of incretins. Show less

Diabetes is an increasingly prevalent global disease and is often accompanied by sarcopenia, particularly in older adults. While insulin resistance is a well-known contributor to muscle loss in diabetes, the role of glucose signaling in diabetic skeletal muscle atrophy, particularly under insulin-deficient conditions, remains poorly understood. This study aimed to elucidate the pathophysiological role of the carbohydrate-responsive element-binding protein (ChREBP), a glucose-sensing transcription factor encoded by the Chrebp gene in mice, in diabetic sarcopenia by generating Chrebp-deficient, insulin-deficient Ins2Akita/+ mice. We evaluated Chrebp +/+, Chrebp -/-, Ins2Akita/+ /Chrebp +/+, and Ins2Akita/+ /Chrebp -/- mice for muscle strength, endurance, survival, body composition, and muscle histology. Skeletal muscles were analyzed for gene expressions related to anabolic and catabolic pathways. We found that Ins2Akita/+ /Chrebp -/- mice exhibited significant reductions in body weight, grip strength, survival, and skeletal muscle mass - particularly in the tibialis anterior, soleus, gastrocnemius, and quadriceps - compared to Ins2Akita/+ controls, despite similar hyperglycemia. Histological analysis revealed a smaller mean muscle fiber size and reduced cross-sectional area of type 2A and 2B fibers, without changes in fiber-type composition. Furthermore, Igf-1 expression was suppressed, while the atrophy marker Fbxo32/Atrogin-1 was upregulated. These findings demonstrate that Chrebp deletion exacerbates muscle atrophy and frailty in insulin-deficient mice, underscoring a key role for ChREBP-mediated glucose signaling in maintaining muscle mass under diabetic conditions. The Ins2Akita/+ /Chrebp -/- model provides a valuable platform for exploring diabetic sarcopenia mechanisms and potential therapeutic targets. Show less

Glucose and insulin positively regulate glycolysis and lipogenesis through the activation of carbohydrate response element-binding protein (ChREBP) and sterol regulatory element-binding protein 1c (SREBP1c), but their respective roles in the regulation of gluconeogenic and ureagenic genes remain unclear. We compared the effects of the insulin antagonist S961 and Chrebp deletion on hepatic glycolytic, lipogenic, gluconeogenic, and ureagenic gene expression in mice. S961 markedly increased the plasma glucose, insulin, and 3-OH-butyrate concentrations and reduced the hepatic triglyceride content, but Chrebp deletion had no additive effect. We subsequently estimated the expression of genes involved in the pathways of glycolysis, gluconeogenesis, and lipogenesis. S961 potently decreased both Chrebp and Srebf1c, but Chrebp deletion weakly decreased Srebf1c mRNA expression. Both the S961 and Chrebp deletion caused decreases in glycolytic (Gck and Pklr) and lipogenic (Fasn, Scd1, Me1, Spot14, Elovl6) gene expression. S961 increased the expression of many gluconeogenic genes (G6pc, Fbp1, Aldob, Slc37a4, Pck), whereas Chrebp deletion reduced the expression of gluconeogenic genes other than Pck1. Finally, we checked the metabolites and gene expression in the ureagenesis pathway. S961 increased ureagenic gene (Arg1, Asl, Ass1, Cps1, Otc) expression, which was consistent with the metabolite data: there were reductions in the concentrations of glutamate and aspartate and increases in those of citrulline, ornithine, urea, and proline. However, Chrebp deletion had no additive effect on ureagenesis. In conclusion, insulin rather than glucose regulate ureagenic gene expression, whereas glucose and insulin regulate gluconegenic gene expression in opposite directions. Show less

Type 1 diabetes mellitus is a major risk factor for both sarcopenia and osteoporosis, primarily due to the body's inability to utilize glucose as a result of insulin deficiency. Impairments in insulin and glucose signaling can accelerate the decline in muscle and bone health. To investigate this interaction, we examined whether insulin deficiency exacerbates muscle and bone deterioration in Show less

