Binding of Akkermansia muciniphila to mucin is O-glycan specific.

The intestinal anaerobic bacterium Akkermansia muciniphila is specialized in the degradation of mucins, which are heavily O-glycosylated proteins that constitute the major components of the mucus lining the intestine. Despite that adhesion to mucins is considered critical for the persistence of A. muciniphila in the human intestinal tract, our knowledge of how this intestinal symbiont recognizes and binds to mucins is still limited. Here, we first show that the mucin-binding properties of A. muciniphila are independent of environmental oxygen concentrations and not abolished by pasteurization. We then dissected the mucin-binding properties of pasteurized A. muciniphila by use of a recently developed cell-based mucin array that enables display of the tandem repeats of human mucins with distinct O-glycan patterns and structures. We found that A. muciniphila recognizes the unsialylated LacNAc (Galß1-4GlcNAcß1-R) disaccharide selectively on core2 and core3 O-glycans. This disaccharide epitope is abundantly found on human colonic mucins capped by sialic acids, and we demonstrated that endogenous A. muciniphila neuraminidase activity can uncover the epitope and promote binding. In summary, our study provides insights into the mucin-binding properties important for colonization of a key mucin-foraging bacterium.

Parental education and occupation in relation to childhood type 1 diabetes: nationwide cohort study.

BackgroundSocioeconomic status in the risk of developing type 1 diabetes seems inconsistent. We investigated whether risk of childhood-onset type 1 diabetes differed by parental education or occupation in a nationwide cohort. METHODS: This cohort study included all children born in Norway from 1974 to 2013. In individually linked data from nationwide population registries following children born in Norway up to 15 years of age, we identified 4647 with newly diagnosed type 1 diabetes during 15 381 923 person-years of follow-up. RESULTS: Children of mothers with a master's degree had lower risk of type 1 diabetes than children of mothers with completed upper secondary education only (adjusted incidence rate ratio, aIRR=0.82 95% CI: 0.70 to 0.95). There was no difference between upper secondary and lower secondary maternal education (aIRR=0.98, 95% CI: 0.89 to 1.08). Paternal education was not significantly associated with type 1 diabetes, lower secondary compared with upper secondary aIRR 0.96 (0.88-1.05) and master compared with upper secondary aIRR 0.93 (0.83-1.05). While maternal elementary occupation was associated with a lower risk of type 1 diabetes, specific maternal or paternal occupations were not. CONCLUSIONS: Our results suggested inverse U-shaped associations between maternal socioeconomic status and risk of type 1 diabetes. Non-linear associations may be part of the reason why previous literature has been inconsistent.

Pharmacological treatment of obesity in adults in Norway 2004-2022.

AIMS: To describe trends in the use of anti-obesity drugs in Norway during the period 2004-2022. MATERIALS AND METHODS: We assessed the annual utilization of any available drug indicated for obesity recorded in the nationwide Norwegian Prescribed Drug Register for adults (age 18-79 years) from 1 January 2004 to 31 December 2022. Prevalence was stratified by sex and age group (18-29 years and 10-year age groups thereafter). Additional analyses were performed in individuals initiating treatment with an anti-obesity drug and on the cost of the anti-obesity drugs since 2017. RESULTS: The prevalence of anti-obesity drug use decreased from 2009, when sibutramine and rimonabant were withdrawn from the market, and increased again after the approval of bupropion-naltrexone in 2017 and liraglutide in 2018. The use of the peripheral-acting anti-obesity drug orlistat decreased from 2004. In 2022, 1.04% of the adult Norwegian population (72.8% women) filled at least one prescription of bupropion-naltrexone, 0.91% used liraglutide (Saxenda; 74.2% women), and semaglutide without reimbursement was used by 0.68% (76.7% women). The prevalence increased with age, peaking in the age group 50 to 59 years, and decreased in older age groups. From 2017 to 2022, 2.8% of the adult residents initiated treatment with an anti-obesity drug. The total sale of those drugs increased from 1.1 million euros in 2017 to 91.8 million euros in 2022. CONCLUSIONS: The use of anti-obesity drugs in Norway has increased substantially in recent years, especially among women aged 40 to 59 years. Changes in availability and reimbursement have influenced the use of these drugs in recent years.

