Renal Cortical Glucose Uptake Is Decreased in Insulin Resistance and Correlates Inversely With Serum Free-fatty Acids.

CONTEXT: Studies on human renal metabolism are scanty. Nowadays, functional imaging allows the characterization of renal metabolism in a noninvasive manner. We have recently demonstrated that fluorodeoxyglucose F18 (18F FDG) positron emission tomography can be used to analyze renal glucose uptake (GU) rates, and that the renal cortex is an insulin-sensitive tissue. OBJECTIVE: To confirm that renal GU is decreased in people with obesity and to test whether circulating metabolites are related to renal GU. DESIGN, SETTING AND PARTICIPANTS: Eighteen people with obesity and 18 nonobese controls were studied with [18F]FDG positron emission tomography during insulin clamp. Renal scans were obtained ∼60 minutes after [18F]FDG injection. Renal GU was measured using fractional uptake rate and after correcting for residual intratubular [18F]FDG. Circulating metabolites were measured using high-throughput proton nuclear magnetic resonance metabolomics. RESULTS: Cortical GU was higher in healthy nonobese controls compared with people with obesity (4.7 [3.4-5.6] vs 3.1 [2.2-4.3], P = .004, respectively), and it associated positively with the degree of insulin sensitivity (M value) (r = 0.42, P = .01). Moreover, cortical GU was inversely associated with circulating ß-OH-butyrate (r = -0.58, P = .009), acetoacetate (r = -0.48, P = .008), citrate (r = -0.44, P = .01), and free fatty acids (r = -0.68, P < .0001), even when accounting for the M value. On the contrary, medullary GU was not associated with any clinical parameters. CONCLUSION: These data confirm differences in renal cortical GU between people with obesity and healthy nonobese controls. Moreover, the negative correlations between renal cortex GU and free fatty acids, ketone bodies, and citrate are suggestive of substrate competition in the renal cortex.

Insulin-stimulated brain glucose uptake correlates with brain metabolites in severe obesity: A combined neuroimaging study.

The human brain undergoes metabolic adaptations in obesity, but the underlying mechanisms have remained largely unknown. We compared concentrations of often reported brain metabolites measured with magnetic resonance spectroscopy (1H-MRS, 3 T MRI) in the occipital lobe in subjects with obesity and lean controls under different metabolic conditions (fasting, insulin clamp, following weight loss). Brain glucose uptake (BGU) quantified with 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET)) was also performed in a subset of subjects during clamp. In dataset A, 48 participants were studied during fasting with brain 1H-MRS, while in dataset B 21 participants underwent paired brain 1H-MRS acquisitions under fasting and clamp conditions. In dataset C 16 subjects underwent brain 18F-FDG-PET and 1H-MRS during clamp. In the fasting state, total N-acetylaspartate was lower in subjects with obesity, while brain myo-inositol increased in response to hyperinsulinemia similarly in both lean participants and subjects with obesity. During clamp, BGU correlated positively with brain glutamine/glutamate, total choline, and total creatine levels. Following weight loss, brain creatine levels were increased, whereas increases in other metabolites remained not significant. To conclude, insulin signaling and glucose metabolism are significantly coupled with several of the changes in brain metabolites that occur in obesity.

Decreased Weight Loss Following Bariatric Surgery in Patients with Type 2 Diabetes.

