A life course perspective on diabetes: developmental origins and beyond |
Upfront |
The diabesity epidemic in the light of evolution: insights from the capacity–load modelAbstract
The global nutrition transition, which embraces major changes in how food is produced, distributed and consumed, is associated with rapid increases in the prevalence of obesity, but the implications for diabetes differ between populations. A simple conceptual model treats diabetes risk as the function of two interacting traits: ‘metabolic capacity,’ which promotes glucose homeostasis, and ‘metabolic load’, which challenges glucose homoeostasis. Population variability in diabetes prevalence is consistent with this conceptual model, indicating that the effect of obesity varies by ethnicity. Evolutionary life history theory can help explain why variability in metabolic capacity and metabolic load emerges. At the species level (hominin evolution), across human populations and within individual life courses, phenotypic variability emerges under selective pressure to maximise reproductive fitness rather than metabolic health. Those exposed to adverse environments may express or develop several metabolic traits that are individually beneficial for reproductive fitness, but which cumulatively increase diabetes risk. Public health interventions can help promote metabolic capacity, but there are limits to the benefits that can emerge within a single generation. This means that efforts to curb metabolic load (obesity, unhealthy lifestyles) must remain at the forefront of diabetes prevention. Such efforts should go beyond individuals and target the broader food system and socioeconomic factors, in order to maximise their efficacy.
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The role of GIP and pancreatic GLP-1 in the glucoregulatory effect of DPP-4 inhibition in miceAbstractAims/hypothesis
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are two peptides that function to promote insulin secretion. Dipeptidyl peptidase-4 (DPP-4) inhibitors increase the bioavailability of both GLP-1 and GIP but the dogma continues to be that it is the increase in GLP-1 that contributes to the improved glucose homeostasis. We have previously demonstrated that pancreatic rather than intestinal GLP-1 is necessary for improvements in glucose homeostasis in mice. Therefore, we hypothesise that a combination of pancreatic GLP-1 and GIP is necessary for the full effect of DPP-4 inhibitors on glucose homeostasis.
Methods
We have genetically engineered mouse lines in which the preproglucagon gene (Gcg) is absent in the entire body (GcgRAΔNull) or is expressed exclusively in the intestine (GcgRAΔVilCre) or pancreas and duodenum (GcgRAΔPDX1Cre). These mice were used to examine oral glucose tolerance and GLP-1 and GIP responses to a DPP-4 inhibitor alone, or in combination with incretin receptor antagonists.
Results
Administration of the DPP-4 inhibitor, linagliptin, improved glucose tolerance in GcgRAΔNull mice and control littermates and in GcgRAΔVilCre and GcgRAΔPDX1Cre mice. The potent GLP-1 receptor antagonist, exendin-[9–39] (Ex9), blunted improvements in glucose tolerance in linagliptin-treated control mice and in GcgRAΔPDX1Cre mice. Ex9 had no effect on glucose tolerance in linagliptin-treated GcgRAΔNull or in GcgRAΔVilCre mice. In addition to GLP-1, linagliptin also increased postprandial plasma levels of GIP to a similar degree in all genotypes. When linagliptin was co-administered with a GIP-antagonising antibody, the impact of linagliptin was partially blunted in wild-type mice and was fully blocked in GcgRAΔNull mice.
Conclusions/interpretation
Taken together, these data suggest that increases in pancreatic GLP-1 and GIP are necessary for the full effect of DPP-4 inhibitors on glucose tolerance.
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Intrauterine programming of obesity and type 2 diabetesAbstract
The type 2 diabetes epidemic and one of its predisposing factors, obesity, are major influences on global health and economic burden. It is accepted that genetics and the current environment contribute to this epidemic; however, in the last two decades, both human and animal studies have consolidated considerable evidence supporting the ‘developmental programming’ of these conditions, specifically by the intrauterine environment. Here, we review the various in utero exposures that are linked to offspring obesity and diabetes in later life, including epidemiological insights gained from natural historical events, such as the Dutch Hunger Winter, the Chinese famine and the more recent Quebec Ice Storm. We also describe the effects of gestational exposure to endocrine disruptors, maternal infection and smoking to the fetus in relation to metabolic programming. Causal evidence from animal studies, motivated by human observations, is also discussed, as well as some of the proposed underlying molecular mechanisms for developmental programming of obesity and type 2 diabetes, including epigenetics (e.g. DNA methylation and histone modifications) and microRNA interactions. Finally, we examine the effects of non-pharmacological interventions, such as improving maternal dietary habits and/or increasing physical activity, on the offspring epigenome and metabolic outcomes.