Prevalence and treatment of gestational diabetes in Norway 2010-2020.

AIMS: Estimate prevalence of gestational diabetes mellitus (GDM) and its treatment in Norway 2010-2020 and explore impact of new national GDM guidelines in 2017. METHODS: We identified women giving birth in a nationwide cohort study using registers on births, prescriptions, education, primary and specialist care. For each year, we estimated prevalence of GDM overall, by BMI, age, education, and mother's birthplace; proportions of GDM pregnancies receiving pharmacological treatment; and distribution of the gestational week when GDM was diagnosed. RESULTS: In 633,169 pregnancies, prevalence of GDM increased from 2.6 % in 2010 to 6.0 % in 2016, then stabilized. Similar patterns were seen across strata of BMI, age, education, and maternal birthplace, although prevalence was higher with higher BMI, higher age, lower education, and mothers born in Asia, Africa, or Middle East. The proportion of the GDM population pharmacologically treated increased from 11.6 % in 2010 to 13.6 % in 2016 and 31.6 % in 2020. GDM was diagnosed in recommended gestational week 24-28 in 19 % versus 45 % of GDM pregnancies in 2010 and 2020, respectively. CONCLUSIONS: Both the proportion diagnosed with GDM within recommended time of screening, and who received pharmacological treatment, increased substantially following new guidelines in 2017. Prevalence of GDM increased from 2010 to 2016, then plateaued.

Metformin Versus Insulin and Risk of Major Congenital Malformations in Pregnancies With Type 2 Diabetes: A Nordic Register-Based Cohort Study.

OBJECTIVE: To assess the risk of major congenital malformations with metformin versus insulin in pregnancies with type 2 diabetes. RESEARCH DESIGN AND METHODS: This cohort study used four Nordic countries' nationwide registers of live and stillborn infants exposed to metformin or insulin during first trimester organogenesis. Main exclusion criteria were type 1 diabetes, polycystic ovary syndrome, fertility treatment, and exposure to other diabetes drugs. Adjusted risk ratios (RRs) and 95% CIs were estimated for any and cardiac malformations. RESULTS: Of 3,734,125 infants in the source population, 25,956 were exposed to metformin or insulin in the first trimester, and 4,023 singleton infants were included. A malformation was diagnosed in 147 (4.7%) of 3,145 infants with exposure to any metformin (alone or in addition to insulin) and 50 (5.7%) of 878 infants with exposure to insulin alone (RR 0.84, 95% CI 0.46-1.54). Among 2,852 infants exposed to metformin alone and 293 infants exposed to metformin in addition to insulin 127 (4.4%) and 20 (6.8%), respectively, had a malformation. The adjusted risk was not increased for either metformin alone (0.83, 0.44-1.58) or both metformin and insulin (0.98, 0.56-1.69) versus insulin alone. Corresponding RRs for cardiac malformations were 1.01 (0.55-1.84) for any metformin, 0.92 (0.47-1.81) for metformin alone, and 1.72 (0.76-3.91) for both metformin and insulin. CONCLUSIONS: No evidence of an increased malformation risk with metformin versus insulin in the first trimester was found. Results should be interpreted with caution since information on glycemic control was missing.

Human Milk Oligosaccharides, Important Milk Bioactives for Child Health: A Perspective.

Human milk contains all nutritive and bioactive compounds to give infants the best possible start in life. Human milk bioactives cover a broad range of components, including immune cells, antimicrobial proteins, microbes, and human milk oligosaccharides (HMOs). Over the last decade, HMOs have gained special attention as their industrial production has allowed the study of their structure-function relation in reductionist experimental setups. This has shed light on how HMOs steer microbiome and immune system development in early life but also how HMOs affect infant health (e.g., antibiotic use, respiratory tract infections). We are on the verge of a new era where we can examine human milk as a complex biological system. This allows not only study of the mode of action and causality of individual human milk components but also investigation of synergistic effects that might exist between different bioactives. This new wave in human milk research is largely fueled by significant advances in analytical tools in the field of systems biology and network analysis. It will be exciting to explore how human milk composition is affected by different factors, how different human milk compounds work together, and how this influences healthy infant development.

