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Glucose intolerance in type 2 diabetes is related to enhanced hepatic glucose production (HGP) due to the increased expression of hepatic gluconeogenic enzymes. Previously, we revealed that hepatic STAT3 decreases the expression of hepatic gluconeogenic enzymes and suppresses HGP. Here, we show that increased plasma histidine results in hepatic STAT3 activation. Intravenous and intracerebroventricular (ICV) administration of histidine-activated hepatic STAT3 reduced G6Pase protein and mRNA levels and augmented HGP suppression by insulin. This suppression of hepatic gluconeogenesis by histidine was abolished by hepatic STAT3 deficiency or hepatic Kupffer cell depletion. Inhibition of HGP by histidine was also blocked by ICV administration of a histamine [H.sub.1] receptor antagonist. Therefore, histidine activates hepatic STAT3 and suppresses HGP via central histamine action. Hepatic STAT3 phosphorylation after histidine ICV administration was attenuated in histamine [H.sub.1] receptor knockout (Hrh1KO) mice but not in neuron-specific insulin receptor knockout (NIRKO) mice. Conversely, hepatic STAT3 phosphorylation after insulin ICV administration was attenuated in NIRKO but not in Hrh1KO mice. These findings suggest that central histidine action is independent of central insulin action, while both have additive effects on HGP suppression. Our results indicate that central histidine/histamine-mediated suppression of HGP is a potential target for the treatment of type 2 diabetes., Increased glucose production in type 2 diabetes is caused by elevated gluconeogenesis in the liver (1), while in actual clinical settings, treatment for diabetes includes remedies, such as metformin, that [...]

Chronic inflammation in adipose tissue contributes to obesity-related insulin resistance. The 3-phosphoinositide-dependent protein kinase 1 (Pdk1)/forkhead transcription factor (Foxo1) pathway is important in regulating glucose and energy homeostasis, but little is known about this pathway in adipose tissue macrophages (ATMs). To investigate this, we generated transgenic mice that carried macrophage/granulocyte-specific mutations, including a Pdk1 knockout ([LysMPdk1.sup.-/-]), a Pdk1 knockout with transactivation-defective Foxo1 (Δ256[LysMPdk1.sup.-/-]), a constitutively active nuclear (CN) Foxo1 (CN[Foxo1.sup.LysM]), or a transactivation-defective Foxo1 (Δ256[Foxo1.sup.LysM]). We analyzed glucose metabolism and gene expression in ATM populations isolated with fluorescence-activated cell sorting. The [LysMPdk1.sup.-/-] mice exhibited elevated M1 macrophages in adipose tissue and insulin resistance. Overexpression of transactivation-defective Foxo1 rescued these phenotypes. CN[Foxo1.sup.LysM] promoted transcription of the C-C motif chemokine receptor 2 (Ccr2) in ATMs and increased M1 macrophages in adipose tissue. On a high-fat diet, CN[Foxo1.sup.LysM] mice exhibited insulin resistance. Pdk1 deletion or Foxo1 activation in bone marrow-derived macrophages abolished insulin and interleukin-4 induction of genes involved in alternative macrophage activation. Thus, Pdk1 regulated macrophage infiltration by inhibiting Foxo1-induced Ccr2 expression. This shows that the macrophage Pdk1/Foxo1 pathway is important in regulating insulin sensitivity in vivo. Diabetes 61:1935-1948, 2012, Obesity is a predisposing factor for the development of type 2 diabetes, hypertension, hyperlipidemia, and atherosclerosis (1). Chronic activation of intracellular proinflammatory pathways in adipose tissue contributes to obesity-related insulin [...]

