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This survey reviews glucose regulatory systems using mathematical methods. We discuss the utilization of various minimal and comprehensive models of glucose metabolism combined with model predictive control, data assimilation, and physics-informed neural networks to develop decision support systems. These systems will help doctors and nurses administrating insulin levels in patients with diabetes and those in intensive care units. [ABSTRACT FROM AUTHOR]

Increased oxidative stress in the adipose tissue of obese individuals causes abnormal glucose and lipid metabolism, leading to metabolic syndrome onset. Therefore, intake of food-derived antioxidants can effectively prevent metabolic syndrome. Peanut (Arachis hypogaea L.) seed coat is usually discarded in large quantities during processing because of its low economic value, but has been reported to contain a large amount of polyphenols with antioxidant properties. Therefore, in this study, we extracted peanut seed coat using black vinegar, which is also reported to have a high polyphenol content, and examined the effects on glucose and lipid metabolism in high-fat diet-induced obese mice. Six-week-old male C57BL/6J mice were fed a high-fat diet containing 60 kcal% fat and a black vinegar drink containing peanut seed coat extract diluted 40 fold (low dose: LD) or 20 fold (high dose: HD) for 20 weeks. As a result, the final body weight was significantly decreased in both the LD and HD groups compared with the control group. Fasting plasma triglyceride level was significantly lower in the HD group than in the control group. In the HD group, the homeostasis model assessment-insulin resistance (HOMA-IR) value and the quantitative insulin-sensitivity check index (QUICKI) value were significantly decreased and increased, respectively. These results suggest that the black vinegar drink containing peanut seed coat extract improves obesity and glucose metabolism. [ABSTRACT FROM AUTHOR]

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A 69-year-old male patient was referred to our hospital for further examination of hypoglycemia, splenomegaly, and para-aortic lymphadenopathy. The patient was diagnosed with diffuse large B-cell lymphoma (DLBCL) by para-aortic lymph node biopsy. Hypoglycemia was refractory to glucose supplementation but improved shortly after chemotherapy. This situation suggested that hypoglycemia was caused by lymphoma. We compared the expression levels of glyceraldehyde 3-phosphate dehydrogenase, a glycolytic enzyme whose expression is positively correlated with the glycolytic activity of cells, between the current case and two cases of DLBCL without hypoglycemia to explore the possibility that hypoglycemia was due to intense glucose consumption by lymphoma cells through their high glycolytic activity. Results revealed substantially higher expression levels of glyceraldehyde 3-phosphate dehydrogenase in the current case than in DLBCL without hypoglycemia, suggesting that the glycolytic pathway was enhanced in the current case. These results implied that intense glucose consumption by lymphoma cells through their high glycolytic activity causes hypoglycemia.

Postprandial glucose concentration is dependent on the time of day and its concentration in the morning is lower than in the evening. The circadian rhythm of glucose metabolism is regulated by the central circadian pacemaker in the suprachiasmatic nucleus (SCN). Both the SCN circadian clock and the pancreatic clock play important role in generating and maintaining the circadian rhythm of glucose metabolism. Also, short sleep duration and circadian misalignment are closely associated with a decrease in insulin sensitivity and an increase in type2 diabetes. Increased frequency of mastication and/or thorough chewing has been reported to alter the secretion of hormones related to appetite and energy metabolism. Furthermore, we have reported that the effect of mastication on postprandial glucose metabolism is dependent on the time of day and frequency of mastication. Morning mastication but not evening decreases postprandial blood glucose concentrations and increases insulin secretion at 30 min and so-called the insulinogenic index as a marker of early-phase β-cell function. This novel finding may aid in reducing the incidence of obesity and type 2 diabetes mellitus. This review covers the basic concept of the mammalian human circadian system, the underlying mechanism causing phase adjustment of the circadian rhythms in the SCN and peripheral organs, and the effect of eating behavior (e.g., chewing frequency) on the circadian rhythm of glucose metabolism.

