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Atypical eating habits are more common in children with autism spectrum disorders (ASD) than typically developing (TD) peers. Feeding problems may lead to the double burden of specific nutrient deficiencies and excessive weight gain, with a consequent increase in obesity prevalence. The dietary intake of Italian preschoolers with ASD compared to their TD peers and the impact of their dietary choices on their weight status and relationship to food selectivity (FS) were investigated. Dietary patterns and their associations with body mass index (BMI) were evaluated in 65 children with ASD and 82 peers with TD aged 1.3–6.4 years. Eating habits were assessed with a modified version of a parent-rated semi-quantitative Food Frequency Questionnaire. Moreover, the prevalence of FS and possible links with dietary patterns and BMI were investigated in the ASD group. Children with ASD consumed significantly higher amounts of simple sugars, processed and ultra-processed carbohydrates, both low- and high-fat animal proteins, and lower amounts of vegetables and fruits compared to peers with TD. The obesity rate was 1.5% in children with TD and more than fourfold (6.2%) in children with ASD, although the difference between groups was not statistically significant. FS was significantly more frequent in children with ASD than in peers with TD. Children with ASD and FS showed significantly lower annual intakes of vegetable proteins and fiber (considered essential nutrients for a healthy diet) than children with ASD without FS. Our results showed that children with ASD showed different dietary habits than those with TD, with the higher consumption of energy-dense foods and lower amounts of food-sourced fibers, which could place them at increased risk to develop overweight, obesity, and micronutrient deficiencies later in life.

Maternal high-fat diet (HFD) affects metabolic and immune development. We aimed to characterize the effects of maternal HFD, and the subsequent diet-normalization of the mothers during a second pregnancy, on the liver and thymus metabolism in their offspring, in minipigs. Offspring born to high-fat (HFD) and normal diet (ND) fed mothers were studied at week 1 and months 1, 6, 12 of life. Liver and thymus glucose uptake (GU) was measured with positron emission tomography during hyperinsulinemic-isoglycemia. Histological analyses were performed to quantify liver steatosis, inflammation, and hepatic hematopoietic niches (HHN), and thymocyte size and density in a subset. The protocol was repeated after maternal-diet-normalization in the HFD group. At one week, HFDoff were characterized by hyperglycemia, hyperinsulinemia, severe insulin resistance (IR), and high liver and thymus GU, associating with thymocyte size and density, with elevated weight-gain, liver IR, and steatosis in the first 6 months of life. Maternal diet normalization reversed thymus and liver hypermetabolism, and increased HHN at one week. It also normalized systemic insulin-sensitivity and liver fat content at all ages. Instead, weight-gain excess, hyperglycemia, and hepatic IR were still observed at 1 month, i.e., end-lactation. We conclude that intra-uterine HFD exposure leads to time-changing metabolic and immune-correlated abnormalities. Maternal diet-normalization reversed most of the effects in the offspring.

Background: Prediabetes (preT2D) is considered a subtle adverse cardiovascular (CV) risk factor after acute myocardial infarction. Glycated hemoglobin (HbA1c) ranges to identify preT2D are different between ADA and WHO guidelines (5.7–6.4 vs. 6.0–6.4%, respectively). Aim: To evaluate the prognostic value of HbA1c different preT2D-ranges and their correlation with demographic, instrumental, and laboratory parameters in STEMI. Methods: A total of 1681 patients (mean age 67 ± 13 years, 1217 males) were enrolled. Admission HbA1c was used to identify patients with no-T2D (&lt, 5.7%), HbA1c 5.70–5.99%, and WHO-preT2D with HbA1c 6–6.49%, and T2D (HbA1c ≥ 6.5). Results: HbA1c 5.7–5.99, WHO-preT2D, and T2D progressively correlated with an increasing number of CV risk factors. However, only T2D, but not preT2D, was significantly associated with adverse prognosis (in-hospital and one-year death). Conclusions: PreT2D is correlated with CV risk factors, but not with adverse prognosis as compared to no-T2D. Nonetheless, routine HbA1c testing in the STEMI population and HbA1c-5.7–5.99 patient inclusion in the preT2D category may help to identify those who may benefit from intervention and lifestyle strategies to early prevent preT2D progression.

