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Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, UK
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Hormones have an important role in the regulation of fetal growth and development, especially in response to nutrient availability in utero. Using micro-CT and an electromagnetic three-point bend test, this study examined the effect of pancreas removal at 0.8 fraction of gestation on the developing bone structure and mechanical strength in fetal sheep. When fetuses were studied at 10 and 25 days after surgery, pancreatectomy caused hypoinsulinaemia, hyperglycaemia and growth retardation which was associated with low plasma concentrations of leptin and a marker of osteoclast activity and collagen degradation. In pancreatectomized fetuses compared to control fetuses, limb lengths were shorter, and trabecular (Tb) bone in the metatarsi showed greater bone volume fraction, Tb thickness, degree of anisotropy and porosity, and lower fractional bone surface area and Tb spacing. Mechanical strength testing showed that pancreas deficiency was associated with increased stiffness and a greater maximal weight load at fracture in a subset of fetuses studied near term. Overall, pancreas deficiency in utero slowed the growth of the fetal skeleton and adapted the developing bone to generate a more compact and connected structure. Maintenance of bone strength in growth-retarded limbs is especially important in a precocial species in preparation for skeletal loading and locomotion at birth.
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Adelaide Medical School, University of Adelaide, Adelaide, Australia
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Adelaide Medical School, University of Adelaide, Adelaide, Australia
College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia
College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia
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Adelaide Medical School, University of Adelaide, Adelaide, Australia
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The growth hormone (GH)–insulin-like growth factor (IGF) axis is one of the main drivers of mammalian growth and development. Pituitary secretion of GH is pulsatile and under positive and negative hypothalamic control, as well as stimulation from gastric-secreted acyl-ghrelin. GH acts both directly via the GH-receptor (GHR) and indirectly via stimulation of IGF1 production to induce anabolic and metabolic responses at multiple target tissues. In this review, we describe the major changes to this axis during pregnancy, with increasing GH abundance in the maternal circulation across multiple species. This stimulates the secretion of IGFs, whose bioavailability is also increased by proteolytic cleavage of their circulating binding proteins during pregnancy. These changes in turn induce maternal metabolic adaptations to pregnancy and promote placental function and fetal growth, as does exogenous GH or IGF treatment in animal models of normal and compromised pregnancy. Finally, we explore alternative approaches to enhance maternal GH abundance during pregnancy to promote maternal adaptations, placental function and hence fetal growth.
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Gestational diabetes mellitus (GDM) reduces maternal adiponectin and docosahexaenoic acid (DHA) materno-fetal transfer, which may have negative consequences for the offspring. Our aim was to evaluate the effects of the administration of a novel adiponectin agonist (AdipoRon) to GDM rats on the long-term consequences in glycaemia and fatty acids (FA) profile in the offspring. Pregnant rats were randomized to three groups: GDM rats (GDM, n = 8), GDM rats treated with AdipoRon (GDM + ADI, n = 9), and control rats (n = 10). Diabetes was induced with streptozotocin (50 mg/kg) on day 12 of gestation. GDM+ADI received 50 mg/kg/day AdipoRon from day 14 until delivery. Glycaemia and FA profile were determined in mothers and adult offspring (12 weeks old). AdipoRon tended to reduce fasting glucose in diabetic mothers. Diabetic rats presented the foetus with intrauterine growth restriction and higher adiposity, which tried to be counteracted by AdipoRon. In the adult offspring, both GDM + ADI and control animals showed better glucose recovery after oral glucose overload with respect to GDM. DHA in offspring plasma was significantly reduced in both GDM and GDM + ADI compared to controls (P = 0.043). Nevertheless, n-6/n-3 polyunsaturated FA (PUFA) ratio improved in plasma of GDM + ADI adult offspring (GDM: 14.83 ± 0.85a%; GDM + ADI: 11.49 ± 0.58b%; control: 10.03 ± 1.22b%, P = 0.034). Inflammatory markers and oxidative stress were reduced in the adult offspring of AdipoRon-treated mothers. In conclusion, AdipoRon administration to pregnant diabetic rats improved glycaemia in the mothers and long-term glucose tolerance in the offspring. In addition, it tended to reduce excessive foetal fat accumulation and improved n-6/n-3 PUFA ratio significantly in offspring at the adult state.
