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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 β-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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To investigate whether alterations in brain glucose uptake (BGU), insulin action in the brain-liver axis and whole-body insulin sensitivity occur in young adults in pre-obese state., Methods: Healthy males with either high risk (HR; n = 19) or low risk (LR; n = 22) for developing obesity were studied with [18F]fluoro-d-glucose ([18F]FDG)-positron emission tomography during hyperinsulinemic-euglycemic clamp. Obesity risk was assessed according to BMI, physical activity and parental overweight/obesity and type 2 diabetes. Brain, skeletal muscle, brown adipose tissue (BAT), visceral adipose tissue (VAT) and abdominal and femoral s.c. adipose tissue (SAT) glucose uptake (GU) rates were measured. Endogenous glucose production (EGP) was calculated by subtracting the exogenous glucose infusion rate from the rate of disappearance of [18F]FDG. BGU was analyzed using statistical parametric mapping, and peripheral tissue activity was determined using Carimas Software imaging processing platform., Results: BGU was higher in the HR vs LR group and correlated inversely with whole-body insulin sensitivity (M value) in the HR group but not in the LR group. Insulin-suppressed EGP did not differ between the groups but correlated positively with BGU in the whole population, and the correlation was driven by the HR group. Skeletal muscle, BAT, VAT, abdominal and femoral SAT GU were lower in the HR group as compared to the LR group. Muscle GU correlated negatively with BGU in the HR group but not in the LR group., Conclusion: Increased BGU, alterations in insulin action in the brain-liver axis and decreased whole-body insulin sensitivity occur early in pre-obese state.

Aim: Obesity is associated with glomerular hyperfiltration which may precede the development of overt renal damage. Few studies evaluated the link between inflammasome signalling and hyperfiltration. The aim is to evaluate the relationship between IL1-β/Caspase-1, insulin sensitivity and hyperfiltration in subjects with severe obesity, before and after weight loss., Methods: Forty-six patients with BMI > 35 kg/m 2 , without type-2-diabetes or hypertension, were evaluated at baseline and 6 months after bariatric surgery with oral glucose tollerance test, bioimpedance analysis and blood tests. The eGFR was calculated according to EPIcr-cys formula and insulin sensitivity by Oral Glucose Insulin Sensitivity. IL-1β/Caspase-1 were measured with the ELISA-kit. HF was defined as eGFR ≥ 140 ml/min (non-indexed for BSA)., Results: Sixteen subjects at baseline had hyperfiltration, with a higher insulin resistance, BMI, lean mass and plasma levels of IL-1β/Caspase-1. After surgery, there was a reduction in BMI and improvement in insulin resistance in all patients. However, in 8 of 16 patients hyperfiltration persisted and IL-1β/Caspase-1 levels did not decrease (3.22 ± 0.79 vs. 3.13 ± 1.03 and 23.7 ± 12.1 vs. 20.6 ± 9.1, pre vs. post, pg/ml), while cytokines normalized in all the other patients in parallel with the eGFR. In a logistic regression model, correcting for the main covariates, lean mass and IL-1β before surgery (p = .01 and p = .03, respectively), were the only predictors of hyperfiltration., Conclusion: Weight loss is effective in reducing hyperfiltration in most, but not all patients. Hyperfiltration remains unchanged in subjects who do not have a reduction in IL-1β/Caspase-1, suggesting a pathogenetic role of the inflammasome signalling in the early stages of nephropathy., (© 2022 Asian Pacific Society of Nephrology.)

