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Abnormally elevated blood triacylglycerol (TAG) level in the postprandial period is a feature of metabolic syndrome (MetS) and is predictive of an increased risk of cardiovascular disease (1-3). Hypertriglyceridemia is [...], The aim was to determine whether fed VLDL and chylomicron (CM) triacylglycerol (TAG) production rates are elevated in metabolic syndrome (MetS). Eight men with MetS (BMI 29.7 ± 1.1) and eight lean age-matched healthy men (BMI 23.1 ± 0.4) were studied using a frequent feeding protocol. After 4 h of feeding, an intravenous bolus of ²[H.sub.5]-glycerol was administered to label VLDL1, VLDL2, and TAG. [sup.13]C-glycerol tripalmitin was administered orally as an independent measure of CM TAG metabolism. Hepatic and intestinal lipoproteins were separated by an immunoaffinity method. In MetS, fed TAG and the increment in TAG from fasting to feeding were higher (P = 0.03 and P = 0.04, respectively) than in lean men. Fed CM, VLDL1, and VLDL2 TAG pool sizes were higher (P = 0.006, P = 0.03, and P < 0.02, respectively), and CM, VLDL1, and VLDL2 TAG production rates were higher (P < 0.002, P < 0.05, and P = 0.06, respectively) than in lean men. VLDL1, VLDL2, and CM TAG clearance rates were not different between groups. In conclusion, prandial hypertriglyceridemia in men with MetS was due to an increased production rate of both VLDL and CM TAG. Since both groups received identical meals, this suggests that in MetS the intestine is synthesizing more TAG de novo for export in CMs.

OBJECTIVE--Insulin detemir lacks the usual propensity for insulin to cause weight gain. We investigated whether this effect was a result of reduced energy intake and/or increased energy expenditure. RESEARCH DESIGN [...]

IGF-I enhances insulin in sensitivity subjects with and without diabetes (1,2), and administration of physiological doses of recombinant human IGF-I (rhIGF-I) improves glycemic control in young subjects with type 1 [...], Recombinant human IGF-I (rhIGF-I) complexed with its natural binding protein IGF-binding protein (IGFBP)-3 (rhIGF-I/IGFBP-3) is a novel formulation that has been shown to improve insulin sensitivity in type 1 diabetes, yet the mechanisms are not clear. We used stable isotopes to investigate the effects of rhIGF-I/IGFBP-3 on glucose and glycerol metabolism in type 1 diabetes. Fifteen subjects (age 13-24 years; 10 males) were studied on three occasions in random order. Each study period lasted for two days, and an injection of either placebo or rhIGF-I/IGFBP-3 (0.1-0.8 mg * [kg.sup.-1] * [day.sup.-1]) was given subcutaneously at 6:00 P.M. on days 1 and 2. Following the second injection, the subjects were kept euglycemic overnight by a variable rate insulin infusion, followed by a 4-h, two-step (insulin 0.6 and 1.5 mU * [kg.sup.-1] * [min.sup.-1]) hyperinsulinemic-euglycemic clamp. During the overnight basal steady state, rhIGF-I/ IGFBP-3 dose-dependently reduced endogenous glucose production rate ([R.sub.a]) (P = 0.004), while peripheral glucose uptake ([R.sub.d]) was not different from placebo. The increase in glucose [R.sub.d] during hyperinsulinemic clamp was greater following rhIGF-I/IGFBP-3 than placebo, both during the first (P = 0.008) and second step (P = 0.008) of the clamp. No significant differences were found in glycerol [R.sub.a], a measure of lipolysis, between rhIGF-I/IGFBP-3 and placebo. In conclusion, rhIGF-I/IGFBP-3 enhances glucose metabolism by controlling both endogenous glucose output and peripheral glucose uptake.

