Alan Morris

Diabetes: Linking diabetes and schizophrenia

(T2DM) are higher in cohorts of patients with schizophrenia than in the general population, an association that is typically attributed to antipsychotic medications and poor lifestyle habits. New research published in JAMA Psychiatry reports that patients with first-episode schizophrenia exhibit impaired glucose homeostasis compared with healthy control individuals. These new data could suggest that patients with schizophrenia have an inherent risk of developing T2DM. The meta-analysis conducted by Toby Pillinger and colleagues included studies that provided fasting glucose concentration, glucose concentration following the oral glucose tolerance test (OGTT), fasting insulin and insulin resistance derived from homeostatic model assessment. To limit the effects of exposure to antipsychotic drugs, the authors only included patients who had been prescribed antipsychotics for ≤2 weeks. The team demonstrated that individuals with first-episode schizophrenia have increased levels of fasting glucose, raised levels of glucose post-OGTT, raised levels of fasting insulin and increased insulin resistance, compared with matched controls. The results remained significant in sensitivity analyses that focused on patients and controls that were matched for diet, levels of regular exercise and ethnicity, and also in analyses that only considered entirely antipsychotic naive patients. “We recognize that our findings might still, at least in part, reflect poorer lifestyle habits in patients with schizophrenia,” says Pillinger. “There are, however, other mechanisms that could be contributing to the association between schizophrenia and T2DM, for example, common susceptibility genes and shared developmental risk factors, such as maternal malnutrition.” The authors hope that their findings will encourage health practitioners to consider diabetes prevention from the onset of schizophrenia. “The mortality gap between patients with schizophrenia and the general population is growing, and, in that context, our findings have major clinical implications,” concludes Pillinger. “There is a need for clinicians to select an appropriate antipsychotic at an appropriate dose so as to limit the risk of developing diabetes, provide patient education regarding diet and exercise, ensure regular screening for diabetes, and offer prompt management to those who go on to develop diabetes.”

Ageing: Are the secrets of healthy ageing within 'young blood'?

umbilical cord can ameliorate certain brain ageing phenotypes in mice, according to new research published in Nature. The findings, reported by Joseph Castellano and colleagues, are the first to show that proteins from human blood can improve age-related reductions in synaptic plasticity and cognition in aged mice. Ageing is characterized by a decline in cellular function and increased risk of age-related diseases and death. In the brain, ageing is associated with a marked decline in self-renewal and repair. The hippocampus, a region of the brain that is essential for spatial and episodic memory, is particularly vulnerable to age-related changes. To assess the effect of ‘young blood’ on the brain function of aged mice, Castellano and colleagues injected human plasma derived from umbilical cords, young adults and elderly donors into aged immunodeficient mice. The authors reported that plasma from young participants, in particular umbilical cord plasma, increased hippocampal plasticity and improved the cognitive function of the aged mice. “While it might seem obvious that plasma of an early developmental stage might possess pro-plasticity activity, our study is an important proof of concept,” explains Castellano. “We also identified a specific protein, TIMP2, as an important mediator of the cognitive benefits conferred by cord plasma.” The mechanisms by which TIMP2 exerts its pro-plasticity effects within the hippocampus are not well understood. For example, the protein might have a direct mode of action on the brain or it could act indirectly by influencing systems throughout the body. Castellano says that one of the next steps will be to address this question. “An additional area for exploration is the potential role of TIMP2 and related proteins in the context of age-related diseases, including Alzheimer disease,” concludes Castellano. “We believe that these are exciting times in our field with many opportunities to learn about the biology of how we age.” Alan Morris AG E I N G

