A Case of Hereditary Coproporphyria in which the Patient's Course Improved after the Discontinuation of Givosiran.

Hereditary coproporphyria (HCP) is caused by a partial deficiency of coproporphyrinogen oxidase during heme biosynthesis. Givosiran is approved for the treatment of acute hepatic porphyria. We herein report the case of a 47-year-old woman with HCP. Monthly givosiran administration improved her subjective symptoms and reduced her δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) levels to the normal range. However, givosiran was discontinued after six months due to a decreased renal function. The patient's ALA and PBG levels remained within the normal ranges, and her HCP-related symptoms resolved more than 2 years after the discontinuation of givosiran.

Epac2 activation mediates glucagon-induced glucogenesis in primary rat hepatocytes.

AIMS/INTRODUCTION: Glucagon plays an essential role in hepatic glucogenesis by enhancing glycogen breakdown, inducing gluconeogenesis, and suppressing glycogenesis. Moreover, glucagon increases cyclic adenosine monophosphate (cAMP) levels, thereby activating protein kinase A (PKA) and cAMP guanine nucleotide exchange factor (also known as Epac). Although the function of PKA in the liver has been studied extensively, the function of hepatic Epac is poorly understood. The aim of this study was to elucidate the role of Epac in mediating the action of glucagon on the hepatocytes. MATERIALS AND METHODS: Epac mRNA and protein expression, localization, and activity in the hepatocytes were analyzed by reverse transcription polymerase chain reaction, western blotting, immunofluorescence staining, and Rap1 activity assay, respectively. Additionally, we investigated the effects of an Epac-specific activator, 8-CPT, and an Epac-specific inhibitor, ESI-05, on glycogen metabolism in isolated rat hepatocytes. Further mechanisms of glycogen metabolism were evaluated by examining glucokinase (GK) translocation and mRNA expression of gluconeogenic enzymes. RESULTS: Epac2, but not Epac1, was predominantly expressed in the liver. Moreover, 8-CPT inhibited glycogen accumulation and GK translocation and enhanced the mRNA expression of gluconeogenic enzymes. ESI-05 failed to reverse glucagon-induced suppression of glycogen storage and partially inhibited glucagon-induced GK translocation and the mRNA expression of gluconeogenic enzymes. CONCLUSIONS: Epac signaling plays a role in mediating the glucogenic action of glucagon in the hepatocytes.

Investigation of d-allulose effects on high-sucrose diet-induced insulin resistance via hyperinsulinemic-euglycemic clamps in rats.

d-Allulose, a C-3 epimer of d-fructose, is a rare sugar that has no calories. Although d-allulose has been reported to have several health benefits, such as anti-obesity and anti-diabetic effects, there have been no reports evaluating the effects of d-allulose on insulin resistance using a hyperinsulinemic-euglycemic clamp (HE-clamp). Therefore, we investigated the effects of d-allulose on a high-sucrose diet (HSD)-induced insulin resistance model. Wistar rats were randomly divided into three dietary groups: HSD containing 5% cellulose (HSC), 5% d-allulose (HSA), and a commercial diet. The insulin tolerance test (ITT) and HE-clamp were performed after administration of the diets for 4 and 7 weeks. After 7 weeks, the muscle and adipose tissues of rats were obtained to analyze Akt signaling via western blotting, and plasma adipocytokine levels were measured. ITT revealed that d-allulose ameliorated systemic insulin resistance. Furthermore, the results of the 2-step HE-clamp procedure indicated that d-allulose reversed systemic and muscular insulin resistance. d-Allulose reversed the insulin-induced suppression of Akt phosphorylation in the soleus muscle and epididymal fat tissues and reduced plasma TNF-α levels. This study is the first to show that d-allulose improves systemic and muscle insulin sensitivity in conscious rats.

Normal plasma apoB48 despite the virtual absence of apoB100 in a compound heterozygote with novel mutations in the MTTP gene.