Objective Phthalates are non-persistent pollutants related to impaired metabolism and high cardiovascular risk. Their toxic metabolites are eliminated through urine and feces. Prevention policies are considered by the governments, although no therapeutic strategy to facilitate their elimination from the human body has been proposed so far. Aim of the present study was to verify, for the first time in humans, whether diuretics might be able to enhance phthalates’ toxic metabolites urinary output. Design and methods We conducted a two-armed, parallel-design, randomized clinical trial. Thirty patients with type 2 diabetes and hypertension received a four week-treatment with Dapagliflozin 10 mg or Hydrochlorothiazide 12.5 mg. 24-hours urine were collected to measure urinary excretion of three major 2-ethylhexyl-phthalate (DEHP) metabolites, i.e. mono 2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP) and mono 2-ethyl-5-hydroxyhexyl phthalate (MEHHP). Results 24-h urinary excretion of DEHP and MEHP was increased (+44%, p = 0.036; +49%, p = 0.0016) while MEOHP e MEHHP showed only a positive trend (+25%, p = 0.016; +36%, p = 0.062). Irrespective of the specific treatment, induced variations of daily urinary eliminations of MEHP metabolites were related with the 24-h urinary sodium (r = 0.42, p = 0.0226) and potassium (r = 0.54, p = 0.0026) excretion. Also, DEHP and MEOHP were related to sodium (r = 0·43, p = 0.0205; r = 0·44, p = 0.0168 respectively) but not to potassium. Conclusions Urinary phthalates excretion seems to occur mainly through sodium- and potassium-related mechanisms, apparently independent from the different diuretic effect. Both thiazide diuretics and SLGT2 inhibitors are effective into the removal of phthalates metabolites from the human body, reducing the human tissues’ exposure to their toxicity.

Leptin resistance occurs in obese patients, but its independent contribution to adiposity and the accompanying metabolic diseases, i.e., diabetes, liver steatosis, and steatohepatitis, remains to be established. This study was conducted in an extreme model of leptin resistance to investigate mechanisms initiating diabetes, fat expansion, liver steatosis, and inflammatory disease, focusing on the involvement of glucose intolerance and organ-specific glucose uptake in brown and subcutaneous adipose tissues (BAT, SAT) and in the liver. We studied preobese and adult Zucker rats (fa/fa, fa/+ ) during fasting or glucose loading to assess glucose tolerance. Relevant pancreatic and intestinal hormonal levels were measured by Milliplex. Imaging of 18F-fluorodeoxyglucose by positron emission tomography was used to quantify glucose uptake in SAT, BAT, and liver, and evaluate its relationship with adipocyte size and biopsy-proven nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). Preobese fa/fa pups showed impaired glucose tolerance, adipocyte enlargement, hepatic microsteatosis, and lobular inflammation, with elevated hepatic post-glucose load glucose uptake and production. Adult fa/fa rats had more severe glucose intolerance, fasting hyperglycemia, hormonal abnormalities, elevated glucose uptake in SAT and BAT, and more markedly in the liver, together with macrosteatosis, and highly prevalent hepatic inflammation. Organ glucose uptake was proportional to the degree of fat accumulation and tissue inflammation and was able to dissect healthy from NAFLD and NAFLD/NASH livers. Most severe NASH livers showed a decline in glucose uptake and liver enzymes. In fa/fa Zucker rats, leptin resistance leads to glucose intolerance, mainly due to hepatic glucose overproduction, preceding obesity, and explaining pancreatic and intestinal hormonal changes and fat accumulation in adipocytes and hepatocytes. Our data support the involvement of liver glucose uptake in the pathogenesis of liver inflammatory disease. Its potential as more generalized biomarker or diagnostic approach remains to be established outside of our leptin-receptor-deficient rat model.

The microbiota-gut-brain axis has been recently recognized as a key modulator of neuropsychiatric health. In this framework, probiotics (recently named "psychobiotics") may modulate brain activity and function, possibly improving the behavioral profiles of children with Autism Spectrum Disorder (ASD). We evaluated the effects of probiotics on autism in a double-blind randomized, placebo-controlled trial of 85 preschoolers with ASD (mean age, 4.2 years; 84% boys). Participants were randomly assigned to probiotics (De Simone Formulation) (n=42) or placebo (n=43) for six months. Sixty-three (74%) children completed the trial. No differences between groups were detected on the primary outcome measure, the Total Autism Diagnostic Observation Schedule - Calibrated Severity Score (ADOS-CSS). An exploratory secondary analysis on subgroups of children with or without Gastrointestinal Symptoms (GI group, n= 30; NGI group, n=55) revealed in the NGI group treated with probiotics a significant decline in ADOS scores as compared to that in the placebo group, with a mean reduction of 0.81 in Total ADOS CSS and of 1.14 in Social-Affect ADOS CSS over six months. In the GI group treated with probiotics we found greater improvements in some GI symptoms, adaptive functioning, and sensory profiles than in the GI group treated with placebo. These results suggest potentially positive effects of probiotics on core autism symptoms in a subset of ASD children independent of the specific intermediation of the probiotic effect on GI symptoms. Further studies are warranted to replicate and extend these promising findings on a wider population with subsets of ASD patients which share targets of intervention on the microbiota-gut-brain axis. Clinical trial registration ClinicalTrials.gov, identifier NCT02708901.

