Introduction and Objective: Brain insulin sensitivity plays a central role in coordinating whole-body metabolism. In humans, reduced brain insulin responsiveness is linked to weight gain, visceral adiposity, and impaired metabolic control. Experimental work shows that intranasal insulin (INI) delivers insulin to the brain with minimal systemic effects. Building on this concept, we aimed to enhance central insulin signaling in humans through long-term INI treatment. We hypothesized that INI treatment enhances brain insulin sensitivity while leading to a more favorable body fat distribution. Methods: In this randomized, controlled, blinded study, 39 healthy individuals (age 60.6 ± 7.4 years; 67% women) were randomized to daily INI (160 IU, n=19) or placebo (PLA, n=20) spray treatment for 8 weeks. Before (t=0) and after (t=8wk) the treatment period, individuals were deeply phenotyped, including whole-body MRI for body fat quantification and functional MRI combined with acute INI to assess brain insulin sensitivity. Data are displayed as median ± 95% CI. Results: Body mass index (BMI) was similar between groups at baseline (t=0, INI: 28.2 ± 2.3 vs PLA 29.7 ± 3.1 kg/m2; p=0.51) and decreased only in the INI group (t=8wk, BMI: INI 27.3 ± 2.3, vs t=0; p=0.046, PLA: 30.2 ± 3.0 kg/m2, vs t=0; p=0.14). This was paralleled by a reduction in subcutaneous adipose tissue in the INI but not in the PLA group (Time point X Treatment p=0.01; t=0 vs t=8wk: INI 13.3 ± 2.2 L vs 12.5 ± 2.3 L; p=0.03; PLA 14.0 ± 2.7 L vs 15.4 ± 3.0 L; p=0.93). Hypothalamic insulin sensitivity increased in the INI but not in the placebo group (Time point X Treatment p=0.01; t=0 vs t=8wk: INI p=0.007; PLA p>0.99). Conclusion: Chronic INI treatment improves hypothalamic insulin sensitivity in adults with overweight or obesity, and this effect is accompanied by a reduction in BMI and subcutaneous fat. These findings highlight brain insulin responsiveness as a therapeutic target to counteract elevated body weight and body fat content. Disclosure L. Sandforth: None. R. Veit: None. C. Dannecker: None. R.J. von Schwartzenberg: None. A. Vosseler: None. M. Hallschmid: None. R. Wagner: Advisory Panel; Current; Sanofi. Speaker's Bureau; Ended; Daiichi Sankyo, Novo Nordisk. A.L. Birkenfeld: None. P. Hubert: None. A. Fritsche: None. M. Heni: Advisory Panel; Ended; Chiesi USA, Inc. Speaker's Bureau; Ended; Chiesi USA, Inc. Advisory Panel; Ended; Boehringer Ingelheim International GmbH. Speaker's Bureau; Ended; Boehringer Ingelheim International GmbH, AstraZeneca, Lilly, Novartis AG, Novo Nordisk, Bayer AG. S. Kullmann: None.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) represent a major advancement in obesity treatment, offering robust efficacy in weight loss and metabolic regulation. Beyond these effects, emerging evidence indicates that GLP-1 RAs also modulate appetite, reward sensitivity, and self-regulation, domains that intersect with behavioral and psychological functioning. This review adopts a biopsychosocial perspective to examine how GLP-1 RAs interact with eating behavior, mood, identity, and self-regulation, particularly in individuals with binge eating disorder (BED) or other psychiatric comorbidities. A clinical framework is proposed to integrate pharmacotherapy with lifestyle and psychological interventions. The temporary reduction in appetite and food reward may create a "low-drive window" in which behavioral strategies such as self-monitoring or stimulus control become more effective. However, high emotional eating, mood symptoms, or identity conflicts may moderate treatment response. Given the high prevalence of psychiatric comorbidities, structured screening using tools like the Patient Health Questionnaire-9 (PHQ-9) or Binge Eating Scale (BES) is recommended. A stepped-care approach from brief digital interventions to formal psychotherapy may help address varying support needs. Crucially, weight regain after discontinuation is common. The review discusses behavioral, psychological, and social mechanisms of relapse and highlights strategies for long-term stabilization. These include emotion regulation, body image work, and maintenance-focused behavioral interventions. GLP-1 RAs should therefore be seen not as standalone treatments but as facilitators of self-directed, sustainable change within integrated care models. Future research should define composite outcomes, explore digital tools for relapse prevention, and develop adaptive pathways tailored to individual psychological profiles.