"Normotriglyceridemic abetalipoproteinemia (ABL)" was originally described as a clinical entity distinct from either ABL or hypobetalipoproteinemia. Subsequent studies identified mutations in APOB gene which encoded truncated apoB longer than apoB48. Therefore, "Normotriglyceridemic ABL" can be a subtype of homozygous familial hypobetalipoproteinemia. Here, we report an atypical female case of ABL who was initially diagnosed with "normotriglyceridemic ABL", because she had normal plasma apoB48 despite the virtual absence of apoB100 and low plasma TG level. Next generation sequencing revealed that she was a compound heterozygote of two novel MTTP mutations: nonsense (p.Q272X) and missense (p.G709R). We speculate that p.G709R might confer residual triglyceride transfer activity of MTTP preferentially in the intestinal epithelium to the hepatocytes, allowing production of apoB48. Together, "normotriglyceridemic ABL" may be a heterogenous disorder which is caused by specific mutations in either APOB or MTTP gene.

Successful treatment of myxedema coma with a combination of levothyroxine and liothyronine.

Myxedema coma is a rare endocrine emergency resulting from the decompensation of severe hypothyroidism, which is associated with a high mortality rate. It is characterized by the deterioration of mental status, hypothermia, hypotension, hyponatremia, and hypoventilation. Early disease diagnosis and advancements in intensive supportive care have reduced the mortality rate. Besides intensive supportive care, appropriate management of the underlying thyroid hormone deficiency is essential. However, as the disease is rare and unrecognized, evidence-based treatment of myxedema has not yet been established in many countries. An 84-year-old Japanese man with a history of Hashimoto's thyroiditis was referred to our hospital. On arrival, conscious disturbance, hypothermia, hypotension, and hypoventilation were observed. He had discontinued thyroid hormone replacement therapy for a year. He was diagnosed with myxedema coma. Immediately, he received intensive supportive care and a combination therapy of 200 µg levothyroxine and 50 µg liothyronine until the fifth hospital day. Subsequently, monotherapy with levothyroxine was continued at a dose of 150 µg daily. The thyroid hormone level reached the normal range a few days later, and cardiovascular disease did not develop during hospitalization. This case demonstrated the efficacy of the combination of levothyroxine and liothyronine in treating myxedema coma.

Rare Sugar Syrup Containing d-Allulose but Not High-Fructose Corn Syrup Maintains Glucose Tolerance and Insulin Sensitivity Partly via Hepatic Glucokinase Translocation in Wistar Rats.

Ingestion of high-fructose corn syrup (HFCS) is associated with the risk of both diabetes and obesity. Rare sugar syrup (RSS) has been developed by alkaline isomerization of HFCS and has anti-obesity and anti-diabetic effects. However, the influence of RSS on glucose metabolism has not been explored. We investigated whether long-term administration of RSS maintains glucose tolerance and whether the underlying mechanism involves hepatic glucokinase translocation. Wistar rats were administered water, RSS, or HFCS in drinking water for 10 weeks and then evaluated for glucose tolerance, insulin tolerance, liver glycogen content, and subcellular distribution of liver glucokinase. RSS significantly suppressed body weight gain and abdominal fat mass (p < 0.05). The glucose tolerance test revealed significantly higher blood glucose levels in the HFCS group compared to the water group, whereas the RSS group had significantly lower blood glucose levels from 90 to 180 min (p < 0.05). At 30, 60, and 90 min, the levels of insulin in the RSS group were significantly lower than those in the water group (p < 0.05). The amount of hepatic glycogen was more than 3 times higher in the RSS group than that in the other groups. After glucose loading, the nuclear export of glucokinase was significantly increased in the RSS group compared to the water group. These results imply that RSS maintains glucose tolerance and insulin sensitivity, at least partly, by enhancing nuclear export of hepatic glucokinase.

Endogenous GIP ameliorates impairment of insulin secretion in proglucagon-deficient mice under moderate beta cell damage induced by streptozotocin.

AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS/INTERPRETATION: 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.

Identification of physical and psychosocial problems associated with diabetic nephropathy using the International Classification of Functioning, Disability and Health Core Set for Diabetes Mellitus.