Background: Several studies have tried to investigate the role of inflammatory biomarkers in Autism Spectrum Disorder (ASD), and their correlations with clinical phenotypes. Despite the growing research in this topic, existing data are mostly contradictory. Methods: Eighty-five ASD preschoolers were assessed for developmental level, adaptive functioning, gastrointestinal (GI), socio-communicative and psychopathological symptoms. Plasma levels of leptin, resistin, plasminogen activator inhibitor-1 (PAI-1), macrophage chemoattractant protein-1 (CCL2), tumor necrosis factor-alfa (TNF-&alpha, ), and interleukin-6 (IL-6) were correlated with clinical scores and were compared among different ASD subgroups according to the presence or absence of: (i) GI symptoms, (ii) regressive onset of autism. Results: Proinflammatory cytokines (TNF-&alpha, IL-6 and CCL2) were lower than those reported in previous studies in children with systemic inflammatory conditions. GI symptoms were not correlated with levels of inflammatory biomarkers except for resistin that was lower in ASD-GI children (p = 0.032). Resistin and PAI-1 levels were significantly higher in the group with &ldquo, regression plus a developmental delay&rdquo, onset (Reg+DD group) compared to groups without regression or with regression without a developmental delay (p &lt, 0.01 for all). Conclusions: Our results did not highlight the presence of any systemic inflammatory state in ASD subjects neither disentangling children with/without GI symptoms. The Reg + DD group significantly differed from others in some plasmatic values, but these differences failed to discriminate the subgroups as possible distinct ASD endo-phenotypes.

Evaluation of calcium status is important in the osteoporotic risk assessment. Although guidelines indicate total calcium (tCa) as first-line measurement, directly measured ionized calcium (m-iCa), considered as the gold standard, is more and more often required. Aim of this study is to evaluate the agreement between m-iCa, tCa and iCa calculated from a formula based on total calcium and albumin (c-iCa) in osteopenic/osteoporotic postmenopausal outpatients.A total of 140 postmenopausal outpatients, 41 osteopenic (OPN) and 99 osteoporotic (OP) were enrolled. Levels of tCa, m-iCa, c-iCa, total protein and albumin, vitamin D (25-OHD), parathyroid hormone 1-84 (PTH), bone alkaline phosphatase, osteocalcin and serum collagen type 1 cross-linked C-telopeptide (CTX) were also measured.There were no statistically significant differences between OPN and OP groups regarding values of tCa, m-iCa, and c-iCa, 25-OHD and PTH. However, OP women had lower levels of CTX (p 0.05). A significant direct correlation between m-iCa and tCa (r = 0.60, p 0.001) and c-iCa (r = 0.61, p 0.001) was found. Women with isolated hyper-m-iCa had similar DEXA parameter levels respect to the other patients. However, one patient with confirmed primary hyperparathyroidism presented hyper-m-iCa versus normal tCa and c-iCa values.The use of tCa could be sufficient to characterize the calcium status in postmenopausal outpatients, but reflexive calcium testing strategy for m-iCa test is necessary to women presenting the low or high extremes of tCa levels, or in women with suspected PHPT.

International audience; Introduction: The microbiota-gut brain (MGB) axis is the bidirectional communication between the intestinal microbiota and the brain. An increasing body of preclinical and clinical evidence has revealed that the gut microbial ecosystem can affect neuropsychiatric health. However, there is still a need of further studies to elucidate the complex gene-environment interactions and the role of the MGB axis in neuropsychiatric diseases, with the aim of identifying biomarkers and new therapeutic targets, to allow early diagnosis and improving treatments. Areas covered: To review the role of MGB axis in neuropsychiatric disorders, prediction and prevention of disease through exploitation, integration, and combination of data from existing gut microbiome/microbiota projects and appropriate other International '-Omics' studies. The authors also evaluated the new technological advances to investigate and modulate, through nutritional and other interventions, the gut microbiota. Expert opinion: The clinical studies have documented an association between alterations in gut microbiota composition and/or function, whereas the preclinical studies support a role for the gut microbiota in impacting behaviors which are of relevance to psychiatry and other central nervous system (CNS) disorders. Targeting MGB axis could be an additional approach for treating CNS disorders and all conditions in which alterations of the gut microbiota are involved.

