Unraveling the molecular detail of insulin receptor activation has proved challenging, but a major advance is the recent determination of crystallographic structures of insulin in complex with its primary binding site on the receptor. The current model for insulin receptor activation is that two distinct surfaces of insulin monomer engage sequentially with two distinct binding sites on the extracellular surface of the insulin receptor, which is itself a disulfide‐linked (αβ)2 homodimer. In the process, conformational changes (...) occur both within the hormone and the receptor, the latter resulting in the disruption of the intracellular interactions that hold the kinase domains in their basal state and in the initiation of the phosphorylation events that drive insulin signaling. The purpose of this paper is to summarize the extant structural data relating to hormone binding and how it effects receptor activation, as well as to discuss the issues that remain unresolved. (shrink)

The molecular pathways for insulin's signal transduction from its cell surface receptor to the cell's interior metabolic machinery remain in many ways uncharted. Lately two molecules have been proposed as second messengers transducing the insulin signal into the target cell. One is a phospholigosaccharide/inositolphosphoglycan and the other is diacylglycerol, both deriving from the same plasma membrane glycolipid, which is hydrolysed in response to insulin treatment. The phospho‐oligosaccharide appears to mediate many metabolic effects of insulin through control (...) of the phosphorylation state of key regulatory metabolic enzymes. Diacylglycerol may mediate insulin's stimulation of glucose transport over the plasma membrane. The glycolipid precursor of these putative second messengers, as well as the receptor for insulin, appear to be localized in caveolae microdomains of the plasma membrane, and glucose transporters accumulate in caveolae in response to insulin treatment, suggesting a focal role for caveolae in insulin signalling. (shrink)

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. It is a complex disease with varied clinical manifestations. Multiple factors contribute to its pathogenesis insulin resistance being the common pathway; about 30–80% of PCOS patients have insulin resistance. Genetic factors contribute to the development of PCOS and insulin resistance. This review looks at the data available in literatures for insulin resistance in PCOS patients. Weight reduction by dietary intervention and increased (...) physical activity is the primary target in obese PCOS patients. Metformin is the drug of first choice for treating insulin resistance in PCOS patients with impaired glucose tolerance if lifestyle modification fails, other important option is pioglitazone, but weight gain is a concern; new therapeutic options like incretin mimetics and SGLT2 inhibitors which seem to hold promise but need further validation in PCOS before they can be used on a widespread scale. (shrink)

Insulin is stored within the pancreas in an inactive Zn2+‐bound hexameric form prior to release. Similarly, clinical insulins contain Zn2+ and form multimeric complexes. Upon release from the pancreas or upon injection, insulin only becomes active once Zn2+ disengages from the complex. In plasma and other extracellular fluids, the majority of Zn2+ is bound to human serum albumin (HSA), which plays a vital role in controlling insulin pharmacodynamics by enabling removal of Zn2+. The Zn2+‐binding properties of HSA (...) are attenuated by non‐esterified fatty acids (NEFAs) also transported by HSA. Elevated NEFA concentrations are associated with obesity and type 2 diabetes. Here we present the hypothesis that higher NEFA levels in obese and/or diabetic individuals may contribute to insulin resistance and affect therapeutic insulin dose‐response profiles, through modulation of HSA/Zn2+ dynamics. We envisage this novel concept to have important implications for personalized treatments and management of diabetes‐related conditions in the future. (shrink)

I present here a personal perspective on more than three decades of research into the structural biology of the insulin–receptor interaction. The solution of the three‐dimensional structure of insulin in 1969 provided a detailed understanding of the insulin surfaces involved in self‐assembly. In subsequent years, hundreds of insulin analogues were prepared by insulin chemists and molecular biologists, with the goal of relating the structure to the biological function of the molecule. The design of methods for (...) direct receptor‐binding studies in the 1970s, and the cloning of the receptor in the mid 1980s, provided the required tools for detailed structure–function studies. In the absence of a full three‐dimensional structure of the insulin–receptor complex, I attempt to assemble the existing pieces of the puzzle generated by our and other laboratories, in order to generate a plausible mechanistic model of the insulin–receptor interaction that explains its kinetics and negative cooperativity. BioEssays 26:1351–1362, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The insulin/insulin‐like growth factor‐1 (IGF‐1) signaling (IIS) pathway is a pivotal genetic program regulating cell growth, tissue development, metabolic physiology, and longevity of multicellular organisms. IIS integrates a fine‐tuned cascade of signaling events induced by insulin/IGF‐1, which is precisely controlled by post‐translational modifications. The ubiquitin/proteasome‐system (UPS) influences the functionality of IIS through inducible ubiquitylation pathways that regulate internalization of the insulin/IGF‐1 receptor, the stability of downstream insulin/IGF‐1 signaling targets, and activity of nuclear receptors for control (...) of gene expression. An age‐related decline in UPS activity is often associated with an impairment of IIS, contributing to pathologies such as cancer, diabetes, cardiovascular, and neurodegenerative disorders. Recent findings identified a key role of diverse ubiquitin modifications in insulin signaling decisions, which governs dynamic adaption upon environmental and physiological changes. In this review, we discuss the mutual crosstalk between ubiquitin and insulin signaling pathways in the context of cellular and organismal homeostasis. (shrink)