Insulin and Body Mass Index Decrease Serum Soluble Leptin Receptor Levels in Humans.

CONTEXT: Serum soluble leptin receptor (sOb-R) may protect against future type 2 diabetes or serve as a marker for protective features, but how sOb-R is regulated is largely unknown. OBJECTIVE: This work aimed to test how serum sOb-R is influenced by glucose, insulin, body fat, body mass index (BMI), food intake, and physical activity. METHODS: We performed an epidemiological triangulation combining cross-sectional, interventional, and Mendelian randomization study designs. In 5 independent clinical studies (n = 24-823), sOb-R was quantified in serum or plasma by commercial enzyme-linked immunosorbent assay kits using monoclonal antibodies. We performed mixed-model regression and 2-sample Mendelian randomization. RESULTS: In pooled, cross-sectional data, leveling by study, sOb-R was associated inversely with BMI (ß [95% CI] -0.19 [-0.21 to -0.17]), body fat (-0.12 [-0.14 to -0.10), and fasting C-peptide (-2.04 [-2.46 to -1.62]). sOb-R decreased in response to acute hyperinsulinemia during euglycemic glucose clamp in 2 independent clinical studies (-0.5 [-0.7 to -0.4] and -0.5 [-0.6 to -0.3]), and immediately increased in response to intensive exercise (0.18 [0.04 to 0.31]) and food intake (0.20 [0.06 to 0.34]). In 2-sample Mendelian randomization, higher fasting insulin and higher BMI were causally linked to lower sOb-R levels (inverse variance weighted, -1.72 [-2.86 to -0.58], and -0.20 [-0.36 to -0.04], respectively). The relationship between hyperglycemia and sOb-R was inconsistent in cross-sectional studies and nonsignificant in intervention studies, and 2-sample Mendelian randomization suggested no causal effect of fasting glucose on sOb-R. CONCLUSION: BMI and insulin both causally decreased serum sOb-R levels. Conversely, intensive exercise and food intake acutely increased sOb-R. Our results suggest that sOb-R is involved in short-term regulation of leptin signaling, either directly or indirectly, and that hyperinsulinemia may reduce leptin signaling.

Lifetime risk, life expectancy, and years of life lost to type 2 diabetes in 23 high-income jurisdictions: a multinational, population-based study.

