Insulin and beta cell function -
Notably, individuals with MetS have significantly increased risk for type 2 diabetes mellitus T2DM , independent of many other risk factors 5. The prevailing view is that insulin resistance causes elevation of plasma glucose levels, which promotes increased demand on pancreatic β cells to produce and secrete more insulin 6.
During the past several years, however, the idea that insulin resistance precedes β cell dysfunction has been challenged, and there is a growing appreciation that, at least in a subset of patients, the contribution of islet β cell hyperresponsiveness is a primary event in the development of carbohydrate intolerance 7 , 8.
Furthermore, there is mounting evidence that the hyperinsulinemic state contributes to some of the other disorders associated with MetS, including cardiovascular disease, nonalcoholic fatty liver disease, and polycystic ovarian disease 8.
These findings suggest that understanding β cell dysfunction in MetS may inform novel approaches to treating T2DM, cardiovascular disease, and other associated MetS complications. In this Review, we will discuss the well-characterized mechanisms that contribute to disease-mediated β cell dysfunction and death, as well as potential alternative β cell adaptive responses to external stressors associated with MetS based on recent studies in mice and evidence from human cadaveric pancreas tissue.
There are four hormone-producing endocrine cell populations within the adult pancreatic islets of Langerhans: α, β, δ, and PP pancreatic polypeptide cells. Islet β cells are defined by their ability to produce, store, and secrete insulin in response to nutrients such as glucose, lipids, and a subset of amino acids.
The α and δ cells secrete the hormones glucagon and somatostatin, respectively, to achieve a glucose-homeostatic condition reviewed in ref.
The β cell is exquisitely sensitive to the nutrient environment and can respond to extremely small changes in blood glucose concentrations between 4. However, because the β cell is fine-tuned for acute fluctuations in nutrient concentrations, chronic exposure to elevated levels of glucose and free fatty acids, as seen in MetS, results in progressive β cell adaptation and failure.
As discussed below, β cell response to physiologic and pathophysiologic states of nutrient excess can occur through several mechanisms, including adaptive changes in β cell mass and function. Furthermore, β cell adaptations can occur both prior to and in response to MetS.
Both rodent and human studies have contributed to the evolution of our understanding of these processes. Metabolic syndrome presents a set of unique stressors to the β cell, including elevated glucose, increased free fatty acids, and inflammation 11 — In this adverse environment, β cells initially mount a compensatory response to ramp up β cell functional capacity and insulin secretion to meet the elevated metabolic demand.
On the other hand, in some individuals, excess nutrient conditions first impair insulin responses in peripheral tissues, such as the liver, to initiate the insulin-resistant environment that will subsequently induce a compensatory response by β cells.
Ultimately, this again triggers enhanced insulin secretion that can progress to β cell dysfunction in an environment of chronic metabolic demand Figure 1 and refs.
How and why these distinct scenarios are initiated is not well understood, but certainly partially depends on genetic differences between individuals. For example, β cell defects tend to be more important in Asian populations in contrast to the predominance of insulin resistance in White populations 15 — Ultimately, however, regardless of whether the initial trigger is nutrient excess, insulin resistance, or both, the transition from an adaptive β cell response to a pathological β cell response represents a critical step in the progression to diabetes.
β Cell compensation and dysfunction in MetS and T2DM. In each case, a feedback cycle can be established to exacerbate insulin resistance and increase insulin secretion; both conditions can trigger MetS and its related complications.
Initially, β cells are able to functionally compensate for the increased metabolic demand by increasing β cell mass, inducing an unfolded protein response UPR and improving mitochondrial function.
However, over time, in a subset of individuals, β cell compensation cannot be sustained, and β cells become dysfunctional, presenting with ER stress, mitochondrial dysfunction, oxidative stress, and inflammation.
Ultimately, the stressed β cells undergo cell death, dedifferentiation, transdifferentiation, or phenotypic alterations that compromise function.
Disrupted β cell function can feed back to exacerbate MetS. One of the most well-studied features of β cell adaptation in MetS is β cell proliferation. Studies in rodent models have provided the most compelling data for the role of adaptive β cell mass in environmental conditions mimicking MetS.
