Second-Line Pharmaceutical Treatments for Patients with Type 2 Diabetes.

Importance: Assessing the relative effectiveness and safety of additional treatments when metformin monotherapy is insufficient remains a limiting factor in improving treatment choices in type 2 diabetes. Objective: To determine whether data from electronic health records across the University of California Health system could be used to assess the comparative effectiveness and safety associated with 4 treatments in diabetes when added to metformin monotherapy. Design, Setting, and Participants: This multicenter, new user, multidimensional propensity score-matched retrospective cohort study with leave-one-medical-center-out (LOMCO) sensitivity analysis used principles of emulating target trial. Participants included patients with diabetes receiving metformin who were then additionally prescribed either a sulfonylurea, dipeptidyl peptidase-4 inhibitor (DPP4I), sodium-glucose cotransporter-2 inhibitor (SGLT2I), or glucagon-like peptide-1 receptor agonist (GLP1RA) for the first time and followed-up over a 5-year monitoring period. Data were analyzed between January 2022 and April 2023. Exposure: Treatment with sulfonylurea, DPP4I, SGLT2I, or GLP1RA added to metformin monotherapy. Main Outcomes and Measures: The main effectiveness outcome was the ability of patients to maintain glycemic control, represented as time to metabolic failure (hemoglobin A1c [HbA1c] ≥7.0%). A secondary effectiveness outcome was assessed by monitoring time to new incidence of any of 28 adverse outcomes, including diabetes-related complications while treated with the assigned drug. Sensitivity analysis included LOMCO. Results: This cohort study included 31 852 patients (16 635 [52.2%] male; mean [SD] age, 61.4 [12.6] years) who were new users of diabetes treatments added on to metformin monotherapy. Compared with sulfonylurea in random-effect meta-analysis, treatment with SGLT2I (summary hazard ratio [sHR], 0.75 [95% CI, 0.69-0.83]; I2 = 37.5%), DPP4I (sHR, 0.79 [95% CI, 0.75-0.84]; I2 = 0%), GLP1RA (sHR, 0.62 [95% CI, 0.57-0.68]; I2 = 23.6%) were effective in glycemic control; findings from LOMCO sensitivity analysis were similar. Treatment with SGLT2I showed no significant difference in effectiveness compared with GLP1RA (sHR, 1.26 [95% CI, 1.12-1.42]; I2 = 47.3%; no LOMCO) or DPP4I (sHR, 0.97 [95% CI, 0.90-1.04]; I2 = 0%). Patients treated with DPP4I and SGLT2I had fewer cardiovascular events compared with those treated with sulfonylurea (DPP4I: sHR, 0.84 [95% CI, 0.74-0.96]; I2 = 0%; SGLT2I: sHR, 0.78 [95% CI, 0.62-0.98]; I2 = 0%). Patients treated with a GLP1RA or SGLT2I were less likely to develop chronic kidney disease (GLP1RA: sHR, 0.75 [95% CI 0.6-0.94]; I2 = 0%; SGLT2I: sHR, 0.77 [95% CI, 0.61-0.97]; I2 = 0%), kidney failure (GLP1RA: sHR, 0.69 [95% CI, 0.56-0.86]; I2 = 9.1%; SGLT2I: sHR, 0.72 [95% CI, 0.59-0.88]; I2 = 0%), or hypertension (GLP1RA: sHR, 0.82 [95% CI, 0.68-0.97]; I2 = 0%; SGLT2I: sHR, 0.73 [95% CI, 0.58-0.92]; I2 = 38.5%) compared with those treated with a sulfonylurea. Patients treated with an SGLT2I, vs a DPP4I, GLP1RA, or sulfonylurea, were less likely to develop indicators of chronic hepatic dysfunction (sHR vs DPP4I, 0.68 [95% CI, 0.49-0.95]; I2 = 0%; sHR vs GLP1RA, 0.66 [95% CI, 0.48-0.91]; I2 = 0%; sHR vs sulfonylurea, 0.60 [95% CI, 0.44-0.81]; I2 = 0%), and those treated with a DPP4I were less likely to develop new incidence of hypoglycemia (sHR, 0.48 [95% CI, 0.36-0.65]; I2 = 22.7%) compared with those treated with a sulfonylurea. Conclusions and Relevance: These findings highlight familiar medication patterns, including those mirroring randomized clinical trials, as well as providing new insights underscoring the value of robust clinical data analytics in swiftly generating evidence to help guide treatment choices in diabetes.