BACKGROUND: Diabetes is a major public health issue. Because lifetime risk, life expectancy, and years of life lost are meaningful metrics for clinical decision making, we aimed to estimate these measures for type 2 diabetes in the high-income setting. METHODS: For this multinational, population-based study, we sourced data from 24 databases for 23 jurisdictions (either whole countries or regions of a country): Australia; Austria; Canada; Denmark; Finland; France; Germany; Hong Kong; Hungary; Israel; Italy; Japan; Latvia; Lithuania; the Netherlands; Norway; Scotland; Singapore; South Korea; Spain; Taiwan; the UK; and the USA. Our main outcomes were lifetime risk of type 2 diabetes, life expectancy in people with and without type 2 diabetes, and years of life lost to type 2 diabetes. We modelled the incidence and mortality of type 2 diabetes in people with and without type 2 diabetes in sex-stratified, age-adjusted, and calendar year-adjusted Poisson models for each jurisdiction. Using incidence and mortality, we constructed life tables for people of both sexes aged 20-100 years for each jurisdiction and at two timepoints 5 years apart in the period 2005-19 where possible. Life expectancy from a given age was computed as the area under the survival curves and lifetime lost was calculated as the difference between the expected lifetime of people with versus without type 2 diabetes at a given age. Lifetime risk was calculated as the proportion of each cohort who developed type 2 diabetes between the ages of 20 years and 100 years. We estimated 95% CIs using parametric bootstrapping. FINDINGS: Across all study cohorts from the 23 jurisdictions (total person-years 1 577 234 194), there were 5 119 585 incident cases of type 2 diabetes, 4 007 064 deaths in those with type 2 diabetes, and 11 854 043 deaths in those without type 2 diabetes. The lifetime risk of type 2 diabetes ranged from 16·3% (95% CI 15·6-17·0) for Scottish women to 59·6% (58·5-60·8) for Singaporean men. Lifetime risk declined with time in 11 of the 15 jurisdictions for which two timepoints were studied. Among people with type 2 diabetes, the highest life expectancies were found for both sexes in Japan in 2017-18, where life expectancy at age 20 years was 59·2 years (95% CI 59·2-59·3) for men and 64·1 years (64·0-64·2) for women. The lowest life expectancy at age 20 years with type 2 diabetes was observed in 2013-14 in Lithuania (43·7 years [42·7-44·6]) for men and in 2010-11 in Latvia (54·2 years [53·4-54·9]) for women. Life expectancy in people with type 2 diabetes increased with time for both sexes in all jurisdictions, except for Spain and Scotland. The life expectancy gap between those with and without type 2 diabetes declined substantially in Latvia from 2010-11 to 2015-16 and in the USA from 2009-10 to 2014-15. Years of life lost to type 2 diabetes ranged from 2·5 years (Latvia; 2015-16) to 12·9 years (Israel Clalit Health Services; 2015-16) for 20-year-old men and from 3·1 years (Finland; 2011-12) to 11·2 years (Israel Clalit Health Services; 2010-11 and 2015-16) for 20-year-old women. With time, the expected number of years of life lost to type 2 diabetes decreased in some jurisdictions and increased in others. The greatest decrease in years of life lost to type 2 diabetes occurred in the USA between 2009-10 and 2014-15 for 20-year-old men (a decrease of 2·7 years). INTERPRETATION: Despite declining lifetime risk and improvements in life expectancy for those with type 2 diabetes in many high-income jurisdictions, the burden of type 2 diabetes remains substantial. Public health strategies might benefit from tailored approaches to continue to improve health outcomes for people with diabetes. FUNDING: US Centers for Disease Control and Prevention and Diabetes Australia.

ß-Cell Function, Hepatic Insulin Clearance, and Insulin Sensitivity in South Asian and Nordic Women After Gestational Diabetes Mellitus.

South Asian women have a higher risk of type 2 diabetes after gestational diabetes mellitus (GDM) than Nordic women; however, the mechanisms behind this difference remain unclear. We investigated insulin sensitivity, ß-cell function, and hepatic insulin clearance in 179 South Asian and 108 Nordic women ∼17 months after GDM (mean age 35.3 years, BMI 29.1 kg/m2) by oral glucose tolerance test using deconvolution of C-peptide kinetics. Thirty-one percent of South Asian and 53% of Nordic participants were normoglycemic at the time of measurement. South Asian women had higher areas under the curve (AUCs) for glucose, prehepatic insulin, and peripheral insulin and lower insulin sensitivity, disposition index, and fasting hepatic insulin clearance than Nordic women. In the group with prediabetes or diabetes, South Asian women had similar AUCs for glucose and prehepatic insulin but a higher AUC for peripheral insulin, lower disposition index, and lower fasting hepatic insulin clearance than Nordic women. The waist-to-height ratio mediated ∼25-40% of the ethnic differences in insulin sensitivity in participants with normoglycemia. Overall, our novel data revealed that South Asian women with normoglycemia after GDM showed lower insulin secretion for a given insulin resistance and lower hepatic insulin clearance than Nordic women. South Asian women are at high risk of developing type 2 diabetes after GDM, and preventive efforts should be prioritized.

High prevalence and significant ethnic differences in actionable HbA1C after gestational diabetes mellitus in women living in Norway.