BACKGROUND: Bariatric surgery represents the most effective treatment for achieving significant and sustained weight loss. We aimed to assess whether presence of type 2 diabetes (T2D) at baseline, and T2D remission following bariatric surgery affect the weight loss outcome. METHODS: Data of 312 consecutive morbidly obese subjects who underwent bariatric surgery were analysed. Patients underwent either RYGB (77%), or sleeve gastrectomy (23%), and their body weight was followed-up for 1, 2, 3, 4, and 5 years at regular ambulatory visits (N = 269, 312, 210, 151, 105, at each year, respectively). T2D remission was assessed according to the ADA criteria. RESULTS: In the whole dataset, 92 patients were affected by T2D. Patients with T2D were older than patients without T2D (52 ± 9 vs 45 ± 11 years, p < 0.0001), but there were no differences in baseline BMI, sex, and type of intervention received. We found that presence of T2D at baseline was associated with smaller weight loss at 1, 2, 3, 4, and 5 years following bariatric surgery (δ BMI at 2 years: - 13.7 [7.7] vs - 16.4 [7.3] kg/m2; at 5 years - 12.9 [8.8] vs - 16.3 [8.7] kg/m2 in patients with T2D vs patients without T2D respectively, all p < 0.05). When dividing the patients with T2D in remitters and non-remitters, non-remitters had significantly smaller weight loss compared to remitters (δ BMI at 2 years: - 11.8 [6.3] vs - 15.4 [7.8] kg/m2; at 5 years: - 8.0 [7.1] vs - 15.0 [7.2] kg/m2, non-remitters vs remitters respectively, all p < 0.05). CONCLUSIONS: T2D is independently associated to smaller weight loss following bariatric surgery, especially in subjects not achieving diabetes remission. • Patients with T2D achieve smaller weight loss following bariatric surgery • When dividing the T2D patients in remitters and non-remitters, non-remitters achieve significantly smaller weight loss compared to remitters.

Microbiota in anorexia nervosa: potential for treatment.

Anorexia nervosa (AN) is characterised by the restriction of energy intake in relation to energy needs and a significantly lowered body weight than normally expected, coupled with an intense fear of gaining weight. Treatment of AN is currently based on psychological and refeeding approaches, but their efficacy remains limited since 40% of patients after 10 years of medical care still present symptoms of AN. The intestine hosts a large community of microorganisms, called the "microbiota", which live in symbiosis with the human host. The gut microbiota of a healthy human is dominated by bacteria from two phyla: Firmicutes and, majorly, Bacteroidetes. However, the proportion in their representation differs on an individual basis and depends on many external factors including medical treatment, geographical location and hereditary, immunological and lifestyle factors. Drastic changes in dietary intake may profoundly impact the composition of the gut microbiota, and the resulting dysbiosis may play a part in the onset and/or maintenance of comorbidities associated with AN, such as gastrointestinal disorders, anxiety and depression, as well as appetite dysregulation. Furthermore, studies have reported the presence of atypical intestinal microbial composition in patients with AN compared with healthy normal-weight controls. This review addresses the current knowledge about the role of the gut microbiota in the pathogenesis and treatment of AN. The review also focuses on the bidirectional interaction between the gastrointestinal tract and the central nervous system (microbiota-gut-brain axis), considering the potential use of the gut microbiota manipulation in the prevention and treatment of AN.

Diagnostic Accuracy of 18F-FDG-PET/CT and 18F-FDG-PET/MRI in Detecting Locoregional Recurrence of HNSCC 12 Weeks after the End of Chemoradiotherapy: Single-Center Experience with PET/MRI.

Purpose: In head and neck squamous cell carcinoma (HNSCC), the early diagnosis and efficient detection of recurrences and/or residual tumor after treatment play a very important role in patient's prognosis. Positron emission tomography (PET) using 2-deoxy-2-18F-fluoro-D-glucose (18F-FDG) has become an established method for the diagnosis of suspected recurrence in head and neck carcinomas. In particular, integrated PET/MRI imaging that provides optimal soft tissue contrast and less dental implant artifacts compared to PET/CT is an intriguing technique for the follow-up imaging of HNSCC patients. The aim of this study was to evaluate the benefit of PET/MRI compared to PET/CT in post-treatment follow-up imaging of HNSCC patients. Methods: This retrospective observational cohort study consists of 104 patients from our center with histologically confirmed HNSCC. All patients received chemoradiotherapy (CRT) and underwent 18F-FDG-PET/CT (n = 52) or 18F-FDG-PET/MRI (n = 52) scan 12 weeks after the end of treatment. Image analysis was performed by two independent readers according to a five-point Likert scale analysis. Results: PET/MRI was more sensitive (1.00 vs. 0.77) than PET/CT in the detection of locoregional recurrence. PET/MRI also had better negative (1.00 vs. 0.87) predictive values. AUCs for PET/MRI and PET/CT on patient-based analysis were 0.997 (95% CI 0.989-1.000) and 0.890 (95% CI 0.806-0.974), respectively. The comparison of sensitivity, AUCs, and negative predictive values revealed a statistically significant difference, p < 0.05. In PET/CT, false-negative and positive findings were observed in the more advanced disease stages, where PET/MRI performed better. Also, false-negative findings were located in the oropharyngeal, laryngeal, and nasopharyngeal regions, where PET/MRI made no false-negative interpretations. Conclusion: Based on these results, PET/MRI might be considered the modality of choice in detecting locoregional recurrence in HNSCC patients, especially in the more advanced stages in the oral cavity, larynx, or nasopharynx.