Impairments in peripheral glucose metabolism and reduced brain insulin sensitivity are linked to an increased risk of both metabolic and neurodegenerative diseases. Brain insulin resistance represents a shared pathological mechanism underlying these disorders. Notably, hippocampal insulin responsiveness declines with age and differs between men and women. This study aimed to identify clinically relevant metabolic predictors of hippocampal insulin sensitivity in the context of age and sex. In 260 non-diabetic participants (165 women, mean BMI 29.7 ± 6.2 kg/m2, mean age 44.2 ± 16.6 years), functional MRI was performed before and after intranasal insulin administration to assess hippocampal insulin response. Metabolic phenotyping comprised laboratory assessments including oral glucose tolerance tests, whole-body MRI and 1H-MRS. In addition, participants were assigned to high- and low-risk prediabetes clusters using the Tübingen risk cluster tool. Prediabetes was defined as impaired fasting glucose and/or impaired glucose tolerance and/or elevated HbA1c. We used linear regression models to select the most relevant predictors, including interactions with sex and age. Fasting plasma glucose levels predicted lower hippocampal insulin response with age independently of sex (estimate 0.533, p=0.016). Significant interactions were present between age, sex and body fat distribution (waist-to-hip ratio [WHR]: estimate 0.233, p=0.010; visceral adipose tissue [VAT]: estimate 0.007, p=0.013; intrahepatic lipid content [IHL]: estimate 0.003, p=0.010). In women, higher WHR, VAT and IHL were predictors of lower hippocampal insulin responsiveness with increasing age. These effects remained significant after adjusting for BMI. Postmenopausal women showed lower hippocampal insulin responsiveness with higher WHR and IHL (p<0.05), and women in high-risk Tübingen prediabetes clusters also showed lower hippocampal insulin responsiveness than men (sex × cluster type: estimate 0.39, p=0.02). The hippocampal insulin response did not correlate with hippocampal volume (p>0.05). Unhealthy body fat distribution was a sex-dependent predictor for decreased hippocampal insulin sensitivity with increasing age. Older women with high abdominal fat and/or those assigned to high-risk clusters were most vulnerable to impaired insulin responsiveness in the hippocampus. These findings may contribute to explaining sex differences in the development of type 2 diabetes and neurodegenerative diseases.

The menstrual cycle impacts food intake, peripheral metabolism, and brain function. One well-known central regulator of eating behavior is the hormone insulin. Here, we show that the responsiveness of functional brain networks to central insulin varies dynamically across the menstrual cycle in premenopausal women. Intranasal insulin (INI) administration increases functional connectivity within networks that support decision-making processes (namely the default mode and salience network) in the follicular compared to the luteal phase of the menstrual cycle. In contrast, INI decreases functional connectivity within the somatosensory network during the follicular phase relative to the luteal phase. In response to visual food cues, hippocampus and dorsal striatum activity are higher in the luteal compared to the follicular phase, particularly to sweet food. Estradiol and progesterone levels predict these changes. This could contribute to higher food craving and food intake observed in the luteal phase. Our findings emphasize sex hormones' role in modulating brain sensitivity to hormonal signals and external stimuli.

BACKGROUND:Pregnancy-induced food cravings are associated with excessive gestational weight gain and gestational diabetes mellitus (GDM). This study aimed to measure brain responses to food pictures with varying fat and carbohydrate content during pregnancy in women with and without GDM. METHODS:To characterize brain-metabolism coupling, we recorded visual evoked potentials (VEPs) in pregnant individuals with and without GDM (24-36 weeks gestation) while they viewed food pictures varying in fat and carbohydrate content. Eighteen women with untreated GDM and 21 healthy pregnant controls participated. HbA1c levels were obtained from blood samples. Statistical analyses assessed group differences and interactions. RESULTS:Within the initial ~150 ms post-stimulus onset, VEPs exhibited Group × Fat (p = 0.047, ηp2 = 0.103), but no Group × Carb, interactions: Healthy pregnant controls showed stronger responses to images of high- versus low-fat foods, whereas individuals with GDM did not. Source estimations localized these effects to brain regions associated with control, attention, and reward. Moreover, brain responses correlated with HbA1c levels in GDM (p = 0.01, ηp2 = 0.351), but not with pre-pregnancy BMI in either group. CONCLUSION:These results provide evidence of links between spatiotemporal brain responses to visual food cues and metabolic health in pregnancy.