BACKGROUND: The type 2 diabetes risk after gestational diabetes mellitus (GDM) is twice as high in South Asian compared to European women. Current guidelines differ regarding which test to use as a screening-tool post-GDM. We aimed to identify ethnic differences in the prevalence rates and early predictors for actionable HbA1c (defined as prediabetes and diabetes) short time after GDM. METHODS: This cross-sectional study, enrolling South Asian and Nordic women 1-3 years after a diagnosis of GDM, was undertaken at three hospitals in Norway. We performed a clinical and laboratory evaluation including an oral glucose tolerance test (OGTT). Medical records were used to retrieve data during pregnancy. Prediabetes was classified with HbA1c alone or combined with OGTT glucose measurements according to the WHO, WHO-IEC, and ADA criteria (fasting plasma glucose (FPG) 6.1-6.9 mmol/L, FPG 6.1-6.9 mmol/L and/or HbA1c 42-47 mmol/mol (6.0-6.4%), and FPG 5.6-6.9 mmol/L and/or HbA1c 39-47 mmol/mol (5.7-6.4%)). Ethnic differences in prevalence and predictors of glucose deterioration were assed by χ2 (Pearson) tests and logistic regression models. RESULTS: We included 163 South Asian and 108 Nordic women. Actionable HbA1c levels were highly prevalent and more so among South Asian than Nordic women (WHO-IEC-HbA1c: 25.8% vs. 6.5% (p ≤ 0.001), ADA-HbA1c: 58.3% vs. 22.2% (p ≤ 0.001)). Although adding OGTT-data gave higher combined prevalence rates of prediabetes and diabetes (WHO: 65.6% vs. 47.2% (p ≤ 0.05), WHO-IEC: 70.6% vs. 47.2% (p ≤ 0.001), ADA: 87.8% vs. 65.7% (p ≤ 0.001)), the excess risk in the South Asian women was best captured by the HbA1c. Important predictors for glucose deterioration after GDM were: South Asian ethnicity, GDM before the index pregnancy, use of glucose-lowering drugs in pregnancy, higher age, and higher in-pregnancy fasting glucose levels. CONCLUSIONS: In women with GDM 1-3 year previously, we found high prevalence and significant ethnic differences in actionable ADA-HbA1c levels, with South Asian ethnicity, GDM before the index pregnancy, and the use of glucose-lowering drugs in pregnancy as the most important risk factors. This study reinforces the importance of annual screening-preferably with HbA1c measurements-to facilitate early intervention after GDM.

Comparative Genomics and Physiology of Akkermansia muciniphila Isolates from Human Intestine Reveal Specialized Mucosal Adaptation.

Akkermansia muciniphila is a champion of mucin degradation in the human gastrointestinal tract. Here, we report the isolation of six novel strains from healthy human donors and their genomic, proteomic and physiological characterization in comparison to the type-strains A. muciniphila MucT and A. glycaniphila PytT. Complete genome sequencing revealed that, despite their large genomic similarity (>97.6%), the novel isolates clustered into two distinct subspecies of A. muciniphila: Amuc1, which includes the type-strain MucT, and AmucU, a cluster of unassigned strains that have not yet been well characterized. CRISPR analysis showed all strains to be unique and confirmed that single healthy subjects can carry more than one A. muciniphila strain. Mucin degradation pathways were strongly conserved amongst all isolates, illustrating the exemplary niche adaptation of A. muciniphila to the mucin interface. This was confirmed by analysis of the predicted glycoside hydrolase profiles and supported by comparing the proteomes of A. muciniphila strain H2, belonging to the AmucU cluster, to MucT and A. glycaniphila PytT (including 610 and 727 proteins, respectively). While some intrinsic resistance was observed among the A. muciniphila straind, none of these seem to pose strain-specific risks in terms of their antibiotic resistance patterns nor a significant risk for the horizontal transfer of antibiotic resistance determinants, opening the way to apply the type-strain MucT or these new A. muciniphila strains as next generation beneficial microbes.

Host-microbial co-metabolites modulated by human milk oligosaccharides relate to reduced risk of respiratory tract infections.