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. 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 Body composition analysis revealed that 104-week-old Gipr 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. Show less

We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. In genic CNVs, we found an increased burden of smaller (<100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (>500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25-0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD. Show less

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 WT 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, was 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. Show less

Carbohydrate response element-binding protein (ChREBP) plays an important role in the development of type 2 diabetes, dyslipidemia, and non-alcoholic fatty liver disease, as well as tumorigenesis. ChREBP is highly expressed in lipogenic organs, such as liver, intestine, and adipose tissue, in which it regulates the production of acetyl CoA from glucose by inducing Show less

Unimolecular peptide-based dual agonists against glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) have been gaining much attention recently as novel antidiabetic agents that can potentially control glycemia and bodyweight. Although GLP-1 and GIP both enhance insulin secretion and subsequently ameliorate postprandial glucose excursion, most research has focused on GLP-1R as a therapeutic target for type 2 diabetes. This is partly because the effects of GIPR activation on glycemia and bodyweight have been controversial. GIPR-deficient mice showed impaired glucose tolerance with reduced β-cell function and resistance to high-fat diet-induced obesity, whereas GIPR agonists improved glycemia and prevented high-fat diet-induced obesity in mice. Conflicting results in mice might be explained by pharmacological levels of GIP signal in the central nervous systems decreasing food intake and overcoming the obesogenic effects of GIP at physiological levels in adipose tissues. Thus, GIPR activation at pharmacological levels might result in bodyweight reduction. Indeed, bodyweight reduction by GIPR/GLP-1R dual agonists was greater than GLP-1R single agonists in individuals with type 2 diabetes. Thus, GLP-1R/GIPR dual agonists can add additional therapeutic efficacy to tailored diabetes care, especially among obese individuals with type 2 diabetes. However, caution should be exercised as to whether or not these drugs are appropriate for the management of Asian type 2 diabetes patients, which are primarily characterized by non-obesity and impaired β-cell function, as well as in that of elderly adults with type 2 diabetes, who tend to develop sarcopenia and frailty as a result of poor energy intake. Show less

The action of incretin hormones including glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) is potentiated in animal models defective in glucagon action. It has been reported that such animal models maintain normoglycaemia under streptozotocin (STZ)-induced beta cell damage. However, the role of GIP in regulation of glucose metabolism under a combination of glucagon deficiency and STZ-induced beta cell damage has not been fully explored. In this study, we investigated glucose metabolism in mice deficient in proglucagon-derived peptides (PGDPs)-namely glucagon gene knockout (GcgKO) mice-administered with STZ. Single high-dose STZ (200 mg/kg, hSTZ) or moderate-dose STZ for five consecutive days (50 mg/kg × 5, mSTZ) was administered to GcgKO mice. The contribution of GIP to glucose metabolism in GcgKO mice was also investigated by experiments employing dipeptidyl peptidase IV (DPP4) inhibitor (DPP4i) or Gcg-Gipr double knockout (DKO) mice. GcgKO mice developed severe diabetes by hSTZ administration despite the absence of glucagon. Administration of mSTZ decreased pancreatic insulin content to 18.8 ± 3.4 (%) in GcgKO mice, but ad libitum-fed blood glucose levels did not significantly increase. Glucose-induced insulin secretion was marginally impaired in mSTZ-treated GcgKO mice but was abolished in mSTZ-treated DKO mice. Although GcgKO mice lack GLP-1, treatment with DPP4i potentiated glucose-induced insulin secretion and ameliorated glucose intolerance in mSTZ-treated GcgKO mice, but did not increase beta cell area or significantly reduce apoptotic cells in islets. These results indicate that GIP has the potential to ameliorate glucose intolerance even under STZ-induced beta cell damage by increasing insulin secretion rather than by promoting beta cell survival. Show less