Heterozygous mutations in hepatocyte nuclear factor (HNF)-1[alpha] and -1[beta] can cause maturity-onset diabetes of the young (MODY) (1,2). HNF-1[alpha] and -1[beta] are homeodomain-containing transcription factors that share >90% sequence homology [...], Heterozygous mutations in the transcription factors hepatocyte nuclear factor (HNF)-1[alpha] and -1[beta] result in MODY (maturity-onset diabetes of the young). Despite structural similarity between HNF-1[alpha] and -1[beta], HNF-1[beta] mutation carriers have hyperinsulinemia, whereas HNF-1[alpha] mutation carriers have normal or reduced insulin concentrations. We examined whether HNF-1[beta] mutation carriers are insulin resistant. The endogenous glucose production rate and rate of glucose uptake were measured with a two-step, low-dose (0.3 mU x [kg.sup.-1] x [min.sup.-1]) and high-dose (1.5 mU x [kg.sup.-1] x [min.sup.-1]) hyperinsulinemic-euglycemic clamp, with an infusion of [6,6-[sup.2][H.sub.2]]glucose, in six subjects with HNF-1[alpha] mutations, six subjects with HNF-1[beta] mutations, and six control subjects, matched for age, sex, and BMI. Endogenous glucose production rate was not suppressed by low-dose insulin in HNF-1[beta] subjects but was suppressed by 89% in HNF-1[alpha] subjects (P = 0.004) and 80% in control subjects (P < 0.001). Insulin-stimulated glucose uptake and suppression of lipolysis were similar in all groups at low- and high-dose insulin. Subjects with HNF-1[beta] mutations have reduced insulin sensitivity of endogenous glucose production but normal peripheral insulin sensitivity. This is likely to reflect reduced action of HNF-1[beta] in the liver and possibly the kidney. This may be mediated through regulation by HNF-1[beta] of the key gluconeogenic enzymes glucose-6-phosphatase or PEPCK.

Studies with a covalently linked thyroxyl-insulin complex in humans OBJECTIVE -- To test whether a thyroxyl-insulin analog with restricted access to receptor sites in peripheral tissues displays relative hepatoselectivity in [...]

Glucagon-like peptide-1 (GLP-1) agonists control postprandial glucose and lipid excursion in type 2 diabetes; however, the mechanisms are unclear.

Prandial Hypertriglyceridemia in Metabolic Syndrome Is Due to an Overproduction of Both Chylomicron and VLDL Triacylglycerol. Diabetes 2013;62:4063-4069 DOI: 10.2337/db14-er02a In the Acknowledgments of the article listed above, the number [...]

Background Antiretroviral (ARV) treatment has been associated with abnormalities in lipid and mitochondrial metabolism. We compared patterns of gene expression in the subcutaneous adipose tissue (SAT) of HIV-positive subjects before and after 18–24 months of ARV therapy with HIV-negative controls.Methods HIV patients naive to ARV were randomized to receive zidovudine (AZT), lamivudine (3TC) with efavirenz (EFV) or tenofovir disoproxil fumarate (TDF) with emtricitabine (FTC) and EFV. Healthy controls (n=15) were matched for age, ethnicity and gender. Patients on a regimen containing abacavir (ABC), 3TC and EFV for 18–24 months were also tested. Genes involved in adipocyte glucocorticoid, lipid and mitochondrial metabolism, and adipocyte differentiation, were profiled with real-time PCR.Results AZT led to increased visceral adipose tissue (VAT; P=0.012) and VAT:SAT ratio (P=0.036), whereas TDF increased SAT (P=0.047) and peripheral fat/ lean body mass ratio (P=0.017). HIV treatment-naive patients had lower plasma lipoprotein lipase (LPL) activity (P=0.0001) versus controls (remaining below controls after ARV; P=0.038–0.0001). The overall pattern of gene expression was similar across all treatment groups, being most marked with AZT and least with TDF. There was up-regulation of peroxisome proliferator-activated receptor-? coactivator-1a, uncoupling protein-2 and hexose 6-phosphate dehydrogenase, and down-regulation of nuclear respiratory factor-1, cytochrome oxidase B, cytochrome c oxidase-4, uncoupling protein-3, 11ß-hydroxysteroid dehydrogenase type-1, glucocorticoid receptor-a, fatty acid synthase, fatty acid binding protein-4, LPL and hormone sensitive lipase (18–24 months post-treatment versus pretreatment levels and controls; P<0.05 to <0.0001).Conclusions The decreased expression of genes involved in lipid and mitochondrial metabolism 18–24 months post-ARV treatment in SAT of HIV patients, in conjunction with the increase in uncoupling protein-2 and decrease in cytochrome oxidase B gene expression, provides evidence of mitochondrial dysfunction and a shift to anaerobic metabolism within SAT in EFV-containing ARV regimens.