AIMS:Elevated fasting glucagon is linked to hyperglycemia, but postprandial glucagon effects are less understood. Recent evidence suggests metabolic benefits of rising glucagon after oral glucose intake, potentially impacting brain-mediated whole-body metabolism. To elucidate the translational relevance of these findings, we studied postprandial effects of glucagon on the human brain. MATERIALS AND METHODS:We performed oral glucose tolerance tests (OGTT) combined with functional magnetic resonance imaging to quantify brain activity and connectivity at fasting, 30 and 120 min post glucose load in 30 volunteers. In 14 participants with suppressed glucagon, low-dose glucagon infusion mimicked non-suppressed glucagon after OGTT. This was compared to 7 participants with endogenous rising glucagon during OGTT. RESULTS:Low-dose glucagon infusion did not elevate plasma glucose levels during OGTT. Also, no changes in insulin sensitivity and insulin secretion were observed. However, experimentally elevating glucagon during OGTT in individuals with physiological suppression of glucagon significantly increased postprandial brain responsivity in the hippocampal gyrus and in brain regions important for the homeostatic and hedonic regulation of food intake as well as systemic metabolism (i.e., hypothalamus and ventral striatum). Most postprandial brain responsiveness during glucagon infusion was directionally consistent with the findings in persons with endogenously rising glucagon. Moreover, the postprandial brain response correlated with the rise in glucagon, regardless of exogenous or endogenous source of glucagon. Although the overall glucagon trajectory during OGTT was not significantly different over the full 0-150 min period, the groups differed at key post-challenge timepoints and in integrated glucagon exposure. Together with the infusion and correlation analyses, this supports a relationship between postprandial glucagon and brain responsivity, while more subtle differences in glucagon kinetics will require larger studies. CONCLUSIONS:Our findings demonstrate postprandial effects of glucagon in metabolically relevant human brain areas. This may underlie the promising effects on body weight achieved with pharmacological multi-agonists that activate the glucagon receptor.