In the liver, signal transducer and activator of transcription 3 (STAT3) plays an important role in the suppression of gluconeogenic enzyme expression. While obesity-associated endoplasmic reticulum (ER) stress has been shown to increase hepatic gluconeogenic enzyme expression, the role of ER stress in STAT3-dependent regulation of such expression is unclear. The current study aimed to elucidate the effect of ER stress on the STAT3-dependent regulation of hepatic gluconeogenic enzyme expression. Genetically obese/diabetic db/db mice and db/db mouse-derived isolated hepatocytes were used as ER stress models. A tyrosine phosphatase inhibitor, a deacetylation inhibitor, and an acetylated mutant of STAT3 were used to examine the effect of ER stress on hepatic STAT3 action. ER stress inhibited STAT3-dependent suppression of gluconeogenic enzyme gene expression by suppressing hepatic Janus kinase (JAK)2 and STAT3 phosphorylation. A tyrosine phosphatase inhibitor restored ER stress-induced suppression of JAK2 phosphorylation but exhibited no improving effect on suppressed STAT3 phosphorylation. STAT3 acetylation is known to correlate with its phosphorylation. ER stress also decreased STAT3 acetylation. An acetylated mutant of STAT3 was resistant to ER stress-induced inhibition of STAT3-phosphorylation and STAT3-dependent suppression of hepatic gluconeogenic enzyme gene expression in vitro and in vivo. Trichostatin A, a histone deacetylase (HDAC) inhibitor, ameliorated ER stress-induced inhibition of STAT3 acetylation and phosphorylation. The current study revealed that ER stress inhibits STAT3-dependent suppression of hepatic gluconeogenic enzymes via JAK2 dephosphorylation and HDAC-dependent STAT3 deacetylation, playing an important role in the increase of hepatic glucose production in obesity and diabetes. Diabetes 61:61-73, 2012, Increased hepatic glucose production in diabetes has widely been attributed to increased hepatic gluconeogenesis (1), and transcriptional regulation of the expression of gluconeogenic enzymes, such as G6pc and Pckl, coding [...]

OBJECTIVE--An increase in the rate of gluconeogenesis is largely responsible for the hyperglycemia in individuals with type 2 diabetes, with the antidiabetes action of metformin being thought to be achieved at least in part through suppression of gluconeogenesis. RESEARCH DESIGN AND METHODS--We investigated whether the transcription factor KLF15 has a role in the regulation of gluconeogenesis and whether KLF15 participates in the antidiabetes effect of metformin. RESULTS--Here we show that KLF15 regulates the expression of genes for gluconeogenic or amino acid-degrading enzymes in coordination with the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1α. Liver-specific ablation of KLF15 in diabetic mice resulted in downregulation of the expression of genes for gluconeogenic or amino acid catabolic enzymes and in amelioration of hyperglycemia. Exposure of cultured hepatocytes to metformin reduced the abundance of KLF15 through acceleration of its degradation and downregulation of its mRNA. Metformin suppressed the expression of genes for gluconeogenic or amino acid-degrading enzymes in cultured hepatocytes, and these effects of metformin were attenuated by restoration of KLF15 expression. Administration of metformin to mice inhibited both the expression of KLFI5 and glucose production in the liver, the latter effect also being attenuated by restoration of hepatic KLF15 expression. CONCLUSIONS--KLF15 plays an important role in regulation of the expression of genes for gluconeogenic and amino acid-degrading enzymes and that the inhibitory effect of metformin on glueoneogenesis is mediated at least in part by down-regulation of KLF15 and consequent attenuation of the expression of such genes. Diabetes 59:1608-1615, 2010, An increase in the rate of gluconeogenesis is one of the most important pathological disorders in individuals with diabetes. Regulation of gluconeogenesis in the liver is thought to be achieved [...]

OBJECTIVE--Resistin is an adipocyte-secreted cytokine associated with insulin resistance in mice. We previously reported that the G/G genotype of a resistin single nucleotide polymorphism (SNP) at -420 increases type 2 [...]

Phosphoinositide-dependent kinase-1 (PDK1) is implicated in the metabolic effects of insulin as a key mediator of phosphoinositide 3-kinase-dependent signaling. Here we show that mice with liver-specific PDK1 deficiency manifest various defects in the metabolic actions of insulin in the liver as well as a type 2 diabetes-like phenotype characterized by marked hyperinsulinemia and postprandial hyperglycemia. The hepatic abundance of glucokinase, an important determinant of glucose flux and glucose-evoked signaling in hepatocytes, was substantially reduced in these mice. Restoration of hepatic glucokinase expression, with the use of an adenoviral vector, induced insulin-like effects in the liver and almost completely normalized the fasting hyperinsulinemia and postprandial hyperglycemia in these animals. These results indicate that, if the hepatic abundance of glucokinase is maintained, ingested glucose is normally disposed of even in the absence of acute activation of proximal insulin signaling, such as the activation of Akt, in the liver., The liver is one of the most important target organs of insulin and thus plays an essential role in nutrient metabolism (1,2). Such effects of insulin in the liver are [...]