Purpose. Oral bisphosphonates (BPs) are the most commonly used medications for osteoporosis (OP), but their poor gastrointestinal (GI) absorption and tolerance hamper compliance. Intramuscular (IM) neridronate (NE), an amino-BP, is an easy-to-administer, effective, and safe alternative to oral BPs. We assessed the 6-year effects of monthly IM NE on bone mineral density (BMD) and bone turnover biomarkers (BMs) in postmenopausal OP. Methods. This single-center, prospective study enrolled postmenopausal osteoporotic outpatients with gastric intolerance to BPs (based on Tuscany Region’s law GRT n. 836 20/10/2008). They received 25 mg IM NE once a month (with vitamin D and calcium if necessary) for 6 years. BMD was evaluated at lumbar spine (L1-L4), femoral neck (FN), and total femur (TF) at baseline (BL) and every 12 months afterwards. At BL, month 3, and every 12 months after BL, total and ionized calcium, vitamin D, parathyroid hormone 1-84, bone alkaline phosphatase (BALP), osteocalcin, and N- and C-terminal telopeptides were assayed. Results. Overall, 60 women (mean age: 62.3±7.5 years) received monthly IM NE for 6 years, with vitamin D and calcium supplementation in 81.3% of cases. Compared to BL, BMD increased significantly already after 1 year at all sites (4.5±0.9% for L1-L4, 4.5±0.8% for TF, and 2.1±0.6% for FN, P≤0.05), and the changes were maintained over time, whereas FN further improved up to year 3 and remained stable afterwards (P≤0.05). All BMs, except for total calcium and BALP, progressively decreased over time (P≤0.05). No fractures and significant adverse events were reported. Conclusion. The monthly administration of IM NE represents a manageable and effective option, in terms of BMD and bone BM improvement, for the long-term treatment of postmenopausal OP women with gastric intolerance to BPs. This trial is registered with ClinicalTrials.gov Identifier: NCT03699150.

Low-calorie Mediterranean-style or low-carbohydrate dietary regimens are widely used nutritional strategies against obesity and associated metabolic diseases, including type 2 diabetes. The aim of this study was to compare the effectiveness of a balanced Mediterranean diet with a low-carbohydrate diet on weight loss and glucose homeostasis in morbidly obese individuals at high risk to develop diabetes. Insulin secretion, insulin clearance, and different β-cell function components were estimated by modeling plasma glucose, insulin and C-peptide profiles during 75-g oral glucose tolerance tests (OGTTs) performed at baseline and after 4 weeks of each dietary intervention. The average weight loss was 5%, being 58% greater in the low-carbohydrate-group than Mediterranean-group. Fasting plasma glucose and glucose tolerance were not affected by the diets. The two dietary regimens proved similarly effective in improving insulin resistance and fasting hyperinsulinemia, while enhancing endogenous insulin clearance and β-cell glucose sensitivity. In summary, we demonstrated that a low-carbohydrate diet is a successful short-term approach for weight loss in morbidly obese patients and a feasible alternative to the Mediterranean diet for its glucometabolic benefits, including improvements in insulin resistance, insulin clearance and β-cell function. Further studies are needed to compare the long-term efficacy and safety of the two diets.

Aim: To assess gender differences in uric acid (UA) as predictor for hard events (HE, mortality and nonfatal myocardial infarction) in a large cohort of patients referred for coronary angiography. Design & patients: 3020 inpatients (2177 males, age: 68 ± 9 years, mean ± SD) were retrospectively studied, collecting data from the Institute electronic databank which included demographic, clinical, instrumental and follow-up data. Results: Although the Kaplan–Meier survival estimates showed a significantly worst outcome in female patients, high UA did not remained a significant predictor for HE after adjustment. Moreover, UA correlated with antioxidant capacity in both sexes. Conclusion: Hyperuricemia was not an independent risk for HE, and being correlated with antioxidant capacity, its elevation appears more likely compensatory than causative for HE.

Purpose. A clear link between obesity and brown adipose tissue (BAT) dysfunction has been recently demonstrated. The purpose of this pilot study is to determine if near-infrared spectroscopy (NIRS) 2D imaging together with infrared thermography (IRT) is capable of identifying thermal and vascular response in the supraclavicular (SCV) areas after the ingestion of an oral glucose load as a thermogenic stimulation. Method. We studied two groups of women (obese versus lean) for discerning their different responses. NIRS and IRT images were acquired on the neck in the left SCV region during a 3 h oral glucose tolerance test (OGTT) and immediately after a cold stimulation. Results. We detected a significant thermal response of BAT in SCV fossa in both groups. Both during OGTT and after cold stimulation, skin temperature was persistently higher in lean versus obese. This response was not coupled with changes in oxygen saturation of subcutaneous tissue in that area. Discussion and Conclusion. The results show that NIRS/IRT may be a novel, noninvasive, radiation-free, easy to use, and low-cost method for monitoring, during the standard clinical practice, the diet and pharmacological intervention which aims to stimulate BAT as a potential therapeutic target against obesity and diabetes.