Renal Sinus Fat Is Expanded in Patients with Obesity and/or Hypertension and Reduced by Bariatric Surgery Associated with Hypertension Remission.

Renal sinus fat is a fat depot at the renal hilum. Because of its location around the renal artery, vein, and lymphatic vessels, an expanded renal sinus fat mass may have hemodynamic and renal implications. We studied whether renal sinus fat area (RSF) associates with hypertension and whether following bariatric surgery a decrease in RSF associates with improvement of hypertension. A total of 74 severely obese and 46 lean controls were studied with whole-body magnetic resonance imaging (MRI). A total of 42 obese subjects were re-studied six months after bariatric surgery. RSF was assessed by two independent researchers using sliceOmatic. Glomerular filtration rate (eGFR) was estimated according to the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). Patients with obesity accumulated more RSF compared to lean controls (2.3 [1.7-3.1] vs. 1.8 [1.4-2.5] cm2, p = 0.03). Patients with hypertension (N = 36) had a larger RSF depot compared to normotensive subjects (2.6 [2.0-3.3] vs. 2.0 [1.4-2.5] cm2, p = 0.0007) also after accounting for body mass index (BMI). In the pooled data, RSF was negatively associated with eGFR (r = -0.20, p = 0.03), whereas there was no association with systolic or diastolic blood pressure. Following bariatric surgery, RSF was reduced (1.6 [1.3-2.3] vs. 2.3 [1.7-3.1] cm2, p = 0.03) along with other markers of adiposity. A total of 9/27 of patients achieved remission from hypertension. The remission was associated with a larger decrease in RSF, compared to patients who remained hypertensive (-0.68 [-0.74 to -0.44] vs. -0.28 [-0.59 to 0] cm2, p = 0.009). The accumulation of RSF seems to be involved in the pathogenesis of hypertension in obesity. Following bariatric surgery, loss of RSF was associated with remission from hypertension.

Circulating neurofilament is linked with morbid obesity, renal function, and brain density.

Neurofilament light chain (NfL) is a novel biomarker reflecting neuroaxonal damage and associates with brain atrophy, and glial fibrillary acidic protein (GFAP) is a marker of astrocytic activation, associated with several neurodegenerative diseases. Since obesity is associated with increased risk for several neurodegenerative disorders, we hypothesized that circulating NfL and GFAP levels could reflect neuronal damage in obese patients. 28 morbidly obese and 18 lean subjects were studied with voxel based morphometry (VBM) MRI to assess gray and white matter densities. Serum NfL and GFAP levels were determined with single-molecule array. Obese subjects were re-studied 6 months after bariatric surgery. Morbidly obese subjects had lower absolute concentrations of circulating NfL and GFAP compared to lean individuals. Following bariatric surgery-induced weight loss, both these levels increased. Both at baseline and after weight loss, circulating NfL and GFAP values correlated inversely with eGFR. Cross-sectionally, circulating NfL levels correlated inversely with gray matter (GM) density, and this association remained significant also when accounting for age and total eGFR. GFAP values did not correlate with GM density. Our data suggest that when determining circulating NfL and GFAP levels, eGFR should also be measured since renal function can affect these measurements. Despite the potential confounding effect of renal function on NfL measurement, NfL correlated inversely with gray matter density in this group of subjects with no identified neurological disorders, suggesting that circulating NfL level may be a feasible biomarker of cerebral function even in apparently neurologically healthy subjects.

