Effect of Hydrolyzed Infant Formula vs Conventional Formula on Risk of Type 1 Diabetes: The TRIGR Randomized Clinical Trial.

Importance: Early exposure to complex dietary proteins may increase the risk of type 1 diabetes in children with genetic disease susceptibility. There are no intact proteins in extensively hydrolyzed formulas. Objective: To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of type 1 diabetes in young children. Design, Setting, and Participants: An international double-blind randomized clinical trial of 2159 infants with human leukocyte antigen-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1081 were randomized to be weaned to the extensively hydrolyzed casein formula and 1078 to a conventional formula. The follow-up of the participants ended on February 28, 2017. Interventions: The participants received either a casein hydrolysate or a conventional adapted cow's milk formula supplemented with 20% of the casein hydrolysate. The minimum duration of study formula exposure was 60 days by 6 to 8 months of age. Main Outcomes and Measures: Primary outcome was type 1 diabetes diagnosed according to World Health Organization criteria. Secondary outcomes included age at diabetes diagnosis and safety (adverse events). Results: Among 2159 newborn infants (1021 female [47.3%]) who were randomized, 1744 (80.8%) completed the trial. The participants were observed for a median of 11.5 years (quartile [Q] 1-Q3, 10.2-12.8). The absolute risk of type 1 diabetes was 8.4% among those randomized to the casein hydrolysate (n = 91) vs 7.6% among those randomized to the conventional formula (n = 82) (difference, 0.8% [95% CI, -1.6% to 3.2%]). The hazard ratio for type 1 diabetes adjusted for human leukocyte antigen risk group, duration of breastfeeding, duration of study formula consumption, sex, and region while treating study center as a random effect was 1.1 (95% CI, 0.8 to 1.5; P = .46). The median age at diagnosis of type 1 diabetes was similar in the 2 groups (6.0 years [Q1-Q3, 3.1-8.9] vs 5.8 years [Q1-Q3, 2.6-9.1]; difference, 0.2 years [95% CI, -0.9 to 1.2]). Upper respiratory infections were the most common adverse event reported (frequency, 0.48 events/year in the hydrolysate group and 0.50 events/year in the control group). Conclusions and Relevance: Among infants at risk for type 1 diabetes, weaning to a hydrolyzed formula compared with a conventional formula did not reduce the cumulative incidence of type 1 diabetes after median follow-up for 11.5 years. These findings do not support a need to revise the dietary recommendations for infants at risk for type 1 diabetes. Trial Registration: clinicaltrials.gov Identifier: NCT00179777.

Regional differences in milk and complementary feeding patterns in infants participating in an international nutritional type 1 diabetes prevention trial.

Differences in breastfeeding, other milk feeding and complementary feeding patterns were evaluated in infants at increased genetic risk with and without maternal type 1 diabetes (T1D). The Trial to Reduce IDDM in the Genetically at Risk is an international nutritional primary prevention double-blinded randomized trial to test whether weaning to extensively hydrolyzed vs. intact cow's milk protein formula will decrease the development of T1D-associated autoantibodies and T1D. Infant diet was prospectively assessed at two visits and seven telephone interviews between birth and 8 months. Countries were grouped into seven regions: Australia, Canada, Northern Europe, Southern Europe, Central Europe I, Central Europe II and the United States. Newborn infants with a first-degree relative with T1D and increased human leukocyte antigen-conferred susceptibility to T1D were recruited. A lower proportion of infants born to mothers with than without T1D were breastfed until 6 months of age in all regions (range, 51% to 60% vs. 70% to 80%). Complementary feeding patterns differed more by region than by maternal T1D. In Northern Europe, a higher proportion of infants consumed vegetables and fruits daily compared with other regions. Consumption of meat was more frequent in all European regions, whereas cereal consumption was most frequent in Southern Europe, Canada and the United States. Maternal T1D status was associated with breastfeeding and other milk feeding patterns similarly across regions but was unrelated to the introduction of complementary foods. Infant feeding patterns differed significantly among regions and were largely inconsistent with current recommended guidelines.

Hydrolyzed infant formula and early ß-cell autoimmunity: a randomized clinical trial.