BACKGROUND: We previously demonstrated validation of the Comprehensive International Classification of Functioning, Disability and Health Core Set for Diabetes Mellitus (ICF-CS for DM) in patients with diabetic nephropathy (DMN). The objective of the present study was to identify differences in experience of physical and psychosocial problems between DMN patients with and without hemodialysis (HD), and diabetes patients without nephropathy using the ICF-CS for DM. METHODS: A total of 302 diabetes outpatients (men, 68 %; mean age, 62 years) were interviewed using four components of the ICF-CS for DM including "Body functions", "Body structures", "Activities and participation", and "Environmental factors". RESULTS: The mean number of categories in which difficulty was experienced in the four components was significantly greater in DMN patients with HD followed by DMN patients without HD, and diabetes patients without nephropathy (23.9 vs. 18.0 vs. 13.1, respectively). Multivariate logistic regression models revealed that, compared with diabetes patients without nephropathy, diabetes patients with nephropathy were more likely to have difficulty with physical problems and social activities and participation. Among DMN patients, dialysis patients were found to have larger numbers of problems, and face difficulty with employment status after adjusting for sex, age, type, and duration of diabetes. CONCLUSION: The results of this study using the ICF-CS for DM identified the areas for improvement among physical and psychosocial problems in DMN patients with and without HD in contrast to diabetes patients without nephropathy.

Mice Deficient in Proglucagon-Derived Peptides Exhibit Glucose Intolerance on a High-Fat Diet but Are Resistant to Obesity.

Homozygous glucagon-GFP knock-in mice (Gcggfp/gfp) lack proglucagon derived-peptides including glucagon and GLP-1, and are normoglycemic. We have previously shown that Gcggfp/gfp show improved glucose tolerance with enhanced insulin secretion. Here, we studied glucose and energy metabolism in Gcggfp/gfp mice fed a high-fat diet (HFD). Male Gcggfp/gfp and Gcggfp/+ mice were fed either a normal chow diet (NCD) or an HFD for 15-20 weeks. Regardless of the genotype, mice on an HFD showed glucose intolerance, and Gcggfp/gfp mice on HFD exhibited impaired insulin secretion whereas Gcggfp/+ mice on HFD exhibited increased insulin secretion. A compensatory increase in ß-cell mass was observed in Gcggfp/+mice on HFD, but not in Gcggfp/gfp mice on the same diet. Weight gain was significantly lower in Gcggfp/gfp mice than in Gcggfp/+mice. Oxygen consumption was enhanced in Gcggfp/gfp mice compared to Gcggfp/+ mice on an HFD. HFD feeding significantly increased uncoupling protein 1 mRNA expression in brown adipose and inguinal white adipose tissues of Gcggfp/gfp mice, but not of Gcggfp/+mice. Treatment with the glucagon-like peptide-1 receptor agonist liraglutide (200 mg/kg) improved glucose tolerance in Gcggfp/gfp mice and insulin content in Gcggfp/gfp and Gcggfp/+ mice was similar after liraglutide treatment. Our findings demonstrate that Gcggfp/gfp mice develop diabetes upon HFD-feeding in the absence of proglucagon-derived peptides, although they are resistant to diet-induced obesity.

Long-term pancreatic beta cell exposure to high levels of glucose but not palmitate induces DNA methylation within the insulin gene promoter and represses transcriptional activity.