Obesity-associated microglial inflammatory activation paradoxically improves glucose tolerance.

Hypothalamic gliosis associated with high-fat diet (HFD) feeding increases susceptibility to hyperphagia and weight gain. However, the body-weight-independent contribution of microglia to glucose regulation has not been determined. Here, we show that reducing microglial nuclear factor κB (NF-κB) signaling via cell-specific IKKß deletion exacerbates HFD-induced glucose intolerance despite reducing body weight and adiposity. Conversely, two genetic approaches to increase microglial pro-inflammatory signaling (deletion of an NF-κB pathway inhibitor and chemogenetic activation through a modified Gq-coupled muscarinic receptor) improved glucose tolerance independently of diet in both lean and obese rodents. Microglial regulation of glucose homeostasis involves a tumor necrosis factor alpha (TNF-α)-dependent mechanism that increases activation of pro-opiomelanocortin (POMC) and other hypothalamic glucose-sensing neurons, ultimately leading to a marked amplification of first-phase insulin secretion via a parasympathetic pathway. Overall, these data indicate that microglia regulate glucose homeostasis in a body-weight-independent manner, an unexpected mechanism that limits the deterioration of glucose tolerance associated with obesity.

Twenty-first century management of diabetes with shared telemedicine appointments.

This commentary article discusses the benefits of utilizing telemedicine to conduct shared medical appointments for people with type 1 diabetes and type 2 diabetes. We conducted a literature review of articles about shared medical appointments or group medical visits in people with diabetes with associated clinical data. We identified 43 articles. Models of this approach to care have demonstrated positive outcomes in adults and children with type 1 diabetes. Shared telemedicine appointments also have the potential to improve diabetes self-management, reduce the treatment burden, and improve psychosocial outcomes in adults with type 2 diabetes. Ten key recommendations for implementation are presented to guide the development of shared telemedicine appointments for diabetes. These recommendations can improve care for diabetes.

The Impact of Insulin Resistance on Loss of Lung Function and Response to Treatment in Asthma.

Rationale: The role of obesity-associated insulin resistance (IR) in airflow limitation in asthma is uncertain. Objectives: Using data in the Severe Asthma Research Program 3 (SARP-3), we evaluated relationships between homeostatic measure of IR (HOMA-IR), lung function (cross-sectional and longitudinal analyses), and treatment responses to bronchodilators and corticosteroids. Methods: HOMA-IR values were categorized as without (<3.0), moderate (3.0-5.0), or severe (>5.0). Lung function included FEV1 and FVC measured before and after treatment with inhaled albuterol and intramuscular triamcinolone acetonide and yearly for 5 years. Measurements and Main Results: Among 307 participants in SARP-3, 170 (55%) were obese and 140 (46%) had IR. Compared with patients without IR, those with IR had significantly lower values for FEV1 and FVC, and these lower values were not attributable to obesity effects. Compared with patients without IR, those with IR had lower FEV1 responses to ß-adrenergic agonists and systemic corticosteroids. The annualized decline in FEV1 was significantly greater in patients with moderate IR (-41 ml/year) and severe IR (-32 ml/year,) than in patients without IR (-13 ml/year, P < 0.001 for both comparisons). Conclusions: IR is common in asthma and is associated with lower lung function, accelerated loss of lung function, and suboptimal lung function responses to bronchodilator and corticosteroid treatments. Clinical trials in patients with asthma and IR are needed to determine if improving IR might also improve lung function.

ASB4 modulates central melanocortinergic neurons and calcitonin signaling to control satiety and glucose homeostasis.

Variants in the gene encoding ankyrin repeat and SOCS box-containing 4 (ASB4) are linked to human obesity. Here, we characterized the pathways underlying the metabolic functions of ASB4. Hypothalamic Asb4 expression was suppressed by fasting in wild-type mice but not in mice deficient in AgRP, which encodes Agouti-related protein (AgRP), an appetite-stimulating hormone, suggesting that ASB4 is a negative target of AgRP. Many ASB4 neurons in the brain were adjacent to AgRP terminals, and feeding induced by AgRP neuronal activation was disrupted in Asb4-deficient mice. Acute knockdown of Asb4 in the brain caused marked hyperphagia due to increased meal size, and Asb4 deficiency led to increased meal size and food intake at the onset of refeeding, when very large meals were consumed. Asb4-deficient mice were resistant to the meal-terminating effects of exogenously administered calcitonin and showed decreased neuronal expression of Calcr, which encodes the calcitonin receptor. Pro-opiomelanocortin (POMC) neurons in the arcuate nucleus in mice are involved in glucose homeostasis, and Asb4 deficiency specifically in POMC neurons resulted in glucose intolerance that was independent of obesity. Furthermore, individuals with type 2 diabetes showed reduced ASB4 abundance in the infundibular nuclei, the human equivalent of the arcuate nucleus. Together, our results indicate that ASB4 acts in the brain to improve glucose homeostasis and to induce satiety after substantial meals, particularly those after food deprivation.