In 1941, Gellhorn and colleagues reported experiments in which modest reductions of blood sugar were induced in hypophysectomized/adrenodemedullated (HA) rats by intraperitoneal injection of human blood. Based on the effects of intraperitoneal injections of known amounts of Lilly insulin on blood sugar in HA rats, Gellhorn estimated that the "insulin" content of normal human blood (collected two and a half hours "after luncheon") was 200uU/ml (Gellhorn, Feldman, and Allen 1941). However, discrepancies between measurements of plasma insulin concentration (...) by in vitro bioassays, which began in earnest in the late 1940s and early 1950s, and, beginning in 1960, by radioimmunoassay (RIA), intimated that insulin was not.. (shrink)

Progress in solving the structure of insulin bound to its receptor has been slow and stepwise, but a milestone has now been reached with a refined structure of a complex of insulin with a “microreceptor” that contains the primary binding site. The insulin receptor is a dimeric allosteric enzyme that belongs to the family of receptor tyrosine kinases. The insulin binding process is complex and exhibits negative cooperativity. Biochemical evidence suggested that insulin, through two distinct (...) binding sites, crosslinks two receptor sites located on each α subunit. The structure of the unliganded receptor ectodomain showed a symmetrical folded‐over conformation with an antiparallel disposition. Further work resolved the detailed structure of receptor site 1, both without and with insulin. Recently, a missing piece in the puzzle was added: the C‐terminal portion of insulin's B‐chain known to be critical for binding and negative cooperativity. Here I discuss these findings and their implications. (shrink)

Several protective cellular mechanisms protect against the accumulation of reactive oxygen species (ROS) and the concomitant oxidative stress. Therefore, any reduction in glucose or fatty acid flux into cells leading to a decrease in the production of reducing equivalents would also lead to a decreased ROS production and protect cells against oxidative stress. In the presence of insulin, FOXO proteins are localized from the nucleus to the cytoplasm and degraded. An increase in cellular glucose uptake will lead to increased (...) production of ROS. This in turn activates the stress‐responsive Jun‐N‐terminal kinase (JNK), which promotes nuclear translocation of FOXO proteins, upregulating some important target genes including stress resistance. Consequently, insulin resistance should result in decreased cellular ROS production. For this reason, insulin resistance could be a physiological mechanism activated at the cellular level in response to conditions stimulating ROS production and leading to the prevention of oxidative stress, and extension of life. Concerning the whole organism, however, IR is a maladaptive process in the long term causing a diabetic state. BioEssays 29:811–818, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Galectin-3 and LTB4 are pro-inflammatory molecules recently shown to directly cause insulin resistance in mouse and human cells. They are highly expressed in the obese state, and can be targeted both genetically and pharmacologically to improve insulin sensitivity in vivo. This expands on previous research showing that targeting inflammatory cytokines can be insulin sensitizing in animal models. However, translating these potential therapies into the human setting remains challenging. Here we review this latest research, and discuss how balancing (...) their pleiotropic functions, the action of the microbiome, and the ability to identify relevant patient populations are vital considerations for successful anti-inflammatory insulin sensitizing therapy. Recent advances have indicated that a diverse range of inflammatory molecules, including leukotriene B4 and Galectin-3 can cause insulin resistance. Key challenges for translating these new targets into therapies include their pleiotropic effects and likely patient heterogeneity, such as is caused by the intestinal microbiome. (shrink)

Insulin is well known for its essential role in carbohydrate metabolism: insulin deficiency results in the development of diabetes mellitus. It has been known for many years that people with diabetes mellitus are predisposed to develop thrombotic diseases including myocardial infarction. It was thought that the thrombus formation was the consequence of impaired carbohydrate metabolism. In recent years, it has become apparent that insulin is capable of ameliorating several pathophysiological events, leading to the inhibition and dissolution of (...) the formed thrombus in the system. These insulin‐induced events include inhibition of platelet aggregation by prompting the synthesis of NO in platelet and prostacyclin in endothelial cells. Furthermore, insulin upregulates prostacyclin receptors and downregulates α2 adrenergic receptor in platelets, thereby amplifying the inhibition of platelet aggregation. Insulin also releases tissue plasminogen activator, a potent thrombolytic enzyme, from the platelet membrane which dissolves the formed thrombus leading to the resumption of normal blood circulation. In effect, insulin could be an essential tool in the control of thrombotic disorders. BioEssays 26:91–98, 2004. © 2003 Wiley Periodicals, Inc. (shrink)

Insulin is a member of a family of hormones, growth factors and neuropeptides which are found in both vertebrates and invertebrates. A common ‘insulin fold’ is probably adopted by all family members. Although the specificities of receptor binding are different, there is possibility of co‐evolution of polypeptides and their receptors.