Because impaired insulin secretion is characteristic of type 2 diabetes in Asians, including Japanese, the genes involved in pancreatic β-cell function are candidate susceptibility genes for type 2 diabetes. We examined the association of variants in genes encoding several transcription factors (TCF1, TCF2, HNF4A, ISL1, IPF1, NEUROG3, PAX6, NKX2-2, NKX6-1, and NEUROD1) and genes encoding the ATP-sensitive [K.sup.+] channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) with type 2 diabetes in a Japanese cohort of 2,834 subjects. The exon 16 -3c/t variant rs1799854 in ABCC8 showed a significant association (P = 0.0073), and variants in several genes showed nominally significant associations (P < 0.05) with type 2 diabetes. Although the E23K variant rs5219 in KCNJ11 showed no association with diabetes in Japanese (for the K allele, odds ratio [OR] 1.08 [95% CI 0.97-1.21], P = 0.15), 95% CI around the OR overlaps in meta-analysis of European populations, suggesting that our results are not inconsistent with the previous studies. This is the largest association study so far conducted on these genes in Japanese and provides valuable information for comparison with other ethnic groups. Diabetes 55:2379-2386, 2006, Impaired insulin secretion and insulin resistance both contribute to the pathogenesis of type 2 diabetes. The former is a characteristic feature of type 2 diabetes, especially in Asians including Japanese [...]

AMP-activated protein kinase (AMPK) acts as a fuel gauge for glucose and lipid metabolism. The gene encoding the α2 isoform of the catalytic subunit of AMPK (PRKAA2) is located at [...]

OBJECTIVE -- 3-Deoxyglucosone (3-DG), a highly reactive intermediate of the glycation reaction, has been suggested to contribute to the development of diabetes complications. To verify this hypothesis, we assessed the [...]

Peroxisome proliferator-activated receptor (PPAR)-γ plays an important role in adipogenesis. However, the functions of PPAR-γ in differentiated adipocytes have remained unclear. The role of PPAR-γ in mature 3T3-L1 adipocytes was therefore investigated by overexpression of a dominant negative mutant of this protein (PPAR-γ-ΔC) that lacks the 16 COOH-terminal amino acids and that has been shown to prevent the thiazolidinedione-induced differentiation of 3T3-L1 cells into adipocytes. Overexpression of PPAR-γ-ΔC in mature 3T3-L1 adipocytes by adenovirus gene transfer resulted in a decrease in both cell size and intracellular triglyceride content, an increase in the extent of lipolysis, and a reduction in the rate of free fatty acid uptake. Furthermore, overexpression of this mutant reduced the abundance of mRNAs for several key enzymes that contribute to triglyceride and free fatty acid metabolism as well as the amounts of GLUT4, insulin receptor, insulin receptor substrate (IRS), and C/EBPα mRNAs. It also reduced both the concentration of IRS2 and the insulin-stimulated glucose uptake. These results suggest that PPAR-γ plays an important role in mature 3T3-L1 adipocytes at least in part by maintaining the expression of genes that confer the characteristics of mature adipocytes., Peroxisome proliferator-activated receptors (PPARs) constitute a subfamily of nuclear hormone receptors, the transcriptional activities of which are regulated by interaction with the corresponding ligand (1). Among PPARs, the expression of [...]