In adult diseases, chronic inflammation-related angiopathy is the main pathological condition of organ disorders such as arteriosclerosis, chronic kidney disease, and non-alcoholic steatohepatitis (NASH). Macrophages play an important role in chronic inflammation. For example, macrophage foaming is important for atherosclerosis development. In our study using Apolipoprotein E knockout mice, hyperglycemia caused by the administration of nicotinamide-streptozotocin, which is a non-obese type 2 diabetes model, promoted arteriosclerosis, while the administration of sodium glucose co-transporter 2 inhibitor markedly reduced lesions. In further studies, arteriosclerosis was ameliorated in resistin like molecule β knockout mice, or by xanthine inhibitors. Xanthine oxidase (XO) inhibitors also improved kidney damage in a diabetic renal disorder model using KK/Ay mice and liver damage in a NASH model using high-fat, high-sucrose trans fatty acid loading. These studies suggested that atherosclerosis can be ameliorated independently of glucose and/or lipid lowering therapy, by interventions targeting macrophages. In a study using J774.1 cells, acetylated low density lipoprotein (LDL), which is a typical denatured LDL, is taken up by macrophages regardless of glucose concentrations, but very low density lipoprotein (VLDL) is taken up into cells in a glucose-dependent manner. The glucose concentration-dependent uptake of VLDL was suppressed by XO inhibitors. In addition, the overexpression of XO increased the VLDL uptake and the VLDLR expression was also increased. The glucose and nucleic acid metabolism, which are associated with its metabolism, are involved in the uptake of VLDL. In conclusion, it was strongly suggested that macrophages regulate inflammation and intracellular lipids depending on metabolism and that they may be involved in angiopathy in adult diseases.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease characterized by chronic, profound, disabling, and unexplained fatigue. A variety of studies have been performed to establish objective biomarkers of the disease, including positron emission tomography (PET) molecular imaging and neuro-functional imaging using magnetic resonance imaging (MRI) and magnetoencephalogram (MEG). In this chapter, we summarize the results from PET, MRI, and MEG imaging. Regional cerebral blood flow and glucose utilization rates are decreased in patients with ME/CFS as compared with age- and sex-matched healthy subjects. Acetyl-L-carnitine uptake into the releasable pool of glutamate and serotonin transporters densities are decreased in a few specific brain regions, mostly in the anterior cingulate in the patients. Although it is hypothesized that brain inflammation is involved in the pathophysiology of ME/CFS, there was no direct evidence of neuroinflammation in patients. Our recent PET study successfully demonstrated that neuroinflammation is present in widespread brain areas in ME/CFS patients, and is associated with the severity of neuropsychological symptoms. Evaluation of neuroinflammation in patients with ME/CFS may be essential for understanding the core pathophysiology, as well as for developing objective diagnostic criteria and effective medical treatments for ME/CFS. By using specific neurological features of these patients such as prefrontal cortical atrophies and the over-guarding phenomenon were found using MRI and functional MRI, respectively. We here describe related pathophysiological findings and topics in order to aid in the development of future therapies for ME/CFS patients.

Vascular endothelial function is important for maintaining the homeostasis of the living body. Especially, nitric oxide (NO) produced in vascular endothelial cells regulates blood vessel tone and has an antiatherosclerotic effect. Type 2 diabetes is a typical disease that causes impaired vascular endothelial function, resulting in various vascular complications and damage to organs. Cardiovascular disease associated with type 2 diabetes is a chronic inflammatory disease that starts with endothelial dysfunction (ED), and vascular ED is important as an initial change in arteriosclerotic lesions. Vascular ED in type 2 diabetes is thought to be caused by hyperglycemia, hyperinsulinemia associated with insulin resistance, and hypoglycemia, in which elevated oxidative stress accompanying postprandial hyperglycemia and blood glucose fluctuation are involved. Vascular ED is also caused by postprandial metabolic abnormalities, so correcting postprandial metabolic abnormalities is also important. Meanwhile, Glucagon-like peptide-1 (GLP-1) receptor agonist, thiazolidine, biguanide and Dipeptidyl peptidase-4 (DPP-4) inhibitor have an effect of protecting vascular endothelial function beyond glycemic control. In order to promote a healthy lifestyle for diabetes patients, it is important not only to lower HbA1c but also to avoid postprandial hyperglycemia, blood glucose fluctuation, and hypoglycemia. It is also important to conduct treatment with a view to suppressing vascular complications, such as the selection of antiarteriosclerosis medications.