Metabolic factors in the regulation of hypothalamic innate immune responses in obesity.

The hypothalamus is a central regulator of body weight and energy homeostasis. There is increasing evidence that innate immune activation in the mediobasal hypothalamus (MBH) is a key element in the pathogenesis of diet-induced obesity. Microglia, the resident immune cells in the brain parenchyma, have been shown to play roles in diverse aspects of brain function, including circuit refinement and synaptic pruning. As such, microglia have also been implicated in the development and progression of neurological diseases. Microglia express receptors for and are responsive to a wide variety of nutritional, hormonal, and immunological signals that modulate their distinct functions across different brain regions. We showed that microglia within the MBH sense and respond to a high-fat diet and regulate the function of hypothalamic neurons to promote food intake and obesity. Neurons, glia, and immune cells within the MBH are positioned to sense and respond to circulating signals that regulate their capacity to coordinate aspects of systemic energy metabolism. Here, we review the current knowledge of how these peripheral signals modulate the innate immune response in the MBH and enable microglia to regulate metabolic control.

A gene-diet interaction controlling relative intake of dietary carbohydrates and fats.

OBJECTIVE: Preference for dietary fat vs. carbohydrate varies markedly across free-living individuals. It is recognized that food choice is under genetic and physiological regulation, and that the central melanocortin system is involved. However, how genetic and dietary factors interact to regulate relative macronutrient intake is not well understood. METHODS: We investigated how the choice for food rich in carbohydrate vs. fat is influenced by dietary cholesterol availability and agouti-related protein (AGRP), the orexigenic component of the central melanocortin system. We assessed how macronutrient intake and different metabolic parameters correlate with plasma AGRP in a cohort of obese humans. We also examined how both dietary cholesterol levels and inhibiting de novo cholesterol synthesis affect carbohydrate and fat intake in mice, and how dietary cholesterol deficiency during the postnatal period impacts macronutrient intake patterns in adulthood. RESULTS: In obese human subjects, plasma levels of AGRP correlated inversely with consumption of carbohydrates over fats. Moreover, AgRP-deficient mice preferred to consume more calories from carbohydrates than fats, more so when each diet lacked cholesterol. Intriguingly, inhibiting cholesterol biosynthesis (simvastatin) promoted carbohydrate intake at the expense of fat without altering total caloric consumption, an effect that was remarkably absent in AgRP-deficient mice. Finally, feeding lactating C57BL/6 dams and pups a cholesterol-free diet prior to weaning led the offspring to prefer fats over carbohydrates as adults, indicating that altered cholesterol metabolism early in life programs adaptive changes to macronutrient intake. CONCLUSIONS: Together, our study illustrates a specific gene-diet interaction in modulating food choice.

Continuous Ketone Monitoring Consensus Report 2021.

This article is the work product of the Continuous Ketone Monitoring Consensus Panel, which was organized by Diabetes Technology Society and met virtually on April 20, 2021. The panel consisted of 20 US-based experts in the use of diabetes technology, representing adult endocrinology, pediatric endocrinology, advanced practice nursing, diabetes care and education, clinical chemistry, and bioengineering. The panelists were from universities, hospitals, freestanding research institutes, government, and private practice. Panelists reviewed the medical literature pertaining to ten topics: (1) physiology of ketone production, (2) measurement of ketones, (3) performance of the first continuous ketone monitor (CKM) reported to be used in human trials, (4) demographics and epidemiology of diabetic ketoacidosis (DKA), (5) atypical hyperketonemia, (6) prevention of DKA, (7) non-DKA states of fasting ketonemia and ketonuria, (8) potential integration of CKMs with pumps and automated insulin delivery systems to prevent DKA, (9) clinical trials of CKMs, and (10) the future of CKMs. The panelists summarized the medical literature for each of the ten topics in this report. They also developed 30 conclusions (amounting to three conclusions for each topic) about CKMs and voted unanimously to adopt the 30 conclusions. This report is intended to support the development of safe and effective continuous ketone monitoring and to apply this technology in ways that will benefit people with diabetes.