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The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Australia
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Institute for Women’s Health, University College London, London, UK
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Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, UK
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In adults, glucocorticoids act to match the supply and demand for energy during physiological challenges, partly through actions on tissue mitochondrial oxidative phosphorylation (OXPHOS) capacity. However, little is known about the role of the natural prepartum rise in fetal glucocorticoid concentrations in preparing tissues for the increased postnatal energy demands. This study examined the effect of manipulating cortisol concentrations in fetal sheep during late gestation on mitochondrial OXPHOS capacity of two skeletal muscles with different postnatal locomotive functions. Mitochondrial content, biogenesis markers, respiratory rates and expression of proteins and genes involved in the electron transfer system (ETS) and OXPHOS efficiency were measured in the biceps femoris (BF) and superficial digital flexor (SDF) of fetuses either infused with cortisol before the prepartum rise or adrenalectomised to prevent this increment. Cortisol infusion increased mitochondrial content, biogenesis markers, substrate-specific respiration rates and abundance of ETS complex I and adenine nucleotide translocator (ANT1) in a muscle-specific manner that was more pronounced in the SDF than BF. Adrenalectomy reduced mitochondrial content and expression of PGC1α and ANT1 in both muscles, and ETS complex IV abundance in the SDF near term. Uncoupling protein gene expression was unaffected by cortisol manipulations in both muscles. Gene expression of the myosin heavy chain isoform, MHCIIx, was increased by cortisol infusion and reduced by adrenalectomy in the BF alone. These findings show that cortisol has a muscle-specific role in prepartum maturation of mitochondrial OXPHOS capacity with important implications for the health of neonates born pre-term or after intrauterine glucocorticoid overexposure.
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School of Science and Technology, Nottingham Trent University, Nottingham, UK
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Pediatric Research Center, Hospital for Child and Adolescent Medicine, Leipzig University, Leipzig, Germany
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Supplementation with precursors of NAD has been shown to prevent and reverse insulin resistance, mitochondrial dysfunction, and liver damage in mouse models of diet-induced obesity. We asked whether the beneficial effects of supplementation with the NAD precursor nicotinamide riboside (NR) are dependent on mouse strain. We compared the effects of NR supplementation on whole-body energy metabolism and mitochondrial function in mildly obese C57BL/6N and C57BL/6J mice, two commonly used strains to investigate metabolism. Male C57BL/6N and C57BL/6J mice were fed a high-fat diet (HFD) or standard chow with or without NR supplementation for 8 weeks. Body and organ weights, glucose tolerance, and metabolic parameters as well as mitochondrial O2 flux in liver and muscle fibers were assessed. We found that NR supplementation had no influence on body or organ weight, glucose metabolism or hepatic lipid accumulation, energy expenditure, or metabolic flexibility but increased mitochondrial respiration in soleus muscle in both mouse strains. Strain-dependent differences were detected for body and fat depot weight, fasting blood glucose, hepatic lipid accumulation, and energy expenditure. We conclude that, in mild obesity, NR supplementation does not alter metabolic phenotype in two commonly used laboratory mouse strains.
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Stanford Diabetes Research Center, Stanford University, Stanford, California, USA
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Since the discovery of insulin 100 years ago, our knowledge and understanding of diabetes have grown exponentially. Specifically, with regards to the genetics underlying diabetes risk, our discoveries have paralleled developments in our understanding of the human genome and our ability to study genomics at scale; these advancements in genetics have both accompanied and led to those in diabetes treatment. This review will explore the timeline and history of gene discovery and how this has coincided with progress in the fields of genomics. Examples of genetic causes of monogenic diabetes are presented and the continuing expansion of allelic series in these genes and the challenges these now cause for diagnostic interpretation along with opportunities for patient stratification are discussed.
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Polycystic ovary syndrome (PCOS) is the most common female endocrine disorder in women in their reproductive age. In recent years, the role of advanced glycation end products (AGEs) in PCOS has gained great attention. AGEs are highly reactive molecules that can be assumed by diet or endogenously synthesized as by-products of metabolic processes. AGE deposition increases with aging, hyperglycemia, insulin resistance, and glycotoxin-rich diet. Therefore, it has become imperative to understand the underlying mechanism of AGEs actions and its downstream effects in PCOS pathophysiology. By integrating evidence from human studies and experimental models, the present review points out that altered AGE deposition is a common feature in all PCOS phenotypes. Searching for possible mechanisms involved in the adaptive response against glycation injury in oocytes and ovaries, the role of SIRT1, the main member of the mammalian sirtuin family, has also recently emerged. Therefore, further studies based on anti-AGE interventions could be helpful in creating innovative strategies for counteracting PCOS and its effects on fertility.
Division of Cardiology, Elmhurst Hospital Center, Elmhurst, New York, USA
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Metformin is a biguanide drug widely used as the initial treatment of type 2 diabetes. Despite its widespread use, its precise mechanisms of action remain incompletely characterised. Its effect in lowering blood glucose is largely related to the suppression of gluconeogenesis in the liver, which is probably accomplished by partial inhibition of the mitochondrial respiratory chain complex 1 with a subsequent increase in intracellular AMP levels and activation of AMP kinase. Several local and systemic anti-inflammatory effects of metformin have been described. Many of these effects seem to be mediated by AMP kinase activation and downstream effects inhibiting mTOR and NF-κB pro-inflammatory signalling cascades. However, there are also studies describing actions independent of AMP kinase action. In this review, we summarise the currently known mechanisms of metformin on inflammatory pathways and the clinical evidence underpinning the use of metformin as a potential anti-inflammatory drug.