IMPORTANCE: The disease process leading to clinical type 1 diabetes often starts during the first years of life. Early exposure to complex dietary proteins may increase the risk of ß-cell autoimmunity in children at genetic risk for type 1 diabetes. Extensively hydrolyzed formulas do not contain intact proteins. OBJECTIVE: To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of diabetes-associated autoantibodies in young children. DESIGN, SETTING, AND PARTICIPANTS: A double-blind randomized clinical trial of 2159 infants with HLA-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1078 were randomized to be weaned to the extensively hydrolyzed casein formula and 1081 were randomized to be weaned to a conventional cows' milk-based formula. The participants were observed to April 16, 2013. INTERVENTIONS: The participants received either a casein hydrolysate or a conventional cows' milk formula supplemented with 20% of the casein hydrolysate. MAIN OUTCOMES: AND MEASURES: Primary outcome was positivity for at least 2 diabetes-associated autoantibodies out of 4 analyzed. Autoantibodies to insulin, glutamic acid decarboxylase, and the insulinoma-associated-2 (IA-2) molecule were analyzed using radiobinding assays and islet cell antibodies with immunofluorescence during a median observation period of 7.0 years (mean, 6.3 years). RESULTS: The absolute risk of positivity for 2 or more islet autoantibodies was 13.4% among those randomized to the casein hydrolysate formula (n = 139) vs 11.4% among those randomized to the conventional formula (n = 117). The unadjusted hazard ratio for positivity for 2 or more autoantibodies among those randomized to be weaned to the casein hydrolysate was 1.21 (95% CI, 0.94-1.54), compared with those randomized to the conventional formula, while the hazard ratio adjusted for HLA risk, duration of breastfeeding, vitamin D use, study formula duration and consumption, and region was 1.23 (95% CI, 0.96-1.58). There were no clinically significant differences in the rate of reported adverse events between the 2 groups. CONCLUSIONS AND RELEVANCE: Among infants at risk for type 1 diabetes, the use of a hydrolyzed formula, when compared with a conventional formula, did not reduce the incidence of diabetes-associated autoantibodies after 7 years. These findings do not support a benefit from hydrolyzed formula. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00179777.

Process epistemology in the COVID-19 era: rethinking the research process to avoid dangerous forms of reification.

Whether we live in a world of autonomous things, or a world of interconnected processes in constant flux, is an ancient philosophical debate. Modern biology provides decisive reasons for embracing the latter view. How does one understand the practices and outputs of science in such a dynamic, ever-changing world - and particularly in an emergency situation such as the COVID-19 pandemic, where scientific knowledge has been regarded as bedrock for decisive social interventions? We argue that key to answering this question is to consider the role of the activity of reification within the research process. Reification consists in the identification of more or less stable features of the flux, and treating these as constituting stable things. As we illustrate with reference to biological and biomedical research on COVID-19, reification is a necessary component of any process of inquiry and comes in at least two forms: (1) means reification (phenomena-to-object), when researchers create objects meant to capture features of the world, or phenomena, in order to be able to study them; and (2) target reification (object-to-phenomena), when researchers infer an understanding of phenomena from an investigation of the epistemic objects created to study them. We note that both objects and phenomena are dynamic processes and argue that have no reason to assume that changes in objects and phenomena track one another. We conclude that failure to acknowledge these forms of reification and their epistemic role in scientific inquiry can have dire consequences for how the resulting knowledge is interpreted and used.

Breastfeeding patterns of mothers with type 1 diabetes: results from an infant feeding trial.

BACKGROUND: Both the initiation and maintenance of breastfeeding have been reported to be negatively affected by maternal type 1 diabetes (T1D). The aim of this study was to prospectively examine the breastfeeding patterns among mothers with and without T1D participating in a large international randomized infant feeding trial (TRIGR). METHODS: Families with a member affected by T1D and with a newborn infant were invited into the study. Those who had HLA-conferred genetic susceptibility for T1D tested at birth with gestation > 35 weeks and were healthy were eligible to continue in the trial. Among the 2160 participating children, 1096 were born to women with T1D and 1064 to unaffected women. Information on infant feeding was acquired from the family by frequent prospective dietary interviews. RESULTS: Most (>90%) of the infants of mothers with and without T1D were initially breastfed. Breastfeeding rates declined more steeply among mothers with than without T1D being 50 and 72% at 6 months, respectively. Mothers with T1D were younger, less educated and delivered earlier and more often by caesarean section than other mothers (p < 0.01). After adjusting for all these factors associated with the termination of breastfeeding, there was no difference in the duration of breastfeeding among mothers with and without T1D. CONCLUSIONS: Maternal diabetes status per se was not associated with shorter breastfeeding. The lower duration of breastfeeding in mothers with T1D is largely explained by their more frequent caesarean sections, earlier delivery and lower age and education.

From molecules to systems: the importance of looking both ways.