Metabolic associated fatty liver disease (MAFLD), formerly named "nonalcoholic fatty liver disease" occurs in about one-third of the general population of developed countries worldwide and behaves as a major morbidity and mortality risk factor for major causes of death, such as cardiovascular, digestive, metabolic, neoplastic and neuro-degenerative diseases. However, progression of MAFLD and its associated systemic complications occur almost invariably in patients who experience the additional burden of intrahepatic and/or systemic inflammation, which acts as disease accelerator. Our review is focused on the new knowledge about the brain-gut-liver axis in the context of metabolic dysregulations associated with fatty liver, where insulin resistance has been assumed to play an important role. Special emphasis has been given to digital imaging studies and in particular to positron emission tomography, as it represents a unique opportunity for the noninvasive in vivo study of tissue metabolism. An exhaustive revision of targeted animal models is also provided in order to clarify what the available preclinical evidence suggests for the causal interactions between fatty liver, dysregulated endogenous glucose production and insulin resistance., Competing Interests: Conflict-of-interest statement: Authors declare that they have no conflicting interests., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: Whereas insulin resistance is expressed as reduced glucose uptake in peripheral tissues, the relationship between insulin resistance and brain glucose metabolism remains controversial. Our aim was to examine the association of insulin resistance and brain glucose uptake (BGU) during a euglycemic hyperinsulinemic clamp in a large sample of study participants across a wide range of age and insulin sensitivity., Research Design and Methods: [ 18 F]-fluorodeoxyglucose positron emission tomography (PET) data from 194 participants scanned under clamp conditions were compiled from a single-center cohort. BGU was quantified by the fractional uptake rate. We examined the association of age, sex, M value from the clamp, steady-state insulin and free fatty acid levels, C-reactive protein levels, HbA 1c , and presence of type 2 diabetes with BGU using Bayesian hierarchical modeling., Results: Insulin sensitivity, indexed by the M value, was associated negatively with BGU in all brain regions, confirming that in insulin-resistant participants BGU was enhanced during euglycemic hyperinsulinemia. In addition, the presence of type 2 diabetes was associated with additional increase in BGU. On the contrary, age was negatively related to BGU. Steady-state insulin levels, C-reactive protein and free fatty acid levels, sex, and HbA 1c were not associated with BGU., Conclusions: In this large cohort of participants of either sex across a wide range of age and insulin sensitivity, insulin sensitivity was the best predictor of BGU., (© 2021 by the American Diabetes Association.)