The quantification of global myocardial blood flow (MBF) by measuring coronary sinus flow by magnetic resonance (MRI) was demonstrated to be very well correlated with positron emission tomography (PET). We proposed a new method for the quantification of regional myocardial perfusion with MRI by the integration of MBF and first pass technique. The aim of this study was to validate this new method for quantification of regional perfusion by comparing it with 13NH13-PET in swine models of myocardial infarction and in humans in resting and hyperemic conditions. MRI and 13NH3-PET was performed in 2 healthy swine, 11 swine models of myocardial infarction (5 reperfused, 6 non reperfused) and in 12 humans at rest and during hyperemia. MBF was estimated by MRI through the quantification of coronary sinus flow and left ventricular (LV) mass. The upslope of signal intensity (SI-upslope) of each myocardial segment was obtained by the first pass gadolinium technique. Regional SI-upslope was indexed by the upslope of the entire left ventricular myocardium (global upslope). Regional myocardial perfusion was estimated as the product of MBF and SI-upslope/global upslope. Regional perfusion was also estimated by 13NH3-PET. A close agreement of the MRI and PET techniques for measurement of regional myocardial perfusion was found in all myocardial segments by Bland-Altman analysis (mean difference 5.1 %; limits of agreement, -37.2-27.5 %). With the integration of the first pass technique and the measurement of global MBF by coronary sinus flow/LV mass, MRI allows direct quantification of regional myocardial perfusion.

BACKGROUND & AIMS: Hepatic lipotoxicity results from and contributes to obesity-related disorders. It is a challenge to study human metabolism of fatty acids (FAs) in the liver. We combined (11)C-palmitate imaging by positron emission tomography (PET) with compartmental modeling to determine rates of hepatic FA uptake, oxidation, and storage, as well as triglyceride release in pigs and human beings. METHODS: Anesthetized pigs underwent (11)C-palmitate PET imaging during fasting (n = 3) or euglycemic hyperinsulinemia (n = 3). Metabolic products of FAs were measured in arterial, portal, and hepatic venous blood. The imaging methodology then was tested in 15 human subjects (8 obese subjects); plasma (11)C-palmitate kinetic analyses were used to quantify systemic and visceral lipolysis. RESULTS: In pigs, PET-derived and corresponding measured FA fluxes (FA uptake, esterification, and triglyceride FA release) did not differ and were correlated with each other. In human beings, obese subjects had increased hepatic FA oxidation compared with controls (mean +/- standard error of the mean, 0.16 +/- 0.01 vs 0.08 +/- 0.01 mu mol/min/mL; P = .0007); FA uptake and esterification rates did not differ between obese subjects and controls. Liver FA oxidation correlated with plasma insulin levels (r = 0.61, P = .016), adipose tissue (r = 0.58, P = .024), and systemic insulin resistance (r = 0.62, P = .015). Hepatic FA esterification correlated with the systemic release of FA into plasma (r = 0.71, P = .003). CONCLUSIONS: PET imaging can be used to measure FA metabolism in the liver. By using this technology, we found that obese individuals have increased hepatic oxidation of FA, in the context of adipose tissue insulin resistance, and increased FA flux from visceral fat. FA flux from visceral fat is proportional with the mass of the corresponding depot.

Aims/hypothesis: Cardiac steatosis and myocardial insulin resistance elevate the risk of cardiac complications in obesity and diabetes. We aimed to disentangle the effects of circulating glucose, insulin and NEFA on myocardial triacylglycerol (TG) content and myocardial glucose uptake. Methods: Twenty-two pigs were stratified according to four protocols: low NEFA + low insulin (nicotinic acid), high NEFA + low insulin (fasting) and high insulin + low NEFA ± high glucose (hyperinsulinaemia-hyperglycaemia or hyperinsulinaemia- euglycaemia). Positron emission tomography, [U-13C]palmitate enrichment techniques and tissue biopsies were used to assess myocardial metabolism. Heart rate and rate-pressure product (RPP) were monitored. Results: Myocardial glucose extraction was increased by NEFA suppression and was similar in the hyperinsulinaemia-hypergylcaemia, hyperinsulinaemia-euglycaemia and nicotinic acid groups. Hyperglycaemia enhanced myocardial glucose uptake due to a mass action. Myocardial TG content was greatest in the fasting group, whereas hyperinsulinaemia had a mild effect. Heart rate and RPP increased in hyperinsulinaemia-euglycaemia, in which cardiac glycogen content was reduced. Heart rate correlated with myocardial TG and glycogen content. Conclusions/interpretation: Elevated NEFA levels represent a powerful, self-sufficient promoter of cardiac TG accumulation and are a downregulator of myocardial glucose uptake, indicating that the focus of treatment should be to 'normalise' adipose tissue function to lower the risk of cardiac TG accumulation and myocardial insulin resistance. The observation that hyperinsulinaemia and nicotinic acid led to myocardial fuel deprivation provides a potential explanation for the cardiovascular outcomes reported in recent intensive glucose-lowering and NEFA-lowering clinical trials. © 2014 Springer-Verlag Berlin Heidelberg.