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are intestinal hormones secreted in response to ingestion of various nutrients. These incretins stimulate insulin secretion from pancreatic β cells in a glucose-dependent fashion. GIP and GLP-1 actions are mediated by specific receptors, the GIP receptor (GIPR) and the GLP-1 receptor (GLP-1R), which are expressed in pancreatic β cells and various other tissues and organs. Investigations using mice deficient in GIPR and/or GLP-1R have clarified roles of the incretins in enhancement of glucose-dependent insulin secretion from βcells as well as divergent biological activities with therapeutic implications for diabetes-related complications, such as cardiovascular diseases, retinopathy, nephropathy and neuropathy, and comorbidities, such as cognitive impairment, bone fracture and obesity. We review here recent findings on the extra-pancreatic effects of GIP and GLP-1 from the perspective of diabetes treatment. Show less

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the two primary incretin hormones secreted from the intestine on ingestion of various nutrients to stimulate insulin secretion from pancreatic β-cells glucose-dependently. GIP and GLP-1 undergo degradation by dipeptidyl peptidase-4 (DPP-4), and rapidly lose their biological activities. The actions of GIP and GLP-1 are mediated by their specific receptors, the GIP receptor (GIPR) and the GLP-1 receptor (GLP-1R), which are expressed in pancreatic β-cells, as well as in various tissues and organs. A series of investigations using mice lacking GIPR and/or GLP-1R, as well as mice lacking DPP-4, showed involvement of GIP and GLP-1 in divergent biological activities, some of which could have implications for preventing diabetes-related microvascular complications (e.g., retinopathy, nephropathy and neuropathy) and macrovascular complications (e.g., coronary artery disease, peripheral artery disease and cerebrovascular disease), as well as diabetes-related comorbidity (e.g., obesity, non-alcoholic fatty liver disease, bone fracture and cognitive dysfunction). Furthermore, recent studies using incretin-based drugs, such as GLP-1 receptor agonists, which stably activate GLP-1R signaling, and DPP-4 inhibitors, which enhance both GLP-1R and GIPR signaling, showed that GLP-1 and GIP exert effects possibly linked to prevention or treatment of diabetes-related complications and comorbidities independently of hyperglycemia. We review recent findings on the extrapancreatic effects of GIP and GLP-1 on the heart, brain, kidney, eye and nerves, as well as in the liver, fat and several organs from the perspective of diabetes-related complications and comorbidities. Show less

Gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the two primary incretin hormones secreted from the intestine upon ingestion of glucose or nutrients to stimulate insulin secretion from pancreatic β cells. GIP and GLP-1 exert their effects by binding to their specific receptors, the GIP receptor (GIPR) and the GLP-1 receptor (GLP-1R), which belong to the G-protein coupled receptor family. Receptor binding activates and increases the level of intracellular cAMP in pancreatic β cells, thereby stimulating insulin secretion glucose-dependently. In addition to their insulinotropic effects, GIP and GLP-1 have been shown to preserve pancreatic β cell mass by inhibiting apoptosis of β cells and enhancing their proliferation. Due to such characteristics, incretin hormones have been gaining mush attention as attractive targets for treatment of type 2 diabetes, and indeed incretin-based therapeutics have been rapidly disseminated worldwide. However, despites of plethora of rigorous studies, molecular mechanisms underlying how GIPR and GLP-1R activation leads to enhancement of glucose-dependent insulin secretion are still largely unknown. Here, we summarize the similarities and differences of these two incretin hormones in secretion and metabolism, their insulinotropic actions and their effects on pancreatic β cell preservation. We then try to discuss potential of GLP-1 and GIP in treatment of type 2 diabetes. Show less

Gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the two primary incretin hormones secreted from the intestine on ingestion of glucose or nutrients to stimulate insulin secretion from pancreatic β cells. GIP and GLP-1 exert their effects by binding to their specific receptors, the GIP receptor (GIPR) and the GLP-1 receptor (GLP-1R), which belong to the G-protein coupled receptor family. Receptor binding activates and increases the level of intracellular cyclic adenosine monophosphate in pancreatic β cells, thereby stimulating insulin secretion glucose-dependently. In addition to their insulinotropic effects, GIP and GLP-1 play critical roles in various biological processes in different tissues and organs that express GIPR and GLP-1R, including the pancreas, fat, bone and the brain. Within the pancreas, GIP and GLP-1 together promote β cell proliferation and inhibit apoptosis, thereby expanding pancreatic β cell mass, while GIP enhances postprandial glucagon response and GLP-1 suppresses it. In adipose tissues, GIP but not GLP-1 facilitates fat deposition. In bone, GIP promotes bone formation while GLP-1 inhibits bone absorption. In the brain, both GIP and GLP-1 are thought to be involved in memory formation as well as the control of appetite. In addition to these differences, secretion of GIP and GLP-1 and their insulinotropic effects on β cells have been shown to differ in patients with type 2 diabetes compared to healthy subjects. We summarize here the similarities and differences of these two incretin hormones in secretion and metabolism, their insulinotropic action on pancreatic β cells, and their non-insulinotropic effects, and discuss their potential in treatment of type 2 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00022.x, 2010). Show less

Mutations in the cardiac myosin-binding protein C gene (MYBPC3) have been reported to be associated with delayed expression of hypertrophic cardiomyopathy (HCM) and a relatively good prognosis. The aim of this study was to evaluate clinical manifestations in patients with familial HCM caused by a novel nonsense mutation, S297X, in MYBPC3. We analyzed the sarcomere protein genes in 93 probands with HCM. The nonsense mutation S297X in MYBPC3 was present in nine subjects from two unrelated families. Eight of those nine subjects with this mutation were found to be phenotype-positive and the remaining individual was not affected phenotypically. The age range at diagnosis was 9-75 years. There was no family history of sudden death in either family. At presentation, there were various left ventricular hypertrophy (LVH) patterns, including Maron type III hypertrophy from the LV base to apex, hypertrophy confined to the anterolateral wall at the basal LV wall. Two patients showed a significant LV outflow tract gradient and one patient showed intra-right-ventricular obstruction. During follow-up, one patient was repeatedly hospitalized for the treatment of heart failure after development of paroxysmal atrial fibrillation at the age of 86 years and the remaining eight subjects were in relatively stable condition and did not require hospitalization for the treatment of HCM-related events. The novel mutation S297X in MYBPC3 causes HCM in a broad range of ages and heterogeneous clinical manifestations, though the clinical course in patients with this mutation seems to be benign. Show less

In zebrafish, the program for dorsal specification begins soon after fertilization. Dorsal determinants are localized initially to the vegetal pole, then transported to the blastoderm, where they are thought to activate the canonical Wnt pathway, which induces the expression of dorsal-specific genes. We identified a novel maternal-effect recessive mutation, tokkaebi (tkk), that affects formation of the dorsal axis. Severely ventralized phenotypes, including a lack of dorso-anterior structures, were seen in 5-100% of the embryos obtained from tkk homozygous transmitting females. tkk embryos displayed defects in the nuclear accumulation of beta-catenin on the dorsal side, and reduced or absent expression of dorsal-specific genes. Mesoderm and endoderm formation outside the dorsal axis was not significantly affected. Injection of RNAs for activated beta-catenin, dominant-negative forms of Axin1 and GSK3beta, and wild-type Dvl3, into the tkk embryos suppressed the ventralized phenotypes and/or dorsalized the embryos, and restored or induced an ectopic and expanded expression of bozozok/dharma and goosecoid. However, dorsalization by wnt RNAs was affected in the tkk embryos. Inhibition of cytoplasmic calcium release elicited an ectopic and expanded expression of chordin in the wild-type, but did not restore chordin expression efficiently in the tkk embryos. These data indicate that the tkk gene product functions upstream of or parallel to the beta-catenin-degradation machinery to control the stability of beta-catenin. The tkk locus was mapped to chromosome 16. These data provide genetic evidence that the maternally derived canonical Wnt pathway upstream of beta-catenin is involved in dorsal axis formation in zebrafish. Show less