For example, mice given corticosterone in their drinking water for 5 weeks displayed many features of MetS, including dyslipidemia, insulin resistance, glucose intolerance, and hypertension, and displayed increased islet volume due to β cell proliferation Interestingly, when the leptin mutation is induced in the BTBR Black and Tan Brachyury background, the mice are unable to increase β cell proliferation and progress to diabetes Although adaptive increases in β cell proliferation have been well documented in insulin-resistant and HFD-fed rodent models, the extent of these early adaptive changes in β cell mass is more difficult to characterize in humans, in whom there are no available technologies to accurately track longitudinal changes in β cell mass.
Currently, measures of human β cell mass are performed at static time points and rely predominantly on the availability of cadaveric tissue samples. One of the earliest studies to examine β cell mass compared autopsy tissues from approximately 20 obese individuals versus lean controls to demonstrate that obese individuals had higher β cell mass than the control group Since that time, several additional cadaveric studies have suggested that the ability to increase β cell mass in the context of obesity and insulin resistance is necessary to prevent the development of diabetes 24 , These analyses were reinforced by a recent autopsy study that reported that human obese, nondiabetic patients have a significantly higher β cell mass than individuals with diabetes who are either lean or obese Furthermore, a study that was able to evaluate pancreatic samples from nondiabetic insulin-resistant subjects who had undergone pancreatoduodenectomy also identified a marked increase in β cell numbers However, these human studies remain somewhat controversial.
For example, Butler et al. In addition to the adaptive β cell proliferative response that occurs in a high-nutrient environment, β cells adapt to metabolic challenges by employing intrinsic mechanisms to enhance β cell performance.
Studies in Wistar rats demonstrated that nutrient-challenged β cells increased their expression of the glucose transporter GLUT2 and enhanced glucokinase activity to promote insulin hypersecretion 33 , Islets of Zucker fatty ZF rats also displayed 3- to fold increases in stimulated insulin secretion due to increased glucose utilization and oxidation This study further demonstrated that β cell mitochondrial metabolism was elevated as a result of increased flux through pyruvate carboxylase and the malate-pyruvate and citrate-pyruvate shuttles.
In humans, similar compensatory increases in augmented insulin secretion have been reported in obese, nondiabetic patients and individuals with prediabetes 36 , The same study identified the transient upregulation of UPR genes to protect against decompensating ER stress responses.
In an analogous proteomics study, transient increases in molecules involved in protein synthesis and folding and cell survival were also observed Furthermore, an interesting study by Sharma et al.
These studies all demonstrate the remarkable ability of β cells to adapt to increased metabolic demand and suggest that interventions that promote optimal β cell physiology in the face of increased insulin demand are a potential therapeutic strategy. While increased insulin secretion allows the β cell to respond to excess metabolic demand, prolonged elevated circulating insulin can impact insulin sensing in peripheral tissues, such as liver and muscle.
Although it is clear that insulin resistance is a central component of MetS, there is mounting evidence that prolonged insulin hypersecretion could be an initiating event in the syndrome. Several studies in mice and humans have demonstrated that prolonged elevated insulin secretion in excess nutrient environments precedes and promotes insulin resistance 40 , For example, human cross-sectional studies by Ferrannini et al.
Furthermore, recent data in youth with prediabetes and T2DM from the NIH Restored Insulin Secretion RISE study demonstrated that insulin hypersecretion in youth predicted progression to diabetes.
Interestingly, this pattern differs in adults who have T2DM or are at risk of developing T2DM 43 , These human studies strongly support an initiating role for insulin hypersecretion in the development of MetS. In several rodent models, there is also evidence for transient increases in β cell proliferation and intrinsic β cell functional adaptations in response to increased insulin demand, before substantial changes in insulin resistance can be detected.
Furthermore, mutations in IRS1 have been linked to β cell dysfunction and association with T2DM in several human populations 49 , Fasting and glucose-stimulated insulin secretion in the progression to T2DM.
Fasting insulin secretion blue increases as people progress from normal glucose tolerance to T2DM; in contrast, glucose-stimulated insulin secretion GSIS; green represents a lower percentage of overall insulin secretion in impaired glucose tolerance IGT and less than half of insulin secretion in T2DM.
Adapted with permission from Frontiers in Endocrinology 41 based on data in ref. Despite evidence that β cells can mount a compensatory response to insulin resistance and overnutrition, in individuals who develop T2DM the ability to compensate is transient.
Over time, production of large amounts of insulin by the compensating β cells exerts continuous demand on the ER for proper protein synthesis, folding, trafficking, and secretion.
Ultimately, β cells are unable to sustain the increased workload, and the initial adaptive responses become progressively maladaptive. β Cell dysfunction has been extensively studied in MetS, insulin-resistant conditions, and T2DM, both in rodent models and in humans, to reveal similar underlying molecular defects reviewed in refs.