Human milk oligosaccharides (HMOs) are structurally diverse oligosaccharides present in breast milk, supporting the development of the gut microbiota and immune system. Previously, 2-HMO (2'fucosyllactose, lacto-N-neotetraose) compared to control formula feeding was associated with reduced risk of lower respiratory tract infections (LRTIs), in part linked to lower acetate and higher bifidobacteria proportions. Here, our objective was to gain further insight into additional molecular pathways linking the 2-HMO formula feeding and LRTI mitigation. From the same trial, we measured the microbiota composition and 743 known biochemical species in infant stool at 3 months of age using shotgun metagenomic sequencing and untargeted mass spectrometry metabolomics. We used multivariate analysis to identify biochemicals associated to 2-HMO formula feeding and LRTI and integrated those findings with the microbiota compositional data. Three molecular pathways stood out: increased gamma-glutamylation and N-acetylation of amino acids and decreased inflammatory signaling lipids. Integration of stool metagenomic data revealed some Bifidobacterium and Bacteroides species to be implicated. These findings deepen our understanding of the infant gut/microbiome co-metabolism in early life and provide evidence for how such metabolic changes may influence immune competence at distant mucosal sites such as the airways.

Peptidoglycan from Akkermansia muciniphila MucT: chemical structure and immunostimulatory properties of muropeptides.

Akkermansia muciniphila is an intestinal symbiont known to improve the gut barrier function in mice and humans. Various cell envelope components have been identified to play a critical role in the immune signaling of A. muciniphila, but the chemical composition and role of peptidoglycan (PG) remained elusive. Here, we isolated PG fragments from A. muciniphila MucT (ATCC BAA-835), analyzed their composition and evaluated their immune signaling capacity. Structurally, the PG of A. muciniphila was found to be noteworthy due of the presence of some nonacetylated glucosamine residues, which presumably stems from deacetylation of N-acetylglucosamine. Some of the N-acetylmuramic acid (MurNAc) subunits were O-acetylated. The immunological assays revealed that muropeptides released from the A. muciniphila PG could both activate the intracellular NOD1 and NOD2 receptors to a comparable extent as muropeptides from Escherichia coli BW25113. These data challenge the hypothesis that non-N-acetylattion of PG can be used as a NOD-1 evasion mechanism. Our results provide new insights into the diversity of cell envelope structures of key gut microbiota members and their role in steering host-microbiome interactions.

Effects of liraglutide vs. lifestyle changes on soluble suppression of tumorigenesis-2 (sST2) and galectin-3 in obese subjects with prediabetes or type 2 diabetes after comparable weight loss.

BACKGROUND: Soluble suppression of tumorigenesis-2 (sST2) and galectin (Gal)-3 are two biomarkers related to inflammation, metabolic disturbances and to myocardial fibrosis that characterize several cardiac pathological conditions. Increased circulating levels of these molecules have been associated with risk of cardiovascular death. Treatment with liraglutide, a glucagon-like peptide 1 analog, is associated with weight loss, improved glycemic control, and reduced cardiovascular risk. We wanted to assess (I) potential differences between subjects with prediabetes or type 2 diabetes mellitus (T2DM) and healthy controls in sST2 and Gal-3 circulating levels, and their relationship with glycemic control and markers of beta cell function and myocardial injury; (II) whether liraglutide treatment modulates these markers in subjects with prediabetes or early T2DM independently of weight loss; (III) whether baseline levels of any of these two molecules may predict the response to liraglutide treatment. METHODS: Forty metformin-treated obese subjects (BMI ≥ 30) with prediabetes [impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) or both (n = 23)] or newly diagnosed T2DM (n = 17), were randomized to liraglutide or lifestyle counseling until achieving a comparable weight loss (7% of initial body weight). Thirteen subjects were enrolled as healthy controls for baseline sST2 and Gal-3 levels. RESULTS: Baseline sST2 levels were comparable between controls and obese patients (p = 0.79) whereas Gal-3 levels were significantly higher in patients as compared to controls (p < 0.001). Liraglutide treatment, but not weight loss achieved by lifestyle counseling, decreased plasma sST2 levels (- 9%, beta = - 14.9, standard deviation 6.9, p = 0.037) while Gal-3 levels did not change. A reduction in serum hs-Troponin I was observed after intervention, due to a 19% (p = 0.29) increase in the lifestyle arm, and a 25% decrease (p = 0.033) in the liraglutide arm (between-group difference p = 0.083). Lower baseline Gal-3 levels predicted a better improvement in beta cell function after liraglutide treatment. CONCLUSIONS: Liraglutide-induced reduction in sST2 and possibly hs-TnI suggests that in obese patients with prediabetes or early T2DM this drug may have a positive effect on (cardiac) fibrosis, whereas plasma level of Gal-3 before liraglutide initiation may predict response to the drug in terms of beta cell function improvement. Trial registration Eudract: 2013-001356-36.