Genetics: New insights into Turner syndrome

the complete or partial loss of an X chromosome, affects 1 in every 2,500 female live births. The condition is associated with a range of morbidities including hypothyroidism, diabetes mellitus and osteoporosis. New research describes novel phenotypic differences between 5 common forms of Turner syndrome as defined by their karyotype. The present study is part of The Turner Syndrome Life Course Project, which was established in 2014 to document medical outcomes and life experiences of women with Turner syndrome. The cohort of over 780 women is one of the largest data sets of women with the condition. “Owing to the size of our cohort, we were able to focus on the [rarer] forms of Turner syndrome,” explains Antoinette Cameron-Pimblett, corresponding author on the study. “We found that patients with a ring X chromosome (45,X/46,X,r(X); 7.3% of participants) were more likely to have features of the metabolic syndrome characterized by elevated liver enzymes and HbA1c than patients with the classical karyotype (45,X; 41.6% of participants).” In addition, the authors report that Turner syndrome caused by X chromosome mosaicism with a Y chromosome (45,X/46,XY; 10.7% of participants) is associated with a decreased incidence of thyroid disease and hearing loss. These data indicate that, as it has been observed in the general population, the Y chromosome in Turner syndrome could be protective against autoimmunity. The authors now plan to explore the association between diabetes mellitus and X chromosome abnormalities in Turner syndrome. “We believe that the X chromosome has more secrets to reveal with regards to its contribution to sex-related health risks and that studying women with Turner syndrome will lead to new insights.” Alan Morris G E N E T I C S

Acute effects of glucagon on the liver

© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. Nature reviews | Endocrinology Studies on the effects of glucagon on the liver typically focus on the role of gluconeogenic genes and their products, but these genes and proteins do not explain the acute effects of glucagon on hepatic metabolism. Now, a new study reports that elevated levels of glucagon promote the release of glutamine from the liver and increase gluconeogenesis. In addition, the authors show that reducing glutamine metabolism in the liver reduces the severity of hyperglycaemia. “Among the early studies on the hepatic actions of glucagon, there are numerous reports detailing rapid metabolic changes, some studies even showed increases in glutamine metabolism,” explains Russell Miller, lead author on the study. “In the present study, we used stable isotopebased mass spectrometry, which tracks heavy isotopes through metabolic pathways, to analyse the metabolic changes that occur in the liver in response to glucagon.” The team found that hepatic glucose release following stimulation with glucagon was concomitant with a large increase in hepatic glutaminolysis. Further analysis revealed that a marked proportion of this metabolized glutamine contributed to the carbons of glucose generated during the glucagonstimulated gluconeogenesis. The authors then genotyped cryopreserved human hepatocytes and identified the L581P variant of liverexpressed glutaminase 2 (GLS2) as a gainof-function variant. Importantly, lossof-function of GLS2 in mice recapitulated the L581P GLS2 phenotype observed in humans (low fasting levels of glucose and increased plasma levels of glutamine). “There are a number of paths forward,” concludes Miller. “Levels of plasma glutamine and the L581P GLS2 variant could potentially be used in future clinical work to inform therapeutic approaches to type 2 diabetes mellitus. For example, plasma levels of glutamine could possibly be used to identify populations of patients who will respond to treatment with a glucagon antagonist.” Alan Morris D I A B E T E S

Microbiota alters behaviour

© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. Nature reviews | Endocrinology Original article Soto, M. et al. Gut microbiota modulate neurobehavior through changes in brain insulin sensitivity and metabolism. Mol. Psychiatry https://doi. org/10.1038/s41380-018-0086-5 (2018) type 2 diabetes mellitus and obesity are associated with increased rates of depression, anxiety and other mood disorders. Furthermore, a diet that contains large quantities of fat can alter the gut microbiota by reducing bacterial diversity and modifying the microbial composition. in addition, research suggests that changes to the overall bacterial composition of the gut microbiota can induce systemic insulin resistance, which is notable for neuropsychiatric disorders as the brain is sensitive to fluctuations in serum levels of insulin. what remained unclear, however, was whether dietary changes and changes to the gut microbiota by antibiotics affected mood and behaviour and, more importantly, whether these changes to behaviour were mediated by changes in the microbiome in the gut. Now, C. ronald Kahn and colleagues have reported that the modification of gut microbiota due to high-fat diet (HFD) feeding results in multiple behavioural metabolites in the blood that can affect brain function. “Our current goal is to identify the metabolites that are produced by the microbiome that cause these behavioural changes,” concludes Khan. “if [we can achieve this], we can potentially use these metabolites to design new targets for treatment of anxiety and depressive disorders.” Alan Morris g U t M i c r O B i Ota