Probing Insulin Sensitivity with Metabolically Competent Human Stem Cell-Derived White Adipose Tissue Microphysiological Systems.

Impaired white adipose tissue (WAT) function has been recognized as a critical early event in obesity-driven disorders, but high buoyancy, fragility, and heterogeneity of primary adipocytes have largely prevented their use in drug discovery efforts highlighting the need for human stem cell-based approaches. Here, human stem cells are utilized to derive metabolically functional 3D adipose tissue (iADIPO) in a microphysiological system (MPS). Surprisingly, previously reported WAT differentiation approaches create insulin resistant WAT ill-suited for type-2 diabetes mellitus drug discovery. Using three independent insulin sensitivity assays, i.e., glucose and fatty acid uptake and suppression of lipolysis, as the functional readouts new differentiation conditions yielding hormonally responsive iADIPO are derived. Through concomitant optimization of an iADIPO-MPS, it is abled to obtain WAT with more unilocular and significantly larger (≈40%) lipid droplets compared to iADIPO in 2D culture, increased insulin responsiveness of glucose uptake (≈2-3 fold), fatty acid uptake (≈3-6 fold), and ≈40% suppressing of stimulated lipolysis giving a dynamic range that is competent to current in vivo and ex vivo models, allowing to identify both insulin sensitizers and desensitizers.

The East Asian gut microbiome is distinct from colocalized White subjects and connected to metabolic health.

East Asians (EAs) experience worse metabolic health outcomes compared to other ethnic groups at lower body mass indices; however, the potential role of the gut microbiota in contributing to these health disparities remains unknown. We conducted a multi-omic study of 46 lean and obese East Asian and White participants living in the San Francisco Bay Area, revealing marked differences between ethnic groups in bacterial richness and community structure. White individuals were enriched for the mucin-degrading Akkermansia muciniphila. East Asian subjects had increased levels of multiple bacterial phyla, fermentative pathways detected by metagenomics, and the short-chain fatty acid end-products acetate, propionate, and isobutyrate. Differences in the gut microbiota between the East Asian and White subjects could not be explained by dietary intake, were more pronounced in lean individuals, and were associated with current geographical location. Microbiome transplantations into germ-free mice demonstrated stable diet- and host genotype-independent differences between the gut microbiotas of East Asian and White individuals that differentially impact host body composition. Taken together, our findings add to the growing body of literature describing microbiome variations between ethnicities and provide a starting point for defining the mechanisms through which the microbiome may shape disparate health outcomes in East Asians.

The community of microbes living in the human gut varies based on where a person lives, in part because of differences in diets but also due to factors still incompletely understood. In turn, this 'microbiome' may have wide-ranging effects on health and diseases such as obesity and diabetes. Many scientists want to understand how differences in the microbiome emerge between people, and whether this may explain why certain diseases are more common in specific populations. Self-identified race or ethnicity can be a useful tool in that effort, as it can serve as a proxy for cultural habits (such as diets) or genetic information. In the United States, self-identified East Asian Americans often have worse 'metabolic health' (e.g. levels of sugar or certain fat molecules in the blood) at a lower weight than those identifying as White. Ang, Alba, Upadhyay et al. investigated whether this health disparity was linked to variation in the gut microbiome. Samples were collected from 46 lean and obese individuals living in the San Francisco Bay Area who identified as White or East Asian. The analyses showed that while the gut microbiome of White participants changed in association with obesity, the microbiomes of East Asian participants were distinct from their White counterparts even at normal weight, with features mirroring what was seen in White individuals in the context of obesity. Although these differences were connected to people's current address, they were not attributable to dietary differences. Ang, Alba, Upadhyay et al. then transplanted the microbiome of the participants into genetically identical mice with microbe-free guts. The differences between the gut microbiomes of White and East Asian participants persisted in recipient animals. When fed the same diet, the mice also gained different amounts of weight depending on the ethnic identity of the microbial donor. These results show that self-identified ethnicity may be an important variable to consider in microbiome studies, alongside other factors such as geography. Ultimately, this research may help to design better, more personalized treatments for an array of conditions.