Although molecular biology has meant different things at different times, the term is often associated with a tendency to view cellular causation as conforming to simple linear schemas in which macro-scale effects are specified by micro-scale structures. The early achievements of molecular biologists were important for the formation of such an outlook, one to which the discovery of recombinant DNA techniques, and a number of other findings, gave new life even after the complexity of genotype-phenotype relations had become apparent. Against this background we outline how a range of scientific developments and conceptual considerations can be regarded as enabling and perhaps necessitating contemporary systems approaches. We suggest that philosophical ideas have a valuable part to play in making sense of complex scientific and disciplinary issues.

Drawing and the dynamic nature of living systems.

Representing the dynamic nature of biological processes is a challenge. This article describes a collaborative project in which the authors - a philosopher of biology, an artist and a cell biologist - explore how best to represent the entire process of cell division in one connected image. This involved a series of group Drawing Labs, one-to-one sessions, and discussions between the authors. The drawings generated during the collaboration were then reviewed by four experts in cell division. We propose that such an approach has value, both in communicating the dynamic nature of biological processes and in generating new insights and hypotheses that can be tested by artists and scientists.

The study of socioethical issues in systems biology.

Systems biology is the rapidly growing and heavily funded successor science to genomics. Its mission is to integrate extensive bodies of molecular data into a detailed mathematical understanding of all life processes, with an ultimate view to their prediction and control. Despite its high profile and widespread practice, there has so far been almost no bioethical attention paid to systems biology and its potential social consequences. We outline some of systems biology's most important socioethical issues by contrasting the concept of systems as dynamic processes against the common static interpretation of genomes. New issues arise around systems biology's capacities for in silico testing, changing cultural understandings of life, synthetic biology, and commercialization. We advocate an interdisciplinary and interactive approach that integrates social and philosophical analysis and engages closely with the science. Overall, we argue that systems biology socioethics could stimulate new ways of thinking about socioethical studies of life sciences.

Metagenomics and biological ontology.

Metagenomics is an emerging microbial systems science that is based on the large-scale analysis of the DNA of microbial communities in their natural environments. Studies of metagenomes are revealing the vast scope of biodiversity in a wide range of environments, as well as new functional capacities of individual cells and communities, and the complex evolutionary relationships between them. Our examination of this science focuses on the ontological implications of these studies of metagenomes and metaorganisms, and what they mean for common sense and philosophical understandings of multicellularity, individuality and organism. We show how metagenomics requires us to think in different ways about what human beings are and what their relation to the microbial world is. Metagenomics could also transform the way in which evolutionary processes are understood, with the most basic relationship between cells from both similar and different organisms being far more cooperative and less antagonistic than is widely assumed. In addition to raising fundamental questions about biological ontology, metagenomics generates possibilities for powerful technologies addressed to issues of climate, health and conservation. We conclude with reflections about process-oriented versus entity-oriented analysis in light of current trends towards systems approaches.

The metaphysics of evolution.

This paper briefly describes process metaphysics, and argues that it is better suited for describing life than the more standard thing, or substance, metaphysics. It then explores the implications of process metaphysics for conceptualizing evolution. After explaining what it is for an organism to be a process, the paper takes up the Hull/Ghiselin thesis of species as individuals and explores the conditions under which a species or lineage could constitute an individual process. It is argued that only sexual species satisfy these conditions, and that within sexual species the degree of organization varies. This, in turn, has important implications for species' evolvability. One important moral is that evolution will work differently in different biological domains.

Sex-Linked Behavior: Evolution, Stability, and Variability.

Common understanding of human sex-linked behaviors is that proximal mechanisms of genetic and hormonal sex, ultimately shaped by the differential reproductive challenges of ancestral males and females, act on the brain to transfer sex-linked predispositions across generations. Here, we extend the debate on the role of nature and nurture in the development of traits in the lifetime of an individual, to their role in the cross-generation transfer of traits. Advances in evolutionary theory that posit the environment as a source of trans-generational stability, and new understanding of sex effects on the brain, suggest that the cross-generation stability of sex-linked patterns of behavior are sometimes better explained in terms of inherited socioenvironmental conditions, with biological sex fostering intrageneration variability.

Viruses as living processes.

The view that life is composed of distinct entities with well-defined boundaries has been undermined in recent years by the realisation of the near omnipresence of symbiosis. What had seemed to be intrinsically stable entities have turned out to be systems stabilised only by the interactions between a complex set of underlying processes (Dupré, 2012). This has not only presented severe problems for our traditional understanding of biological individuality but has also led some to claim that we need to switch to a process ontology to be able adequately to understand biological systems. A large group of biological entities, however, has been excluded from these discussions, namely viruses. Viruses are usually portrayed as stable and distinct individuals that do not fit the more integrated and collaborative picture of nature implied by symbiosis. In this paper we will contest this view. We will first discuss recent findings in virology that show that viruses can be 'nice' and collaborate with their hosts, meaning that they form part of integrated biological systems and processes. We further offer various reasons why viruses should be seen as processes rather than things, or substances. Based on these two claims we will argue that, far from serving as a counterexample to it, viruses actually enable a deeper understanding of the fundamentally interconnected and collaborative nature of nature. We conclude with some reflections on the debate as to whether viruses should be seen as living, and argue that there are good reasons for an affirmative answer to this question.