Introduction: Insulin regulates renal glucose production and utilization; both these fluxes are increased in type 2 diabetes (T2D). Whether insulin also controls urinary glucose excretion is not known., Methods: We applied the pancreatic clamp technique in 12 healthy subjects and 13 T2D subjects. Each participant received a somatostatin infusion and a variable glucose infusion to achieve (within 1 hour) and maintain glycemia at 22 mmol/L for 3 hours; next, a constant insulin infusion (240 pmol/min/kg) was added for another 3 hours. Urine was collected separately in each period for glucose and creatinine determination., Results: During saline, glucose excretion was lower in T2D than controls in absolute terms (0.49 (0.32) vs 0.69 (0.18) mmol/min, median (IQR), p=0.01) and as a fraction of filtered glucose (16.2 (6.4) vs 19.9 (7.5)%, p<0.001). With insulin, whole-body glucose disposal rose more in controls than T2D (183 (48) vs 101 (48) µmol/kg FFM /min, p<0.0003). Insulin stimulated absolute and fractional glucose excretion in controls (p<0.01) but not in T2D. Sodium excretion paralleled glucose excretion. In the pooled data, fractional glucose excretion was directly related to whole-body glucose disposal and to fractional sodium excretion (r=0.52 and 0.54, both p<0.01). In another group of healthy controls, empagliflozin was administered before starting the pancreatic clamp to block sodium-glucose cotransporter 2 (SGLT2). Under these conditions, insulin still enhanced both glucose and sodium excretion., Conclusions: Acute exogenous insulin infusion jointly stimulates renal glucose and sodium excretion, indicating that the effect may be mediated by SGLTs. This action is resistant in patients with diabetes, accounting for their increased retention of glucose and sodium, and is not abolished by partial SGLT2 inhibition by empagliflozin., Competing Interests: Competing interests: EF has participated in scientific advisory boards for Boehringer Ingelheim, Eli Lilly, and Sanofi; has been involved in ad hoc consulting for Janssen, AstraZeneca, and Mitsubishi Tanabe; has participated in occasional speaking engagements for AstraZeneca, Novo Nordisk, Sanofi, Mitsubishi Tanabe, Eli Lilly, Boehringer Ingelheim, and Merck Sharp & Dohme; and has received research grant support from Boehringer Ingelheim and AstraZeneca., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Previous work has shown that potentiation of insulin release is impaired in non-diabetic insulin resistance; we tested the hypothesis that this defect may be related to altered glucagon-like peptide-1 (GLP-1) release. On consecutive days, 82 non-diabetic individuals, classified as insulin sensitive (IS, n =41) or insulin resistant (IR, n =41) by the euglycaemic clamp, were given two sequential mixed meals with standard (75 g, LCD) or double (150 g, HCD) carbohydrate content. Plasma glucose, insulin, C-peptide, non-esterified fatty acids (NEFA) and GLP-1 concentrations were measured; β-cell function (glucose sensitivity and potentiation) was resolved by mathematical modelling. Fasting GLP-1 levels were higher in IR than IS (by 15%, P =0.006), and reciprocally related to insulin sensitivity after adjustment for sex, age, fat mass, fasting glucose or insulin concentrations. Mean postprandial GLP-1 responses were tightly correlated with fasting GLP-1, were higher for the second than the first meal, and higher in IR than IS subjects but only with LCD. In contrast, incremental GLP-1 responses were higher during (i) the second than the first meal, (ii) on HCD than LCD, and (iii) significantly smaller in IR than IS independently of meal and load. Potentiation of insulin release was markedly reduced in IR vs IS across meal and carbohydrate loading. In the whole dataset, incremental GLP-1 was directly related to potentiation, and both were inversely related to mean NEFA concentrations. We conclude that (a) raised GLP-1 tone may be inherently linked with a reduced GLP-1 response and (b) defective post-meal GLP-1 response may be one mechanism for impaired potentiation of insulin release in insulin resistance., (© 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Restoring euglycaemia for weeks or months improves insulin secretion in patients with type 2 diabetes (T2D). We tested whether mild decrements in fasting glucose (FPG) acutely affect β-cell function and insulin sensitivity. Thirteen normotolerant (NGT) and 10 T2D patients volunteered in pairs. In an isoglycemic test (Iso), after 100 min of stabilization, an incremental glucose infusion over 3 h was applied to raise plasma glucose to >22 mmol/l, followed by an arginine challenge; in a subisoglycemic test (Sub), a glucose infusion matching the plasma glucose time course of Iso was preceded by an insulin infusion period (100 min) aimed at maintaining a mild FPG reduction while avoiding hypoglycaemia. β-Cell function was assessed by mathematical modeling, whereas the acute insulin response (AIR) to arginine was determined from C-peptide levels. In the Sub, FPG was lowered by 17% in NGT and 31% in T2D patients. On the glucose ramp, total insulin release was lower in Sub than in Iso in both groups [from 106 (43) to 75 (39) nmol/m(-2) in NGT and from 71 (63) to 64 (41) nmol/m(-2) in T2D, P = 0.001]. In the Sub, β-cell glucose sensitivity was significantly (P = 0.008) reduced in NGT [from 50 (31) to 43 (21) pmol·min(-1)·m(-2)·mM(-1)] but not in T2D [19 (20) to 20 (20) pmol·min(-1)·m(-2)·mM(-1)]. Likewise, AIR was lowered in NGT [8.9 (4.6) to 7.1 (4.4) nmol/l, P = 0.048] but not in T2D [4.7 (3.3) to 5.3 (3.2) nmol/l]. Insulin sensitivity improved in NGT but only marginally in T2D. Prestimulatory glucose levels acutely influence both β-cell function and insulin sensitivity differentially in nondiabetic and type 2 diabetic individuals., (Copyright © 2016 the American Physiological Society.)

