Insulin exposure and unifying aging

BACKGROUND: Absence of a widely agreed upon central paradigm for mammalian aging. OBJECTIVE: Detailed elaboration of a proposed mammalian aging paradigm. METHODS: Elaboration of a new theoretical model. RESULTS: Hormonal imbalance-growth factor exposure theory (HI-GFE theory) can account for two major aging phenomena: (1) decline in mammalian 'reserve capacity' and consequent rise of diseases of maintenance, and (2) rise then peaking of most age-associated proliferative diseases. Reserve capacity decline via gradual decline in mitochondrial maximal energy production (state 3) accounts for the gradual redirection of declined maximal energy production toward survival functions like ion pumping to the relative detriment of RNA and protein synthesis as seen in lesser synthetic rates and slower turnover with consequent gradual cellular impairment. Developmental program triggered, and over-ample nutritionally driven, growth factor exposure in youth to middle age encourages promotional events that lead to proliferative diseases that rise coincident to rapidly declining reserve capacity and cumulative increased mutational status of age. CONCLUSIONS: Declining mitochondrial state 3 aging energy production status is easily and safely reversible with probable consequences of greatly postponing the decline in overall 'reserve capacity' which may also improve insulin: growth hormone balance and result in lower overall growth factor exposure and consequent longer healthy life of a potentially greater magnitude increase in life spans than that seen in calorie-restricted animals.     

Insulin receptor and cancer

The widespread epidemic of obesity and type 2 diabetes has raised concern for the impact of these disorders as risk factors for cancer and has renewed the interest for studies regarding the involvement of hyperinsulinemia and insulin receptor (IR) in cancer progression. Overexpression of IR in cancer cells may explain their increased sensitivity to hyperinsulinemia. Moreover, IR isoform A (IR-A) together with autocrine production of its ligand IGF2 is emerging as an important mechanism of normal and cancer stem cell expansion and is a feature of several malignancies. De novo activation of the IR-A/IGF2 autocrine loop also represents a mechanism of resistance to anticancer therapies. Increasing knowledge of the IR role in cancer has important implications for cancer prevention, which should include control of insulin resistance and hyperinsulinemia in the population and meticulous evaluation of new antidiabetic drugs for their metabolic:mitogenic ratio. We are now aware that several anticancer treatments may induce or worsen insulin resistance that may limit therapy efficacy. Future anticancer therapies need to target the IR-A pathway in order to inhibit the tumor promoting effect of IR without impairing the metabolic effect of insulin.     

Insulin and glucagon relationships during aging in man

To determine if the glucoregulatory hormones, insulin and glucagon, are altered with aging in man, 44 healthy volunteers, 22–81 yr of age, were evaluated by measurement of basal levels of glucose, insulin, and glucagon in relationship to their fat mass. In addition, the secretory capacities of the alpha and beta cells were assessed by measurement of the amounts of glucagon and insulin released after intravenous administration of glucose and arginine, respectively. Although no significant differences in weight could be distinguished longitudinally, the percentage adiposity was found to increase with age. Basal concentrations of glucose, glucagon, and insulin were not appreciably altered as a function of advancing years. After intravenous glucose, the glucose disappearance rate (K_g) was significantly slower in the elderly in comparison with the young, yet no differences in glucose-induced release were found. Similarly, insulin responses after arginine infusion between young and old were indistinguishable. The release of glucagon in response to arginine infusion was not perceptibly altered during aging. Thus, despite a decline in K_g with advancing age in this healthy population, gross changes in insulin and glucagon release were not apparent. We infer from these data that decreased carbohydrate tolerance accompanying aging in some populations may be due to factors other than abnormalities in secretion of insulin and glucagon.     