Insulin resistance is a condition where the sensitivity to insulin of the tissues expressing insulin receptor (InsR) is decreased due to a functional disturbance of InsR-mediated intracellular signaling. Insulin promotes the entry of glucose into the tissues and skeletal muscle is the most important tissue responsible for the insulin's action of decreasing blood glucose levels. Endothelin-1 (ET-1), a potent vasoconstrictor and pro-inflammatory peptide, induces insulin resistance through a direct action on skeletal muscle. However, the signaling pathways of ET-1-induced insulin resistance in skeletal muscle remain unclear. Here we show molecular mechanism underlying the inhibitory effect of ET-1 on insulin-stimulated Akt phosphorylation and glucose uptake in myotubes of rat L6 skeletal muscle cell line. mRNA expression levels of differentiation marker genes, MyoD and myogenin, were increased during L6 myoblasts differentiation into myotubes. Some of myotubes possessed the ability to spontaneously contract. In myotubes, insulin promoted Akt phosphorylation at Thr 308 and Ser 473 , and [ 3 H]-labelled 2-deoxy-D-glucose ([ 3 H]2-DG) uptake. The insulin-facilitated Akt phosphorylation and [ 3 H]2-DG uptake were inhibited by ET-1. The inhibitory effect of ET-1 was counteracted by blockade of ET type A receptor (ET A R), inhibition of G q/11 protein, and siRNA knockdown of G protein-coupled receptor kinase 2 (GRK2). The exogenously overexpressed GRK2 directly bound to endogenous Akt and their association was facilitated by ET-1. In summary, activation of ET A R with ET-1 inhibits insulin-induced Akt phosphorylation and [ 3 H]2-DG uptake in a G q/11 protein- and GRK2-dependent manner in skeletal muscle. These findings indicate that ET A R and GRK2 are potential targets for insulin resistance.

Accumulating evidence indicates close and tight relationship between bone tissue and energy expenditure, especially glucose metabolism. In molecular mechanisms, osteocalcin secreted from osteoblasts, as a hormone, is demonstrated in mice to be involved not only in insulin secretion from islet β-cells but also in insulin resistance in adipose tissue. In addition, since signaling cascades in liver activated by RANK ligand has been shown to participate in augmentation of insulin resistance, pharmacological inhibition of RANK ligand for treatment of osteoporosis is speculated to improve insulin resistance in human. However, data from several clinical trials of ant-osteoporosis drugs have not supported an idea that they were clinically involved in glucose metabolism. Interestingly, some retrospective observational studies demonstrate that long-term administration of bisphosphonates may decrease the incidence of newly onset of type 2 diabetes, although mechanisms by which they do so are totally uncertain.

Cerebral ischemic stress often induces a hyperglycemic condition. This postischemic hyperglycemia exacerbates the development of cerebral ischemic neuronal damage, although the mechanism of this exacerbation remains to be clarified. We previously discovered that the cerebral sodium-glucose transporter (SGLT) was closely involved in the development of cerebral ischemic neuronal damage. SGLT is a member of the glucose transporter family and moves glucose together with sodium ions. SGLT-1, -3, -4, and -6 are distributed in the brain. We conducted further experiments to elucidate the detailed mechanism of the exacerbation of cerebral ischemia by cerebral SGLT. The results clarified: 1) the relationship between cerebral SGLT and postischemic hyperglycemia; 2) the involvement of cerebral SGLT-1 (a cerebral SGLT isoform) in cerebral ischemic neuronal damage; and 3) the effects of sodium influx through cerebral SGLT on the development of cerebral ischemic neuronal damage. This paper presents our data on the involvement of cerebral SGLT in the exacerbation of cerebral ischemic neuronal damage.

Metabolic pathways tightly regulate T cell response in host defense against infection and cancer. Glycolysis plays a key role in effector T cell differentiation and its function. More recent studies have demonstrated that tumor microenvironment forms hypoxia and metabolic disadvantage of immune cells. These environmental attributions impair the effector T cell survival, proliferation and function. Therefore repurposing of metabolic drugs might develop a novel cancer immunotherapy based on the targeting of T cell immunometabolism. In this review, we abridge basis of cancer cell and T cell metabolism and discuss recent advances elucidating "metabolic competition" exerted on tumor-infiltrating T cells that drive their dysfunction in tumor microenvironment.

Numerous epidemiological studies and meta-analyses have indicated that there is a link between Vitamin D insufficiency/deficiency and metabolic disorders such as type 1 and type 2 diabetes mellitus as well as metabolic syndrome. However, vitamin D supplementation has not demonstrated improvement effects in obesity, disorders of glucose and lipid metabolism in any of these illnesses;therefore, the details of the causal relationship remain unclear. Improvement in glucose metabolism was observed in a study in which only vitamin D deficient patients with 25-hydroxyvitamin D[25(OH)D]levels of less than 20 ng/mL were given native vitamin D supplementation. Further studies are needed to determine the 25(OH)D level at which intervention is needed along with the required amount and duration of such supplementation.