Microglial Lipid Biology in the Hypothalamic Regulation of Metabolic Homeostasis.

In mammals, myeloid cells help maintain the homeostasis of peripheral metabolic tissues, and their immunologic dysregulation contributes to the progression of obesity and associated metabolic disease. There is accumulating evidence that innate immune cells also serve as functional regulators within the mediobasal hypothalamus (MBH), a critical brain region controlling both energy and glucose homeostasis. Specifically, microglia, the resident parenchymal myeloid cells of the CNS, play important roles in brain physiology and pathology. Recent studies have revealed an expanding array of microglial functions beyond their established roles as immune sentinels, including roles in brain development, circuit refinement, and synaptic organization. We showed that microglia modulate MBH function by transmitting information resulting from excess nutrient consumption. For instance, microglia can sense the excessive consumption of saturated fats and instruct neurons within the MBH accordingly, leading to responsive alterations in energy balance. Interestingly, the recent emergence of high-resolution single-cell techniques has enabled specific microglial populations and phenotypes to be profiled in unprecedented detail. Such techniques have highlighted specific subsets of microglia notable for their capacity to regulate the expression of lipid metabolic genes, including lipoprotein lipase (LPL), apolipoprotein E (APOE) and Triggering Receptor Expressed on Myeloid Cells 2 (TREM2). The discovery of this transcriptional signature highlights microglial lipid metabolism as a determinant of brain health and disease pathogenesis, with intriguing implications for the treatment of brain disorders and potentially metabolic disease. Here we review our current understanding of how changes in microglial lipid metabolism could influence the hypothalamic control of systemic metabolism.

Lack of association between either outpatient or inpatient glycemic control and COVID-19 illness severity or mortality in patients with diabetes.

INTRODUCTION: To evaluate whether outpatient insulin treatment, hemoglobin A1c (HbA1c), glucose on admission, or glycemic control during hospitalization is associated with SARS-CoV-2 (COVID-19) illness severity or mortality in hospitalized patients with diabetes mellitus (DM) in a geographical region with low COVID-19 prevalence. RESEARCH DESIGN AND METHODS: A single-center retrospective study of patients hospitalized with COVID-19 from January 1 through August 31, 2020 to evaluate whether outpatient insulin use, HbA1c, glucose on admission, or average glucose during admission was associated with intensive care unit (ICU) admission, mechanical ventilation (ventilator) requirement, or mortality. RESULTS: Among 111 patients with DM, 48 (43.2%) were on outpatient insulin and the average HbA1c was 8.1% (65 mmol/mol). The average glucose on admission was 187.0±102.94 mg/dL and the average glucose during hospitalization was 173.4±39.8 mg/dL. Use of outpatient insulin, level of HbA1c, glucose on admission, or average glucose during hospitalization was not associated with ICU admission, ventilator requirement, or mortality among patients with COVID-19 and DM. CONCLUSIONS: Our findings in a region with relatively low COVID-19 prevalence suggest that neither outpatient glycemic control, glucose on admission, or inpatient glycemic control is predictive of illness severity or mortality in patients with DM hospitalized with COVID-19.

Autoregulation of insulin receptor signaling through MFGE8 and the αvß5 integrin.

The role of integrins, in particular αv integrins, in regulating insulin resistance is incompletely understood. We have previously shown that the αvß5 integrin ligand milk fat globule epidermal growth factor like 8 (MFGE8) regulates cellular uptake of fatty acids. In this work, we evaluated the impact of MFGE8 on glucose homeostasis. We show that acute blockade of the MFGE8/ß5 pathway enhances while acute augmentation dampens insulin-stimulated glucose uptake. Moreover, we find that insulin itself induces cell-surface enrichment of MFGE8 in skeletal muscle, which then promotes interaction between the αvß5 integrin and the insulin receptor leading to dampening of skeletal-muscle insulin receptor signaling. Blockade of the MFGE8/ß5 pathway also enhances hepatic insulin sensitivity. Our work identifies an autoregulatory mechanism by which insulin-stimulated signaling through its cognate receptor is terminated through up-regulation of MFGE8 and its consequent interaction with the αvß5 integrin, thereby establishing a pathway that can potentially be targeted to improve insulin sensitivity.

Continuous Ketone Monitoring: A New Paradigm for Physiologic Monitoring.