The liver is inaccessible to organ balance measurements in humans. To validate [(18)F]fluorodeoxyglucose ([(18)F]FDG) positron emission tomography (PET) in the quantification of hepatic glucose uptake (HGU), we determined [(18)F]FDG modeling parameters, lumped constant (LC), and input functions (single arterial versus dual).Anesthetized pigs were studied during fasting (n = 6), physiologic (n = 4), and supraphysiologic (n = 4) hyperinsulinemia. PET was performed with C(15)O (blood pool) and [(18)F]FDG (glucose uptake). 6,6-Deuterated glucose ([(2)H]G) was coinjected with [(18)F]FDG and blood collected from the carotid artery and portal and hepatic veins to compute LC as ratio between tracers fractional extraction. HGU was estimated from PET images and ex vivo from high-performance liquid chromatography measurements of liver [(18)F]FDG versus [(18)F]FDG-6-phosphate and [(18)F]-glycogen. Endogenous glucose production was measured with [(2)H]G and hepatic blood flow by flowmeters.HGU was increased in hyperinsulinemia versus fasting (P.05). Fractional extraction of [(18)F]FDG and [(2)H]G was similar (not significant), intercorrelated (r = 0.98, P.0001), and equally higher during hyperinsulinemia than fasting (Por= .05), with an LC of 0.98 +/- 0.10 and 1.18 +/- 0.26, respectively. [(18)F]FDG-PET modeling provided HGU values that did not differ from, and were correlated with, those from ex vivo measurements (r = 0.61, Por= .02); proportional estimates of liver perfusion and endogenous glucose production were also obtained. Single and dual input functions produced strongly intercorrelated results (r0.95, P.0001), with a modest underestimation of HGU by the former.[(18)F]FDG-PET-derived parameters provide accurate quantification of HGU and estimates of liver perfusion and glucose production. In the liver, LC of [(18)F]FDG is nearly unitary. Using a single arterial input introduces only a small error in estimation of HGU.

Insulin resistance (IR) associated with obesity represents a well-known risk factor for chronic disease. IR development may occur to hinder stressful conditions to provide an appropriate energetic supply to non-insulin-sensitive tissues. However, conditions of stress turn out to be 'maladaptive' in the long term, leading to chronic diseases. Paradoxically, insulin hypersensitivity and/or hypersecretion causing post-prandial hypoglycemia resulting in increased food intake and weight gain, can represent an event preceding obesity and IR. By performing an OGTT in obese or obese-prone individuals we observed that tardive post-prandial hypoglycemia (3h from glucose load) is not a rare event (32%); in 12% of cases it paralleled with low insulin levels, resulting in the 'true insulin hypersensitivity'. By using Matsuda-method, we confirmed the presence of insulin hypersensitivity in this group. Therefore the early recognition of this phenomenon could be useful as a predictive biomarker to identify patients prone to develop obesity and obesity related-disorders.

Type 2 diabetes and insulin resistance are often associated with the co-occurrence of coronary atherosclerosis and cardiac dysfunction. The aim of this study was to define the independent relationships between left ventricular dysfunction or ischaemia and patterns of myocardial perfusion and metabolism in type 2 diabetes.Twenty-four type 2 diabetic patients--12 with coronary artery disease (CAD) and preserved left ventricular function and 12 with non-ischaemic heart failure (HF)--were enrolled in a cross-sectional study. Positron emission tomography (PET) was used to assess myocardial blood flow (MBF) at rest, after pharmacological stress and under euglycaemic hyperinsulinaemia. Insulin-mediated myocardial glucose disposal was determined with 2-deoxy-2-[(18)F]fluoroglucose PET.There was no difference in myocardial glucose uptake (MGU) between the healthy myocardium of CAD patients and the dysfunctional myocardium of HF patients. MGU was strongly influenced by levels of systemic insulin resistance in both groups (CAD, r = 0.85, p = 0.005; HF, r = 0.77, p = 0.01). In HF patients, there was an inverse association between MGU and the coronary flow reserve (r = -0.434, p = 0.0115). A similar relationship was observed in non-ischaemic segments of CAD patients. Hyperinsulinaemia increased MBF to a similar extent in the non-ischaemic myocardial of CAD and HF patients.In type 2 diabetes, similar metabolic and perfusion patterns can be detected in the non-ischaemic regions of CAD patients with normal cardiac function and in the dysfunctional non-ischaemic myocardium of HF patients. This suggests that insulin resistance, rather than diagnosis of ischaemia or left ventricular dysfunction, affects the metabolism and perfusion features of patients with type 2 diabetes.

