Hyperglycemia and Adverse Pregnancy Outcomes

https://onlinelibrary.wiley.com/doi/pdf/10.1002/j.2051-5545.2011.tb00014.x

Physical illness in patients with severe mental disorders.I. Prevalence, impact of medications and disparities in health care

There is currently widespread interest in the IGFs (IGF-I and IGF-II) and their roles in the regulation of growth and differentiation of an ever increasing number of tissues are being reported. This selective review focused on the current state of our knowledge about the structure of mammalian IGFs and the multiple forms of mRNAs which arise from alternative splicing and promoter sites which arise from gene transcription. Current progress in the immunological measurement of the IGF is reviewed including different strategies for avoiding binding protein interference. The results of measurements of serum IGF-I and IGF-II in fetus and mother and at various stages of postnatal life are described. Existing knowledge of the concentration of these peptides in body fluids and tissues are considered. Last, an attempt is made to indicate circumstances in which the IGFs are exerting their actions in an autocrine/paracrine mode and when endocrine actions predominate. In the latter context it was concluded that an important role for GH action on skeletal tissues via hepatic production of IGF-I and endocrine action of IGF-I on growth cartilage is likely.

Insulin-Like Growth Factors I and II. Peptide, Messenger Ribonucleic Acid and Gene Structures, Serum, and Tissue Concentrations

PRL is an anterior pituitary hormone that, along with GH and PLs, forms a family of hormones that probably resulted from the duplication of an ancestral gene. The PRLR is also a member of a larger family, known as the cytokine class-1 receptor superfamily, which currently has more than 20 different members. PRLRs or binding sites are widely distributed throughout the body. In fact, it is difficult to find a tissue that does not express any PRLR mRNA or protein. In agreement with this wide distribution of receptors is the fact that now more than 300 separate actions of PRL have been reported in various vertebrates, including effects on water and salt balance, growth and development, endocrinology and metabolism, brain and behavior, reproduction, and immune regulation and protection. Clearly, a large proportion of these actions are directly or indirectly associated with the process of reproduction, including many behavioral effects. PRL is also becoming well known as an important regulator of immune function. A number of disease states, including the growth of different forms of cancer as well as various autoimmune diseases, appear to be related to an overproduction of PRL, which may act in an endocrine, autocrine, or paracrine manner, or via an increased sensitivity to the hormone. The first step in the mechanism of action of PRL is the binding to a cell surface receptor. The ligand binds in a two-step process in which site 1 on PRL binds to one receptor molecule, after which a second receptor molecule binds to site 2 on the hormone, forming a homodimer consisting of one molecule of PRL and two molecules of receptor. The PRLR contains no intrinsic tyrosine kinase cytoplasmic domain but associates with a cytoplasmic tyrosine kinase, JAK2. Dimerization of the receptor induces tyrosine phosphorylation and activation of the JAK kinase followed by phosphorylation of the receptor. Other receptor-associated kinases of the Src family have also been shown to be activated by PRL. One major pathway of signaling involves phosphorylation of cytoplasmic State proteins, which themselves dimerize and translocate to nucleus and bind to specific promoter elements on PRL-responsive genes. In addition, the Ras/Raf/MAP kinase pathway is also activated by PRL and may be involved in the proliferative effects of the hormone. Finally, a number of other potential mediators have been identified, including IRS-1, PI-3 kinase, SHP-2, PLC gamma, PKC, and intracellular Ca2+. The technique of gene targeting in mice has been used to develop the first experimental model in which the effect of the complete absence of any lactogen or PRL-mediated effects can be studied. Heterozygous (+/-) females show almost complete failure to lactate after the first, but not subsequent, pregnancies. Homozygous (-/-) females are infertile due to multiple reproductive abnormalities, including ovulation of premeiotic oocytes, reduced fertilization of oocytes, reduced preimplantation oocyte development, lack of embryo implantation, and the absence of pseudopregnancy. Twenty per cent of the homozygous males showed delayed fertility. Other phenotypes, including effects on the immune system and bone, are currently being examined. It is clear that there are multiple actions associated with PRL. It will be important to correlate known effects with local production of PRL to differentiate classic endocrine from autocrine/paracrine effects. The fact that extrapituitary PRL can, under some circumstances, compensate for pituitary PRL raises the interesting possibility that there may be effects of PRL other than those originally observed in hypophysectomized rats. The PRLR knockout mouse model should be an interesting system by which to look for effects activated only by PRL or other lactogenic hormones. On the other hand, many of the effects reported in this review may be shared with other hormones, cytokines, or growth factors and thus will be more difficult to study. (ABSTRACT TRUNCATED)

Prolactin (PRL) and Its Receptor: Actions, Signal Transduction Pathways and Phenotypes Observed in PRL Receptor Knockout Mice

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140673697103841.pdf

Circulating concentrations of insulin-like growth factor I and risk of breast cancer

We show that transplantation of adult bone marrow-derived cells expressing c-kit reduces hyperglycemia in mice with streptozotocin-induced pancreatic damage. Although quantitative analysis of the pancreas revealed a low frequency of donor insulin-positive cells, these cells were not present at the onset of blood glucose reduction. Instead, the majority of transplanted cells were localized to ductal and islet structures, and their presence was accompanied by a proliferation of recipient pancreatic cells that resulted in insulin production. The capacity of transplanted bone marrow-derived stem cells to initiate endogenous pancreatic tissue regeneration represents a previously unrecognized means by which these cells can contribute to the restoration of organ function.

