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Individuals with metabolic syndrome and frank type 2 diabetes are at increased risk of atherosclerotic cardiovascular disease, partially due to the presence of lipid and lipoprotein abnormalities. In these conditions, the liver and intestine overproduce lipoprotein particles, exacerbating the hyperlipidemia of fasting and post-prandial states. Incretin-based, antidiabetes therapies (i.e., glucagon-like peptide [GLP]-1 receptor agonists and dipeptidyl peptidase-4 inhibitors) have proven efficacy for the treatment of hyperglycemia. Evidence is accumulating that these agents also improve fasting and postprandial lipemia, the latter more significantly than the former. In contrast, the gut-derived peptide GLP-2, cosecreted from intestinal L cells with GLP-1, has recently been demonstrated to enhance intestinal lipoprotein release. Understanding the roles of these emerging regulators of intestinal lipoprotein secretion may offer new insights into the regulation of intestinal lipoprotein assembly and secretion and provide new opportunities for devising novel strategies to attenuate hyperlipidemia, with the potential for cardiovascular disease reduction. [ABSTRACT FROM AUTHOR]

There is growing evidence suggesting intestinal insulin resistance and overproduction of apolipoprotein (apo) B48-containing chylomicrons in insulin-resistant states. In the current study, we investigated the potential role of the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) in the development of insulin resistance and aberrant lipoprotein metabolism in the small intestine in a Syrian golden hamster model. TNF-alpha infusion decreased whole-body insulin sensitivity, based on in vivo euglycemic clamp studies in chow-fed hamsters. Analysis of intestinal tissue in TNF-alpha-treated hamsters indicated impaired phosphorylation of insulin receptor-beta, insulin receptor substrate-1, Akt, and Shc and increased phosphorylation of p38, extracellular signal-related kinase-1/2, and Jun NH(2)-terminal kinase. TNF-alpha infusion also increased intestinal production of total apoB48, triglyceride-rich lipoprotein apoB48, and serum triglyceride levels in both fasting and postprandial (fat load) states. The effects of TNF-alpha on plasma apoB48 levels could be blocked by the p38 inhibitor SB203580. Ex vivo experiments using freshly isolated enterocytes also showed TNF-alpha-induced p38 phosphorylation and intestinal apoB48 overproduction, effects that could be blocked by SB203580. Interestingly, TNF-alpha increased the mRNA and protein mass of intestinal microsomal triglyceride transfer protein without altering apoB mRNA levels. Enterocytes were found to have detectable levels of both TNF-alpha receptor types (p55 and p75), and antibodies against either of the two TNF-alpha receptors partially blocked the stimulatory effect of TNF-alpha on apoB48 production and p38 phosphorylation. In summary, these data suggest that intestinal insulin resistance can be induced in hamsters by TNF-alpha infusion, and it is accompanied by intestinal overproduction of apoB48-containing lipoproteins. TNF-alpha-induced stimulation of intestinal lipoprotein production appears to be mediated via TNF-alpha receptors and the p38 mitogen-activated protein kinase pathway. [ABSTRACT FROM AUTHOR]

There is growing evidence suggesting intestinal insulin resistance and overproduction of apolipoprotein (apo) B48-containing chylomicrons in insulin-resistant states. In the current study, we investigated the potential role of the inflammatory cytokine tumor necrosis factor-α (TNF-α) in the development of insulin resistance and aberrant lipoprotein metabolism in the small intestine in a Syrian golden hamster model. TNF-α infusion decreased whole-body insulin sensitivity, based on in vivo euglycemic clamp studies in chow-fed hamsters. Analysis of intestinal tissue in TNF-α-treated hamsters indicated impaired phosphorylation of insulin receptor-β, insulin receptor substrate-1, Akt, and Shc and increased phosphorylation of p38, extracellular signal-related kinase-½, and Jun NH2-terminal kinase. TNF-α infusion also increased intestinal production of total apoB48, triglyceride-rich lipoprotein apoB48, and serum triglyceride levels in both fasting and postprandial (fat load) states. The effects of TNF-α on plasma apoB48 levels could be blocked by the p38 inhibitor SB203580. Ex vivo experiments using freshly isolated enterocytes also showed TNF-a-induced p38 phosphorylation and intestinal apoB48 overproduction, effects that could be blocked by SB203580. Interestingly, TNF-α increased the mRNA and protein mass of intestinal microsomal triglyceride transfer protein without altering apoB mRNA levels. Enterocytes were found to have detectable levels of both TNF-α receptor types (p55 and p75), and antibodies against either of the two TNF-α receptors partially blocked the stimulatory effect of TNF-α on apoB48 production and p38 phosphorylation. In summary, these data suggest that intestinal insulin resistance can be induced in hamsters by TNF-α infusion, and it is accompanied by intestinal overproduction of apoB48-containing lipoproteins. TNF-α-induced stimulation of intestinal lipoprotein production appears to be mediated via TNF-α receptors and the p38 mitogen-activated protein kinase pathway. Diabetes 56: 450-461, 2007 [ABSTRACT FROM AUTHOR]

