Relationship Between Circulating Metabolic Hormones and Their Central Receptors During Ovariectomy-Induced Weight Gain in Rats

Although increasing research focuses on the phenomenon of body weight gain in women after menopause, the complexity of body weight regulation and the array of models used to investigate it has proven to be challenging. Here, we used ovariectomized (OVX) rats, which rapidly gain weight, to determine if receptors for ghrelin, insulin, or leptin in the dorsal vagal complex (DVC), arcuate nucleus (ARC), or paraventricular nucleus (PVN) change during post-ovariectomy weight gain. Female Sprague-Dawley rats with ad libitum access to standard laboratory chow were bilaterally OVX or sham OVX. Subgroups were weighed and then terminated on day 5, 33, or 54 post-operatively; blood and brains were collected. ELISA kits were used to measure receptors for ghrelin, insulin, and leptin in the DVC, ARC, and PVN, as well as plasma ghrelin, insulin, and leptin. As expected, body weight increased rapidly after ovariectomy. However, ghrelin receptors did not change in any of the areas for either group, nor did circulating ghrelin. Thus, the receptor:hormone ratio indicated comparable ghrelin signaling in these CNS areas for both groups. Insulin receptors in the DVC and PVN decreased in the OVX group over time, increased in the PVN of the Sham group, and were unchanged in the ARC. These changes were accompanied by elevated circulating insulin in the OVX group. Thus, the receptor:hormone ratio indicated reduced insulin signaling in the DVC and PVN of OVX rats. Leptin receptors were unchanged in the DVC and ARC, but increased over time in the PVN of the Sham group. These changes were accompanied by elevated circulating leptin in both groups that was more pronounced in the OVX group. Thus, the receptor:hormone ratio indicated reduced leptin signaling in the DVC and PVN of both groups, but only in the OVX group for the ARC. Together, these data suggest that weight gain that occurs after removal of ovarian hormones by ovariectomy is associated with selective changes in metabolic hormone signaling in the CNS. While these changes may reflect behavioral or physiological alterations, it remains to be determined whether they cause post-ovariectomy weight gain or result from it.

Hepatocyte-Specific Co-Delivery of Zinc Ions and Plasmid DNA by Lactosylated Poly(1-vinylimidazole) for Suppression of Insulin Receptor Internalization

The lactosylated poly(1-vinylimidazole) (PVIm-Lac) with various lactosylated degrees has been synthesized for the co-delivery of zinc ions (Zn) and plasmid DNA (pDNA). The Zn/DNA/PVIm-Lac complex formation has achieved the specific delivery of zinc ions to HepG2 cells. Especially, the resulting hepatocyte-specific delivery of zinc ions has increased the number of insulin receptors on the cell surface. Consequently, the Zn/DNA/PVIm-Lac complexes have suppressed insulin receptor internalization on the surface of the HepG2 cells, expecting to offer unique therapy to inhibit hepatic insulin clearance.

Cerebrovascular insulin receptors are defective in Alzheimerˈs disease

Central response to insulin is suspected to be defective in Alzheimer’s disease (AD), but its localization in the brain remains unknown. While most insulin is secreted in the bloodstream by the pancreas, how it interacts with the blood-brain barrier (BBB) to alter brain function remains poorly defined.Here, we show that human and murine cerebral insulin receptors (INSR), particularly the long isoform INSRα-B, are concentrated in microvessels rather than in the parenchyma. Vascular concentrations of INSRα-B were lower in the parietal cortex of subjects diagnosed with AD, positively correlating with cognitive scores, leading to a shift toward a higher INSRα-A/B ratio, consistent with cerebrovascular insulin resistance in the AD brain. Vascular INSRα was inversely correlated with β-amyloid (Aβ) plaques and β-site APP cleaving enzyme 1 (BACE1), but positively correlated with insulin-degrading enzyme (IDE), neprilysin and ABCB1. Using brain cerebral intracarotid perfusion, we found that the transport rate of insulin across the BBB remained very low (<0.03 µl.g-1.s-1) and was not inhibited by an INSR antagonist. However, intracarotid perfusion of insulin induced the phosphorylation of INSRβ which was restricted to microvessels. Such an activation of vascular INSR was blunted in 3xTg-AD mice, suggesting that AD neuropathology induces insulin resistance at the level of the BBB.Overall, the present data in postmortem AD brains and an animal model of AD indicate that defects in the INSR localized at the BBB strongly contribute to brain insulin resistance in AD, in association with Aβ pathology.HighlightsCirculating insulin activates brain insulin receptors in microvessels.BBB INSR contribute to cerebral insulin resistance in AD.Cognitive impairment in AD is associated with a loss of cerebrovascular INSRα-B.Loss of isoform INSRα-B is associated with increased BACE1 activity.SummaryLeclerc et al. show that circulating insulin activates cerebral insulin receptor localized on the blood-brain-barrier level (BBB), not in the parenchyma. Experiments with human brain samples and animal models provide evidence that INSR at the BBB are impaired in Alzheimer’s disease, thereby contributing to brain insulin resistance.