Bone marrow-derived stem cells initiate pancreatic regeneration.

Developmental regulation of insulin-like growth factor II mRNA in different rat tissues.

In neonatal rodents, the beta-cell mass undergoes a phase of remodeling that includes a wave of apoptosis. Using both mathematical modeling and histochemical detection methods, we have demonstrated that beta-cell apoptosis is significantly increased in neonates as compared with adult rats, peaking at approximately 2 weeks of age. Other tissues, including the kidney and nervous system, also exhibit neonatal waves of apoptosis, suggesting that this is a normal developmental phenomenon. We have demonstrated that increased neonatal beta-cell apoptosis is also present in animal models of autoimmune diabetes, including both the BB rat and NOD mouse. Traditionally, apoptosis has been considered a process that does not induce an immune response. However, recent studies indicate that apoptotic cells can do the following: 1) display autoreactive antigen in their surface blebs; 2) preferentially activate dendritic cells capable of priming tissue-specific cytotoxic T-cells; and 3) induce the formation of autoantibodies. These findings suggest that in some circumstances physiological apoptosis may, in fact, initiate autoimmunity. Initiation of beta-cell-directed autoimmunity in murine models appears to be fixed at approximately 15 days of age, even when diabetes onset is dramatically accelerated. Taken together, these observations have led us to hypothesize that the neonatal wave of beta-cell apoptosis is a trigger for beta-cell-directed autoimmunity.

https://diabetes.diabetesjournals.org/content/diabetes/49/1/1.full.pdf

Neonatal beta-cell apoptosis: a trigger for autoimmune diabetes?

Insulin is a potent mitogen for many cell types in vitro. During tissue culture, supraphysiological concentrations of insulin are necessary to promote cell replication in connective or musculoskeletal tissues. Insulin promotes the growth of these cells by binding, with low affinity, to the type I insulin-like growth factor (IGF) receptor, not through the high affinity insulin receptor. In other cell types, such as hepatocytes, embryonal carcinoma cells, or mammary tumor cells, the type I IGF receptor is virtually absent, and insulin stimulates the growth of these cells at physiological concentrations by binding to the high affinity insulin receptor. Both receptor systems activate phosphorylation reactions within the cell which extend to ribosomal proteins. Insulin acts synergistically with other factors, such as platelet-derived growth factor and epidermal growth factor, to stimulate the progression of cells through the cycle of proliferation. Abnormal insulin secretion or action, before or after birth, often is associated with disordered growth suggesting that insulin may function as a growth factor in vivo. Poor growth follows impaired insulin secretion in diabetes mellitus. This is associated with reduced circulating levels of IGF's which may be partly responsible for the growth failure. Insulin has a direct action on release of IGF's from the liver in vitro, but during experimental diabetes there is a reduced number of hepatic somatotropic receptors which could limit the ability of growth hormone to regulate IGF release. Diabetic children, treated conventionally, have normal circulating IGF levels, but both growth rate and serum IGF concentration may increase dramatically when diabetic control is optimized.(ABSTRACT TRUNCATED AT 250 WORDS)

/pdf/insulin-as-a-growth-factor-1cnxngirmj.pdf

Insulin as a Growth Factor

Islet cell ontogeny will define adult beta-cell mass and will consist of a balance of islet cell birth and death We have investigated the ontogeny of factors that may be related to developmental apoptosis in the islets, insulin-like growth factor II (IGF-II) and inducible nitric oxide synthase (iNOS), in pancreata of young Wistar rats Pancreata were collected from rats of 21 days gestation to 29 days postnatal age In situ hybridization and immunohistochemistry showed that IGF-II was expressed and present in fetal and neonatal islet cells, but declined rapidly 2 weeks after birth Little IGF-I was associated with fetal or postnatal islets Apoptosis in islet cells was visualized by molecular histochemistry for DNA breakage in tissue sections Apoptosis was low in the fetus, but increased in incidence postnatally so that 13% of islet cells were undergoing apoptosis on postnatal day 14, with the incidence declining thereafter Immunohistochemistry for iNOS showed that it was expressed within beta-cells and was most abundant 12 days after birth When islets were isolated from rat pancreata 20-22 days after birth, islet cell viability, DNA synthetic rate, and insulin release were reduced after incubation with interleukin-1beta, tumor necrosis factor, or interferon-gamma An increased rate of islet cell survival was found after simultaneous incubation with IGF-I or -II Cytokine-mediated islet cell death involved the induction of apoptosis Islets isolated from neonatal rats were not killed after exposure to these cytokines at the same concentrations, but cytokine-induced cell death was seen when neonatal islets were incubated with a neutralizing antibody against IGF-II These experiments show that a peak of islet cell apoptosis that is maximal in the rat pancreas 14 days after birth is temporally associated with a fall in the islet cell expression of IGF-II IGF-II was shown to function as an islet survival factor in vitro The induction of islet cell apoptosis in vivo may involve an increased expression of iNOS within beta-cells

Apoptosis in the pancreatic islet cells of the neonatal rat is associated with a reduced expression of insulin-like growth factor II that may act as a survival factor.

David J. Hill

Papers

Bone marrow-derived stem cells initiate pancreatic regeneration.

Developmental regulation of insulin-like growth factor II mRNA in different rat tissues.

Neonatal beta-cell apoptosis: a trigger for autoimmune diabetes?

Insulin as a Growth Factor

Apoptosis in the pancreatic islet cells of the neonatal rat is associated with a reduced expression of insulin-like growth factor II that may act as a survival factor.