Background Abnormal lipid metabolism and cell oxidative mechanisms are reported in patients on antiretroviral treatment. We compared the expression of several key adipocyte genes in HIV-infected patients randomized to antiretroviral regimens containing zidovudine (AZT) or tenofovir disoproxil fumarate (TDF).Methods Subcutaneous fat was sampled from 32 HIV-positive treatment-naive patients before and 6 months after randomization to AZT/lamivudine/efavirenz (n=15) or TDF/emtricitabine/efavirenz (n=17) plus 15 HIV-negative matched controls. Expression of genes involved in adipocyte differentiation, lipid metabolism, mitochondrial function and glucocorticoid generation were pro-filed using real-time PCR. Lipoprotein lipase and hepatic lipase activity were assessed.Results Before treatment, 11ß-hydroxysteroid dehydrogenase expression was down-regulated compared with controls. Following 6 months treatment with AZT, there was a significant increase in visceral adipose tissue (VAT; P=0.02) and the ratio of VAT to subcutaneous adipose tissue (P=0.008), down-regulation of cytochrome B (P=0.003) and cytochrome oxidase (COX)-3 gene expression (P=0.03), up-regulation of NADH dehydrogenase (P=0.008) and nuclear-encoded COX-4 (complex IV) gene expression (P=0.012). Genes involved with adipocyte cortisol generation, fatty acid metabolism and the tricarboxylic acid cycle were up-regulated. In the TDF-treated patients, there was no significant change in regional body fat or mitochondrial genes compared with pretreatment values. Changes in the expression of genes involved with cortisol and fatty acid metabolism were less marked with TDF.Conclusions Interference with the mitochondrial electron transport chain appears to occur early in an AZT- containing regimen and occurs at a time when there is increased visceral fat and up-regulation of genes involved with adipocyte differentiation and fatty acid flux.

Background Dyslipidaemia and lipodystrophy have been described in treated HIV patients and in a small percentage of untreated HIV patients. Lipodystrophy in these patients has been shown to be associated with a lower expression of low density lipoprotein (LDL) receptors.Methods We have investigated the effect of antiretroviral treatment with either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) on body fat distribution and LDL apolipoprotein B (apoB) kinetics in 12 HIV-negative controls and 52 HIV-infected patients, including antiretroviral treatment-naive (TN) patients (n=13) and patients taking two nucleoside analogues plus either a PI (n=15) or an NNRTI (n=24).Results LDL cholesterol was not different between groups. Compared with the controls, LDL apoB absolute synthetic rate (ASR) and fractional catabolic rate (FCR) were lower and residence time (RT) was higher in the PI and NNRTI groups (P<0.05). In the TN patients, LDL ASR was lower (P<0.05) and there was a trend for a lower FCR and higher RT compared with the controls (P=0.07). LDL apoB pool size was greater in the PI group compared with the controls (P<0.05). In the PI group, patients on ritonavir (RTV)-containing regimens had a lower LDL apoB ASR (P=0.009) and a trend to a lower LDL apoB FCR and increased RT compared with non-RTV-containing PI regimens (P=0.05). There was a positive correlation between LDL apoB FCR and limb fat/lean body mass (P=0.004) in all subjects.Conclusions Decreased LDL FCR, despite unchanged LDL cholesterol, was demonstrated in both treated and untreated HIV patients. It was more marked with RTV-containing regimens and was associated with reduced limb fat. The increased LDL RT may lead to an increased risk of atherogenesis thus contributing to the risk for cardiovascular disease in these patients.

Certain thyronine-insulin analogues, which form non-covalent complexes with plasma proteins, have been shown to act preferentially in the liver. We hypothesized that this property may be dependant on the ability of the analogue to bind to the insulin receptor without prior dissociation from the binding protein. NαB1-L-thyroxyl-insulin, NαB1-3,3′,5′-triiodothyronine-insulin, NαB1-D-thyroxyl-insulin and NαB1-L-thyroxyl-aminolauroyl-insulin were compared with insulin for their capacity to inhibit the binding of [125I]TyrA14-insulin to rat liver plasma membrane in albumin-free buffer. Effective doses at 50% maximum inhibition of binding (ED50) were calculated with and without addition of the thyroid hormone binding proteins transthyretin, thyroxine binding globulin and human serum albumin. The binding of thyronine-insulin analogues to insulin receptors was inhibited in a dose-dependant manner by the addition of thyroid hormone binding proteins at concentrations in the physiological range. Complexes of thyronine-insulin analogues with thyroid hormone binding proteins exhibit impaired insulin receptor binding affinities compared with those of the analogues in their free form. Hepatoselectivity in vivo may not depend on binding of the intact complexes to hepatocytes. These results have implications for the physiological role of hormone binding proteins and the in vivo properties of other insulin analogues which bind to plasma proteins.