Hepatic Positron Emission Tomography: Applications in Metabolism, Haemodynamics and Cancer.

Evaluating in vivo the metabolic rates of the human liver has been a challenge due to its unique perfusion system. Positron emission tomography (PET) represents the current gold standard for assessing non-invasively tissue metabolic rates in vivo. Here, we review the existing literature on the assessment of hepatic metabolism, haemodynamics and cancer with PET. The tracer mainly used in metabolic studies has been [18F]2-fluoro-2-deoxy-D-glucose (18F-FDG). Its application not only enables the evaluation of hepatic glucose uptake in a variety of metabolic conditions and interventions, but based on the kinetics of 18F-FDG, endogenous glucose production can also be assessed. 14(R,S)-[18F]fluoro-6-thia-Heptadecanoic acid (18F-FTHA), 11C-Palmitate and 11C-Acetate have also been applied for the assessment of hepatic fatty acid uptake rates (18F-FTHA and 11C-Palmitate) and blood flow and oxidation (11C-Acetate). Oxygen-15 labelled water (15O-H2O) has been used for the quantification of hepatic perfusion. 18F-FDG is also the most common tracer used for hepatic cancer diagnostics, whereas 11C-Acetate has also shown some promising applications in imaging liver malignancies. The modelling approaches used to analyse PET data and also the challenges in utilizing PET in the assessment of hepatic metabolism are presented.

Novel effects of the gastrointestinal hormone secretin on cardiac metabolism and renal function.

The cardiac benefits of gastrointestinal hormones have been of interest in recent years. The aim of this study was to explore the myocardial and renal effects of the gastrointestinal hormone secretin in the GUTBAT trial (NCT03290846). A placebo-controlled crossover study was conducted on 15 healthy males in fasting conditions, where subjects were blinded to the intervention. Myocardial glucose uptake was measured with [18F]2-fluoro-2-deoxy-d-glucose ([18F]FDG) positron emission tomography. Kidney function was measured with [18F]FDG renal clearance and estimated glomerular filtration rate (eGFR). Secretin increased myocardial glucose uptake compared with placebo (secretin vs. placebo, means ± SD, 15.5 ± 7.4 vs. 9.7 ± 4.9 µmol/100 g/min, 95% confidence interval (CI) [2.2, 9.4], P = 0.004). Secretin also increased [18F]FDG renal clearance (44.5 ± 5.4 vs. 39.5 ± 8.5 mL/min, 95%CI [1.9, 8.1], P = 0.004), and eGFR was significantly increased from baseline after secretin, compared with placebo (17.8 ± 9.8 vs. 6.0 ± 5.2 ΔmL/min/1.73 m2, 95%CI [6.0, 17.6], P = 0.001). Our results implicate that secretin increases heart work and renal filtration, making it an interesting drug candidate for future studies in heart and kidney failure.NEW & NOTEWORTHY Secretin increases myocardial glucose uptake compared with placebo, supporting a previously proposed inotropic effect. Secretin also increased renal filtration rate.

Sarcopenia and chronic illness: from diagnosis to treatment approaches.

Sarcopenia is a progressive clinical syndrome characterized by general loss of skeletal muscle mass and impaired muscle function. Due to the general progressive aging of population, sarcopenia has gradually grown into a global health problem, with great negative impact on the quality of life of the affected patients as well as an adverse societal impact. In this review, we discuss the pathophysiology, diagnosis, and determination of severity of sarcopenia. Special attention is given to the rehabilitative treatment against sarcopenia, pointing out that a thorough evaluation and intervention of nutritional deficits and exercise capacity as well as treatment with medical agents are needed in order to personalize the treatment according to the patient's needs. By targeting goals to improve musculoskeletal and functional disorders associated with chronic conditions, clinicians could apply a therapeutic plan focusing on how to prevent/delay the development of sarcopenia and improve the quality of the patients' lives.