Recent studies have implicated epigenetics in the pathophysiology of diabetes. Furthermore, DNA methylation, which irreversibly deactivates gene transcription, of the insulin promoter, particularly the cAMP response element, is increased in diabetes patients. However, the underlying mechanism remains unclear. We aimed to investigate insulin promoter DNA methylation in an over-nutrition state. INS-1 cells, the rat pancreatic beta cell line, were cultured under normal-culture-glucose (11.2 mmol/l) or experimental-high-glucose (22.4 mmol/l) conditions for 14 days, with or without 0.4 mmol/l palmitate. DNA methylation of the rat insulin 1 gene (Ins1) promoter was investigated using bisulfite sequencing and pyrosequencing analysis. Experimental-high-glucose conditions significantly suppressed insulin mRNA and increased DNA methylation at all five CpG sites within the Ins1 promoter, including the cAMP response element, in a time-dependent and glucose concentration-dependent manner. DNA methylation under experimental-high-glucose conditions was unique to the Ins1 promoter; however, palmitate did not affect DNA methylation. Artificial methylation of Ins1 promoter significantly suppressed promoter-driven luciferase activity, and a DNA methylation inhibitor significantly improved insulin mRNA suppression by experimental-high-glucose conditions. Experimental-high-glucose conditions significantly increased DNA methyltransferase activity and decreased ten-eleven-translocation methylcytosine dioxygenase activity. Oxidative stress and endoplasmic reticulum stress did not affect DNA methylation of the Ins1 promoter. High glucose but not palmitate increased ectopic triacylglycerol accumulation parallel to DNA methylation. Metformin upregulated insulin gene expression and suppressed DNA methylation and ectopic triacylglycerol accumulation. Finally, DNA methylation of the Ins1 promoter increased in isolated islets from Zucker diabetic fatty rats. This study helps to clarify the effect of an over-nutrition state on DNA methylation of the Ins1 promoter in pancreatic beta cells. It provides new insights into the irreversible pathophysiology of diabetes.

Validation of the Comprehensive International Classification of Functioning, Disability and Health (ICF) Core Set for Diabetes Mellitus in patients with diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DMN) is the most common cause of end-stage renal disease. Progression of DMN leads to impairment of physical activity, restriction of daily activities, and diminished social participation. Therefore, the precise assessment of the physical and psychosocial problems of DMN patients is important. The objective of this study was to validate the Comprehensive International Classification of Functioning, Disability and Health Core Set for Diabetes Mellitus (ICF-CS for DM) from the perspective of DMN patients. METHODS: A total of 176 DMN outpatients were interviewed using the ICF-CS for DM. Content and construct validity were evaluated. Patients were divided into 2 groups: DMN patients without hemodialysis (HD) (non-HD group) and DMN patients undergoing HD (HD group). Content validity was evaluated based on the frequency of patients who had a problem in each category. For construct validity, the patients were divided into two groups based on DM duration and hemoglobin A1C levels. RESULTS: Content validity evaluation revealed 58 categories reported as problem categories: 39 categories in the non-HD group and 50 categories in the HD group. Construct validity evaluation showed that longer DM duration and poor glycemic control contributes to increased problems. CONCLUSIONS: Content and construct validity of the ICF-CS for DM was supported from the DMN patients' perspective. Some categories of the "Environmental factors" component need further studies to be appropriate.

KATP channel as well as SGLT1 participates in GIP secretion in the diabetic state.

Glucose-dependent insulinotropic polypeptide (GIP), a gut hormone secreted from intestinal K-cells, potentiates insulin secretion. Both K-cells and pancreatic ß-cells are glucose-responsive and equipped with a similar glucose-sensing apparatus that includes glucokinase and an ATP-sensitive K(+) (KATP) channel comprising KIR6.2 and sulfonylurea receptor 1. In absorptive epithelial cells and enteroendocrine cells, sodium glucose co-transporter 1 (SGLT1) is also known to play an important role in glucose absorption and glucose-induced incretin secretion. However, the glucose-sensing mechanism in K-cells is not fully understood. In this study, we examined the involvement of SGLT1 (SLC5A1) and the KATP channels in glucose sensing in GIP secretion in both normal and streptozotocin-induced diabetic mice. Glimepiride, a sulfonylurea, did not induce GIP secretion and pretreatment with diazoxide, a KATP channel activator, did not affect glucose-induced GIP secretion in the normal state. In mice lacking KATP channels (Kir6.2(-/-) mice), glucose-induced GIP secretion was enhanced compared with control (Kir6.2(+) (/) (+)) mice, but was completely blocked by the SGLT1 inhibitor phlorizin. In Kir6.2(-/-) mice, intestinal glucose absorption through SGLT1 was enhanced compared with that in Kir6.2(+) (/) (+) mice. On the other hand, glucose-induced GIP secretion was enhanced in the diabetic state in Kir6.2(+) (/) (+) mice. This GIP secretion was partially blocked by phlorizin, but was completely blocked by pretreatment with diazoxide in addition to phlorizin administration. These results demonstrate that glucose-induced GIP secretion depends primarily on SGLT1 in the normal state, whereas the KATP channel as well as SGLT1 is involved in GIP secretion in the diabetic state in vivo.