The ongoing epidemics of obesity is one main health concern of the present time. Overeating in some obese individuals shares similarities with the loss of control and compulsive behavior observed in drug-addicted subjects, suggesting that obesity may involve food addiction. Here, we review the contributions provided by the use of positron emission tomography to the current understanding of the cerebral control of obesity and food intake in humans. The available studies have shown that multiple areas in the brain are involved with the reward properties of food, such as prefrontal, orbitofrontal, somatosensory cortices, insula, thalamus, hypothalamus, amygdala, and others. This review summarizes the current evidence, supporting the concepts that i) regions involved in the somatosensory response to food sight, taste, and smell are activated by palatable foods and may be hyperresponsive in obese individuals, ii) areas controlling executive drive seem to overreact to the anticipation of pleasure during cue exposure, and iii) those involved in cognitive control and inhibitory behavior may be resistant to the perception of reward after food exposure in obese subjects. All of these features may stimulate, for different reasons, ingestion of highly palatable and energy-rich foods. Though these same regions are similarly involved in drug abusers and game-addicted individuals, any direct resemblance may be an oversimplification, especially as the heterogeneities between studies and the prevalent exclusion of sensitive groups still limit a coherent interpretation of the findings. Further work is required to comprehensively tackle the multifaceted phenotype of obesity and identify the role of food dependency in its pathophysiology. Copyright © 2012 S. Karger GmbH, Freiburg

Cardiovascular and metabolic vulnerability have an early developmental origin. We evaluated the potential influence of innate life factors, including the metabolism of the mother and the sex of the offspring, on cardiometabolic risk, including organ-specific insulin resistance, subclinical cardiac dysfunction, and DNA oxidative damage throughout the lifespan.Two female minipigs were studied during late pregnancy, and their offspring were restudied at the ages of 1 mo (n = 11), 6 mo (n = 9), and 9 mo (n = 10, 6 offspring and 4 age-matched animals). We measured insulin-mediated glucose disposal in skeletal muscle, adipose tissue, liver, and myocardium using (18)F-FDG PET; cardiac function using 2-dimensional strain echocardiography; and DNA damage using the comet assay.Glucose metabolism showed the 2 sows to have differences similar to those in their respective 1-mo-old offspring. Over time, compared with female animals, male animals developed myocardial insulin resistance (male animals vs. female animals: 34 ± 5 vs. 58 ± 8 μmol/min/kg at 6 mo, P = 0.03; 29 ± 8 vs. 60 ± 7 μmol/min/kg at 9 mo, P = 0.02). Cardiac function progressively deteriorated in male animals from 1 mo (radial strain, -60% ± 7%; strain rate, -5.4 ± 0.9 s(-1)) to 6 mo (radial strain, -41% ± 5%; strain rate, -2.5 ± 0.2 s(-1), P0.05 vs. 1 mo) and 9 mo (radial strain, -32% ± 5%; strain rate, -1.6 ± 0.2 s(-1), P0.01 vs. 1 mo) and was significantly different from that in female animals (radial strain, -48% ± 4%; strain rate, -3.1 ± 0.2 s(-1), P0.05 and P0.01, respectively). Oxidative damage was reduced in female animals and increased in male animals across age categories (P0.05).The metabolism of minipig offspring is influenced by maternal insulin sensitivity during early life stages. Sex-related effects prevail thereafter in healthy minipigs, documenting a precocious onset of cardiometabolic vulnerability in male offspring.

Chronic hyperglycaemia aggravates obesity and diabetes mellitus. The use of glucose by body organs depends on several factors. We sought to investigate the role of blood flow, intrinsic tissue glucose clearance and blood glucose levels in regulating tissue glucose uptake under fasting conditions (FCs) and in response to acute hyperglycaemia (AH) in obese and type 2 diabetic rats.Thirty-six Zucker rats were studied by positron emission tomography to quantify perfusion and glucose uptake during FC and after AH in the liver, myocardium, skeletal muscle and subcutaneous adipose tissue. Progressively higher glucose uptake rates were observed from lean to obese (p 0.05) and to diabetic rats (p 0.05) in all tissues during both FC and AH. In FC, they were increased of 7-18 times in obese rats and 11-30 times in diabetic rats versus controls. Tissue glucose uptake was increased by over 10-fold during AH in controls; this response was severely blunted in diseased groups. AH tended to stimulate organ perfusion in control rats. Tissue glucose uptake was a function of intrinsic clearance and glycaemia (mass action) in healthy animals, but the latter component was lost in diseased animals. Differences in perfusion did not account for those in glucose uptake.Each organ participates actively in the regulation of its glucose uptake, which is dependent on intrinsic tissue substrate extraction and extrinsic blood glucose delivery, but not on perfusion, and it is potently stimulated by AH. Obese and diabetic rats had an elevated organ glucose uptake but a blunted response to acute glucose intake.