Pleiotropic Effects of Secretin: A Potential Drug Candidate in the Treatment of Obesity?

Secretin is the first hormone that has been discovered, inaugurating the era and the field of endocrinology. Despite the initial focus, the interest in its actions faded away over the decades. However, there is mounting evidence regarding the pleiotropic beneficial effects of secretin on whole-body homeostasis. In this review, we discuss the evidence from preclinical and clinical studies based on which secretin may have a role in the treatment of obesity.

The Obesity Risk SNP (rs17782313) near the MC4R Gene Is Not Associated with Brain Glucose Uptake during Insulin Clamp-A Study in Finns.

The melanocortin system is involved in the control of adiposity through modulation of food intake and energy expenditure. The single nucleotide polymorphism (SNP) rs17782313 near the MC4R gene has been linked to obesity, and a previous study using magnetoencephalography has shown that carriers of the mutant allele have decreased cerebrocortical response to insulin. Thus, in this study, we addressed whether rs17782313 associates with brain glucose uptake (BGU). Here, [18F]-fluorodeoxyglucose positron emission tomography (PET) data from 113 Finnish subjects scanned under insulin clamp conditions who also had the rs17782313 determined were compiled from a single-center cohort. BGU was quantified by the fractional uptake rate. Statistical analysis was performed with statistical parametric mapping. There was no difference in age, BMI, and insulin sensitivity as indexed by the M value between the rs17782313-C allele carriers and non-carriers. Brain glucose uptake during insulin clamp was not different by gene allele, and it correlated with the M value, in both the rs17782313-C allele carriers and non-carriers. The obesity risk SNP rs17782313 near the MC4R gene is not associated with brain glucose uptake during insulin clamp in humans, and this frequent mutation cannot explain the enhanced brain glucose metabolic rates in insulin resistance.

Green Tea from the Far East to the Drug Store: Focus on the Beneficial Cardiovascular Effects.

Cardiovascular diseases (CVD) are the leading cause of death worldwide. Evidence from observational and randomized controlled studies showing the potential benefits of green tea on lowering CVD risk has been emerging rapidly during the past few decades. These benefits include reduced risk for major cardiovascular events, lowering of blood pressure, decreased LDL cholesterol levels and weight loss. At the same time, the understanding of the physiological mechanisms behind these alterations is advancing. Consumption of green tea originated from China thousands of years ago, but since then, it expanded all over the world. Recent advances in understanding the role of tea polyphenols, mainly catechins, as mediators of tea's health benefits, have caused the emergence of various types of green tea extracts (GTE) on the market. While taking green tea is generally considered safe, there are concerns about the safety of using tea extracts. The present article reviews the current evidence of green tea consumption leading to reduced CVD risk, its potential biological mechanisms and the safety of using GTE.

Brain substrate metabolism and ß-cell function in humans: A positron emission tomography study.