Introduction and Objective: Gestational diabetes mellitus (GDM) increases the risk of early-onset prediabetes (<40 years). We hypothesized that biological pathways mediating the transition from pregnancy to early-onset prediabetes one year postpartum differ between women with prior GDM and those with normoglycemic (NG) pregnancies, using stratified longitudinal analyses with deep metabolic phenotyping. Methods: In the prospective, multicenter PREG study, we evaluated 181 women (56 GDM; 125 NG) at 24+0-31+6 weeks gestation and again at one year postpartum. Assessments included anthropometrics, OGTT-based indices of insulin resistance (IR) and secretion, hormonal analyses including incretins, MRI/¹H-MRS-based body fat distribution, and untargeted metabolomics. Results: Early-onset prediabetes occurred in 35% of women with prior GDM and 24% of women with NG pregnancies. Among NG women, progression to prediabetes was mainly driven by increasing IR, predominantly hepatic, alongside greater hepatic and visceral fat accumulation compared with NG women who remained normoglycemic. In contrast, among women with GDM, those transitioning to prediabetes versus those regressing to normoglycemia showed similar trajectories of whole-body IR and hepatic/visceral fat but uniquely failed to increase beta-cell function from pregnancy to one year postpartum. Beta-cell function increased postpartum in all groups except the prior-GDM group. Pregnancy metabolomics identified elevated triglyceride-rich lipoproteins and VLDL particles as predictors of early-onset prediabetes independent of GDM status. Conclusion: Early-onset prediabetes within one year postpartum is common after both GDM and NG pregnancies but arises via distinct mechanisms: persistent beta-cell dysfunction after GDM and rising IR with hepatic and visceral fat accumulation after NG pregnancies. These findings support stringent postpartum screening and mechanism-tailored prevention strategies. Disclosure J. Sbierski-Kind: None. M. Ganslmeier: None. Y. Kober: None. A. Vosseler: None. L. Semeia: None. S. Kullmann: None. M. Roden: Advisory Panel; Current; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly, Madrigal Pharmaceuticals, Inc., Novo Nordisk, Sanofi, Echosens. M. Bluher: Consultant; Current; Amgen Inc. Speaker's Bureau; Current; Abbott. Consultant; Current; Bayer AG, Boehringer Ingelheim International GmbH. Speaker's Bureau; Current; Daiichi Sankyo. Consultant; Current; Eli Lilly and Company, Novo Nordisk. Speaker's Bureau; Current; Merck Sharp & Dohme Corp., Sanofi, Novartis AG. M. Schulze: None. N. Stefan: Speaker's Bureau; Current; AstraZeneca. Advisory Panel; Ended; Boehringer Ingelheim International GmbH. Speaker's Bureau; Ended; Boehringer Ingelheim International GmbH. Advisory Panel; Ended; Lilly. Speaker's Bureau; Current; Lilly. Advisory Panel; Ended; Pfizer Inc., Madrigal Pharmaceuticals, Inc. Speaker's Bureau; Ended; Madrigal Pharmaceuticals, Inc. Research Support; Ended; Sanofi. Speaker's Bureau; Current; Sanofi. R.J. von Schwartzenberg: None. A. Fritsche: None. C. Trautwein: None. P. Hubert: None. A.L. Birkenfeld: None. Funding The PREG study is supported in part by a grant from the Federal Ministry of Education and Research 397 (BMBF) (01GI0925) to the German Center for Diabetes Research (DZD). We also thank the Joachim Herz Foundation for supporting L.S. through an Add-on Fellowship. J.S.K. is supported by the Medical Faculty of the University of Tuebingen, the German Diabetes Association (DDG), and the DZD. In addition to funding by the BMBF, RJvS was funded by the Funding Program: Helmholtz Young Investigators Groups. Project ID No.: VH-NG-1619 and the Cluster of Excellence EXC-2124 under the Project Number 03.007. Quantitative NMR spectroscopy analysis was supported by Bruker BioSpin GmbH & Co. KG Ettlingen, Germany. The study was additionally funded by a grant from the German Research Foundation (DFG) to ALB (GRK2816).

Type 2 diabetes (T2D) is associated with cognitive impairment, but it remains unclear whether this reflects primary effects of metabolic dysfunction or secondary consequences of comorbid conditions, as most studies have focused on older adults. To address this, we examined the relationship between prediabetes and cognition in youth with overweight/obesity in a 2-year longitudinal study (n=67 at baseline; n=42 at follow-up). Participants underwent comprehensive cognitive testing, metabolic phenotyping, and structural and functional neuroimaging. At baseline, youth with prediabetes exhibited lower IQ and poorer performance in executive function, psychomotor speed, and visuospatial processing compared to those with normal glucose control, independent of adiposity. Across the full sample, reduced peripheral insulin sensitivity was associated with slower processing speed and altered central insulin sensitivity in the intraparietal sulcus. Longitudinally, cognitive differences between groups were stable over 2 years and were not explained by changes in adiposity or glucose tolerance. In contrast, expected developmental reductions in cortical surface area were observed only in youth with normal glucose control. These findings demonstrate that prediabetes in youth is associated with a broad and stable neurocognitive disadvantage that is independent of adiposity and not readily reversible with short-term changes in metabolic status. The early emergence and persistence of these differences suggest that altered neurocognitive function may be a feature of metabolic risk prior to overt disease onset. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by R01 DK114169 awarded to D.M.S and S.C. from the National Institute of Health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The IRB Human Investigation Committee of Yale University gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes De-identified data may be accessed on a case-by-case basis by contacting the corresponding author.