Glucagon-Like Peptide-½ (GLP-1 and GLP-2) are secreted equimolarly from intestinal enteroendocrine L cells. GLP-1 is insulinotropic while GLP-2 is intestinotropic. Administration of these peptides to humans has been shown to yield opposite effects on plasma triglyceride (TG) levels, although the intestinal contribution in the form of apolipoprotein 1348 (apoB48)-containing lipoproteins to these observations remains unclear. In this study we employed hamsters, which have apoB metabolism similar to humans, to study the effect of the GLPs on postprandial TG-rich lipopoproteins (TRL). Exendin4 (a long-acting GLP-1 receptor agonist), exendin9-39 (a GLP-1 receptor antagonist), hGLP-2[sup (1-33)]), or saline vehicle was injected into conscious male chow-fed or fructose-fed Syrian golden hamsters intraperitoneally in conjunction with an olive oil oral gavage and Triton WR1339 infusion. Blood was sampled to assess apoB48, triglyceride (TG), and cholesterol mass. Following GLP-2 treatment, fatty acid transport protein 4 (FATP4) and fatty acid translocase (FAT)/CD36 protein expression in the jejunum was quantified. In addition, pulse-chase studies were perfomed ex vivo on isolated primary enterocytes. In conjunction with a modest decrease in plasma TG and cholesterol, exendin4 significantly inhibited apoB48 secretion in hamsters by 120 min, while exendin9-39 promoted secretion. Exendin4 yielded no significant difference in apoB48 levels in fructose-fed/insulin resistant hamsters, suggesting that insulin sensitivity was necessary for GLP-1's inhibitory effect. GLP-2 significantly stimulated apoB48 secretion by 60 min. Jejunal expression of CD36 was upregulated with GLP-2 treatment. Ex vivo, exendin4 significantly decreased apoB48 secretion, while increased apoB48 secretion was observed with GLP-2 treatment. GLP-1's inhibitory effect on apoB48 secretion is likely attributable to its insulinotropic effects, while GLP-2 stimulates apoB48-containing lipoprotein secretion possibly through enhanced fat absorption. We postulate that GLPs are critical regulators of intestinal lipid absorption by modulating fatty acid uptake and the assembly and secretion of TRLs from the intestinal enterocytes. [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphatase, non receptor type1 (PTPN1) efficiently dephosphorylates the insulin receptor, and attenuates insulin signaling. Polymorphisms in the coding sequence of PTPN1 have been variably associated with type 2 diabetes (T2D). We hypothesized that variations within PTPN1 promoter might contribute to the genetics T2D and related metabolic traits. Sequence analysis of 2.0 kb of PTPN1 promoter was performed in 174 patients with T2D and 412 control subjects using PCR and denaturing high performance liquid chromatography. Association analysis was performed between diabetes and related waits, and SN-Ps genotypes. Two variants (-1023C>A and -51delA) were functionally tested by measuring their influence on the luciferase activity in HepG2 cells. One common (-1023C>A) and six (-51delA, -451A>G, -467T>C, -1045G>A, -1286-3bp-del and-1291-9bp-del) rare variants were identified in the PTPN1 promoter. The -1023(C) allele had significant association with T2D that disappeared after adjusting for established diabetes risk factors. No significant association was observed between variants of-1023C>A and -51delA with anthropometric and biochemical parameters in non-diabetic and T2D subjects, separately. The -51delA was associated with approximately two-fold decrease in the luciferase gene expression in HepG2 cells, whereas there was no difference in promoter activity between the two alleles of - 1023C>A. In conclusion, the variant -51delA seems to be functional. Both variants (-1023C>A and -51delA) were not associated with T2D and related traits in this study but need to be investigated in a larger population with more statistical power. [ABSTRACT FROM AUTHOR]