AIMS: Recent clinical studies have shown enhanced brain glucose uptake during clamp and brain fatty acid uptake in insulin-resistant individuals. Preclinical studies suggest that the brain may be involved in the control of insulin secretion. The aim of this study was to investigate whether brain metabolism assessed as brain glucose and fatty acid uptake is associated with the parameters of ß-cell function in humans. MATERIALS AND METHODS: We analysed cross-sectional data of 120 subjects across a wide range of BMI and insulin sensitivity. Brain glucose uptake (BGU) was measured during euglycaemic-hyperinsulinaemic clamp (n = 67) and/or during fasting (n = 45) using [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET). In another group of subjects (n = 34), brain fatty acid uptake was measured using [18F]-fluoro-6-thia-heptadecanoic acid (FTHA) PET during fasting. The parameters of ß-cell function were derived from OGTT modelling. Statistical analysis was performed with whole-brain voxel-based statistical parametric mapping. RESULTS: In non-diabetics, BGU during euglycaemic hyperinsulinaemic clamp correlated positively with basal insulin secretion rate (r = 0.51, P = .0008) and total insulin output (r = 0.51, P = .0008), whereas no correlation was found in type 2 diabetics. BGU during clamp correlated positively with potentiation in non-diabetics (r = 0.33, P = .02) and negatively in type 2 diabetics (r = -0.61, P = .02). The associations in non-diabetics were not explained with whole-body insulin sensitivity or BMI. No correlations were found between baseline (fasting) BGU and basal insulin secretion rate, whereas baseline brain fatty acid uptake correlated directly with basal insulin secretion rate (r = 0.39, P = .02) and inversely with potentiation (r = -0.36, P = .04). CONCLUSIONS: Our study provides coherent, though correlative, evidence that, in humans, the brain may be involved in the control of insulin secretion independently of insulin sensitivity.

Predicting Skeletal Muscle and Whole-Body Insulin Sensitivity Using NMR-Metabolomic Profiling.

PURPOSE: Abnormal lipoprotein and amino acid profiles are associated with insulin resistance and may help to identify this condition. The aim of this study was to create models estimating skeletal muscle and whole-body insulin sensitivity using fasting metabolite profiles and common clinical and laboratory measures. MATERIAL AND METHODS: The cross-sectional study population included 259 subjects with normal or impaired fasting glucose or type 2 diabetes in whom skeletal muscle and whole-body insulin sensitivity (M-value) were measured during euglycemic hyperinsulinemic clamp. Muscle glucose uptake (GU) was measured directly using [18F]FDG-PET. Serum metabolites were measured using nuclear magnetic resonance (NMR) spectroscopy. We used linear regression to build the models for the muscle GU (Muscle-insulin sensitivity index [ISI]) and M-value (whole-body [WB]-ISI). The models were created and tested using randomly selected training (n = 173) and test groups (n = 86). The models were compared to common fasting indices of insulin sensitivity, homeostatic model assessment-insulin resistance (HOMA-IR) and the revised quantitative insulin sensitivity check index (QUICKI). RESULTS: WB-ISI had higher correlation with actual M-value than HOMA-IR or revised QUICKI (ρ = 0.83 vs -0.67 and 0.66; P < 0.05 for both comparisons), whereas the correlation of Muscle-ISI with the actual skeletal muscle GU was not significantly stronger than HOMA-IR's or revised QUICKI's (ρ = 0.67 vs -0.58 and 0.59; both nonsignificant) in the test dataset. CONCLUSION: Muscle-ISI and WB-ISI based on NMR-metabolomics and common laboratory measurements from fasting serum samples and basic anthropometrics are promising rapid and inexpensive tools for determining insulin sensitivity in at-risk individuals.

The SGLT2 Inhibitor Dapagliflozin Reduces Liver Fat but Does Not Affect Tissue Insulin Sensitivity: A Randomized, Double-Blind, Placebo-Controlled Study With 8-Week Treatment in Type 2 Diabetes Patients.