Insulin signalling in tanycytes gates hypothalamic insulin uptake and regulation of AgRP neuron activity

Insulin acts on neurons and glial cells to regulate systemic glucose metabolism and feeding. However, the mechanisms of insulin access in discrete brain regions are incompletely defined. Here we show that insulin receptors in tanycytes, but not in brain endothelial cells, are required to regulate insulin access to the hypothalamic arcuate nucleus. Mice lacking insulin receptors in tanycytes (IR∆Tan mice) exhibit systemic insulin resistance, while displaying normal food intake and energy expenditure. Tanycytic insulin receptors are also necessary for the orexigenic effects of ghrelin, but not for the anorexic effects of leptin. IR∆Tan mice exhibit increased agouti-related peptide (AgRP) neuronal activity, while displaying blunted AgRP neuronal adaptations to feeding-related stimuli. Lastly, a highly palatable food decreases tanycytic and arcuate nucleus insulin signalling to levels comparable to those seen in IR∆Tan mice. These changes are rooted in modifications of cellular stress responses and of mitochondrial protein quality control in tanycytes. Conclusively, we reveal a critical role of tanycyte insulin receptors in gating feeding-state-dependent regulation of AgRP neurons and systemic insulin sensitivity, and show that insulin resistance in tanycytes contributes to the pleiotropic manifestations of obesity-associated insulin resistance.

Diabetic Retinopathy and Insulin Insufficiency: Beta Cell Replacement as a Strategy to Prevent Blindness

Diabetic retinopathy (DR) is a potentially devastating complication of diabetes because it puts patients at risk of blindness. Diabetes is a common cause of blindness in the U.S. and worldwide and is dramatically increasing in global prevalence. Thus new approaches are needed to prevent this dreaded complication. There is extensive data that indicates beta cell secretory failure is a risk factor for DR, independent of its influence on glycemic control. This perspective article will provide evidence for insufficient endogenous insulin secretion as an important factor in the development of DR. The areas of evidence discussed are: (a) Presence of insulin receptors in the retina, (b) Clinical studies that show an association of beta cell insufficiency with DR, (c) Treatment with insulin in type 2 diabetes, a marker for endogenous insulin deficiency, is an independent risk factor for DR, (d) Recent clinical studies that link DR with an insulin deficient form of type 2 diabetes, and (e) Beta cell replacement studies that demonstrate endogenous insulin prevents progression of DR. The cumulative data drive our conclusion that beta cell replacement will have an important role in preventing DR and/or mitigating its severity in both type 1 diabetes and insulinopenic type 2 diabetes.

Hyperinsulinemia Induces Insulin Receptor Dysfunction in Brain Microvascular Endothelial Cells

Insulin receptors are internalized by endothelial cells; however, the impact of hyperinsulinemia on this process is not known. Thus, the aim of this study is to determine the role of hyperinsulinemia on insulin receptor function and internalization, as well as the potential impact of protein tyrosine phosphatase 1B (PTP1B). To this end, hippocampal microvessels were isolated from male C57Bl/6J mice on either a control or high-fat diet and assessed for insulin receptor signaling. Cell surface insulin receptors in brain microvascular endothelial cells were labelled with biotin to assess the role hyperinsulinemia plays on receptor internalization in response to stimulation, with and without Claramine treatment, a potent PTP1B antagonist. Our results indicated that insulin receptor levels increased in tandem with insulin receptor dysfunction in the high-fat diet mouse hippocampal microvessels. Hyperinsulinemic cell-receptors demonstrate a shift in splice variation towards decreased IR-A/IR-B ratios and demonstrate a higher membrane-localized proportion. This corresponded with decreased autophosphorylation at sites critical for receptor internalization and signaling, however, Claramine restored signaling and receptor internalization in hyperinsulinemic cells. In conclusion, hyperinsulinemia negatively impacts brain microvascular endothelial cell insulin receptor function and internalization, likely through both alternative splicing and increased negative feedback from PTP1B.

