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Spontaneous glucose uptake by brown adipose tissue (BAT) is lower in overweight or obese individuals and in diabetes. However, BAT metabolism has not been previously investigated in patients with type 2 diabetes during controlled cold exposure. Using positron emission tomography with 11C-acetate, 18F-fluoro-deoxyglucose (18FDG), and 18F-fluoro-thiaheptadecanoic acid (18FTHA), a fatty acid tracer, BAT oxidative metabolism and perfusion and glucose and nonesterified fatty acid (NEFA) turnover were determined in men with well-controlled type 2 diabetes and age-matched control subjects under experimental cold exposure designed to minimize shivering. Despite smaller volumes of 18FDG-positive BAT and lower glucose uptake per volume of BAT compared with young healthy control subjects, cold-induced oxidative metabolism and NEFA uptake per BAT volume and an increase in total body energy expenditure did not differ in patients with type 2 diabetes or their age-matched control subjects. The reduction in 18FDG-positive BAT volume and BAT glucose clearance were associated with a reduction in BAT radiodensity and perfusion. 18FDG-positive BAT volume and the cold-induced increase in BAT radiodensity were associated with an increase in systemic NEFA turnover. These results show that cold-induced NEFA uptake and oxidative metabolism are not defective in type 2 diabetes despite reduced glucose uptake per BAT volume and BAT "whitening." [ABSTRACT FROM AUTHOR]

Oral 14(R,S)-[18F]-fluoro-6-thia-heptadecanoic acid was used to determine whether an increase in cardiac dietary fatty acid (DFA) metabolism in impaired glucose tolerance (IGT) is different in men and women. Myocardial DFA partitioning after 6 h was higher in IGT versus control subjects (P = 0.006) in both men (2.14 [95% CI 1.70-2.18] vs. 1.28 standard uptake value [SUV] units [0.80-1.76]) and women (1.95 [1.57-2.33] vs. 1.64 SUV units [1.32-1.96]) without difference between sexes. Myocardial DFA fractional uptake (Ki) between time 90 and 120 min postprandially was also higher in IGT versus control subjects (P < 0.001) in men (0.063 [0.032-0.095] vs. 0.016 min-1 [0.007-0.025]) and women (0.050 [0.024- 0.077] vs. 0.030 min-1 [0.013-0.047]) without significant sex difference. Men had higher netmyocardial DFA uptake between time 90 and 120 min driven by higher chylomicrontriglyceride (TG) levels. IGT-associated increased cardiac DFA partitioning was directly related to obesity in women, whereas it was associated with IGT per se in men. We conclude that early cardiac DFA uptake is higher in men driven by change in postprandial chylomicron- TG level but that increase in 6-h postprandial cardiac DFA partitioning nevertheless occurs with IGT both in men and women. [ABSTRACT FROM AUTHOR]

Objective Free fatty acids (FFAs) cause insulin resistance and are often elevated in obesity. Chronic ingestion of diets rich in saturated fat induces more insulin resistance than diets rich in unsaturated fat, however, it remains unclear whether different FFAs cause distinct levels of insulin resistance in the short-term, which is relevant to the feeding and fasting cycle. Protein kinase C (PKC)-δ is implicated in hepatic insulin resistance. Therefore, we investigated the effects of short-term elevation of fatty acids with different degrees of unsaturation on hepatic insulin action and liver PKC-δ membrane translocation, a marker of activation. Materials/Methods Triglyceride emulsions of Soybean Oil + Heparin (polyunsaturated (POLY)), Olive Oil + Heparin (monounsaturated (MONO)), Lard Oil + Heparin (saturated (SATU)), or saline (SAL) were infused intravenously for 7 h to elevate plasma FFA concentrations ~ 3–4 fold in rats. During the last 2 h of infusion, a hyperinsulinemic–euglycemic clamp with tritiated glucose methodology was performed to examine hepatic and peripheral insulin sensitivity. Results Surprisingly, SATU, MONO, and POLY impaired peripheral insulin sensitivity (glucose utilization divided by insulin) to a similar extent. Furthermore, all lipids induced a similar degree of hepatic insulin resistance compared to SAL. Although there were changes in hepatic content of lipid metabolites, there were no significant differences in liver PKC-δ membrane translocation across fat groups. Conclusions In summary, in the short-term, FFAs with different degrees of unsaturation impair peripheral insulin sensitivity and induce hepatic insulin resistance as well as hepatic PKC-δ translocation to the same extent. [ABSTRACT FROM AUTHOR]

