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When glucose–fructose dimers are supplied as the slowly digestible, completely absorbable, low glycemic index (GI) sugar isomaltulose, the detrimental effects of high GI sucrose are avoided. This difference requires the presence of intact glucose-induced insulinotropic peptide receptor (GIPR) and is mediated by the rapid uptake of glucose and the stimulation of GIP release from K cells in the upper small intestine. GIP promotes lipogenesis, fatty liver, insulin resistance, and postprandial inflammation, and reduces fat oxidation in skeletal muscle, partly by hypothalamic interference with energy partitioning and epigenetic programming. GIP is similarly required for the detrimental metabolic effects of other high GI carbohydrates. We therefore propose that the release of GIP in the upper small intestine is an important determinant of the metabolic quality of carbohydrates. [ABSTRACT FROM AUTHOR]

Maternal obesity is a worldwide problem associated with increased risk of metabolic diseases in the offspring. Genetic deletion of the gastric inhibitory polypeptide (GIP) receptor (GIPR) prevents high-fat diet (HFD)-induced obesity in mice due to specific changes in energy and fat cell metabolism. We investigated whether GIP-associated pathways may be targeted by fetal programming and mimicked the situation by exposing pregnant mice to control or HFD during pregnancy (intrauterine [IU]) and lactation (L). Male wild-type (WT) and Gipr(-/-) offspring received control chow until 25 weeks of age followed by 20 weeks of HFD. Gipr(-/-) offspring of mice exposed to HFD during IU/L became insulin resistant and obese and exhibited increased adipose tissue inflammation and decreased peripheral tissue substrate utilization after being reintroduced to HFD, similar to WT mice on regular chow during IU/L. They showed decreased hypothalamic insulin sensitivity compared with Gipr(-/-) mice on control diet during IU/L. DNA methylation analysis revealed increased methylation of CpG dinucleotides and differential transcription factor binding of promoter regions of genes involved in lipid oxidation in the muscle of Gipr(-/-) offspring on HFD during IU/L, which were inversely correlated with gene expression levels. Our data identify GIP-regulated metabolic pathways that are targeted by fetal programming. [ABSTRACT FROM AUTHOR]

The product of hexokinase (HK) enzymes, glucose-6-phosphate, can be metabolized through glycolysis or directed to alternative metabolic routes, such as the pentose phosphate pathway (PPP) to generate anabolic intermediates. HK1 contains an N-terminal mitochondrial binding domain (MBD), but its physiologic significance remains unclear. To elucidate the effect of HK1 mitochondrial dissociation on cellular metabolism, we generated mice lacking the HK1 MBD (ΔE1HK1). These mice produced a hyper-inflammatory response when challenged with lipopolysaccharide. Additionally, there was decreased glucose flux below the level of GAPDH and increased upstream flux through the PPP. The glycolytic block below GAPDH is mediated by the binding of cytosolic HK1 with S100A8/A9, resulting in GAPDH nitrosylation through iNOS. Additionally, human and mouse macrophages from conditions of low-grade inflammation, such as aging and diabetes, displayed increased cytosolic HK1 and reduced GAPDH activity. Our data indicate that HK1 mitochondrial binding alters glucose metabolism through regulation of GAPDH. [Display omitted] • HK1 mitochondrial dissociation results in GAPDH inhibition and increased PPP • Cytosolic HK1 increases macrophage-mediated inflammatory cytokine production • HK1 associates with S100A8/A9 and attenuates GAPDH activity through nitrosylation • Diabetic and aging immune cells show cytosolic HK1 and reduced GAPDH activity De Jesus et al. describe how HK1 subcellular localization regulates the metabolic fate of its substrate, G6P, between catabolic and anabolic metabolism through inhibition of GAPDH. Immune cells from models of aging and diabetes show higher levels of cytosolic HK1 and increased inflammation. [ABSTRACT FROM AUTHOR]

• Metabolic responses upon feeding a HFD in Gipr-/- mice show a sexual dimorphism. • Female Gipr-/- mice are more protected from diet induced obesity than males. • This protection is preserved when a HFD is fed during fetal development. Obesity has a multifactorial origin. It is known that alterations of the intra uterine milieu induce developmental programming effects leading to metabolic diseases in offspring. Obesity is diminished in mice lacking the glucose-dependent insulinotropic polypeptide receptor (Gipr-/-) when exposed to a high fat diet (HFD). We investigated whether Gipr-/- mice are still protected from obesity when additionally exposure to a HFD during pregnancy and lactation occurs. Male and female wild type (WT) and Gipr-/- offspring received either a control/ low fat diet or HFD during pregnancy and lactation and were then either left on this diet or placed on the opposite diet after weaning until 24 weeks of life. Female WT mice showed increased body weight and adiposity when exposed to a HFD during pregnancy and lactation and post-weaning compared to female WT that received the HFD after weaning only. This exacerbated effect of a HFD during pregnancy and lactation was abolished in female Gipr-/- mice. Male Gipr-/- mice were protected from obesity to a much lesser extent. Male Gipr-/- mice exposed to a HFD during pregnancy and lactation and after weaning exhibited significantly increased fed serum glucose compared to Gipr-/- mice exposed to a HFD after weaning only. In female Gipr-/- mice no differences in fed blood glucose were observed between these groups. Our data indicate that female Gipr-/- mice are more protected from obesity. This protection is preserved in female Gipr-/- mice when additional deleterious effects of a HFD occur during fetal development. [ABSTRACT FROM AUTHOR]