Leukemia stem cells (LSCs) are responsible for relapse of leukemia. LSCs maintain their self-renewal capacity, stemness properties, and therapeutic resistance in a manner dependent on their cell of origin and genetic alterations acquired during subsequent clonal evolution. Specific mechanisms of metabolic control and nutrient acquisition are implicated in the regulation of LSC survival. Recent advances in gene modification strategies in mice and in sophisticated metabolomics technologies are producing novel inquiries in LSC research performed in vivo. In this review, I examined our current knowledge on the roles of various metabolic pathways, including glucose metabolism, lipid oxidation, and an alternative route of amino acid and peptide supply, that support the maintenance of self-renewal capacity and therapeutic resistance in LSCs in vivo.

Synthesis of type Ⅰ collagen, a major component of the bone matrix, precedes the expression of Runt-related transcription factor 2(Runx2), a master regulator in osteoblast differentiation. Thus, a direct link between osteoblast differentiation and bone formation is seemingly absent, and how these are maintained in a coordinated matter remains unclear. It was recently demonstrated that osteoblasts depend on glucose, which glucose transporter type 1(GLUT1)takes up as an energy source, and it was found that glucose uptake promotes osteoblast differentiation and bone formation via AMP-activated protein kinase. It was also shown that Runx2 upregulates GLUT1 expression, and this Runx2-GLUT1 feedforward regulation integrates and coordinates osteoblast differentiation and bone formation throughout life. These previous findings revealed that the energy metabolism balance in osteoblasts integrates the differentiation and function of osteoblasts, and re-emphasized the importance of crosstalk between bone and sugar metabolism.

It is important for the anesthesiologists to understand pathophysiology of perioperative stress hyperglycemia, because it offers strategies for treatment of stress hyperglycemia. The effect of glucose tolerance is different in the choice of the anesthetic agent used in daily clinical setting. Specifically, the volatile anesthetics inhibit insulin secretion after glucose load and affects glucose tolerance. During minor surgery by the remifentanil anesthesia, the stress reaction is hard to be induced, suggesting that we should consider low-dose glucose load. Finally it is necessary to perform the glycemic control of the patients who fell into stress hyperglycemia depending on the individual patient. However, there are a lot of questions to be answered in the future. The prognosis of the perioperative patients is more likely to be greatly improved if we can control stress hyperglycemia.

The urea breath test was developed for the diagnosis of Helicobacter pylori infection. In this test, we measure exhaled ¹³CO₂ using POCone developed in Japan, which is an infrared spectrometry photometer. Based on the urea breath test, we subsequently developed the in vitro ¹³C-glucose exhaling test. In this test, ¹³C-glucose is added in the circulation culture medium, and ¹³CO₂ generated with a bioartificial liver is measured by the POCone. The quantity of discharged ¹³CO₂ reflects the energy-producing ability of the bioartifi- cial liver. Therefore, we can simply and easily observe the viability of a bioartificial liver and the effect of drugs on carbohydrate metabolism in the bioartificial liver in real time. According to the results of a bioartificial liver study, we developed the fasting ¹³C-glucose breath test, which can quickly determine hepatic insu- lin resistance in humans with marked sensitivity. The bioartificial liver study unexpectedly led to the development of a new stable isotope breath test. [Review].

The appropriate secretion of insulin from pancreatic β-cells is essential for regulating blood glucose levels. Glucose-stimulated insulin secretion (GSIS) involves the following steps: Glucose uptake by pancreatic β-cells is metabolized to produce ATP. Increased ATP levels result in the closure of ATP-sensitive K(+) (KATP) channels, resulting in membrane depolarization that activates voltage-dependent Ca(2+) channels to subsequently trigger insulin secretion. In addition to this primary mechanism through KATP channels, insulin secretion is regulated by cyclic AMP and diacylglycerol (DAG), which mediate the effects of receptor agonists such as GLP-1 and acetylcholine. Glucose by itself can also increase the levels of these second messengers. Recently, we have shown an obligatory role of diacylglycerol kinase (DGK), an enzyme catalyzing the conversion of DAG to phosphatidic acid, in GSIS. Of the 10 known DGK isoforms, we focused on type-I DGK isoforms (i.e., DGKα, DGKβ, and DGKγ), which are activated by Ca(2+). The protein expression of DGKα and DGKγ was detected in mouse pancreatic islets and the pancreatic β-cell line MIN6. Depletion of these DGKs by a specific inhibitor or siRNA decreased both [Ca(2+)]i and insulin secretion in MIN6 cells. Similar [Ca(2+)]i responses were induced by DiC8, a membrane-permeable DAG analog. These results suggest that DGKα and DGKγ play crucial roles in insulin secretion, and that their depletion impairs insulin secretion through DAG accumulation. In this article, we review the current understanding of the roles of DAG- and DGK-signaling in pancreatic β-cells, and discuss their pathophysiological roles in the progression of type-2 diabetes.