Enhanced release of triglycerides (TG) by the liver is implicated in the pathogenesis of the metabolic syndrome. The aim of the study was to evaluate whether a primary elevation in hepatic glucose utilization (HGU), as induced by an acute rise in circulating glucose values during physiological hyperinsulinemia, promotes TG synthesis in spite of the reduction in free fatty acids (FFA) levels.Glucose dose-response studies were conducted in anesthetized pigs using positron emission tomography (PET) to quantify HGU during fasting euglycemic conditions (EF), and under two-step hyperglycemic hyperinsulinemia (1st-HH +3.0, 2nd-HH +6.0 mmol/L over EF glucose values). Liver biopsies were obtained in three animals to evaluate the relationship between glucose exposure and hepatic fat content.Plasma glucose levels were progressively increased in the two-step studies, and otherwise stable within every hour of PET scanning. HGU increased almost fivefold with raising glucose levels, from 0.033 ± 0.009 in EF to 0.149 ± 0.043 in 1st-HH, p = 0.02, and to 0.138 ± 0.050 μmol/min/g in 2nd-HH, p = 0.03. Circulating TG concentrations increased by 50 and 100% in the two hyperglycemic conditions (p = 0.03 2nd-HH vs. EF), in spite of a 70% suppression in plasma FFA levels. The hepatic TG content paralleled the glucose loads. Plasma γ-glutamyl transferase (γ-GT) was increased by 17% (p0.05).A short-term elevation in circulating glucose levels within the physiological postprandial range was sufficient to increase HGU, resulting in a significant synthesis and release of TG by the liver, which was accompanied by an acute rise in γ-GT and liver fat content.

Brain glucose exposure may complicate diabetes and obesity. We used positron emission tomography with 18F-fluorodeoxyglucose in Zucker obese, diabetic, and control rats to determine the contributions of blood glucose mass action versus local mechanisms in regulating central glucose disposal in fasted and acutely glucose-stimulated states, and their adaptations in obesity and diabetes. Our study data indicate that brain glucose uptake is dependent on both local and mass action components, and is stimulated by acute glucose intake in healthy rats. In diseased animals, the organ was chronically overexposed to glucose, due to high fasting glucose uptake, almost abolishing the physiologic response to glucose loading.

Increased glucose utilization and regional differences in contractile function are well-known alterations of the failing heart and play an important pathophysiological role. We tested whether, similar to functional derangement, changes in glucose uptake develop following a regional pattern. Heart failure was induced in 13 chronically instrumented minipigs by pacing the left ventricular (LV) free wall at 180 beats/min for 3 wk. Regional changes in contractile function and stress were assessed by magnetic resonance imaging, whereas regional flow and glucose uptake were measured by positron emission tomography utilizing, respectively, the radiotracers [13N]ammonia and 18F-deoxyglucose. In heart failure, LV end-diastolic pressure was 20 ± 4 mmHg, and ejection fraction was 35 ± 4% (all P < 0.05 vs. control). Sustained pacing-induced dyssynchronous LV activation caused a more pronounced decrease in LV systolic thickening (7.45 ± 3.42 vs. 30.62 ± 8.73%, P < 0.05) and circumferential shortening (−4.62 ± 1.0 vs. −7.33 ± 1.2%, P < 0.05) in the anterior/anterior-lateral region (pacing site) compared with the inferoseptal region (opposite site). Conversely, flow was reduced significantly by ∼32% compared with control and was lower in the opposite site region. Despite these nonhomogeneous alterations, regional end-systolic wall stress was uniformly increased by 60% in the failing LV. Similar to wall stress, glucose uptake markedly increased vs. control (0.24 ± 0.004 vs. 0.07 ± 0.01 μmol·min−1·g−1, P < 0.05), with no significant regional differences. In conclusion, high-frequency pacing of the LV free wall causes a dyssynchronous pattern of contraction that leads to progressive cardiac failure with a marked mismatch between increased glucose uptake and regional contractile dysfunction.