Insulin and Insulin Analogs Research & Studies

The management of type 1 diabetes mellitus entails replacing the actions of the beta cells of the pancreatic islet to detect the need for insulin and to have insulin administered according to the requirements of the patient's body. This activity reviews the indications for the use of insulin, its mechanism of action, routes of administration, contraindications, adverse effects, monitoring its blood concentrations, and toxicity. It also describes in detail how insulin leads to shifts of electrolytes between the intracellular and extracellular compartments. Also, this activity summarizes the cellular production of insulin and its function via its receptor and the numerous effects on carbohydrate, protein, and fat metabolism.

Insulin-stimulated glucose uptake into muscle and adipose tissue is vital for maintaining whole-body glucose homeostasis. Insulin promotes glucose uptake into these tissues by triggering a protein phosphorylation signalling cascade, which converges on multiple trafficking processes to deliver the glucose transporter GLUT4 to the cell surface. Impaired insulin-stimulated GLUT4 translocation in these tissues underlies insulin resistance, which is a major risk factor for type 2 diabetes and other metabolic diseases. Despite this, the precise changes in insulin signalling and GLUT4 trafficking underpinning insulin resistance remain unclear. In this review, we highlight insights from recent unbiased phosphoproteomics studies, which have enabled a comprehensive examination of insulin signalling and have transformed our perspective on how signalling changes may contribute to insulin resistance. We also discuss how GLUT4 trafficking is disrupted in insulin resistance, and underline sites where signalling changes could lead to these trafficking defects. Lastly, we address several major challenges currently faced by researchers in the field. As signalling and trafficking alterations can be examined at increasingly high resolution, integrative approaches examining the two in combination will provide immense opportunities for elucidating how they conspire to cause insulin resistance.

Insulin resistance is a common feature of obesity and type 2 diabetes, but novel approaches of diabetes subtyping (clustering) revealed variable degrees of insulin resistance in people with diabetes. Specifically, the severe insulin resistant diabetes (SIRD) subtype not only exhibits metabolic abnormalities, but also bears a higher risk for cardiovascular, renal and hepatic comorbidities. In humans, insulin resistance comprises dysfunctional adipose tissue, lipotoxic insulin signaling followed by glucotoxicity, oxidative stress and low-grade inflammation. Recent studies show that aside from metabolites (free fatty acids, amino acids) and signaling proteins (myokines, adipokines, hepatokines) also exosomes with their cargo (proteins, mRNA and microRNA) contribute to altered crosstalk between skeletal muscle, liver and adipose tissue during the development of insulin resistance. Reduction of fat mass mainly, but not exclusively, explains the success of lifestyle modification and bariatric surgery to improve insulin sensitivity. Moreover, some older antihyperglycemic drugs (metformin, thiazolidinediones), but also novel therapeutic concepts (new peroxisome proliferator-activated receptor agonists, incretin mimetics, sodium glucose cotransporter inhibitors, modulators of energy metabolism) can directly or indirectly reduce insulin resistance. This review summarizes molecular mechanisms underlying insulin resistance including the roles of exosomes and microRNAs, as well as strategies for the management of insulin resistance in humans.

The 1921 discovery of insulin was a Big Bang from which a vast and expanding universe of research into insulin action and resistance has issued. In the intervening century, some discoveries have matured, coalescing into solid and fertile ground for clinical application; others remain incompletely investigated and scientifically controversial. Here, we attempt to synthesize this work to guide further mechanistic investigation and to inform the development of novel therapies for type 2 diabetes (T2D). The rational development of such therapies necessitates detailed knowledge of one of the key pathophysiological processes involved in T2D: insulin resistance. Understanding insulin resistance, in turn, requires knowledge of normal insulin action. In this review, both the physiology of insulin action and the pathophysiology of insulin resistance are described, focusing on three key insulin target tissues: skeletal muscle, liver, and white adipose tissue. We aim to develop an integrated physiological perspective, placing the intricate signaling effectors that carry out the cell-autonomous response to insulin in the context of the tissue-specific functions that generate the coordinated organismal response. First, in section II, the effectors and effects of direct, cell-autonomous insulin action in muscle, liver, and white adipose tissue are reviewed, beginning at the insulin receptor and working downstream. Section III considers the critical and underappreciated role of tissue crosstalk in whole body insulin action, especially the essential interaction between adipose lipolysis and hepatic gluconeogenesis. The pathophysiology of insulin resistance is then described in section IV. Special attention is given to which signaling pathways and functions become insulin resistant in the setting of chronic overnutrition, and an alternative explanation for the phenomenon of ‟selective hepatic insulin resistanceˮ is presented. Sections V, VI, and VII critically examine the evidence for and against several putative mediators of insulin resistance. Section V reviews work linking the bioactive lipids diacylglycerol, ceramide, and acylcarnitine to insulin resistance; section VI considers the impact of nutrient stresses in the endoplasmic reticulum and mitochondria on insulin resistance; and section VII discusses non-cell autonomous factors proposed to induce insulin resistance, including inflammatory mediators, branched-chain amino acids, adipokines, and hepatokines. Finally, in section VIII, we propose an integrated model of insulin resistance that links these mediators to final common pathways of metabolite-driven gluconeogenesis and ectopic lipid accumulation.

Insulin reactions occur rarely but are of tremendous clinical importance. The first was reported in 1922 as a callus reaction at the injection site of insufficiently purified bovine insulin. Porcine insulin was subsequently found to be less allergenic than bovine insulin. Increasingly pure insulins have decreased the risk of adverse reactions, and the production of recombinant insulin with the same amino sequence as human insulin saw a large decrease in adverse reactions. Currently, the prevalence of allergic reactions to insulin products appears to be approximately 2%, and less than one-third of these events have been considered related to the insulin itself. Other reactions occur due to the preservatives added to insulin, including zinc, protamine, and meta-cresol. Allergic reactions can be type I or immunoglobulin E-mediated, type III or Arthus, and type IV or delayed-type hypersensitivity reactions. Type I reactions are the most common and can, rarely, cause anaphylaxis. In contrast, type IV reactions can occur after a delay of several days. Investigations include skin prick testing, patch testing, intradermal testing, and occasionally, skin biopsy.

As obesity and diabetes reach epidemic proportions in the developed world, the role of insulin resistance and its consequences are gaining prominence. Understanding the role of insulin in wide-ranging physiological processes and the influences on its synthesis and secretion, alongside its actions from the molecular to the whole body level, has significant implications for much chronic disease seen in Westernised populations today. This review provides an overview of insulin, its history, structure, synthesis, secretion, actions and interactions followed by a discussion of insulin resistance and its associated clinical manifestations. Specific areas of focus include the actions of insulin and manifestations of insulin resistance in specific organs and tissues, physiological, environmental and pharmacological influences on insulin action and insulin resistance as well as clinical syndromes associated with insulin resistance. Clinical and functional measures of insulin resistance are also covered. Despite our incomplete understanding of the complex biological mechanisms of insulin action and insulin resistance, we need to consider the dramatic social changes of the past century with respect to physical activity, diet, work, socialisation and sleep patterns. Rapid globalization, urbanisation and industrialization have spawned epidemics of obesity, diabetes and their attendant co-morbidities, as physical inactivity and dietary imbalance unmask latent predisposing genetic traits.