CHRNA2 as a marker for activated beige adipose tissue

© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. Nature reviews | Endocrinology Original article Jun, H. et al. An immune–beige adipocyte communication via nicotinic acetylcholine receptor signaling. Nat. Med. https://doi.org/10.1038/ s41591-018-0032-8 (2018) Beige fat cells are a potential therapeutic target for the prevention and treatment of human obesity, but little is known about the mechanisms underlying beige fat activation. Now, Jun wu and colleagues have moved us one step closer towards this goal by showing that the α2 subunit of the nicotinic acetylcholine receptor (CHrNa2) is upregulated in beige fat cells following their activation. “the therapeutic potential of beige fat cells is clear: genetic manipulations that create more beige fat in mice have strong antiobesity and antidiabetic effects and cumulative evidence supports a protective role of activated thermogenic fat in maintaining systemic metabolic homeostasis in humans,” explains wu. “in our study we used a calciumimaging assay in combination with Ucp1–Cre–rFP primary inguinal fat cell culture and flow cytometric analysis using Chat–GFP reporter mice to investigate the molecular mechanisms and signalling networks that regulate beige fat development and activation.” the authors found that the expression of CHrNa2 is upregulated in activated beige fat cells from subcutaneous adipose depots. they demonstrated that that a subgroup of acetylcholineproducing CD45+ haematopoietic lineage cells within these depots mediate CHrNa2 signalling in beige adipocytes. wu and colleagues then went on to investigate how this immune cell–beige adipocyte communication process is regulated during cold exposure and obesity. “we found that Chrna2-knockout mice (in which the canonical βadrenergic regulation of the beige fat remains intact) demonstrate a compromised adaptation to cold and exacerbated dietinduced obesity,” adds wu. “these results not only further confirm the physiological significance of beige adipocytes as an important metabolic regulator, but also highlight the essential role of catecholamineindependent, acetylcholine–CHrNa2 signalling in energy metabolism.” wu and colleagues now want to investigate whether any of the acetylcholineproducing CD45+ cells within the subcutaneous fat tissue have a dominant role in regulating the activation of beige adipocytes that is mediated by CHrNa2. “the identification of such a subset would help to incorporate the acetylcholine–beige fat signalling pathway into the already identified signalling network between immune cells and adipocytes and place this newly defined pathway within the interconnected metabolic matrix,” concludes wu. Alan Morris C re di t: S te ve G sc hm ei ss ne r/ Sc ie nc e Ph ot o Li br ar y

Livers from Venus and livers from Mars

© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. Nature reviews | Endocrinology New research has reported sex differences in how the livers of mice respond to short-term fasting. Although data exist showing that the liver is a sexually dimorphic organ, the reasons for this dimorphism were unclear until now. In animals, a mutual interaction exists between liver activity and reproductive function. “In oviparous species, the liver is essential for ovarian functions because it provides the proteins for the maturation of the egg,” explain Adriana Maggi and Sara Della Torre. This feature has relevant functional consequences because it ensures that reproduction does not occur when food is scarce. “In mammals the liver can recognize when the female is cycling, pregnant or lactating and adjust its energy production accordingly,” adds Maggi. The team were interested in investigating the mechanisms controlling the sexual dimorphism of the mammalian liver as males are not affected by changes in reproductive status. To do this, Adriana Maggi, Sara Della Torre and colleagues compared the metabolome and transcriptome of livers from adult mice in a condition of short-term fasting. “The mild starvation protocol was necessary to limit activation of the hepatic oestrogen receptor by dietary amino acids, a protocol that we adopted to maximize the sex differences due to physiological sex hormones,” explains Della Torre. The authors report that in response to short-term fasting, the livers of male mice stop producing energy storage molecules, while the livers of female mice make use of all available resources, including amino acids, to increase the available pool of lipids. Intriguingly, the authors found that the hepatic oestrogen receptor-α is integral to the adoption and maintenance of this sex-specific response to short-term fasting. “The finding that in female mice the hepatic oestrogen receptor-α has a key role in the control of energy metabolism points to the possibility of selectively targeting this receptor for a novel generation of therapies for the post-menopause,” concludes Maggi. Alan Morris