In conditions of chronic nutrient exposure, sustained overproduction and secretion of insulin strains the folding capacity of the ER, and misfolded or unfolded proteins accumulate in the ER lumen, resulting in ER stress and activation of β cell apoptosis pathways reviewed in refs.
Consistently, ER stress markers are commonly elevated in pancreatic islets of animals exposed to HFD Studies in islets from human T2DM patients also show a doubling of the ER size compared with controls, indicative of the presence of ER stress responses Increased demand on the β cell also results in increased flux through mitochondria.
Eventually, the overworked β cell mitochondria also become dysfunctional, which impairs the coupling of glucose metabolism and insulin secretion. This then triggers oxidative stress and higher levels of reactive oxygen species, which further worsens β cell function and eventually promotes β cell exhaustion and loss reviewed extensively in refs.
Traditionally, it has been assumed that loss of insulin-producing cells in conditions causing β cell exhaustion was caused by a decrease in β cell numbers through apoptosis and other mechanisms of β cell death. However, our understanding of β cell biology has greatly expanded in recent years, and the simplistic view that β cell death is the primary outcome of β cell exhaustion and dysfunction has evolved considerably.
These phenomena have been most extensively explored in rodent models; however, corroborative evidence from analysis of human cadaveric pancreatic tissue is also emerging Figure 3.
Fates of overexerted β cells. Upon overexertion, in many animal models and humans, β cells initially undergo functional compensation, which can be followed by a pathogenic response.
In the past, overexerted β cells were thought to predominantly undergo cell death. More recently, there has been evidence from animal models and human pancreatic tissue that β cells can respond by undergoing dedifferentiation, transdifferentiation, or β cell subtype transitions.
This observation was reinforced in a genetic model when Talchai et al. However, lineage tracing revealed that the mutant β cells were not lost through apoptosis, but became dedifferentiated to revert to a more progenitor-like state.
This observation has been bolstered by a number of studies that have demonstrated that adoption of a dedifferentiated phenotype was a protective mechanism to support β cell survival under conditions of stress There have since been many additional reports of β cell dedifferentiation in response to genetic and environmental perturbations — in both mice and humans.
Inducible ablation of the transcription factor LDB1 in mature β cells also resulted in impaired insulin secretion and glucose homeostasis due to a reduction in β cell identity genes and induction of the endocrine progenitor marker Neurogenin3 NEUROG3 , again suggesting that β cells have the ability to become dedifferentiated Evidence of dedifferentiated β cells, defined by the presence of hormone-negative endocrine cells, was also reported in a study of human T2D patients with adequate glucose control However, without lineage analyses and more extensive progenitor marker analyses, dedifferentiation is more difficult to prove in humans.
To overcome this challenge, Diedisheim et al. They were also able to identify novel human β cell dedifferentiation markers SOX9, HES1, MYC, PYY, GAST, and NEUROG3 in addition to the previously reported ALDH1A3 marker described by Cinti et al.
In support of this concept, the ADOPT A Diabetes Outcome Progression Trial study demonstrated that promoting insulin sensitisation is a viable approach to reduce beta cell workload and remedy glucose control [ 9 ]. Lifestyle intervention weight loss via exercise and diet and medications improve insulin sensitivity and enhance beta cell function [ 4 , 9 ].
Thiazolidinediones efficiently mitigate a portion of the insulin resistance associated with type 2 diabetes. Although they were widely used in the s and s, their adverse effects weight gain, oedema, bone fractures were felt by many to outweigh their benefits and now they are hardly used.
Metformin, a widely used first-line therapy that ameliorates hyperglycaemia by decreasing hepatic glucose output, is often insufficient on its own, over the longer term [ 8 ].
More recently, the sodium—glucose cotransporter-2 SGLT2 inhibitors were introduced as a workaround for peripheral insulin resistance. These agents induce glycosuria, thereby reducing the need for insulin to dispose of glucose.
Studies in animals and humans suggest that this approach, by reducing chronic hyperglycaemia, may improve insulin sensitivity and beta cell function [ 14 ]. However, it remains unknown whether these agents can maintain long-term glucose control. Recent studies have shown that bariatric surgery rapidly improves beta cell function, preceding any notable change in obesity or adiposity, suggesting that the surgery triggers the release of factors that benefit beta cell function.