OBJECTIVE: The aim of this study was to investigate tissue-specific effects of dapagliflozin on insulin sensitivity and liver and body fat in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This randomized, double-blind, parallel group, placebo-controlled study recruited 32 patients with type 2 diabetes. Enrolled patients were to have HbA1c 6.5-10.5% (48-91 mmol/mol) and ≥3 months of stable treatment with metformin, dipeptidyl peptidase 4 inhibitor, or their combination. Patients were randomized 1:1 to receive 10 mg dapagliflozin or placebo daily for 8 weeks. Before and after the intervention, tissue insulin sensitivity was measured using [18F]-fluorodeoxyglucose and positron emission tomography during hyperinsulinemic-euglycemic clamp. Liver proton density fat fraction (PDFF) and adipose tissue volumes were assessed using MRI, and blood biomarkers were analyzed. RESULTS: After 8 weeks, glycemic control was improved by dapagliflozin (placebo-corrected change in HbA1c -0.39%, P < 0.01), but whole-body glucose uptake was not increased (P = 0.90). Tissue-specific insulin-stimulated glucose uptake did not change in skeletal muscle, liver, myocardium, or white and brown adipose tissue, and endogenous glucose production remained unaffected. However, there were significant placebo-corrected decreases in liver PDFF (-3.74%, P < 0.01), liver volume (-0.10 L, P < 0.05), visceral adipose tissue volume (-0.35 L, P < 0.01), interleukin-6 (-1.87 pg/mL, P < 0.05), and N-terminal prohormone of brain natriuretic peptide (-96 ng/L, P = 0.03). CONCLUSIONS: In this study, 8 weeks of treatment with dapagliflozin reduced liver PDFF and the volume of visceral adipose tissue in obese patients with type 2 diabetes. Although glycemic control was improved, no effect on tissue-level insulin sensitivity was observed.

Brain glucose uptake is associated with endogenous glucose production in obese patients before and after bariatric surgery and predicts metabolic outcome at follow-up.

AIMS: To investigate further the finding that insulin enhances brain glucose uptake (BGU) in obese but not in lean people by combining BGU with measures of endogenous glucose production (EGP), and to explore the associations between insulin-stimulated BGU and peripheral markers, such as metabolites and inflammatory markers. MATERIALS AND METHODS: A total of 20 morbidly obese individuals and 12 lean controls were recruited from the larger randomized controlled SLEEVEPASS study. All participants were studied under fasting and euglycaemic hyperinsulinaemic conditions using fluorodeoxyglucose-positron emission tomography. Obese participants were re-evaluated 6 months after bariatric surgery and were followed-up for ~3 years. RESULTS: In obese participants, we found a positive association between BGU and EGP during insulin stimulation. Across all participants, insulin-stimulated BGU was associated positively with systemic inflammatory markers and plasma levels of leucine and phenylalanine. Six months after bariatric surgery, the obese participants had achieved significant weight loss. Although insulin-stimulated BGU was decreased postoperatively, the association between BGU and EGP during insulin stimulation persisted. Moreover, high insulin-stimulated BGU at baseline predicted smaller improvement in fasting plasma glucose at 2 and 3 years of follow-up. CONCLUSIONS: Our findings suggest the presence of a brain-liver axis in morbidly obese individuals, which persists postoperatively. This axis might contribute to further deterioration of glucose homeostasis.

Adipose tissue and skeletal muscle insulin-mediated glucose uptake in insulin resistance: role of blood flow and diabetes.

Background: Adipose tissue glucose uptake is impaired in insulin-resistant states, but ex vivo studies of human adipose tissue have yielded heterogeneous results. This discrepancy may be due to different regulation of blood supply. Objective: The aim of this study was to test the flow dependency of in vivo insulin-mediated glucose uptake in fat tissues, and to contrast it with that of skeletal muscle. Design: We reanalyzed data from 159 individuals in which adipose tissue depots-subcutaneous abdominal and femoral, and intraperitoneal-and femoral skeletal muscle were identified by MRI, and insulin-stimulated glucose uptake ([18F]-fluoro-2-deoxyglucose) and blood flow ([15O]-H2O) were measured simultaneously by positron emission tomography scanning. Results: Individuals in the bottom tertile of whole-body glucose uptake [median (IQR) 36 (17) µmol. kg fat-free mass (kgFFM)-1 . min-1 .nM-1] displayed all features of insulin resistance compared with the rest of the group [median (IQR) 97 (71) µmol . kgFFM-1 .min-1 . nM-1]. Rates of glucose uptake were directly related to the degree of insulin resistance in all fat depots as well as in skeletal muscle. However, blood flow was inversely related to insulin sensitivity in each fat depot (all P ≤ 0.03), whereas femoral muscle blood flow was not significantly different between insulin-resistant and insulin-sensitive subjects, and was not related to insulin sensitivity. Furthermore, in subjects performing one-leg exercise, blood flow increased 5- to 6-fold in femoral muscle but not in the overlying adipose tissue. The presence of diabetes was associated with a modest increase in fat and muscle glucose uptake independent of insulin resistance. Conclusions: Reduced blood supply is an important factor for the impairment of in vivo insulin-mediated glucose uptake in both subcutaneous and visceral fat. In contrast, the insulin resistance of glucose uptake in resting skeletal muscle is predominantly a cellular defect. Diabetes provides a modest compensatory increase in fat and muscle glucose uptake that is independent of insulin resistance.