Insulin receptor isolation studies

The observation that N^α,B1-biotinylinsulin binds firmly to resins in which succinoylavidin is covalently attached to AH Sepharose 4B and can be retrived by exposure of the resins to 20 mM biotin provided the basis for the present investigations. Solubilized, partially purified insulin receptor from human placenta binds to affinity resins in which N^α,B1-biotinylinsulin is noncovalently attached to AH Sepharose 4B-immobilized-succinoylavidin. Exposure of the receptor loaded resin to 20 mM biotin results in liberation of a high molecular weight material containing bound ¹²⁵I-biotinylinsulin, which precipitates with polyethyleneglycol and cross reacts with human insulin receptor antibodies. The technique is biospecific and appears to be applicable to the purification of insulin receptors on a preparative scale. Crude solubilized insulin receptor from human placenta is contaminated with “insulinase” which is inhibited by N-ethylmaleimide. HPLC provides a tool to assess “insulinase” activity that is more sensitive than the TCA precipitation method.     

Insulin receptor knock-out mice.

Targeted mutagenesis of the insulin receptor gene in mice has yielded unexpected results. This article reviews recent findings and analyzes this animal model can further our understanding of the mechanism of insulin action and its impairment in non-insulin-dependent diabetes mellitus is analyzed. (Trends Endocrinol Metab 1997;8:101-104). Published 1997 by Elsevier Science Inc.     

Insulin receptor autoantibodies in sepsis

This study was undertaken to investigate possible factors contributing to altered glucose homeostasis in a patient with a history of total pancreatectomy and intermittent sepsis. Blood was drawn when the patient had received no exogenous insulin for the previous 24 hours, had a serum insulin level of 0.3 microU/mL, and gave an inappropriately low glucose response to large amounts of infused glucose. The IgG fraction prepared from this serum stimulated glucose oxidation in vitro and inhibited binding of insulin labeled with I 125 to isolated rat adipocytes, thus fulfilling some of the criteria for autoantibodies to the insulin receptor. The results are compatible with the hypothesis that insulin-receptor autoantibodies may have developed as a result of perturbation of this patient's immune status promoted by intermittent septic episodes and that, preterminally, as these antibodies converted in vivo to their in vitro-type behavior, they may have been partially responsible for the severe disturbances of glucose homeostasis.     

Oxidative aging and insulin receptor signaling

The life span of nematodes, fruit flies, and mice can be significantly increased (and aging-related changes decreased) by mutations affecting insulin receptor signaling. This effect involves several cellular functions which are negatively regulated by the insulin receptor and thus typically expressed under fasting conditions. This involvement raises the question of whether the insulin-independent basal receptor kinase activity in the postabsorptive state can be decreased without compromising the physiologically important response to insulin in the postprandial state. Recent studies have shown that (a) the basal human insulin receptor kinase activity is increased under oxidative conditions in the absence of insulin and (b) insulin signaling in the fasted state can be decreased by cysteine supplementation. Cysteine supplementation has also been shown to improve certain aging-related parameters, suggesting that the average dietary cysteine consumption in Western countries may be suboptimal. These findings provide a conceptual framework that extends the "free radical theory of aging."     

胰岛素受体基因突变与Rabson-Mendenhall综合征

Rabson-Mendenhall综合征是胰岛素受体基因突变引起的单基因突变糖尿病,本文就本病的基因突变、临床特点及诊断治疗作一综述。     

胰岛素受体底物-1与骨代谢

胰岛素受体底物(insulin receptor substrate,IRS)是胰岛素信号传导通路中受体后水平的重要信号蛋白。IRS-1对骨骼生长、骨转换以及骨折愈合等均具有重要作用,为代谢性骨病和骨质疏松的防治提供了新思路。     

Insulin release: the receptor hypothesis

It is currently believed that the stimulation of insulin release by nutrient secretagogues reflects their capacity to act as fuel in pancreatic islet beta cells. In this review, it is proposed that such a fuel concept is not incompatible with a receptor hypothesis postulating the participation of cell-surface receptors in the recognition of selected nutrients as insulinotropic agents. Pursuant to this, attention is drawn to such matters as the anomeric specificity of the beta cell secretory response to d-glucose and its perturbation in diabetes mellitus, the insulinotropic action of artificial sweeteners, the possible role of bitter taste receptors in the stimulation of insulin secretion by l-glucose pentaacetate, the recently documented presence of cell-surface sweet taste receptors in insulin-producing cells, the multimodal signalling process resulting from the activation of these latter receptors, and the presence in beta cells of a sweet taste receptor mediating the fructose-induced potentiation of glucose-stimulated insulin secretion.     