Biology of human milk oligosaccharides: From basic science to clinical evidence.

Human milk oligosaccharides (HMOs) have been researched by scientists for over 100 years, driven by the substantial evidence for the nutritional and health benefits of mother's milk. Yet research has truly bloomed during the last decade, thanks to progress in biotechnology, which has allowed the production of large amounts of bona fide HMOs. The availability of HMOs has been particularly crucial for the renewed interest in HMO research because of the low abundance or even absence of HMOs in farmed animal milk. This interest is reflected in the increasing number of original research publications and reviews on HMOs. Here, we provide an overview and critical discussion on structure-function relations of HMOs that highlight why they are such interesting and important components of human milk. Clinical observations in breastfed infants backed by basic research from animal models provide guidance as to what physiological roles for HMOs are to be expected. From an evidence-based nutrition viewpoint, we discuss the current data supporting the clinical relevance of specific HMOs based on randomised placebo-controlled clinical intervention trials in formula-fed infants.

Trends in all-cause mortality among people with diagnosed diabetes in high-income settings: a multicountry analysis of aggregate data.

BACKGROUND: Population-level trends in mortality among people with diabetes are inadequately described. We aimed to examine the magnitude and trends in excess all-cause mortality in people with diabetes. METHODS: In this retrospective, multicountry analysis, we collected aggregate data from 19 data sources in 16 high-income countries or jurisdictions (in six data sources in Asia, eight in Europe, one from Australia, and four from North America) for the period from Jan 1, 1995, to Dec 31, 2016, (or a subset of this period) on all-cause mortality in people with diagnosed total or type 2 diabetes. We collected data from administrative sources, health insurance records, registries, and a health survey. We estimated excess mortality using the standardised mortality ratio (SMR). FINDINGS: In our dataset, there were approximately 21 million deaths during 0·5 billion person-years of follow-up among people with diagnosed diabetes. 17 of 19 data sources showed decreases in the age-standardised and sex-standardised mortality in people with diabetes, among which the annual percentage change in mortality ranged from -0·5% (95% CI -0·7 to -0·3) in Hungary to -4·2% (-4·3 to -4·1) in Hong Kong. The largest decreases in mortality were observed in east and southeast Asia, with a change of -4·2% (95% CI -4·3 to -4·1) in Hong Kong, -4·0% (-4·8 to -3·2) in South Korea, -3·5% (-4·0 to -3·0) in Taiwan, and -3·6% (-4·2 to -2·9) in Singapore. The annual estimated change in SMR between people with and without diabetes ranged from -3·0% (95% CI -3·0 to -2·9; US Medicare) to 1·6% (1·4 to 1·7; Lombardy, Italy). Among the 17 data sources with decreasing mortality among people with diabetes, we found a significant SMR increase in five data sources, no significant SMR change in four data sources, and a significant SMR decrease in eight data sources. INTERPRETATION: All-cause mortality in diabetes has decreased in most of the high-income countries we assessed. In eight of 19 data sources analysed, mortality decreased more rapidly in people with diabetes than in those without diabetes. Further longevity gains will require continued improvement in prevention and management of diabetes. FUNDING: US Centers for Disease Control and Prevention, Diabetes Australia Research Program, and Victoria State Government Operational Infrastructure Support Program.

Neuronal underpinnings of cognitive impairment in bipolar disorder: A large data-driven functional magnetic resonance imaging study.