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Differential expression and release of exosomal miRNAs by human islets under inflammatory and hypoxic stressAbstractAims/hypothesis
Pancreatic islets produce non-coding microRNAs (miRNAs) that regulate islet cell function and survival. Our earlier investigations revealed that human islets undergo significant damage due to various types of stresses following transplantation and release miRNAs. Here, we sought to identify and validate exosomal miRNAs (exo-miRNAs) produced by human islets under conditions of cellular stress, preceding loss of cell function and death. We also aimed to identify islet stress signalling pathways targeted by exo-miRNAs to elucidate potential regulatory roles in islet cell stress.
Methods
Human islets were subjected to proinflammatory cytokine and hypoxic cell stress and miRNA from exosomes was isolated for RNA sequencing and analysis. Stress-induced exo-miRNAs were evaluated for kinetics of expression and release by intact islets for up to 48 h exposure to cytokines and hypoxia. A subset of stress-induced exo-miRNAs were assessed for recovery and detection as biomarkers of islet cell stress in a diabetic nude mouse xenotransplant model and in patients undergoing total pancreatectomy with islet auto-transplantation (TPIAT). Genes and signalling pathways targeted by stress-induced exo-miRNAs were identified by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and direct interactions of miRNAs with downstream signalling targets were validated in human islet cells using the miRNA Tests for Read Analysis and Prediction (MirTrap) system.
Results
Global exo-miRNA sequencing revealed that 879 miRNA species were released from human islets and 190 islet exo-miRNAs were differentially expressed in response to proinflammatory cytokines, hypoxia or both. Release of exo-miRNAs hsa-miR-29b-3p and hsa-miR-216a-5p was detected within 6 h of exposure to cytokines and hypoxia. The remaining subset of stress-induced exo-miRNAs, including hsa-miR-148a-3p and islet cell damage marker hsa-miR-375, showed delayed release at 24–48 h, correlating with apoptosis and cell death. Stress and damage exo-miRNAs were significantly elevated in the circulation in human-to-mouse xenotransplant models and in human transplant recipients. Elevated blood exo-miRNAs negatively correlated with post-transplant islet function based on comparisons of stress and damage exo-miRNA indices with Secretory Unit of Islet Transplant Objects (SUITO) indices. KEGG analysis and further validation of exo-miRNA targets by MirTrap analysis revealed significant enrichment of islet mRNAs involved in phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase signalling pathways.
Conclusions/interpretation
The study identifies exo-miRNAs differentially expressed and released by islets in response to damage and stress. These exo-miRNAs could serve as potential biomarkers for assessing islet damage and predicting outcomes in islet transplantation. Notably, exo-miRNAs 29b-3p and 216a-5p could be detected in islets prior to damage-released miRNAs and indicators of cellular apoptosis and death. Thus, these stress-induced exo-miRNAs may have potential diagnostic value for detecting early islet stress prior to progressive loss of islet cell mass and function. Further investigations are warranted to investigate the utility of these exo-miRNAs as early indicators of islet cell stress during prediabetic conditions.
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Cellular senescence: at the nexus between ageing and diabetesAbstract
Ageing and diabetes lead to similar organ dysfunction that is driven by parallel molecular mechanisms, one of which is cellular senescence. The abundance of senescent cells in various tissues increases with age, obesity and diabetes. Senescent cells have been directly implicated in the generation of insulin resistance. Recently, drugs that preferentially target senescent cells, known as senolytics, have been described and recently entered clinical trials. In this review, we explore the biological links between ageing and diabetes, specifically focusing on cellular senescence. We summarise the current data on cellular senescence in key target tissues associated with the development and clinical phenotypes of type 2 diabetes and discuss the therapeutic potential of targeting cellular senescence in diabetes.