A Tale of Two Diseases: Exploring Mechanisms Linking Diabetes Mellitus with Alzheimer’s Disease

Dementias, including the type associated with Alzheimer’s disease (AD), are on the rise worldwide. Similarly, type 2 diabetes mellitus (T2DM) is one of the most prevalent chronic diseases globally. Although mechanisms and treatments are well-established for T2DM, there remains much to be discovered. Recent research efforts have further investigated factors involved in the etiology of AD. Previously perceived to be unrelated diseases, commonalities between T2DM and AD have more recently been observed. As a result, AD has been labeled as “type 3 diabetes”. In this review, we detail the shared processes that contribute to these two diseases. Insulin resistance, the main component of the pathogenesis of T2DM, is also present in AD, causing impaired brain glucose metabolism, neurodegeneration, and cognitive impairment. Dysregulation of insulin receptors and components of the insulin signaling pathway, including protein kinase B, glycogen synthase kinase 3β, and mammalian target of rapamycin are reported in both diseases. T2DM and AD also show evidence of inflammation, oxidative stress, mitochondrial dysfunction, advanced glycation end products, and amyloid deposition. The impact that changes in neurovascular structure and genetics have on the development of these conditions is also being examined. With the discovery of factors contributing to AD, innovative treatment approaches are being explored. Investigators are evaluating the efficacy of various T2DM medications for possible use in AD, including but not limited to glucagon-like peptide-1 receptor agonists, and peroxisome proliferator-activated receptor-gamma agonists. Furthermore, there are 136 active trials involving 121 therapeutic agents targeting novel AD biomarkers. With these efforts, we are one step closer to alleviating the ravaging impact of AD on our communities.

Influence of potential nanopollutant fullerene C60 on physiological and biochemical responses in mammals

The progressive development of technologies in the manufacture and application of nanomaterials in almost all spheres of human life causes penetration in an organism and accumulation of nanoparticles in its cells. Determinations of the risk of using nanomaterials and mechanisms of their cytotoxicity are extremely relevant current problems that should be studied. Fullerene C60 is the most widespread nanomaterial proposed to use inhibition of tumour growth, microbial infections, and purposeful drug delivery. However, there are contradictory data on cytotoxic and/or cytoprotective effects of this fullerene. In the present paper, the action of fullerene C60 on glucose metabolism, the composition of the intestinal microbiota, and an acid-reducing balance were studied in rats. It is shown that fullerene C60 dissolved in olive oil (2 mg/kg/day) induces insulin resistance, activates the peroxidation of lipids in the brain of animals, but not in the liver, under conditions of chronic influence. In addition, fullerene C60 induced changes in the composition of the intestinal microbiota in rats. Determined disorders may be a cause of insulin production, as an adaptive response to the needs of metabolic energy under local oxidative stress in the nerve tissue. At the same time, the growth of insulin resistance can be induced by nonspecific molecular damage in biomembranes and macromolecules, including insulin receptors. In this regard, the explanation of the molecular mechanisms of insulin resistance induced by fullerene C60 together with the effect of fullerene dose will be of particular interest in further studies.

The Benefits of Consuming Sardines to Prevent Hypertension and Type 2 Diabetes Mellitus for Senior Citizens

Along with the increasing number of senior citizens in Indonesia, the number of cases of non-communicable diseases (NCDs), especially hypertension and diabetes mellitus experience escalation too, which certainly will have a direct impact on human resource productivity, social and economic development. In addition, hypertension and type 2 diabetes mellitus are the causes of the highest mortality rates in Indonesia. This article aims to encourage the public especially the senior citizens to prevent hypertension and type 2 diabetes mellitus by consuming fish containing high omega 3, EPA, and DHA, such as sardines at least twice a week or the equivalent of 200-400 grams a week. In terms of the methods, a literature study approach was employed in elaborating the research topic. The findings of this study demonstrate that sardines contain anti-inflammatory, antioxidant roles, boost the membrane fluidity, boost the number of insulin receptors and insulin action, and also contain hypotensive and hypoglycemic effects. In this manner, sardines are highly proven to be able to effectively prevent type 2 diabetes mellitus, prevent hypertension, and lower blood pressure, especially for senior citizens.

Cupping Therapy Benefit in Glucose Blood Level

Some Muslims have used cupping therapy and occupies a popular position among other alternative therapeutic methods. Modern medical research evidence also confirms the benefits of the therapy recommended by the Prophet. Many medical experts know the efficacy of cupping therapy in treating disease. According to the International Diabetes Federation (IDF), in 2013, Indonesia was ranked seventh with diabetes. Cupping therapy plays a role in stimulating blood circulation in the muscles, thereby increasing the metabolism of nutrients and glucose consumption by the muscles. The increased sensitivity of insulin receptors was helping to reduce blood glucose levels. This effect is like the effect of exercise and physical activity on blood glucose levels. This study aims to determine the effect of cupping therapy on blood glucose levels.