👤 Daisuke Yamane

Glucose-dependent insulinotropic polypeptide (GIP) is secreted by enteroendocrine K cells, primarily located in the upper small intestine, in response to food intake and plays a significant role in the postprandial regulation of nutrient metabolism. Although the importance of GIP in metabolic regulation has long been recognized, progress in developing GIP as a therapeutic target has been limited. However, the GIP/GIP receptor (GIPR) axis has garnered increasing attention in recent years. Emerging evidence suggests that dual GIP/GLP-1 receptor agonists and triple GIP/GLP-1/glucagon receptor agonists provide beneficial metabolic effects in individuals with type 2 diabetes and obesity. In this review, we outline the physiological roles of GIP, detailing the mechanisms of GIP secretion from K cells in response to macronutrients, its actions on key target organs involved in metabolic regulation, and ongoing developments in its therapeutic applications. Show less

Apolipoprotein B (ApoB) is essential for the assembly and secretion of triglyceride (TG)-rich VLDL particles, and its dysfunction is linked to metabolic disorders, including dyslipidemia and liver steatosis. However, less attention has been paid to whether and how other apolipoproteins play redundant or compensatory roles when the ApoB function is compromised. Here, we investigated the effects of microsomal triglyceride transfer protein (MTP), which mediates lipidation of nascent ApoB, on ApoE function. We observed a paradoxical increase in ApoE secretion resulting from increased expression in MTP inhibitor (MTPi)-treated human hepatoma cells. This phenotype was recapitulated in APOB-knockout cells and was associated with impaired ApoB secretion. While MTP-dependent transfer of neutral lipids is dispensable for ApoE secretion, TG biosynthesis, redundantly catalyzed by DGAT1 and DGAT2, is required for efficient ApoE secretion in hepatoma cells. ApoE colocalizes with lipid droplets near the Golgi apparatus and mediates TG export in an ApoB-independent fashion. We found that simultaneous inhibition of both ApoE and ApoB, but not inhibition of either alone, led to TG accumulation in hepatoma cells, indicating that both proteins function redundantly to control TG content. Validation studies in primary human hepatocytes (PHHs) demonstrated DGAT2-dependent secretion of ApoE. While MTPi treatment did not elevate ApoE secretion, it induced increased sialylation of ApoE in the supernatants of PHHs. These results show that enhanced ApoE secretion compensates for the impaired ApoB function to maintain the lipid homeostasis, providing an alternative route to modulate lipid turnover in hepatoma cells. Show less

Lymphoplasmacytic lymphoma (LPL) is a type of low-grade B-cell lymphoma, with 90-95% of cases associated with Waldenström macroglobulinemia, characterized by the presence of IgM-type M-protein. We report, for the first time, a case of LPL-producing Bence Jones (BJ) protein kappa. The patient was a 78-year-old woman admitted to our department due to general fatigue and proteinuria that had persisted for 2 months. No M-protein was detected by blood immunofixation, but kappa-type BJ protein was detected in the urine. Light microscopy of a kidney biopsy sample revealed infiltration of lymphocytes and plasma cells into the perirenal adipose tissue and renal interstitium. The infiltrating cells exhibited kappa light chain restriction. Bone marrow examination revealed clusters of immature plasmacytoid lymphocytes that were CD20 positive, CD5 negative, and exhibited light chain restriction. Genetic analysis detected a MYD88 mutation, leading to the diagnosis of LPL in the patient. Six months after starting treatment with tirabrutinib, urinary protein levels improved to 0.2 g/gCr. Renal infiltration was identified due to urinary protein, and currently, no extramedullary lesions outside the kidneys are observed. Tirabrutinib has been extremely effective, but careful follow-up is still required. Show less

Glucose-dependent insulinotropic polypeptide (GIP) is released during meals and promotes nutrient uptake and storage. GIP receptor knockout mice are protected from diet induced weight gain and thus GIP antagonists have been proposed as a treatment for obesity. In this study, we assessed the role of GIP in hyperphagia induced obesity and metabolic abnormalities in leptin deficient (Lep We crossbred GIP-GFP knock-in homozygous mice (GIP Postprandial GIP levels were markedly elevated in Lep Our results indicate that GIP knockout does not prevent excess weight gain and metabolic derangement in hyperphagic leptin deficient mice. Show less

Gastric inhibitory polypeptide receptor (GIPR) directly induces energy accumulation in adipose tissue in vitro. However, the importance of the direct effect of GIPR signaling on adipose tissue in vivo remains unclear. In the current study, we generated adipose tissue-specific GIPR knockout (GIPR Show less

Aging is associated with increased fat mass and decreased lean mass, which is strongly associated with the development of insulin resistance. Gastric inhibitory polypeptide (GIP) is known to promote efficient storage of ingested nutrients into adipose tissue; we examined aging-associated changes in body composition using 10-week-old and 50-week-old wild-type (WT) and GIP receptor knockout (Gipr-/-) mice on a normal diet, which show no difference in body weight. We found that Gipr-/- mice showed significantly reduced fat mass without reduction of lean mass or food intake, while WT mice showed increased fat mass and decreased lean mass associated with aging. Moreover, aged Gipr-/- mice showed improved insulin sensitivity, which is associated with amelioration in glucose tolerance, higher plasma adiponectin levels, and increased spontaneous physical activity. We therefore conclude that genetic inactivation of GIP signaling can prevent the development of aging-associated insulin resistance through body composition changes. Show less

A comparative assessment has been made regarding efficacy and safety of the double filtration plasmapheresis (DFPP), thermofiltration (TFPP), and low-density lipoprotein (LDL) adsorptive (PA) methods by making a crossover test on heterozygous familial hypercholesterolemia patients. Treatments by DFPP, TFPP (secondary membrane Evalux 5A), and PA (Liposorber LA-40) were carried out 5 times each, with a 2-week interval, in 5 patients with heterozygous familial hypercholesterolemia. The same plasma separator (Plasmacure PS-60, polysulfone) was used in all cases, and the volume of plasma processed was set at 4 L. High removal rates were obtained of total cholesterol, LDL cholesterol, triglycerides TG, and apolipoprotein B (apoB) by all three methods, and no differences were observed. Lipoprotein (a), apoA-2, apoC-3, fibrinogen, and immunoglobulin M (IgM) showed significantly high removal rates by the DFPP and TFPP methods compared with the PA method. The sieving coefficient of albumin and high-density lipoprotein (HDL) cholesterol at 2 and 4 L of plasma processed exhibited high permeabilities using all three methods. Supplementing albumin was not necessary. An increase of the transmembrane pressure was observed in 1 case treated by DFPP but was not observed when using the TFPP or PA method. No changes were observed in serum interleukin 1beta (IL-1beta) or tumor necrosis factor-alpha (TNF-alpha) before and after treatment by any of the three methods. No remarkable side effects were observed using either the DFPP or TFPP method. The DFPP and TFPP methods showed efficacy and safety that was not inferior to the PA method in conventional LDL apheresis, and the dead-end method of the filter operation without the discarding of plasma was shown to be possible. Show less