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What should governments be doing to prevent diabetes throughout the life course?Abstract
Health systems and governments are increasingly required to implement measures that target at-risk populations to prevent noncommunicable diseases. In this review we lay out what governments should be doing to prevent diabetes throughout the life course. The following four target groups were used to structure the specific recommendations: (1) pregnant women and young families, (2) children and adolescents, (3) working age population, and (4) the elderly. The evidence to date supports the effectiveness of some known government policy measures, such as sugar taxes and regulatory measures in the (pre-)school setting for children and adolescents. Many of these appear to be more effective if they are part of a bundle of strategies and if they are supplemented by communication strategies. Although there is a current focus on strategies that target the individual, governments can make use of evidence-based population-level prevention strategies. More research and continuous evaluation of the overall and subgroup-specific effectiveness of policy strategies using high-quality longitudinal studies are needed.
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Paternal impact on the life course development of obesity and type 2 diabetes in the offspringAbstract
The aetiologies of obesity and type 2 diabetes are incredibly complex, but the potential role of paternal influences remains relatively understudied. A better understanding of paternal influences on offspring risk of obesity and type 2 diabetes could have profound implications for public health, clinical practice and society. In this review, we outline potential biological and social mechanisms through which fathers might exert an impact on the health of their offspring. We also present a systematically compiled overview of the current evidence linking paternal factors to offspring development of obesity and type 2 diabetes throughout the life course. Although evidence is accumulating to support paternal associations with offspring outcomes, more high-quality research is needed to overcome specific methodological challenges and provide stronger causal evidence.
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Synergistic activation of thermogenic adipocytes by a combination of PPARγ activation, SMAD3 inhibition and adrenergic receptor activation ameliorates metabolic abnormalities in rodentsAbstractAims/hypothesis
To treat obesity and related diseases, considerable effort has gone into developing strategies to convert white adipocytes into thermogenic brown-like adipocytes (‘browning’). The purpose of this study was to identify the most efficient signal control for browning.
Methods
To identify the most efficient signal control for browning, we examined rat stromal vascular fraction cells. In addition, physiological changes consequent to signal control were examined in vivo using lean and diet-induced obese (DIO) C57BL/6J mice.
Results
Combined treatment with the peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone, the SMAD3 inhibitor SIS3 and the adrenergic receptor agonist noradrenaline (norepinephrine) synergistically induced Ucp1, Fgf21 and Cited1 expression, triggering brown adipogenesis. Synergistic induction of Ucp1 by the three agents was negatively regulated by forkhead box O (FOXO)3 via the inhibition of PPARγ-dependent gene transcription. Moreover, the administration of rosiglitazone, SIS3 and the selective β3 adrenergic receptor agonist CL316,243 to DIO mice reduced the amount of body-fat deposits (body weight from day 0 to 14, 12.3% reduction), concomitant with morphological changes in white adipose tissue, an increase in mitochondrial biosynthesis and a marked induction of uncoupling protein 1 (UCP1). Furthermore, administration of the three agents significantly increased serum adiponectin levels (mean 65.56 μg/ml with the three agents vs 20.79 μg/ml in control mice, p < 0.05) and improved glucose and lipid tolerance.
Conclusions/interpretation
These results suggest that the combined regulation of PPARγ, SMAD and the adrenergic receptor signalling pathway synergistically induces brown adipogenesis and may serve as an effective strategy to treat obesity and related diseases, including type 2 diabetes.
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ΩτοΡινοΛαρυγγολόγος Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,
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Τετάρτη 11 Σεπτεμβρίου 2019
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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,
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Ετικέτες
00302841026182,
00306932607174,
alsfakia@gmail.com,
Anapafseos 5 Agios Nikolaos 72100 Crete Greece,
Medicine by Alexandros G. Sfakianakis
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