Modulation of β-cell function: A translational journey from the bench to the bedside

Section of Clinical Research, Joslin Diabetes Center, Boston, MA 02215, USA.
Diabetes Obesity and Metabolism (Impact Factor: 6.36). 10/2012; 14 Suppl 3(Suppl 3):152-60. DOI: 10.1111/j.1463-1326.2012.01647.x
Source: PubMed


Both decreased insulin secretion and action contribute to the pathogenesis of type 2 diabetes (T2D) in humans. The insulin receptor and insulin signalling proteins are present in the rodent and human β-cell and modulate cell growth and function. Insulin receptors and insulin signalling proteins in β-cells are critical for compensatory islet growth in response to insulin resistance. Rodents with tissue-specific knockout of the insulin receptor in the β-cell (βIRKO) show reduced first-phase glucose-stimulated insulin secretion (GSIS) and with aging develop glucose intolerance and diabetes, phenotypically similar to the process seen in human T2D. Expression of multiple insulin signalling proteins is reduced in islets of patients with T2D. Insulin potentiates GSIS in isolated human β-cells. Recent studies in humans in vivo show that pre-exposure to insulin increases GSIS, and this effect is diminished in persons with insulin resistance or T2D. β-Cell function correlates to whole-body insulin sensitivity. Together, these findings suggest that pancreatic β-cell dysfunction could be caused by a defect in insulin signalling within β-cell, and β-cell insulin resistance may lead to a loss of β-cell function and/or mass, contributing to the pathophysiology of T2D.

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    • "Pancreatic b-cells While pancreatic b-cells are not key sites of glucose utilization or storage, nor producers of metabolic fuel from a whole-body perspective, they are an important insulin-responsive tissue. Insulin signaling is required to maintain proper b-cell mass and firstphase insulin secretion (Kulkarni et al., 1999, Cheng et al., 2012, Goldfine and Kulkarni, 2012, Folli et al., 2011). Insulin secretion by the b-cells, through an autocrine mechanism, stimulates both insulin and b-glucokinase gene transcription (Leibiger et al., 2001), both of which serve to support a robust first phase insulin secretion. "
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    ABSTRACT: Insulin acts as the major regulator of the fasting-to-fed metabolic transition by altering substrate metabolism, promoting energy storage, and helping activate protein synthesis. In addition to its glucoregulatory and other metabolic properties, insulin can also act as a growth factor. The metabolic and mitogenic responses to insulin are regulated by divergent post-receptor signaling mechanisms downstream from the activated insulin receptor (IR). However, the anabolic and growth-promoting properties of insulin require tissue-specific inter-relationships between the two pathways, and the nature and scope of insulin-regulated processes vary greatly across tissues. Understanding the nuances of this interplay between metabolic and growth-regulating properties of insulin would have important implications for development of novel insulin and IR modulator therapies that stimulate insulin receptor activation in both pathway- and tissue-specific manners. This review will provide a unique perspective focusing on the roles of "metabolic" and "mitogenic" actions of insulin signaling in various tissues, and how these networks should be considered when evaluating selective pharmacologic approaches to prevent or treat metabolic disease. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Molecular and Cellular Endocrinology 08/2015; 415. DOI:10.1016/j.mce.2015.08.013 · 4.41 Impact Factor
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    ABSTRACT: In recent years there has been a growing interest in the possibility of a direct autocrine effect of insulin on the pancreatic β-cell. Indeed, there have been numerous intriguing articles and several eloquent reviews written on the subject (1-3); however, the concept is still controversial. Although many in vitro experiments, a few transgenic mouse studies, and some human investigations would be supportive of the notion, there exist different insights, other studies, and circumstantial evidence that question the concept. Therefore, the idea of autocrine action of insulin remains a conundrum. Here we outline a series of thoughts, insights, and alternative interpretations of the available experimental evidence. We ask, how convincing are these, and what are the confusing issues? We agree that there is a clear contribution of certain downstream elements in the insulin signaling pathway for β-cell function and survival, but the question of whether insulin itself is actually the physiologically relevant ligand that triggers this signal transduction remains unsettled.
    Diabetes 07/2013; 62(7):2157-2163. DOI:10.2337/db13-0246 · 8.10 Impact Factor
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    ABSTRACT: Type 2 diabetes affects millions of people worldwide and significantly contributes to morbidity and mortality of those affected by it. Current guidelines recommend individualized treatment regimens following first line metformin therapy. Saxagliptin, a dipeptidyl-peptidase 4 inhibitor, provides a secondary mechanism of action to decrease hyperglycemia when used in combination with metformin. The combination of metformin and saxagliptin has shown improvements in hemoglobin A1c and fasting plasma glucose in greater efficacy than when either agent is used alone. Adverse effects of combination therapy are similar to when these agents are used individually, and are rated as tolerable by patient satisfaction scores. Overall, the combination use of saxagliptin in addition to metformin is an attractive option for clinicians to use in the treatment of type 2 diabetes.
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