The mechanism by which insulin induces the expression of the sterol regulatory element binding protein 1c (SREBP-1c) and glucokinase genes was investigated in cultured rat hepatocytes. Overexpression of an N[H.sub.2]-terminal fragment of IRS-1 that contains the pleckstrin homology and phosphotyrosine binding domains (insulin receptor substrate-1 N[H.sub.2]-terminal fragment [IRS-1N]) inhibited insulin-induced tyrosine phosphorylation of IRS-1 as well as the association of IRS-1 with phosphatidylinositol (PI) 3-kinase activity, whereas the tyrosine phosphorylation of IRS-2 and its association with PI 3-kinase activity were slightly enhanced. The equivalent fragment of IRS-2 (IRS-2N) prevented insulin-induced tyrosine phosphorylation of both IRS-1 and IRS-2, although that of IRS-1 was inhibited more efficiently. The insulin-induced increases in the abundance of SREBP-1c and glucokinase mRNAs, both of which were sensitive to a dominant-negative mutant of PI 3-kinase, were blocked in cells in which the insulin-induced tyrosine phosphorylation of IRS-1 was inhibited by IRS-1N or IRS-2N. A dominant-negative mutant of Akt enhanced insulin-induced tyrosine phosphorylation of IRS-1 (but not that of IRS-2) and its association with PI 3-kinase activity, suggesting that Akt contributes to negative feedback regulation of IRS-1. The Akt mutant also promoted the effects of insulin on the accumulation of SREBP-1c and glucokinase mRNAs. These results suggest that the IRS-1--PI 3-kinase pathway is essential for insulin-induced expression of SREBP-1c and glucokinase genes. Diabetes 51:1672-1680, 2002, Impairment of the mechanism by which insulin reduces the blood concentration of glucose is an important feature of type 2 diabetes (1). However, the pathogenesis of such insulin resistance and [...]

Apoptosis via Fas/Fas ligand (FasL) interactions has been proposed to be a major T-cell-mediated effector mechanism in autoimmune diabetes. To elucidate the role of Fas/FasL interactions in NOD diabetes, the [...]

Neuropeptide Y (NPY), one of the most abundant peptide transmitters in the mammalian brain, is assumed to play an important role in feeding and body weight regulation. However, there is [...]

The allele frequencies for a [Pro.sup.12] → Ala substitution in peroxisome proliferator--activated receptor-γ differ among ethnic groups, and its relationship with diabetes and associated diseases is controversial. The prevalence of [...]

The mouse obese (ob) gene has recently been isolated through the positional cloning technique and has been proved to result in the obese and NIDDM phenotype in mice when mutated [...]

Intercellular adhesion molecule 1 (ICAM-1) plays an important role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM) by being involved in the extravasation of lymphocytes from the circulation into the [...]

The insulin receptors from erythrocytes of 50 patients with non-insulin-dependent diabetes mellitus were tested for their ability to autophosphorylate. The assay was performed by a new enzyme-linked immunosorbent assay system [...]

Extreme insulin resistance occurs in patients with primary defects in insulin action at the receptor or postreceptor levels. The condition commonly is associated with acanthosis nigricans and ovarian masculinization. Despite [...]

Lipoatrophic diabetes is a rare disease characterized by generalized lipodystrophy, severe insulin resistance, hyperlipidemia, hepatomegaly, and a lack of ketoacidosis (1). In this disease, a high incidence of parental consanguinity [...]

A corpus of evidence suggests that T-helper type 1 (Th1)-dependent cellular immunity plays a pivotal role in the pathogenesis of autoimmune diabetes. This study was intended to find ways to [...]

Relevance to the Formation of Advanced Glycation End Products Formation of advanced glycation end products (AGEs) is accelerated in diabetic subjects along with hyperglycemia. Although several lines of evidence indicate [...]

Skeletal muscles play a pivotal role in glucose homeostasis. Glycogen metabolism is one of the processes that plays an important role in maintenance of blood glucose level. Although a key [...]

NOD mice, which bear Fas mutant gene, have recently been reported to show neither insulitis nor diabetes. However, the exact role of Fas/Fas-L in the autoimmune diabetes remains unknown. To [...]

It has been suggested that cyclic nucleotide phosphodiesterase 3B (PDE3B) plays an important role in insulin-induced anti-lipolysis by reducing cellular concentration of cAMP, which in tern attenuates the activity of [...]

Insulin autoimmune syndrome, a relatively rare cause of hypoglycemia, is characterized by the production of autoantibodies to insulin in individuals who have not previously been injected with this hormone (1). [...]