OBJECTIVES: Cognitive impairment occurs in approximately 50% of remitted patients with bipolar disorder (BD). However, there exists no treatment with replicated and robust efficacy on cognition in BD. This is partially due to limited insight into the neuronal underpinnings of cognitive impairment in these patients. This is the first study to investigate neuronal underpinnings of cognitive impairment in a large functional magnetic resonance imaging (fMRI) dataset comparing neural activity patterns between distinct neurocognitive subgroups of partially or fully remitted patients with BD. METHODS: Patients (n = 153) and healthy controls (HC) (n = 52) underwent neuropsychological assessment and fMRI, during which they performed a verbal N-back working memory (WM) task. Based on hierarchical cluster analysis of neuropsychological test performance, patients were grouped into one of two neurocognitive subgroups (cognitively impaired, n = 91; cognitively normal compared to HC, n = 62) that were compared on WM-related neural activity. RESULTS: Cognitively impaired patients displayed WM-related hypo-activity in left dorsolateral prefrontal cortex and frontal and parietal regions within a cognitive control network (CCN) as well as hyper-activity in the default mode network (DMN) compared to cognitively normal patients. In contrast, cognitively normal patients only exhibited hypo-activity within a small cluster in the superior frontal gyrus relative to HC. CONCLUSIONS: Cognitive impairment in BD seems to originate from a failure to recruit key regions in the CCN and to suppress task-irrelevant DMN activity during cognitive performance. These results highlight modulation of aberrant dorsal prefrontal and DMN activity as a putative target for pro-cognitive treatment in BD.

Undiagnosed diabetes based on HbA1c by socioeconomic status and healthcare consumption in the Tromsø Study 1994-2016.

INTRODUCTION: We aimed to investigate whether the proportion of undiagnosed diabetes varies by socioeconomic status and healthcare consumption, in a Norwegian population screened with glycated hemoglobin (HbA1c). RESEARCH DESIGN AND METHODS: In this cohort study, we studied age-standardized diabetes prevalence using data from men and women aged 40-89 years participating in four surveys of the Tromsø Study with available data on HbA1c and self-reported diabetes: 1994-1995 (n=6720), 2001 (n=5831), 2007-2008 (n=11 987), and 2015-2016 (n=20 170). We defined undiagnosed diabetes as HbA1c ≥6.5% (48 mmol/mol) and no self-reported diabetes. We studied the association of education, income and contact with a general practitioner on undiagnosed diabetes and estimated adjusted prevalence ratio (aPR) from multivariable adjusted (age, sex, body mass index) log-binomial regression. RESULTS: Higher education was associated with lower prevalence of diagnosed and undiagnosed diabetes. Those with secondary and tertiary education had lower prevalence of undiagnosed diabetes (aPR for tertiary vs primary: 0.54, 95% CI: 0.44 to 0.66). Undiagnosed as a proportion of all diabetes was also significantly lower in those with tertiary education (aPR:0.78, 95% CI: 0.65 to 0.93). Household income was also negatively associated with prevalence of undiagnosed diabetes. Across the surveys, approximately 80% of those with undiagnosed diabetes had been in contact with a general practitioner the last year, similar to those without diabetes. CONCLUSIONS: Undiagnosed diabetes was lower among participants with higher education. The hypothesis that those with undiagnosed diabetes had been less in contact with a general practitioner was not supported.

A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease usually presenting after infection. Emerging evidence supports that energy metabolism is affected in ME/CFS, but a unifying metabolic phenotype has not been firmly established. We performed global metabolomics, lipidomics, and hormone measurements, and we used exploratory data analyses to compare serum from 83 patients with ME/CFS and 35 healthy controls. Some changes were common in the patient group, and these were compatible with effects of elevated energy strain and altered utilization of fatty acids and amino acids as catabolic fuels. In addition, a set of heterogeneous effects reflected specific changes in 3 subsets of patients, and 2 of these expressed characteristic contexts of deregulated energy metabolism. The biological relevance of these metabolic phenotypes (metabotypes) was supported by clinical data and independent blood analyses. In summary, we report a map of common and context-dependent metabolic changes in ME/CFS, and some of them presented possible associations with clinical patient profiles. We suggest that elevated energy strain may result from exertion-triggered tissue hypoxia and lead to systemic metabolic adaptation and compensation. Through various mechanisms, such metabolic dysfunction represents a likely mediator of key symptoms in ME/CFS and possibly a target for supportive intervention.