Glucagon is essential for adaptive thermogenesis in brown adipose tissue.

Glucagon, a counterregulatory hormone to insulin, serves as a regulator of glucose homeostasis and acts in response to hypoglycemia. Earlier studies have shown that glucagon administration induces thermogenesis in experimental animal models. However, it is not known whether endogenous glucagon is involved in the regulation of brown adipose tissue (BAT) function. Here we investigated the role of glucagon in cold-induced thermogenesis in male mice deficient in proglucagon-derived peptides (GCGKO mice). Upon exposure to cold, GCGKO mice exhibited a greater decrease in rectal temperature than control mice. The cold exposure-induced increase in oxygen consumption in GCGKO mice was less than that seen in control mice. Moreover, the increase in oxygen consumption after administration of a ß3-adrenergic receptor agonist, CL-316,243, was also lesser in GCGKO than in control mice. Expression of thermogenic genes, including the gene encoding uncoupling protein 1 (Ucp1), was reduced in the BAT of GCGKO mice under ambient as well as cold conditions. Administration of glucagon restored the expression of Ucp1 mRNA in the BAT as well as the expression of the fibroblast growth factor 21 gene (Fgf21) in the liver. Supplementation with glucagon for 2 weeks resulted in higher plasma Fgf21 levels and improved responses to CL-316,243 in GCGKO mice. These results indicated that endogenous glucagon is essential for adaptive thermogenesis and that it regulates BAT function, most likely by increasing hepatic Fgf21 production.

Dipeptidyl peptidase-4 inhibitor anagliptin facilitates restoration of dextran sulfate sodium-induced colitis.

OBJECTIVE. Inflammatory bowel disease (IBD) is a chronic debilitating disease associated with severe damage to the intestinal mucosa. Glucagon-like peptide-2 (GLP-2) is a potent and specific gastrointestinal growth factor. GLP-2 released from enteroendocrine cells is inactivated by dipeptidyl peptidase-4 (DPP-4). The aim of this study was to examine whether the DPP-4 inhibitor anagliptin improves experimental murine colitis. MATERIAL AND METHODS. Male C57BL/6 mice aged 8 weeks were exposed to 1.5% dextran sulfate sodium (DSS) in drinking water for 7 days to induce experimental colitis. Anagliptin (0.1% in diet) was administrated from 2 days before the beginning of DSS to 7 days after the end of DSS. Changes in body weight and disease activity index were evaluated daily. Histological colitis severity, cellular proliferation and gene expression were determined in colonic tissues. RESULTS. Treatment with anagliptin clearly improved body weight loss and disease activity index in the recovery phase. Histological score in the DSS + anagliptin group at day 14 was significantly lower than that in the DSS alone group. Treatment with anagliptin increased the Ki67-positive rate at days 10 and 14, and tended to increase insulin-like growth factor-1 mRNA expression in the DSS + anagliptin group. CONCLUSION. In this model of experimental colitis, the DPP-4 inhibitor anagliptin facilitated the restoration of mucosal damage, thereby resulting in the acceleration of healing. These findings suggest a new and novel therapeutic approach for the treatment of IBD.

Transplantation of neural crest-like cells derived from induced pluripotent stem cells improves diabetic polyneuropathy in mice.