In a brilliant, definitive history of one of the most significant and controversial medical events of modern times, award-winning historian Michael Bliss brings to light a bizarre clash of scientific personalities. When F. G. Banting and J. J. R. Macleod won the 1923 Nobel Prize for discovering and isolating insulin, Banting immediately announced that he was dividing his share of the prize with his young associate, C. H. Best. Macleod divided his share with a fourth member of the team, (...) J. B. Collip. For the next sixty years medical opinion was intensely divided over the allotment of credit for the discovery of insulin. In resolving this controversy, Bliss also offers a wealth of new detail on such subjects as the treatment of diabetes before insulin and the life-and-death struggle to manufacture insulin. (shrink)

Soon after the discovery of insulin in the early 1920s, the popular press celebrated the miraculous discovery. Although insulin had no curative effect on the chronic state of diabetes, it was frequently heralded as a “cure.” This paper examines how the discovery of insulin intersected with the rise of diabetic technology and the transfer of medical technology to the home setting. By analyzing diabetic manuals written for patients and physicians, letters exchanged between patient and physician, medical journals, (...) magazines and newspapers, I trace how patients learned about insulin and more significantly how patients adopted measurement technologies designed to allow better home administration of insulin. This included acquiring knowledge about nutritional content and scales, maintaining sterile glass syringes, sharpening needles, using chemistry to measure sugar in the urine, and recording various measurements into meaningful text for patient-physician dialogue. As diabetes was re-imagined as a chronic and controllable illness, patients and physicians alike grappled with the promises and limitations of new medical technologies. This historical perspective offers a lens for better understanding the process of implementing diabetic treatment plans that required home testing, measurement, and recording of medical data. Such processes centered the importance of patient-centered work and the value of diabetic technologies. Much of this discourse is outlined in diabetic manuals of the 1920s. (shrink)

Recent studies of early development in a number of ivertebrate and vertebrate species have suggested that growth factors and their receptors may play important roles in differentiation as well as cell proliferation. In the mouse embryo, the expression of the receptors for insulin and insulin‐like growth factors I and II (IGF‐I and ‐II) are temporally regulated. The ontogeny of receptor and ligand expression within the insulin and IGF gene family suggests that the very earliest stages of mammalian (...) embryogenesis may be subject to regulation by autocrine and paracrine factors from maternal and embryonic sources. (shrink)

Current models of insulin binding to the insulin receptor (IR) propose (i) that there are two binding sites on the surface of insulin which engage with two binding sites on the receptor and (ii) that ligand binding involves structural changes in both the ligand and the receptor. Many of the features of insulin binding to its receptor, namely B‐chain helix interactions with the leucine‐rich repeat domain and A‐chain residue interactions with peptide loops from another part of (...) the receptor, are also seen in models of relaxin and insulin‐like peptide 3 binding to their receptors. We show that these principles can likely be extended to the group of mimetic peptides described by Schäffer and coworkers, which are reported to have no sequence identity with insulin. This review summarizes our current understanding of ligand‐induced activation of the IR and highlights the key issues that remain to be addressed. (shrink)

Nicotinamide adenine dinucleotide (NAD+) biosynthetic pathway, mediated by nicotinamide phosphoribosyltransferase (NAMPT), a key NAD+ biosynthetic enzyme, plays a pivotal role in controlling many biological processes, such as metabolism, circadian rhythm, inflammation, and aging. Over the past decade, NAMPT‐mediated NAD+ biosynthesis, together with its key downstream mediator, namely the NAD+‐dependent protein deacetylase SIRT1, has been demonstrated to regulate glucose and lipid metabolism in a tissue‐dependent manner. These discoveries have provided novel mechanistic and therapeutic insights into obesity and its metabolic complications, such (...) as insulin resistance, an important risk factor for developing type 2 diabetes and cardiovascular disease. This review will focus on the importance of adipose tissue NAMPT‐mediated NAD+ biosynthesis and SIRT1 in the pathophysiology of obesity and insulin resistance. We will also critically explore translational and clinical aspects of adipose tissue NAD+ biology. (shrink)