Risk factors: Breastfeeding reduces risk of type 2 diabetes mellitus

women who breastfeed might be greater than previously thought, according to a new study published in JAMA Internal Medicine. The authors report a strong association of breastfeeding duration with a lower incidence of type 2 diabetes mellitus (T2DM). “Previous studies were limited in their ability to assess early conversion to diabetes mellitus after pregnancy because most women without diabetes entered these studies many years to decades after their pregnancies,” explains lead author Erica Gunderson. “In addition, these studies relied entirely on a self-report of diabetes mellitus, without any systematic longitudinal biochemical testing and they did not account for a history of gestational diabetes in women of childbearing age, which is a very strong risk factor for T2DM.” Gunderson and colleagues analysed data from the CARDIA Study — a longitudinal, prospective cohort study conducted in women of childbearing age that measured glucose tolerance and diabetes mellitus medication use, both before and after pregnancy, approximately every 5 years during the 30-year study follow-up period. In the present study, the authors assessed breastfeeding duration across all births in relation to the incidence of T2DM in women, accounting for pre-pregnancy obesity and metabolic measures, perinatal outcomes, history of gestational diabetes, weight changes and lifestyle behaviours. The authors report that longer duration of breastfeeding was associated with a marked decrease in the risk of T2DM after accounting for lifestyle behaviours, pre-pregnancy metabolic status, gestational diabetes, and perinatal outcomes. Specifically, >6 months of breastfeeding reduced the risk of T2DM by half compared with never breastfeeding. “Research studies are needed to elucidate the biological mechanisms that could underlie the relationship between breastfeeding duration and lower diabetes mellitus risk,” concludes Gunderson. “This is unlikely to be due to obesity because 30-year weight gain did not weaken the association of breastfeeding with diabetes risk in our study.”

Mechanisms of leptin resistance revealed

of ObR in hypothalamic cells. After treatment with MMP2, the expression of the ObR extracellular domain in the cells was reduced by >20%. The authors then used Mmp2knockout mice to determine the effect of MMP2 depletion on HFD-induced obesity. The authors showed that MMP2-depleted mice had reduced weight gain when fed a HFD compared with wild-type littermates. “[Following the Mmp2-knockout experiments], we needed a metho dology that could show that depletion of MMP2 in the hypothalamus alone could result in reduced weight gain, which is why we adopted the lentiviral injections approach,” explains FriedmannMorvinski. The team used lentiviral vectors to either knock down Mmp2 in the hypothalamus or to upregulate the expression of a mutant cleavage-resistant form of the ObR. Compared with control mice, mice lacking hypothalamic MMP2 that were fed a HFD gained less weight and had reduced plasma concentrations of leptin. “I believe we have found a novel target and presented a possible new strategy to develop new treatment approaches to restore leptin sensitivity and hopefully decrease weight gain in people who are obese,” concludes Friedmann-Morvinski. “The challenge now is to find the way to deliver MMP2 inhibitors specifically to the hypothalamus.”

Closed-loop insulin delivery has wide-ranging benefits

levels, time spent in hypoglycaemia and glucose variability. These benefits were observed irrespective of age. “Several studies are ongoing or are planned, including testing a closedloop insulin delivery system in newly diagnosed adolescents with T1DM, as well as young children aged 1–7 years and older adults aged >60 years with T1DM,” concludes Hovorka. “Our ultimate aim is to commercialize our closed-loop algorithm and make it widely available.” Alan Morris