In this issue of JDST, Alva and colleagues present for the first time, development of a continuous ketone monitor (CKM) tested both in vitro and in humans. Their sensor measured betahydroxybutyrate (BHB) in interstitial fluid (ISF). The sensor was based on wired enzyme electrochemistry technology using BHB dehydrogenase. The sensor required only a single retrospective calibration without a need for further adjustments over 14 days. The device produced a linear response over the 0-8 mM range with good accuracy. This novel CKM could provide a new dimension of useful automatically collected information for managing diabetes. Passively collected ISF ketone information would be useful for predicting and managing ketoacidosis in patients with type 1 diabetes, as well as other states of abnormal ketonemia. Although additional studies of this CKM will be required to assess performance in intended patient populations and prospective factory calibration will be required to support real time measurements, this novel monitor has the potential to greatly improve outcomes for people with diabetes. In the future, a CKM might be integrated with a continuous glucose monitor in the same sensor platform.

Quantifying Variation in Treatment Utilization for Type 2 Diabetes Across Five Major University of California Health Systems.

OBJECTIVE: Using the newly created University of California (UC) Health Data Warehouse, we present the first study to analyze antihyperglycemic treatment utilization across the five large UC academic health systems (Davis, Irvine, Los Angeles, San Diego, and San Francisco). RESEARCH DESIGN AND METHODS: This retrospective analysis used deidentified electronic health records (EHRs; 2014-2019) including 97,231 patients with type 2 diabetes from 1,003 UC-affiliated clinical settings. Significant differences between health systems and individual providers were identified using binomial probabilities with cohort matching. RESULTS: Our analysis reveals statistically different treatment utilization patterns not only between health systems but also among individual providers within health systems. We identified 21 differences among health systems and 29 differences among individual providers within these health systems, with respect to treatment intensifications within existing guidelines on top of either metformin monotherapy or dual therapy with metformin and a sulfonylurea. Next, we identified variation for medications within the same class (e.g., glipizide vs. glyburide among sulfonylureas), with 33 differences among health systems and 86 among individual providers. Finally, we identified 2 health systems and 55 individual providers who more frequently used medications with known cardioprotective benefits for patients with high cardiovascular disease risk, but also 1 health system and 8 providers who prescribed such medications less frequently for these patients. CONCLUSIONS: Our study used cohort-matching techniques to highlight real-world variation in care between health systems and individual providers. This demonstrates the power of EHRs to quantify differences in treatment utilization, a necessary step toward standardizing precision care for large populations.

CD81 Controls Beige Fat Progenitor Cell Growth and Energy Balance via FAK Signaling.

Adipose tissues dynamically remodel their cellular composition in response to external cues by stimulating beige adipocyte biogenesis; however, the developmental origin and pathways regulating this process remain insufficiently understood owing to adipose tissue heterogeneity. Here, we employed single-cell RNA-seq and identified a unique subset of adipocyte progenitor cells (APCs) that possessed the cell-intrinsic plasticity to give rise to beige fat. This beige APC population is proliferative and marked by cell-surface proteins, including PDGFRα, Sca1, and CD81. Notably, CD81 is not only a beige APC marker but also required for de novo beige fat biogenesis following cold exposure. CD81 forms a complex with αV/ß1 and αV/ß5 integrins and mediates the activation of integrin-FAK signaling in response to irisin. Importantly, CD81 loss causes diet-induced obesity, insulin resistance, and adipose tissue inflammation. These results suggest that CD81 functions as a key sensor of external inputs and controls beige APC proliferation and whole-body energy homeostasis.

Neuronal modulation of hepatic lipid accumulation induced by bingelike drinking.

Excessive alcohol consumption, including binge drinking, is a common cause of fatty liver disease. Binge drinking rapidly induces hepatic steatosis, an early step in the pathogenesis of chronic liver injury. Despite its prevalence, the process by which excessive alcohol consumption promotes hepatic lipid accumulation remains unclear. Alcohol exerts potent effects on the brain, including hypothalamic neurons crucial for metabolic regulation. However, whether or not the brain plays a role in alcohol-induced hepatic steatosis is unknown. In the brain, alcohol increases extracellular levels of adenosine, a potent neuromodulator, and previous work implicates adenosine signaling as being important for the development of alcoholic fatty liver disease. Acute alcohol exposure also increases both the activity of agouti-related protein (AgRP)-expressing neurons and AgRP immunoreactivity. Here, we show that adenosine receptor A2B signaling in the brain modulates the extent of alcohol-induced fatty liver in mice and that both the AgRP neuropeptide and the sympathetic nervous system are indispensable for hepatic steatosis induced by bingelike alcohol consumption. Together, these results indicate that the brain plays an integral role in alcohol-induced hepatic lipid accumulation and that central adenosine signaling, hypothalamic AgRP, and the sympathetic nervous system are crucial mediators of this process.