Background Drinks with low-no-calorie sweeteners (LNCSs) do not contribute to energy intake but still provide a hedonic experience through sweetness. LNCS can have differential effects on brain areas involved in food intake and reward compared with sugars. Objectives This study determined changes in brain activity and the effect on physiological markers following the ingestion of flavored waters sweetened with the sugar sucrose or LNCS. Methods Thirty healthy individuals participated in a randomized crossover study with 6 treatments. Participants were scanned after an overnight fast using magnetic resonance imaging, including arterial spin labeling to measure cerebral blood flow (CBF), before and after ingestion of 500-mL drinks: water, or equisweet flavored waters with 25 g sucrose, sucralose, stevia extract, allulose+stevia extract, or monk fruit extract. CBF was measured at baseline and 5 and 30 min; gastric content volume was measured at baseline and 25 and 45 min. Serum insulin and glucose were measured, and participants rated their appetite and thirst throughout each visit. Data were analyzed with linear mixed models. Results Primary: Hypothalamus CBF was not differentially affected by any of the drinks. In the ventral tegmental area (midbrain), treatment effects differed, with lower ΔCBF after sucrose than water, sucralose and monk fruit drink ingestion at 30 min (difference: ∼8% ± 3%; all PFDR < 0.05). Exploratory whole-brain analyses showed increased CBF after consumption for allulose+stevia (amygdala) and stevia (putamen) compared with sucrose (PFWE < 0.05). Despite its low energy content, allulose+stevia delayed gastric emptying similar to sucrose, whereas only sucrose increased glucose and insulin concentrations. Conclusions Although flavored waters with LNCS mostly elicit similar neural and gastrointestinal responses as water, they have some distinct effects on the brain compared with 25 g of sucrose, particularly in reward-related brain areas. Further exploration of the neural and physiological effects of allulose and stevia and dose-dependent investigations are warranted.This study was registered at clinicaltrials.gov as NCT05575687 (https://clinicaltrials.gov/study/NCT05575687).

Type 2 diabetes (T2D) prevention efforts have largely focused on intervening when dysglycemia is already established. We propose that T2D prevention be reframed around prediabetes remission, with preservation and restoration of normoglycemia as the optimal clinical goal. The transition from normoglycemia through increasing dysglycemia to T2D is progressive and cumulatively shaped by biological, behavioral and environmental exposures across the life course. Prediabetes (intermediate hyperglycemia) remission is an achievable, pragmatic and measurable prevention target. Here we provide a life-course risk architecture for T2D integrating developmental, transitional and contextual determinants, defining critical windows of amplified metabolic vulnerability and potential restoration of normoglycemia. Precision prevention should target mechanistic heterogeneity, with aligned interventions that remain scalable, affordable and adaptable across socioeconomic settings. Our framework identifies ten priorities in T2D prevention, moving beyond traditional approaches toward context-specific, actionable interventions capable of altering the natural history of disease early in the life course and restoring metabolic health.

Sucralose, a widely used non-caloric sweetener, provides sweet taste without calories. Some studies suggest that non-caloric sweeteners stimulate appetite, possibly owing to the delivery of a sweet taste without the post-ingestive metabolic signals that normally communicate with the hypothalamus to suppress hunger. In a randomized crossover trial (ClinicalTrials.gov identifier: NCT02945475 ), 75 young adults (healthy weight, overweight or with obesity) consumed a drink containing sucralose, sweetness-matched sucrose or water. We show that acute consumption of sucralose versus sucrose stimulates hypothalamic blood flow (P < 0.018) and greater hunger responses (P < 0.001). Sucralose versus water also increases hypothalamic blood flow (P < 0.019) but produces no difference in hunger ratings. Sucrose, but not sucralose, increases peripheral glucose levels, which are associated with reductions in medial hypothalamic blood flow (P < 0.007). Sucralose, compared to sucrose and water, results in increased functional connections between the hypothalamus and brain regions involved in motivation and somatosensory processing. These findings suggest that non-caloric sweeteners could affect key mechanisms in the hypothalamus responsible for appetite regulation. In a randomized, crossover clinical trial in healthy young adults with varying weights, sucralose increased hypothalamic blood flow and its functional connections with brain regions involved in motivation and somatosensory processing.