Impaired vascularity and nerve degeneration are the most important pathophysiological abnormalities of diabetic polyneuropathy (DPN). Therefore, regeneration of both the vascular and nervous systems is required for the treatment of DPN. The neural crest (NC) is a transient embryonic structure in vertebrates that differentiates into a vast range of cells, including peripheral neurons, Schwann cells, and vascular smooth muscle cells. In this study, we investigated the ability of transplantation of NC-like (NCL) cells derived from aged mouse induced pluripotent stem (iPS) cells in the treatment of DPN. iPS cells were induced to differentiate into neural cells by stromal cell-derived inducing activity (SDIA) and subsequently supplemented with bone morphogenetic protein 4 to promote differentiation of NC lineage. After the induction, p75 neurotrophin receptor-positive NCL cells were purified using magnetic-activated cell sorting. Sorted NCL cells differentiated to peripheral neurons, glial cells, and smooth muscle cells by additional SDIA. NCL cells were transplanted into hind limb skeletal muscles of 16-week streptozotocin-diabetic mice. Nerve conduction velocity, current perception threshold, intraepidermal nerve fiber density, sensitivity to thermal stimuli, sciatic nerve blood flow, plantar skin blood flow, and capillary number-to-muscle fiber ratio were evaluated. Four weeks after transplantation, the engrafted cells produced growth factors: nerve growth factor, neurotrophin 3, vascular endothelial growth factor, and basic fibroblast growth factor. It was also confirmed that some engrafted cells differentiated into vascular smooth muscle cells or Schwann cell-like cells at each intrinsic site. The transplantation improved the impaired nerve and vascular functions. These results suggest that transplantation of NCL cells derived from iPS cells could have therapeutic effects on DPN through paracrine actions of growth factors and differentiation into Schwann cell-like cells and vascular smooth muscle cells.

Ectopic expression of GIP in pancreatic ß-cells maintains enhanced insulin secretion in mice with complete absence of proglucagon-derived peptides.

Glucagon and glucagon-like peptide-1 (GLP-1) are produced in pancreatic α-cells and enteroendocrine L-cells, respectively, in a tissue-specific manner from the same precursor, proglucagon, that is encoded by glucagon gene (Gcg), and play critical roles in glucose homeostasis. Here, we studied glucose homeostasis and ß-cell function of Gcg-deficient mice that are homozygous for a Gcg-GFP knock-in allele (Gcg(gfp/gfp)). The Gcg(gfp/gfp) mice displayed improved glucose tolerance and enhanced insulin secretion, as assessed by both oral glucose tolerance test (OGTT) and intraperitoneal glucose tolerance test (IPGTT). Responses of glucose-dependent insulinotropic polypeptide (GIP) to both oral and intraperitoneal glucose loads were unexpectedly enhanced in Gcg(gfp/gfp) mice, and immunohistochemistry localized GIP to pancreatic ß-cells of Gcg(gfp/gfp) mice. Furthermore, secretion of GIP in response to glucose was detected in isolated islets of Gcg(gfp/gfp) mice. Blockade of GIP action in vitro and in vivo by cAMP antagonism and genetic deletion of the GIP receptor, respectively, almost completely abrogated enhanced insulin secretion in Gcg(gfp/gfp) mice. These results indicate that ectopic GIP expression in ß-cells maintains insulin secretion in the absence of proglucagon-derived peptides (PGDPs), revealing a novel compensatory mechanism for sustaining incretin hormone action in islets.

Lesion of area postrema attenuated hyperphagic responses to glucoprivation, but not transcriptional activation of the neuropeptide Y gene in rats.

The area postrema (AP) is a circumventricular organ that lacks a blood-brain barrier. Previous studies have shown that the lesion of AP (APX) attenuated hyperphagic responses to glucoprivation. As the orexigenic neuropeptide Y (NPY) neurons have been implicated in the regulation of food intake, we examined whether the activation of NPY neurons by glucoprivation is mediated through the AP as well. In agreement with previous studies, hyperphagic responses to an injection of 2-deoxy-D-glucose that blocks glucose utilization were significantly attenuated in the APX group compared with the sham-operated (Sham) group. However, the expression levels of NPY heteronuclear RNA, a sensitive indicator for the gene transcription, were significantly increased in the arcuate nucleus by a 2-deoxy-D-glucose injection in both the APX and the Sham groups, and there were no significant differences in the values between groups. These data suggest that the hyperphagic response to glucoprivation, but not the activation of NPY gene transcription in the arcuate nucleus, was mediated through the AP in the hindbrain.