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) have been recognized as metabolic disorders characterized by fatty accumulation in the liver without alcohol consumption. The diseases can cause metabolic syndromes, consisting of obesity, diabetes mellitus (DM), dyslipidemia and hypertension. For the treatment of NAFLD/NASH, losing weight by exercise or diet remains the standard treatment, because no effective pharmacological therapy has yet been developed for NAFLD/NASH. Two incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), stimulate glucose-mediated insulin production in pancreatic β cells. Incretin has also been reported to have various extra-pancreatic effects, including the regulation of hepatic glucose production, appetite and satiety, as well as the stimulation of afferent sensory nerves. Therefore, incretin may have potential as a novel therapeutic agent for NAFLD/NASH.

Basic, clinical and translational metabolic researches in cancer area have been extensively tried to discover and develop novel cancer metabolism drugs. Since tumor cells have metabolic dependencies that distinguish them from their normal counterparts, targeted inhibition of these metabolic dependencies is considered a promising therapeutic strategy against cancer. For example the representative cancer metabolism is that cancer cells exhibit profound metabolic alterations by choosing aerobic glycolysis to metabolize glucose to lactate regardless of the presence of adequate oxygen, although normal cells which mainly utilize glucose by using mitochondrial oxidative phosphorylation to generate ATP. In this review, we focus on several important oncogenes and enzymes, whose alterations have contributed extensively to the metabolic phenotype of cancer cells, with an emphasis on the therapeutic targets.

Hepatitis C virus (HCV) infection often causes intrahepatic diseases, such as chronic hepatitis, liver chirrohsis, and hepatocellular carcinoma (HCC). Moreover, HCV infection exhibits various extrahepatic manifestations, such as thyroiditis, glucose and lipid metabolic disorder, and iron metabolic disorder. HCV infection is often associated with type 2 diabetes, involving hepatic fibrosis and poor prognosis. Type 2 diabetes increases the risk of HCC. We have been investigating molecular mechanisms of HCV-induced glucose metabolic disorder and we reported that HCV infection promotes hepatic gluconeogenesis through forkhead box O1 (FoxO1)-dependent pathway and that HCV infection suppresses the cell surface expression of glucose transporter 2 (GLUT2), resulting in suppression of glucose uptake. We have found that HCV NS5A protein plays important roles in these two independent pathways. Here we discuss the roles of HCV NS5A in HCV-induced glucose metabolic disorder.

Type 2 diabetes is closely associated with our daily diets and has become a global health problem with increasing number of patients. Maintaining energy homeostasis is essentially required for the treatment of diabetes. Energy metabolism starts with taking in a meal. Nutrients including amino acids, fatty acids and glucose in the digest have been shown to act on the neuroendocrine cells in the gastrointestinal (GI) tract, and thereby play important roles in energy homeostasis. Therefore, the GI tract is now recognized as a sensor system for nutrient signals. Taste receptor type 1 member 2 (T1R2) is known to function as a co-receptor with T1R3 to detect sweet chemicals in the taste buds. It has been proposed that the T1R2/T1R3 receptor complex acts as sweet sensor in the intestine, and plays a pivotal role in sensing sugars and maintaining glucose homeostasis through incretin secretion. To clarify the physiological roles of T1R2 in glucose homeostasis, T1r2-lacZ knock-in/knock-out mice were generated. We found lacZ gene expression in the GI tract where T1r3 expression has been reported. Interestingly, the T1r2-lacZ knock-in mice showed impaired glucose tolerance on oral glucose challenge but not on intraperitoneal injection. However, the fasting glucose level in T1r2-lacZ knock-in mice was comparable to that in wild type mice. These results suggest an important role of the sweet taste receptor system in the intestine when stimulated by glucose. Therefore, the roles of T1R2 will be presented and the mechanism for metabolic homeostasis will be discussed.