Understanding viruses: Philosophical investigations.

Viruses have been virtually absent from philosophy of biology. In this editorial introduction, we explain why we think viruses are philosophically important. We focus on six issues (the definition of viruses, the individuality and diachronic identity of a virus, the possibility to classify viruses into species, the question of whether viruses are living, the question of whether viruses are organisms, and finally the biological roles of viruses in ecology and evolution), and we show how they relate to classic questions of philosophy of biology and even general philosophy.

How Do Scientists Define Openness? Exploring the Relationship Between Open Science Policies and Research Practice.

This article documents how biomedical researchers in the United Kingdom understand and enact the idea of "openness." This is of particular interest to researchers and science policy worldwide in view of the recent adoption of pioneering policies on Open Science and Open Access by the U.K. government-policies whose impact on and implications for research practice are in need of urgent evaluation, so as to decide on their eventual implementation elsewhere. This study is based on 22 in-depth interviews with U.K. researchers in systems biology, synthetic biology, and bioinformatics, which were conducted between September 2013 and February 2014. Through an analysis of the interview transcripts, we identify seven core themes that characterize researchers' understanding of openness in science and nine factors that shape the practice of openness in research. Our findings highlight the implications that Open Science policies can have for research processes and outcomes and provide recommendations for enhancing their content, effectiveness, and implementation.

Glycaemic effects of incretins in Type 1 diabetes mellitus: a concise review, with emphasis on studies in humans.

The remission phase of Type 1 diabetes mellitus is associated with substantial recovery of beta-cell function and with marked improvement of endogenous insulin responses to meals in the early months after diagnosis, accompanied by little or no improvement in the insulin response to parenteral glucose, suggesting that the incretin function may be important in glycaemic regulation in this phase of diabetes. Preservation of the insulin response to parenteral glucagon-like peptide-1 (GLP-1), contrasting with lack of stimulation of insulin secretion by the other known incretin gastric inhibitory polypeptide (GIP), prompted studies with exogenous GLP-1 in recent-onset Type 1 diabetes. These studies showed substantial reduction of glycaemic excursions after ingestion of mixed nutrients during intravenous infusion of GLP-1 without administration of insulin, in subjects with a range of endogenous secretion of insulin in response to meals as demonstrated by blood levels of the insulin-connecting peptide (CP). These effects were independent of stimulation of blood levels of CP and were reproduced in volunteers with no endogenous release of CP in response to meals. The glycaemic effects were associated with inhibition of abnormal rises of blood levels of glucagon, and with suppression of endogenous release of human pancreatic polypeptide (HPP), by GLP-1. It was hypothesized that a major component of the glycaemic effect is attributable to the known action of GLP-1 to inhibit gastric emptying and to inhibit glucagon secretion. Studies of the effects of GLP-1 agonists (GLP-1 and exendin-4) given together with established insulin doses before a meal supported the hypothesis. The more prolonged actions of exendin-4 were accompanied by greater and more prolonged reduction of glycaemic effects of ingestion of meals in volunteers with CP-negative Type 1 diabetes mellitus, during intensive insulin therapy, in whom delay of gastric emptying was confirmed by studies of blood levels of acetaminophen ingested with the meals. Side effect-free doses of exendin-4 given together with insulin in volunteers with CP-negative Type 1 diabetes receiving continuing intensive insulin therapy demonstrated the capacity of this combination therapy to normalize blood glucose levels after ingestion of meals that were consistent with the dietary program of the volunteers, without apparent increased risk of hypoglycaemia within a normal between-meals interval. It is suggested that further and more prolonged studies of the use of long-acting GLP-1 agonists as congeners with insulin in Type 1 diabetes mellitus are indicated.

Exendin-4 normalized postcibal glycemic excursions in type 1 diabetes.