Key points Both brown adipose tissue (BAT) and skeletal muscle activation contribute to the metabolic response of acute cold exposure in healthy men even under minimal shivering., Activation of adipose tissue intracellular lipolysis is associated with BAT metabolic response upon acute cold exposure in healthy men., Although BAT glucose uptake per volume of tissue is important, the bulk of glucose turnover during cold exposure is mediated by skeletal muscle metabolic activation even when shivering is minimized., Abstract Cold exposure stimulates the sympathetic nervous system (SNS), triggering the activation of cold-defence responses and mobilizing substrates to fuel the thermogenic processes. Although these processes have been investigated independently, the physiological interaction and coordinated contribution of the tissues involved in producing heat or mobilizing substrates has never been investigated in humans. Using [U-13C]-palmitate and [3-3H]-glucose tracer methodologies coupled with positron emission tomography using 11C-acetate and 18F-fluorodeoxyglucose, we examined the relationship between whole body sympathetically induced white adipose tissue (WAT) lipolysis and brown adipose tissue (BAT) metabolism and mapped the skeletal muscle shivering and metabolic activation pattern during a mild, acute cold exposure designed to minimize shivering response in 12 lean healthy men. Cold-induced increase in whole-body oxygen consumption was not independently associated with BAT volume of activity, BAT oxidative metabolism, or muscle metabolism or shivering intensity, but depended on the sum of responses of these two metabolic tissues. Cold-induced increase in non-esterified fatty acid (NEFA) appearance rate was strongly associated with the volume of metabolically active BAT ( r = 0.80, P = 0.005), total BAT oxidative metabolism ( r = 0.70, P = 0.004) and BAT glucose uptake ( r = 0.80, P = 0.005), but not muscle glucose metabolism. The total glucose uptake was more than one order of magnitude greater in skeletal muscles compared to BAT during cold exposure (674 ± 124 vs. 12 ± 8 μmol min−1, respectively, P < 0.001). Glucose uptake demonstrated that deeper, centrally located muscles of the neck, back and inner thigh were the greatest contributors of muscle glucose uptake during cold exposure due to their more important shivering response. In summary, these results demonstrate for the first time that the increase in plasma NEFA appearance from WAT lipolysis is closely associated with BAT metabolic activation upon acute cold exposure in healthy men. In humans, muscle glucose utilization during shivering contributes to a much greater extent than BAT to systemic glucose utilization during acute cold exposure. [ABSTRACT FROM AUTHOR]

Purpose Hepatocyte nuclear factor 1 alpha (HNF1α) defects cause Mature Onset Diabetes of the Young type 3 (MODY3), characterized by defects in beta-cell insulin secretion. However, HNF1α is involved in many other metabolic pathways with relevance for monogenic or polygenic type 2 diabetes. We aimed to investigate gut hormones, lipids, and insulin regulation in response to a meal test in HNF1α defect carriers (MODY3) compared to non-diabetic subjects (controls) and type 2 diabetes (T2D). Methods: We administered a standardized liquid meal to each participant. Over 6 hours, we measured post-meal responses of insulin regulation (blood glucose, c-peptide, insulin), gut hormones (ghrelin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1) and lipids (non-esterified fatty acids [NEFA] and triglycerides). Results: We found that MODY3 participants had lower insulin secretion indices than controls and T2D participants, showing the expected β-cell defect. MODY3 had similar glycated hemoglobin levels (HbA1c median [IQR]: 6.5 [5.6–7.6]%) compared to T2D (median: 6.6 [6.2–6.9]%; P<0.05). MODY3 had greater insulin sensitivity (Matsuda index: 71.9 [29.6; 125.5]) than T2D (3.2 [4.0; 6.0]; P<0.05). MODY3 experienced a larger decrease in the ratio of NEFA to insulin (NEFA 30–0 / insulin 30–0: -39 [-78; -30] x104) in the early post-prandial period (0–30 minutes) compared to controls and to T2D (-2.0 [-0.6; -6.4] x104; P<0.05). MODY3 had lower fasting (0.66 [0.46; 1.2] mM) and post-meal triglycerides levels compared to T2D (fasting: 2.3 [1.7; 2.7] mM; P<0.05). We did not detect significant post-meal differences in ghrelin and incretins between MODY3 and other groups. Conclusion: In response to a standard meal test, MODY3 showed greater early post-prandial NEFA diminution in response to relatively low early insulin secretion, and they maintained very low post-prandial triglycerides levels.

The mechanisms responsible for the remarkable remission of type 2 diabetes after Roux-en-Y gastric bypass (RYGBP) are still puzzling. To elucidate the role of the gut, we compared β-cell function assessed during an oral glucose tolerance test (OGTT) and an isoglycemic intravenous glucose clamp (iso-IVGC) in: 1) 16 severely obese patients with type 2 diabetes, up to 3 years post-RYGBP; 2) 11 severely obese normal glucose-tolerant control subjects; and 3) 7 lean control subjects. Diabetes remission was observed after RYGBP. β-Cell function during the OGTT, significantly blunted prior to RYGBP, normalized to levels of both control groups after RYGBP. In contrast, during the iso-IVGC, β-cell function improved minimally and remained significantly impaired compared with lean control subjects up to 3 years post-RYGBP. Presurgery, β-cell function, weight loss, and glucagon-like peptide 1 response were all predictors of postsurgery β-cell function, although weight loss appeared to be the strongest predictor. These data show that β-cell dysfunction persists after RYGBP, even in patients in clinical diabetes remission. This impairment can be rescued by oral glucose stimulation, suggesting that RYGBP leads to an important gastrointestinal effect, critical for improved β-cell function after surgery. [ABSTRACT FROM AUTHOR]