BACKGROUND:Reduced inhibitory control is associated with obesity and neuroimaging studies indicate that diminished prefrontal cortex activity influence eating behavior and metabolism. The hypothalamus regulates energy homeostasis and is functionally connected to cortical and subcortical regions especially the frontal areas. OBJECTIVES:We tested network-targeted transcranial direct current stimulation (net-tDCS) to influence the excitability of brain regions involved in appetite control. METHODS:In a randomized, double-blind parallel group design, 44 adults with overweight or obesity (BMI 30.6 kg/m2, 52.3 % female) received active (anodal or cathodal) or sham 12-channel net-tDCS on the hypothalamus appetite-control network for 25 min on three consecutive days while performing a Stop-Signal-Task to measure response inhibition. Before and after stimulation, state questionnaires assessed changes in desire to eat and food craving. Directly after stimulation, participants received a breakfast buffet to evaluate ad-libitum food intake. An oral glucose tolerance test was conducted at follow-up. Resting-state functional MRI was obtained at baseline and follow-up. RESULTS:The Stop-Signal Reaction Time (SSRT) was shorter in both active groups versus sham, indicating improved response inhibition. Additionally, a stronger increase in hypothalamic functional connectivity was associated with shorter SSRT. Caloric intake of sweet food was lower in the anodal group versus sham, but no main effects between groups were observed on total and macronutrient intake, food craving ratings and desire to eat. At follow-up, no differences were observed between groups on peripheral metabolism. CONCLUSION:Our study suggests that modulating hypothalamic functional network connectivity patterns via net-tDCS may improve food choice and inhibitory control.

OBJECTIVE:Insulin resistance during childhood is a risk factor for developing type 2 diabetes and other health problems later in life. Studies in adults have shown that insulin resistance affects regional and network activity in the brain which are vital for behavior, including ingestion and metabolic control. To date, no study has investigated how brain connections during exposure to food cues are association with peripheral insulin sensitivity in children. METHODS:We included 53 children (36 girls) between the age of 7-11 years, who underwent an oral Glucose Tolerance Test (oGTT) to estimate peripheral insulin sensitivity (ISI). Brain responses were measured using functional magnetic resonance imaging (fMRI) before and after glucose ingestion. We compared food-cue task-based activity and functional connectivity (FC) between children with lower and higher ISI, adjusted for age and BMIz. RESULTS:Independent of prandial state (i.e., glucose ingestion), children with lower ISI showed higher FC between the anterior insula and caudate and lower FC between the posterior insula and mid temporal cortex than children with higher ISI. Sex differences were found based on prandial state and peripheral insulin sensitivity in the insular FC. No differences were found on mean brain responses to food cues. CONCLUSIONS:In response to food cues, children with lower peripheral insulin sensitivity exhibited distinctive patterns of neural connectivity, notably in the insula's functional connections, when contrasted with their counterparts with higher peripheral insulin sensitivity. These differences might influence eating behavior and future risk of developing diabetes.

Obesity, particularly pediatric obesity, has dramatically increased over the last three decades, with a wide range of detrimental health outcomes, including negative consequences for brain neurodevelopment. The present article reviewed magnetic resonance imaging studies between January 2011 and March 2024 examining the brain's role in pediatric obesity, including parental influences and diverse interventions. A literature search identified 97 eligible MRI studies in the pediatric population. Findings suggest that altered brain structures and functions in pediatric obesity are strongly dependent on the developmental stage of children and adolescents. The function and structure of limbic regions, such as the hippocampus, amygdala, and striatum, as well as the prefrontal cortex, seem to be particularly affected by higher body mass index during development. In response to palatable foods, children and adolescents with excess weight have increased activation in reward-related regions and decreased activation in regions involved in interoceptive signal processing, especially during decision processes. In addition, children of mothers with obesity and gestational diabetes mellitus show alterations in brain structure and function independent of their current obesity. Behavioral, exercise, and weight-loss intervention studies showed promising effects on the brain, with increased structural integrity, decreased brain responses to reward, and strengthened inhibitory brain responses in children and adolescents with excess weight after the intervention.

Prediabetes is a highly prevalent and increasingly common condition affecting a significant proportion of the global population. The heterogeneous nature of prediabetes presents a challenge in identifying individuals who particularly benefit from lifestyle or other therapeutic interventions aiming at preventing type 2 diabetes (T2D) and associated comorbidities. The phenotypic characteristics of individuals at risk for diabetes are associated with both specific risk profiles for progression and a differential potential to facilitate prediabetes remission and reduce the risk of future T2D. This review examines the current definition and global prevalence of prediabetes and evaluates the potential of prediabetes remission to reduce the alarming increase in the global burden of T2D.