• The induction of fatty liver and insulin resistance by sucrose requires GIP receptors and is prevented by the similarly composed but distally absorbed glucose-fructose dimer, isomaltulose, which releases little GIP but much GLP-1. • Hepatic insulin clearance is improved in humans by isomaltulose as compared to sucrose which correlates with a reduced GIP and increased GLP-1 response. • The most likely mechanism is a regulation of hepatic perfusion by GIP which was shown previously in fluoro-deoxy-glucose (FDG)-PET-Scans in humans as well as by GIP-receptors in the portal vein and hepatic arteries. • We therefore propose that GIP regulates hepatic insulin extraction and action. GIP was proposed to play a key role in the development of non- alcoholic fatty liver disease (NAFLD) in response to sugar intake. Isomaltulose, is a 1,6-linked glucose-fructose dimer which improves glucose homeostasis and prevents NAFLD compared to 1,2-linked sucrose by reducing glucose-dependent insulinotropic peptide (GIP) in mice. We compared effects of sucrose vs. isomaltulose on GIP and glucagon-like peptide-1 (GLP-1) secretion, hepatic insulin clearance (HIC) and insulin sensitivity in normal (NGT), impaired glucose tolerant (IGT) and Type 2 diabetes mellitus (T2DM) participants. A randomized crossover study was performed in 15 NGT, 10 IGT and 10 T2DM subjects. In comparison to sucrose, peak glucose concentrations were reduced by 2.3, 2.1 and 2.5 mmol/l (all p < 0.05) and insulin levels were 88% (p < 0.01, NGT), 32% (p < 0.05, IGT) and 55% (T2DM) lower after the isomaltulose load. Postprandial GIP iAUC concentrations were decreased (56%, p < 0.01 in NGT; 42%, p < 0.05 in IGT and 40%,p < 0.001 in T2DM) whereas GLP-1 iAUC was 77%, 85% and 85% higher compared to sucrose (p < 0.01), respectively. This resulted in ∼35 - 50% improved insulin sensitivity and reduced insulinogenic index after isomaltulose, which correlated closely with improved HIC, respectively (r = 0.62, r=-0.70; p < 0.001). HIC was inversely related to GIP (r=-0.44, p < 0.001) and positively related to GLP-1 levels (r = 0.40, p = 0.001). Endogenously released GIP correlated with reduced, and GLP-1 with increased hepatic insulin extraction. Increased peripheral insulin levels may contribute to insulin resistance and obesity. We propose that the unfavorable effects of high glycemic index Western diets are related to increased GIP-release and reduced HIC. [ABSTRACT FROM AUTHOR]

The article discusses the randomized within-subject crossover study on the impact of palatinose and sucrose intake on type two diabetics' glucose metabolism and incretin secretion. The study reportedly involved older men and women who received palatinose were asked to fast for several nights and undergo a washout period. The results revealed that palatinose intake lowers postprandial endogenous glucagon-like peptide levels.

WISP1 (Wnt1-inducible signaling pathway protein-1, also known as CCN4) is a member of the secreted extracellular matrix-associated proteins of the CCN family and a target gene of the Wingless-type (WNT) signaling pathway. Growing evidence links the WNT signaling pathway to the regulation of adipogenesis and low-grade inflammation in obesity. We aimed to validate WISP1 as a novel adipokine. Human adipocyte differentiation was associated with increased WISP1 expression and secretion. Stimulation of human macrophages with WISP1 led to a proinflammatory response. Circulating WISP1 and WISP1 subcutaneous adipose tissue expression were regulated by weight changes in humans and mice. WISP1 expression in visceral and subcutaneous fat tissue was associated with markers of insulin resistance and inflammation in glucose-tolerant subjects. In patients with nonalcoholic fatty liver disease, we found no correlation among disease activity score, liver fat content, and WISP1 expression. Insulin regulated WISP1 expression in adipocytes in vitro but had no acute effect on WISP1 gene expression in subcutaneous fat tissue in overweight subjects who had undergone hyperinsulinemic clamp experiments. The data suggest that WISP1 may play a role in linking obesity to inflammation and insulin resistance and could be a novel therapeutic target for obesity. [ABSTRACT FROM AUTHOR]