Abstract: Reconstruction of main palaeoenvironmental conditions across the Mid-Cenomanian Event (MCE I) in the hemipelagic Tethyan section of Blieux (Southeast France, Vocontian Basin) is proposed. Quantitative analyses of calcareous nannofossil, ammonoid and clay mineral assemblages have been made and compared with respect to sea level changes and the carbon cycle perturbations. The nannofossil primary productivity, as recorded by nannofossil fluxes and relative abundances of meso-eutrophic taxa, is low just below and during the MCE Ia, then slightly increases in the interval including the MCE Ib. The clay assemblages mainly consist of illite/smectite mixed-layers with a smaller proportion of kaolinite. The percentage of kaolinite strongly decreases in the interval including the MCE Ia and slightly increases in the interval including the MCE Ib. The clay assemblages are mainly detrital in origin and reflect environmental changes including differential settling processes, climate, intensity of runoff and detrital sources. The ammonoid assemblages are characterised by a significant change during the MCE I: planispirals (mainly Schloenbachia) are dominant until the MCE Ia, whereas heteromorphs (mainly Sciponoceras) become dominant from the MCE Ib onwards. Strongly oligotrophic levels in sea surfaces are recorded during the MCE Ia and are related both to arid climatic conditions and major sea level fall (both 3rd order and medium scale lowstand deposits). A decrease in bathymetry could partly explain the decrease in the relative abundance of Schloenbachia. The first occurrence of Sciponoceras took place during the MCE Ib; this second positive increase in δ13C is not associated with enhanced nannofossil primary productivity. No clear relations can be established between the occurrence of Sciponoceras and trophic resources. [Copyright &y& Elsevier]

OBJECTIVE--Elevated plasma free fatty acids (FFAs) are one important link between excess visceral adiposity, insulin resistance, and the development of type 2 diabetes. Effects of lifestyle interventions on FFA metabolism are poorly known. This open-label study was conducted to test the effects of a 1-year healthy eating/physical activity intervention program on plasma FFA homeostasis in 117 viscerally obese men with dyslipidemia associated with insulin resistance (waist circumference ≥90 cm, triglycerides ≥ 1.69 mmol/L, and/or HDL-cholesterol <1.03 mmol/L). RESEARCH DESIGN AND METHODS--Body weight, body composition, and fat distribution were assessed by dual-energy X-ray absorptiometry/computed tomography. Oral loads of lipid (60 g fat/m² body surface area) and glucose (75 g) were measured before and after the intervention. RESULTS--After 1 year of lifestyle intervention, visceral adiposity was reduced by -26% (95% CI -29 to -23), whereas cardiorespiratory fitness improved by +20% (95% CI +16 to +24). After 1 year, the suppression of FFAs after the glucose load improved, whereas insulin concentrations were drastically reduced. After the oral lipid load, the late increase in FFA was reduced together with reduced circulating insulin. We calculated an insulin sensitivity index to reflect the concentration of insulin needed tomanage plasma FFAs after the oral lipid load, which increased after the intervention and was associated with improved glucose tolerance, independent of changes in visceral or total adiposity. CONCLUSIONS--A 1-year healthy eating/physical activity intervention improved the suppression of FFAs after oral glucose and lipid load tests in viscerally obese men, possibly due to improved responsiveness to insulin. This insulin-mediated regulation of postprandial plasma FFA levels could be a link between visceral obesity and impaired glucose homeostasis. [ABSTRACT FROM AUTHOR]

The estrogen-related receptor alpha (ERRα) is a nuclear receptor that acts primarily as a regulator of metabolic processes, particularly in tissues subjected to high-energy demand. In addition to its control of energy metabolism and mitochondrial biogenesis, ERRα has recently been associated with cancer progression. Notably, increased expression of ERRα has been shown in several cancerous tissues, including breast, ovary and colon. However, additional studies are required to gain insight into the action of ERRα in cancer biology, particularly in non-endocrine-related cancers. Therefore, using a short hairpin RNA-mediated approach, we investigated whether ERRα is required for the rapid growth of colon cancer cells and to maintain their neoplastic metabolic state. Results show that silencing ERRα significantly impaired colon cancer cell proliferation and colony formation in vitro as well as their in vivo tumorigenic capacity. A pronounced delay in G1-to-S cell cycle phase transition was observed in ERRα-depleted cells in association with reduced cyclin-dependent kinase 2 activity and hyperphosphorylated state of the retinoblastoma protein along with disturbed expression of several cell cycle regulators, including p15 and p27. Interestingly, ERRα-depleted HCT116 cells also displayed significant reduction in expression of a large set of key genes to glycolysis, tricarboxylic acid cycle and lipid synthesis. Furthermore, using 14C isotope tracer analysis, ERRα depletion in colon cancer cells resulted in reduced glucose incorporation and glucose-mediated lipogenesis in these cells. These findings suggest that ERRα coordinates colon cancer cell proliferation and tumorigenic capacity with energy metabolism. Thus, ERRα could represent a promising therapeutic target in colon cancer. [ABSTRACT FROM PUBLISHER]