Insulin receptor and action mechanism of the hormone

The first step in insulin action consists in binding of the hormone to specific cell surface receptors. This receptor displays two functional domains: an extracellular alpha-subunit containing the majority or the totality of the hormone binding site, and an transmembrane beta-subunit possessing insulin-stimulated tyrosine kinase activity. A general consensus has been reached in favor of the idea that this receptor enzymic function is essential for generation of the metabolic and growth promoting effects of insulin. Concerning the mechanism of transmembrane signalling we like to think that interaction of insulin with the receptor alpha-subunit triggers a conformational change, which is propagated to the beta-subunit and activates it. The active receptor kinase leads then to phosphorylation of cellular protein substrates, which are likely to belong to two broad categories, those generating metabolic effects of insulin, and those resulting in growth-promoting effects. The phosphorylated and active substrates generate then the final effects of insulin.     

胰岛素受体基因突变与遗传性胰岛素抵抗综合征

遗传性胰岛素抵抗综合征是指一类与胰岛素、胰岛素受体及受体后基因突变有关的疾病,其中以胰岛素受体基因突变最为常见,主要包括矮妖综合征、Rabson-Mendenhall综合征及A型胰岛素抵抗.矮妖综合征是遗传性胰岛素抵抗综合征中最严重的一种表型,多在2岁前由于胰岛β细胞功能衰竭,导致酮症酸中毒和各种并发症而死亡.A型胰岛素抵抗多见于青年女性,糖尿病一般不重.可存活至成年后.Rabson-Mendenhall综合征临床表型的严重程度常介于矮妖综合征和A型胰岛素抵抗之间.此三者临床表现的异质性可能与突变的类型、突变位点的差异以及是否合并其他基因缺陷有关.     

Insulin receptor internalization: molecular mechanisms and physiopathological implications

The initial interaction between insulin and its receptor on target cell surface is followed by a series of surface and intracellular steps which participate in the control of insulin action. Abnormalities of any of these steps could result in mishandling of the receptor leading to defective modulation of receptor number on the cell surface and to inappropriate cell sensitivity to the hormone. Thus, the identification of each of these steps as well as understanding the mechanisms governing them is obligatory to unravel some aspects of the pathogenesis of insulin resistance states. This was the goal of the studies we have carried out during recent years using combined molecular and cellular biology as well as biochemical techniques. These studies allowed us to propose the following ordered sequence of events: 1) insulin binds to receptors preferentially associated with microvilli on the cell surface; 2) insulin triggers receptor kinase activation and autophosphorylation which not only results in initiation of the various biological signals leading to insulin action but also in redistribution of the hormone-receptor complex in the plane of the membrane; 3) on the non-villous domain of the cell surface, insulin receptors anchor to clathrin-coated pits through specific internalization sequences present in their cytoplasmic juxtamembrane domain; 4) insulin-receptor complexes are internalized together with other receptors present in the same clathrincoated pits through the formation of clathrin-coated vesicles; 5) the complexes are delivered to endosomes, the acidic pH of which induces the dissociation of insulin molecules from insulin receptors and their sorting in different directions; 6) insulin molecules are targetted to late endosomes and lysosomes where they are degraded; 7) receptors are recycled back to the cell surface in order to be reused.     

Insulin receptor internalization: molecular mechanisms and physiopathological implications

Diabetologia - The initial interaction between insulin and its receptor on target cell surface is followed by a series of surface and intracellular steps which participate in the control of insulin...