Genetic basis for the cooperative bioactivation of plant lignans by Eggerthella lenta and other human gut bacteria.

Plant-derived lignans, consumed daily by most individuals, are thought to protect against cancer and other diseases1; however, their bioactivity requires gut bacterial conversion to enterolignans2. Here, we dissect a four-species bacterial consortium sufficient for all five reactions in this pathway. A single enzyme (benzyl ether reductase, encoded by the gene ber) was sufficient for the first two biotransformations, variable between strains of Eggerthella lenta, critical for enterolignan production in gnotobiotic mice and unique to Coriobacteriia. Transcriptional profiling (RNA sequencing) independently identified ber and genomic loci upregulated by each of the remaining substrates. Despite their low abundance in gut microbiomes and restricted phylogenetic range, all of the identified genes were detectable in the distal gut microbiomes of most individuals living in northern California. Together, these results emphasize the importance of considering strain-level variations and bacterial co-occurrence to gain a mechanistic understanding of the bioactivation of plant secondary metabolites by the human gut microbiome.

mTORC1 to AMPK switching underlies ß-cell metabolic plasticity during maturation and diabetes.

Pancreatic beta cells (ß-cells) differentiate during fetal life, but only postnatally acquire the capacity for glucose-stimulated insulin secretion (GSIS). How this happens is not clear. In exploring what molecular mechanisms drive the maturation of ß-cell function, we found that the control of cellular signaling in ß-cells fundamentally switched from the nutrient sensor target of rapamycin (mTORC1) to the energy sensor 5'-adenosine monophosphate-activated protein kinase (AMPK), and that this was critical for functional maturation. Moreover, AMPK was activated by the dietary transition taking place during weaning, and this in turn inhibited mTORC1 activity to drive the adult ß-cell phenotype. While forcing constitutive mTORC1 signaling in adult ß-cells relegated them to a functionally immature phenotype with characteristic transcriptional and metabolic profiles, engineering the switch from mTORC1 to AMPK signaling was sufficient to promote ß-cell mitochondrial biogenesis, a shift to oxidative metabolism, and functional maturation. We also found that type 2 diabetes, a condition marked by both mitochondrial degeneration and dysregulated GSIS, was associated with a remarkable reversion of the normal AMPK-dependent adult ß-cell signature to a more neonatal one characterized by mTORC1 activation. Manipulating the way in which cellular nutrient signaling pathways regulate ß-cell metabolism may thus offer new targets to improve ß-cell function in diabetes.

Sweet cognition: The differential effects of glucose consumption on attentional food bias in individuals of lean and obese status.

In general, glucose consumption improves cognitive performance; however, it is unknown whether glucose specifically alters attentional food bias, and how this process may vary by BMI status. We hypothesized that glucose consumption would increase attentional food bias among individuals of obese BMI status more so than among individuals of lean BMI status. Participants (N = 35) completed the n-back, a working memory task modified to assess attentional food bias (ATT-Food), under fasting and glucose challenge conditions. We computed pre-post changes in ATT-Food, blood glucose and insulin (∆BG & ∆BI), and perceived task-stress (∆stress). After the second cognitive test and blood draw, participants ate lunch and completed a "taste test" of highly palatable foods, and we recorded food consumption. Pre-post changes in ATT-Food were greater among participants of obese (relative to lean) BMI status (F(1,33) = 5.108, p = .031). Greater ∆ATT-Food was significantly associated with greater ∆BG (r = .462, p = .007) and reduced ∆stress (r =-.422, p = .011), and marginally associated with greater taste-test eating (r =.325, p = .057), but was not associated with ∆BI. Our findings suggest that individuals of obese BMI status may exhibit "sweet cognition," as indexed by greater attentional food bias following glucose ingestion, relative to individuals of lean BMI status. Among individuals of obese BMI status, sweet cognition may arise from difficulty broadening attention toward non-food cues after consuming a high glucose load, thereby potentially perpetuating sugar consumption. If confirmed by further research, measures of sweet cognition may help identify individuals with a phenotype of risk for obesity and greater sugar consumption, who may benefit from tailored interventions.