Aims/hypothesis: It is a commonly held view that chronically elevated NEFA levels adversely affect insulin secretion and insulin action (lipotoxicity). However, the effect of NEFA on beta cell function has only been explored using acute NEFA elevations. Our aim was to analyse the relationship between endogenous NEFA levels and beta cell function., Methods: In 1,267 individuals followed-up for 3 years, we measured insulin sensitivity (by clamp) and beta cell function (by C-peptide modelling during OGTT and as the acute insulin response [AIR] to IVGTT)., Results: At baseline, both fasting and insulin-suppressed NEFA levels were higher across glucose tolerance groups, while insulin sensitivity was lower, insulin output was higher, and beta cell glucose sensitivity and AIR were lower (all p < 0.0001). In multiple logistic analyses adjusting for age, BMI, WHR and glucose tolerance, both fasting and insulin-suppressed NEFA levels were inversely related to insulin sensitivity, as expected (both p < 0.0001). Furthermore, after adjusting for insulin sensitivity, insulin-suppressed NEFA were positively associated with total insulin output (p = 0.0042). In contrast, neither fasting nor insulin-suppressed NEFA were related to beta cell glucose sensitivity or AIR. At follow-up, worsening of glucose tolerance (n = 126) was predicted by lower insulin and beta cell glucose sensitivity. In this model, baseline NEFA were not significant predictors of progression., Conclusions/interpretation: In the non-diabetic state and in subjects with impaired glucose tolerance, circulating endogenous NEFA are not independently associated measures of beta cell function, and do not predict deterioration of glucose tolerance. Thus, in the Relationship Between Insulin Sensitivity and Cardiovascular Disease (RISC) cohort there is no evidence for beta cell lipotoxicity of endogenous total NEFA concentrations.

Objective: Previous studies have found that high insulin sensitivity predicts weight gain; this association has not been confirmed. Our aim was to systematically analyze metabolic predictors of spontaneous weight changes., Research Design and Methods: In 561 women and 467 men from the Relationship Between Insulin Sensitivity and Cardiovascular Disease (RISC) cohort (mean age 44 years, BMI range 19-44 kg/m(2), 9% impaired glucose tolerance) followed up for 3 years, we measured insulin sensitivity (by a euglycemic clamp) and β-cell function (by modeling of the C-peptide response to oral glucose and by acute insulin response to intravenous glucose)., Results: Insulin sensitivity was similar in weight gainers (top 20% of the distribution of BMI changes), weight losers (bottom 20%), and weight stable subjects across quartiles of baseline BMI. By multiple logistic or linear regression analyses controlling for center, age, sex, and baseline BMI, neither insulin sensitivity nor any β-cell function parameter showed an independent association with weight gain; this was true in normal glucose tolerance, impaired glucose tolerance, and whether subjects progressed to dysglycemia or not. Baseline BMI was significantly higher in gainers (26.1 ± 4.1 kg/m(2)) and losers (26.6 ± 3.7 kg/m(2)) than in weight stable subjects (24.8 ± 3.8 kg/m(2), P<0.0001 for both gainers and losers). Baseline waist circumference (or equivalently, BMI or weight) was a positive, independent predictor of both weight gain and weight loss (odds ratio 1.48 [95% CI 1.12-1.97]) in men and (1.67 [1.28-2.12]) in women. In men only, better insulin sensitivity was an additional independent predictor of weight loss., Conclusions: Neither insulin sensitivity nor insulin secretion predicts spontaneous weight gain. Individuals who have attained a higher weight are prone to either gaining or losing weight regardless of their glucose tolerance., (© 2011 by the American Diabetes Association.)

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. [ABSTRACT FROM AUTHOR]

Furthermore, a combined metabolic and neuroimaging study in patients with cognitive decline (for instance, an assessment of brain glucose metabolism under fasting and insulin clamp conditions) could answer the quandary of whether central nervous system insulin resistance is present in patients with prodromal AD, i.e., mild cognitive impairment due to AD, and would shed light on the question of whether central nervous system insulin resistance can be demonstrated in vivo in these patients. While the most important risk factor for AD is old age, there are also acknowledged modifiable risk factors for AD including metabolic risk factors, i.e., obesity, T2D, hypertension, and hypercholesterolemia [[4]]. Second, although insulin resistance has been demonstrated at the cellular level in post-mortem brain tissues in AD patients [[16]], no neuroimaging studies have yet examined central insulin resistance in patients with cognitive decline. A recent review article concluded that altogether 101 million individuals have either Alzheimer's dementia or mild cognitive impairment due to AD [[3]]. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

The physiopathology of fatty liver and metabolic syndrome are influenced by diet, life style and inflammation, which have a major impact on the severity of the clinicopathologic outcome of non-alcoholic fatty liver disease. A short comprehensive review is provided on current knowledge of the pathophysiological interplay among major circulating effectors/mediators of fatty liver, such as circulating lipids, mediators released by adipose, muscle and liver tissues and pancreatic and gut hormones in relation to diet, exercise and inflammation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]