Exendin-4 is a reptilian peptide that activates the mammalian receptor for truncated glucagon-like peptide 1 (tGLP-1) with relatively prolonged actions. Exendin-4 and tGLP-1 can reduce blood glucose levels by stimulating insulin secretion, inhibiting glucagon secretion, and delaying gastric emptying. We tested a range of doses of exendin-4 on postcibal glycemic excursions in nine volunteers with type 1 diabetes, all with negligible endogenous insulin secretion, in paired comparisons with vehicle in at least six volunteers with each of six doses. We established a side effect-free dose and an appropriate antecibal time for sc administration of exendin-4. Subsequently, exendin-4 was administered 15 min before breakfast, with usual insulin, to eight of the volunteers. Acetaminophen was ingested with the meal as an indicator of gastric emptying. The mean plasma glucose excursion was reduced by 90%, falling into the normal range, after breakfast, whereas plasma pancreatic polypeptide, glucagon, and acetaminophen levels were reduced, and insulin levels were not affected. Thus, normalization of postcibal glycemia was associated with delayed gastric emptying and suppression of glucagon secretion, without increased secretion or blood levels of insulin. We suggest that tGLP-1 agonists have therapeutic potential as congeners with insulin in C-peptide-negative type 1 diabetes.

Glucagon-like peptide 1 improved glycemic control in type 1 diabetes.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) and its agonists are under assessment in treatment of type 2 diabetes, by virtue of their antidiabetic actions, which include stimulation of insulin secretion, inhibition of glucagon release, and delay of gastric emptying. We examined the potential of GLP-1 to improve glycemic control in type 1 diabetes with no endogenous insulin secretion. METHODS: Dose-finding studies were carried out to establish mid range doses for delay of gastric emptying indicated by postponement of pancreatic polypeptide responses after meals. The selected dose of 0.63 micrograms/kg GLP-1 was administered before breakfast and lunch in 8-hour studies in hospital to establish the efficacy and safety of GLP-1. In outside-hospital studies, GLP-1 or vehicle was self-administered double-blind before meals with usual insulin for five consecutive days by five males and three females with well-controlled C-peptide-negative type 1 diabetes. Capillary blood glucose values were self-monitored before meals, at 30 and 60 min after breakfast and supper, and at bedtime. Breakfast tests with GLP-1 were conducted on the day before and on the day after 5-day studies. Paired t-tests and ANOVA were used for statistical analysis. RESULTS: In 8-hour studies time-averaged incremental (delta) areas under the curves(AUC) for plasma glucose through 8 hours were decreased by GLP-1 compared to vehicle (3.2 PlusMinus; 0.9, mean PlusMinus; se, vs 5.4 PlusMinus; 0.8 mmol/l, p <.05), and for pancreatic polypeptide, an indicator of gastric emptying, through 30 min after meals (4.0 PlusMinus; 3.1 vs 37 PlusMinus; 9.6 pmol/l, p <.05) with no adverse effects. Incremental glucagon levels through 60 min after meals were depressed by GLP-1 compared to vehicle (-3.7 PlusMinus; 2.5 vs 3.1 PlusMinus; 1.9 ng/l, p <.04). In 5-day studies, AUC for capillary blood glucose levels were lower with GLP-1 than with vehicle (-0.64 PlusMinus; 0.33 vs 0.34 PlusMinus; 0.26 mmol/l, p <.05). No assisted episode of hypoglycaemia or change in insulin dosage occurred. Breakfast tests on the days immediately before and after 5-day trials showed no change in the effects of GLP-1. CONCLUSION: We have demonstrated that subcutaneous GLP-1 can improve glucose control in type 1 diabetes without adverse effects when self-administered before meals with usual insulin during established intensive insulin treatment programs.

The transcultural diabetes nutrition algorithm: a canadian perspective.

The Transcultural Diabetes Nutrition Algorithm (tDNA) is a clinical tool designed to facilitate implementation of therapeutic lifestyle recommendations for people with or at risk for type 2 diabetes. Cultural adaptation of evidence-based clinical practice guidelines (CPG) recommendations is essential to address varied patient populations within and among diverse regions worldwide. The Canadian version of tDNA supports and targets behavioural changes to improve nutritional quality and to promote regular daily physical activity consistent with Canadian Diabetes Association CPG, as well as channelling the concomitant management of obesity, hypertension, dyslipidemia, and dysglycaemia in primary care. Assessing glycaemic index (GI) (the ranking of foods by effects on postprandial blood glucose levels) and glycaemic load (GL) (the product of mean GI and the total carbohydrate content of a meal) will be a central part of the Canadian tDNA and complement nutrition therapy by facilitating glycaemic control using specific food selections. This component can also enhance other metabolic interventions, such as reducing the need for antihyperglycaemic medication and improving the effectiveness of weight loss programs. This tDNA strategy will be adapted to the cultural specificities of the Canadian population and incorporated into the tDNA validation methodology.