Brain insulin responsiveness is linked to long-term weight gain and unhealthy body fat distribution. Here we show that short-term overeating with calorie-rich sweet and fatty foods triggers liver fat accumulation and disrupted brain insulin action that outlasted the time-frame of its consumption in healthy weight men. Hence, brain response to insulin can adapt to short-term changes in diet before weight gain and may facilitate the development of obesity and associated diseases.

Aims/Hypothesis:Type 2 diabetes has a well-established link to cognitive impairment in older adults; however, studies often do not control for adiposity and co-morbid conditions which might mediate this cognitive impairment. To overcome these limitations, we investigated the relation between prediabetes and cognition in youth with overweight/obesity while controlling for adiposity in a cross-sectional ancillary study to the Pathogenesis of Youth Onset Diabetes (PYOD) study. We reasoned that if glucose control directly impacts brain health, then cognitive function should be worse in youth with versus without prediabetes. We also predicted that this effect should be greater on tasks that depend on dopaminergic function, such as working memory and that it may be related to central insulin sensitivity. Methods:We evaluated 69 youth with overweight/obesity for anthropomorphic and metabolic measures, abdominal adiposity, comprehensive cognitive testing, and the effects of intranasal insulin on cognition, resting state brain activity, and functional connectivity. Oral glucose tolerance tests classified 22 participants as having prediabetes (preT2D+) and 44 participants as having normal glucose control (preT2D-). Results:Groups did not differ in age, sex, race, diet, or adiposity measures. IQ was significantly lower (p=0.032) in the preT2D+ group compared to the preT2D-group. The preT2D+ group performed worse than the preT2D-group in tasks of working memory (p<.0.001), reaction time (p=0.01), and visuospatial processing (p=0.02). After considering IQ as a model covariate, only spatial working memory showed a significant difference between groups (p=0.002). Insulin sensitivity across the entire sample was negatively correlated with processing speed in two tasks (reaction time index: p=0.022; and trail making test A: p=0.022) and with the sensitivity of the intraparietal sulcus to intranasal insulin administration. Administration of intranasal insulin showed no effect on cognition within or between groups. However, the extent to which intranasal insulin administration influenced caudate functional connectivity with the right intraparietal sulcus (p (FWE) =0.018) and bilateral medial precuneus (p (FWE) =0.03) was correlated with performance on the spatial working memory task. Conclusions/interpretation:We find evidence for the presence of global cognitive impairment in youth with prediabetes that cannot be accounted for by adiposity, as well as a specific deficit in spatial working memory that is not attributable to global cognitive impairment. We identified associations between central insulin sensitivity and both cognition and peripheral insulin sensitivity; however, central insulin sensitivity did not appear to account for the effect of prediabetes on cognition. These findings show that the association between peripheral glucose intolerance and cognition exists early in the course of the disease, prior to the onset of significant comorbid conditions and independently of adiposity. It also suggests the involvement of both generalized and specific mechanisms contributing to cognitive change. Research in Context:What is already known about this subject? (maximum of 3 bullet points) Type 2 diabetes and prediabetes have been associated with an increased risk of dementia and cognitive impairment on dopaminergic tasksThe mechanism of this cognitive impairment and if it is dissociable from adiposity or comorbid conditions related to old age is unknownIt is unclear whether youth with prediabetes are at risk for cognitive impairment from impaired insulin sensitivity/glucose regulation What is the key question? (one bullet point only; formatted as a question) Do youth with prediabetes show cognitive impairment independent of adiposity, and is this related to insulin sensitivity of dopaminergic systems? What are the new findings? (maximum of 3 bullet points) Youth with prediabetes show global cognitive impairment, as well as particular impairment of spatial working memory, independent of adiposityInsulin sensitivity of caudate functional connectivity with right intraparietal sulcus and bilateral precuneus is correlated with prior performance on a spatial working memory task How might this impact on clinical practice in the foreseeable future? (one bullet point only) These findings provide evidence that suggests that youth with prediabetes are at risk for cognitive impairment, indicating early detection and treatment of impaired insulin sensitivity is crucial.