We have reported previously that cinnamon extract (CE) prevents high-fructose (HF) feeding-induced whole-body insulin resistance by enhancing insulin signaling in skeletal muscle. In this study, we investigated whether intestinal apolipoprotein overproduction is inhibited by CE in this insulin-resistant animal model. After 2-hour acute CE oral treatment (50mg/kg body weigh), CE significantly inhibited total serum and triglyceride rich lipoprotein (TRL)-apoB48 in fasted HF-fed rats. In an olive oil-loading study, we also found that acute CE oral treatment inhibited the serum triglyceride levels in HF-fed rats but did not affect cholesterol or HDL levels. In a Triton-WR-1339 study, our results indicated that acute CE oral administration inhibited the overproduction of total serum and TRL-apoB48. In ex vivo pulse-chase labeling studies, the significant decreases were also observed in apoB48 secretion into media in freshly isolated enterocytes from HF-fed hamsters, together with increased apoB degradation. CE decreased the phosphorylation of p38 and ERK in normal hamster primary enterocytes, and increased the impaired phosphorylation of p38 and ERK in HF-fed hamster enterocytes. CE also decreased the protein mass of intestinal microsomal triglyceride Wansfer protein (MTP) in CE treated HF-hamster enterocytes. In summary, these data suggest that the overproduction of apoB48 can be acutely inhibited by CE treatment in a process involving p38, ERK phosphorylation and MTP expression. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-2 (GLP2) is a 33 amino acid peptide encoded by the proglucagon gene that is co-secreted with GLP-1 by intestinal L cells following nutrient intake. GIP, GLP-1 and GLP-2 are substrates for DPP-4, and plasma levels of these hormones are enhanced by DPP-4 inhibition. Furthermore, DPP-4 inhibition is associated with reduction in levels of postprandial intestinal triglyceride-rich lipoproteins in human subjects with T2DM although the mechanisms for these observations remain unclear. We have now assessed the pharmacological vs. physiological actions of GLP-2 on nutrient absorption and lipid profiles in wild type and Glp2r-/- mice with a targeted disruption of the endogenous Glp2 receptor gene. Following an oral gavage of olive oil, wildtype mice were injected with triton WR1339 to inhibit lipoprotein clearance, with or without a single dose of h[Gly2]-GLP-2, a DPP-4-resistant GLP-2 analogue. GLP-2 administration significantly increased levels of plasma triglycerides and ApoB48 by 50% and doubled triglyceride and ApoB48 levels in the chylomicron fraction of wildtype mice. Similarly, exogenous GLP-2 increased triglyceride levels in the VLDL/chylomicron remnant fraction after an olive oil load when lipoprotein clearance was not inhibited by triton injection. However, no difference was observed in triglyceride levels in total plasma or chylomicron fraction between wildtype and Glp2r -/- mice after an acute fat load. Furthermore glucose absorption and clearance, assessed by oral glucose tolerance test (OGTT), was not different between wildtype and Glp2r-/- mice. After 5 months of high fat feeding (45% calories from fat), Glp2r -/- mice and littermate controls gained body weight and accumulated body fat to the same extent, and no differences in glucose, triglyceride and cholesterol absorption were detected in Glp2r-/- vs. Glp2r+/+ mice. In contrast, histological analysis of sections from the intestinal mucosa of jejunum and colon from high fat fed mice revealed reduced crypt depth and villus height in G1p2r -/- mice compared to wildtype littermate controls. These findings demonstrate that although GLP-2 acutely stimulate glucose and triglyceride absorption, endogenous GLP2-R signaling is essential for the structural but not functional adaptation to enteral nutrient excess. [ABSTRACT FROM AUTHOR]

Mechanisms underlying hepatic overproduction of apolipoprotein B (apoB) 100-containing very low density lipoprotein (VLDL) in insulin resistance induced by tumor necrosis factor (TNF)-α were investigated. In the present study, we examined the potential role of TNF-α in insulin signaling and lipoprotein metabolism in the liver of Syrian golden hamster. In vivo TNF-α infusion induced whole-body insulin resistance in chow-fed hamsters. Analysis of liver in TNF-α-treated hamsters indicated decreased phosphorylation of insulin receptor (IR)-β IR substrate (IRS)-1 (Tyr), Akt (ser[sup 473]), p38, ERK1/2 and JNK, but increased phosphorylation of ser[sup 307]IRS-1 and Shc. TNF-α infusion also significantly increased hepatic production of total serum and VLDL-apoB100 in both fasting and postprandial (fat load) states. Ex vivo experiments, using cultured primary hepatocytes from hamsters also showed TNFα-induced VLDL-apoB 100 oversecretion, an effect that was blocked by TNF receptor 2 antibody. Moreover, TNF-α decreased the sterol regulatory element binding protein-1c mRNA and increased microsomal triglyceride transfer protein mRNA without altering apoB mRNA levels in primary heaptocytes. In summary, we provide direct evidence that TNF-α impairs hepatic insulin signaling in hamsters accompanied by hepatic overproduction of apoB100-containing VLDL particles, affect likely mediated via TNF receptor 2. [ABSTRACT FROM AUTHOR]