Inflammatory changes in adipose tissue enhance expression of GPR84, a medium-chain fatty acid receptor: TNFα enhances GPR84 expression in adipocytes.

In this study we aimed to identify the physiological roles of G protein-coupled receptor 84 (GPR84) in adipose tissue, together with medium-chain fatty acids (MCFAs), the specific ligands for GPR84. In mice, high-fat diet up-regulated GPR84 expression in fat pads. In 3T3-L1 adipocytes, co-culture with a macrophage cell line, RAW264, or TNFα remarkably enhanced GPR84 expression. In the presence of TNFα, MCFAs down-regulated adiponectin mRNA expression in 3T3-L1 adipocytes. Taken together, our results suggest that GPR84 emerges in adipocytes in response to TNFα from infiltrating macrophages and exacerbates the vicious cycle between adiposity and diabesity.

Remodeling of hepatic metabolism and hyperaminoacidemia in mice deficient in proglucagon-derived peptides.

Glucagon is believed to be one of the most important peptides for upregulating blood glucose levels. However, homozygous glucagon-green fluorescent protein (gfp) knock-in mice (Gcg(gfp/gfp): GCGKO) are normoglycemic despite the absence of proglucagon-derived peptides, including glucagon. To characterize metabolism in the GCGKO mice, we analyzed gene expression and metabolome in the liver. The expression of genes encoding rate-limiting enzymes for gluconeogenesis was only marginally altered. On the other hand, genes encoding enzymes involved in conversion of amino acids to metabolites available for the tricarboxylic acid cycle and/or gluconeogenesis showed lower expression in the GCGKO liver. The expression of genes involved in the metabolism of fatty acids and nicotinamide was also altered. Concentrations of the metabolites in the GCGKO liver were altered in manners concordant with alteration in the gene expression patterns, and the plasma concentrations of amino acids were elevated in the GCGKO mice. The insulin concentration in serum and phosphorylation of Akt protein kinase in liver were reduced in GCGKO mice. These results indicated that proglucagon-derived peptides should play important roles in regulating various metabolic pathways, especially that of amino acids. Serum insulin concentration is lowered to compensate the impacts of absent proglucagon-derived peptide on glucose metabolism. On the other hand, impacts on other metabolic pathways are only partially compensated by reduced insulin action.

Ingestion of a moderate high-sucrose diet results in glucose intolerance with reduced liver glucokinase activity and impaired glucagon-like peptide-1 secretion.

UNLABELLED: Aims/Introduction: Excessive intake of sucrose can cause severe health issues, such as diabetes mellitus. In animal studies, consumption of a high-sucrose diet (SUC) has been shown to cause obesity, insulin resistance and glucose intolerance. However, several in vivo experiments have been carried out using diets with much higher sucrose contents (50-70% of the total calories) than are typically ingested by humans. In the present study, we examined the effects of a moderate SUC on glucose metabolism and the underlying mechanism. MATERIALS AND METHODS: C57BL/6J mice received a SUC (38.5% sucrose), a high-starch diet (ST) or a control diet for 5 weeks. We assessed glucose tolerance, incretin secretion and liver glucose metabolism. RESULTS: An oral glucose tolerance test (OGTT) showed that plasma glucose levels in the early phase were significantly higher in SUC-fed mice than in ST-fed or control mice, with no change in plasma insulin levels at any stage. SUC-fed mice showed a significant improvement in insulin sensitivity. Glucagon-like peptide-1 (GLP-1) secretion 15 min after oral glucose administration was significantly lower in SUC-fed mice than in ST-fed or control mice. Hepatic glucokinase (GCK) activity was significantly reduced in SUC-fed mice. During the OGTT, the accumulation of glycogen in the liver was suppressed in SUC-fed mice in a time-dependent manner. CONCLUSIONS: These results indicate that mice that consume a moderate SUC show glucose intolerance with a reduction in hepatic GCK activity and impairment in GLP-1 secretion. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2012.00208.x, 2012).