Insulin resistance is thought to be the primary defect in the pathophysiology of type 2 diabetes. Thus, understanding the cellular mechanisms of insulin action may contribute significantly to developing new treatments for this disease. Although the effects of insulin on glucose and lipid metabolism are well documented, gaps remain in our understanding of the precise molecular mechanisms of signal transduction for the hormone. One potential clue to understanding the unique cellular effects of insulin may lie in (...) the compartmentalization of signaling molecules and metabolic enzymes. We review this evidence, and speculate on how PI-3 kinase-independent and -dependent signaling pathways both diverge from the insulin receptor and converge at discrete targets to insure the specificity of insulin action. BioEssays 23:215–222, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

The calcium signals regulate the production and secretion of many signaling molecules like inositol trisphosphate ( $$IP_{3}$$ ) and adenosine triphosphate (ATP) in various cells including pancreatic $$\beta$$ -cells. The calcium signaling mechanisms regulating $$IP_{3}$$, ATP and insulin responsible for various functions of $$\beta$$ -cells are still not well understood. Any disturbance in these mechanisms can alter the functions of $$\beta$$ -cells leading to diabetes and metabolic disorders. Therefore, a mathematical model is proposed by incorporating the reaction-diffusion equation for (...) calcium dynamics and a system of first-order differential equations for $$IP_{3}$$, ATP-production and insulin secretion with initial and boundary conditions. The model incorporates the temporal dependence of $$IP_{3}$$ -production and degradation, ATP production and insulin secretion on calcium dynamics in a $$\beta$$ -cell. The piecewise linear finite element method has been used for the spatial dimension and the Crank-Nicolson scheme for the temporal dimension to obtain numerical results. The effect of changes in source influxes and buffers on calcium dynamics and production of $$IP_{3}$$, ATP and insulin levels in a $$\beta$$ -cell has been analyzed. It is concluded that the dysfunction of source influx and buffers can cause significant variations in calcium levels and dysregulation of $$IP_{3}$$, ATP and insulin production, which can lead to various metabolic disorders, diabetes, obesity, etc. The proposed model provides crucial information about the changes in mechanisms of calcium dynamics causing proportionate disturbances in $$IP_3$$, ATP and insulin levels in pancreatic cells, which can be helpful for devising protocols for diagnosis and treatment of various metabolic diseases. (shrink)

The information contained in DNA is not definitive, but modifiable. Indeed, the environment has the power to modify the genetic material expression without altering the DNA genes sequence. The principal environmental factors that work in this way, whether in a positive or in a negative way, are diet and stress with their ruling hormones, insulin and cortisol; these hormones are normally antagonists but, when they reach their respective resistances, they become the ubiquitary etiopathogenetic factors in bidirectional convergent relationship, each (...) other causing the disinhibition and development of low grade systemic inflammation that opens the door to a myriad of interconnected sets of problems. Among these problems the greater one is cancer, which represents the extreme junction between hyperinsulinemia and hypercortisolemia, just because cancer cells never become insulin resistant and/or cortisol resistant. (shrink)

The aim of the study was to explore heterogeneity of change in state affect following the introduction of insulin therapy in patients with type 2 diabetes. State affect was assessed twice among 305 patients: just before the introduction of insulin therapy and at 1-month follow-up. Latent class growth modeling showed that negative affect (NA) increased in 78% of the sample, whereas positive affect (PA) improved in only 17% of the participants. On the basis of cross-tabulation of these changes (...) a 4-class model of emotional response to the new treatment was obtained. The largest subgroup of participants (57%) manifested “threat response”, i.e. moderate-stable PA with increase in NA. Participants in the “challenge response” subgroup (11.8%) showed increases in both NA and PA. The third class (10.2%) characterized by “no response”, had low-stable NA and moderate-stable PA. The smallest “stress response” subgroup (9.8%) showed increase in NA and high-stable PA. Gender, age and education level were significant covariates of group membership. Thus, the findings revealed heterogeneous emotional response to the new treatment, which may be of clinical relevance for improving diabetic patients’ adjustment through a more individual, person-centered approach. (shrink)

The discovery of the first intracellular substrate for insulin, IRS‐1, redirected the field of diabetes research and has led to many important advances in our understanding of insulin action. Detailed analysis of IRS‐1 demonstrates structure/function relationships for this modular docking molecule, including mechanisms of substrate recognition and signal propagation. Recent work has also identified other structurally similar molecules, including IRS‐2, the Drosophila protein, DOS, and the Grb2‐binding protein, Gab1, suggesting that this intracellular signalling strategy is conserved evolutionarily and (...) is utilized by an expanding number of receptor systems. In fact, IRS‐1 itself has been shown to be important in other growth factor and cytokine signalling systems, including growth hormone and several interleukins. Analysis of mice lacking IRS‐1 confirms an important physiological role for this protein in glucose metabolism and general cell growth in the intact animal. Disregulation of the signalling pathways integrated by the IRS proteins may contribute to the pathophysiology of non‐insulin‐dependent diabetes mellitus or other diseases. (shrink)