Insulin-stimulated glucose uptake in skeletal muscle, adipose tissue and liver: a positron emission tomography study.

OBJECTIVE: Insulin resistance is reflected by the rates of reduced glucose uptake (GU) into the key insulin-sensitive tissues, skeletal muscle, liver and adipose tissue. It is unclear whether insulin resistance occurs simultaneously in all these tissues or whether insulin resistance is tissue specific. DESIGN AND METHODS: We measured GU in skeletal muscle, adipose tissue and liver and endogenous glucose production (EGP), in a single session using 18F-fluorodeoxyglucose with positron emission tomography (PET) and euglycemic-hyperinsulinemic clamp. The study population consisted of 326 subjects without diabetes from the CMgene study cohort. RESULTS: Skeletal muscle GU less than 33 µmol/kg tissue/min and subcutaneous adipose tissue GU less than 11.5 µmol/kg tissue/min characterized insulin-resistant individuals. Men had considerably worse insulin suppression of EGP compared to women. By using principal component analysis (PCA), BMI inversely and skeletal muscle, adipose tissue and liver GU positively loaded on same principal component explaining one-third of the variation in these measures. The results were largely similar when liver GU was replaced by EGP in PCA. Liver GU and EGP were positively associated with aging. CONCLUSIONS: We have provided threshold values, which can be used to identify tissue-specific insulin resistance. In addition, we found that insulin resistance measured by GU was only partially similar across all insulin-sensitive tissues studied, skeletal muscle, adipose tissue and liver and was affected by obesity, aging and gender.

A Partial Loss-of-Function Variant in AKT2 Is Associated With Reduced Insulin-Mediated Glucose Uptake in Multiple Insulin-Sensitive Tissues: A Genotype-Based Callback Positron Emission Tomography Study.

Rare fully penetrant mutations in AKT2 are an established cause of monogenic disorders of glucose metabolism. Recently, a novel partial loss-of-function AKT2 coding variant (p.Pro50Thr) was identified that is nearly specific to Finns (frequency 1.1%), with the low-frequency allele associated with an increase in fasting plasma insulin level and risk of type 2 diabetes. The effects of the p.Pro50Thr AKT2 variant (p.P50T/AKT2) on insulin-stimulated glucose uptake (GU) in the whole body and in different tissues have not previously been investigated. We identified carriers (N = 20) and matched noncarriers (N = 25) for this allele in the population-based Metabolic Syndrome in Men (METSIM)study and invited these individuals back for positron emission tomography study with [18F]-fluorodeoxyglucose during euglycemic hyperinsulinemia. When we compared p.P50T/AKT2 carriers to noncarriers, we found a 39.4% reduction in whole-body GU (P = 0.006) and a 55.6% increase in the rate of endogenous glucose production (P = 0.038). We found significant reductions in GU in multiple tissues-skeletal muscle (36.4%), liver (16.1%), brown adipose (29.7%), and bone marrow (32.9%)-and increases of 16.8-19.1% in seven tested brain regions. These data demonstrate that the p.P50T substitution of AKT2 influences insulin-mediated GU in multiple insulin-sensitive tissues and may explain, at least in part, the increased risk of type 2 diabetes in p.P50T/AKT2 carriers.