However, the mechanisms by which this might occur have not as yet been definitively identified. Mechanisms involving gut hormones e. GLP-1, GIP , gut microbiota, bile acids, fibroblast growth factor FGF 19 and improved hepatic or skeletal muscle insulin sensitivity, are all active postulates under investigation [ 15 ].
An alternative to targeting either beta cell dysfunction or insulin resistance is to target single factors that multitask in beta cells and peripheral insulin-sensitive cells.
These multitasking factors enhance the efficiency of glucose-stimulated insulin secretion GSIS and insulin-stimulated glucose uptake, respectively, in a coordinated fashion.
Current research efforts are focused on endogenous factors that multitask in beta cells and insulin-sensitive cells and show promise in preclinical studies and ex vivo human islet studies. For example, type 2 diabetic human islets are deficient in the exocytosis factor syntaxin 4 STX4 , and replenishing it restores their function—STX4 enrichment protects beta cell function against diabetogenic stimuli e.
obesity, glucolipotoxicity , while also promoting peripheral insulin sensitivity [ 16 , 17 ] Fig. Another multitasking factor, pactivated kinase 1 PAK1 , is a key mediator of stimulus-induced actin remodelling and is deficient in type 2 diabetic human islets.
Enrichment of PAK1 protects beta cell function and supports skeletal muscle cell glucose uptake [ 18 , 19 ]. BMP7, a member of the TGF-β-superfamily, confers glucose-sensitive insulin release to beta cell progenitors [ 21 ], although the impact of BMP7 on pancreatic islet function in vivo remains to be evaluated.
Moreover, the bone-derived factor osteocalcin also promotes GSIS in beta cells [ 22 ] and enhances skeletal muscle glucose uptake [ 23 ].
Although most of the identified multitasking factors are deficient in type 2 diabetes, some are overexpressed and may contribute to diabetes progression. For instance, thioredoxin interacting protein TXNIP expression is elevated in type 2 diabetic human skeletal muscle, and its silencing confers improved peripheral tissue glucose uptake [ 24 ]; TXNIP inhibition also indirectly promotes beta cell function [ 25 ].
Clearly, further work is needed to determine whether any of these candidates will have applicability to the treatment of humans.
The combined roles of defects in beta cell function and peripheral insulin sensitivity in type 2 diabetes are well established. However, provocative new studies suggest that the opportunities for therapeutic control of insulin sensitivity extend even further beyond this signalling network.
For instance, FGF1 is a multifunctional growth factor that activates all FGF receptor subtypes and is present on both beta cells and peripheral insulin-sensitive tissues. In preclinical studies, when FGF1 was delivered via intracerebroventricular injection rather than peripherally, it resolved diabetes following a single injection without the development of either hypoglycaemia or obesity [ 26 ].
It is particularly notable that the intracerebroventricular mode of delivery confers a therapeutic advantage, supporting a recent surge in research investigating how the central nervous system influences islet function and peripheral insulin sensitivity to orchestrate glucose homeostasis [ 27 ].
In accordance with the goals of precision medicine, diabetes treatment strategies could also benefit from a more refined assessment of the patient phenotype. We have seen this in the identification of neonatal diabetes and MODY genotypes [ 28 , 29 ].
Recently, a study using cluster analysis suggested that optimal treatment strategies and target tissues could differ based upon how individuals with type 2 diabetes cluster phenotypically.
This assessment used an analysis of six variables [ 30 ], as opposed to the one variable typically used to define prediabetes and type 2 diabetes—glycaemia.
Although this study covers populations predominantly from Northern Europe and needs to be reproduced elsewhere, it reveals possibilities that may impact on the choice of glucose-lowering therapies, allowing more nuanced treatment strategies tailored to the particular cluster-type.
We believe this observation now requires rigorous replication in other populations to allow us to determine whether we should rethink how we categorise diabetes that is not immune in nature.
In addition to the targets already the subject of preclinical studies, a growing list of new therapeutic candidates is emerging from genomic studies. Subsequent studies spanning more than 10 years culminated in relatively similar findings.
These observations supported a focus on improving beta cell function and insulin sensitisation as approaches to combat prediabetes and type 2 diabetes. However, one concern is that current approaches may be missing rare variants; rare coding mutations in the genes located near the most associated SNPs can establish causality beyond the GWAS method.
A broad example of the efficacy of this approach has been the successful identification of type 2 diabetic carriers of specific monogenic diabetes MODY mutations who responded better to sulfonylureas than to insulin [ 28 ].
However, the approach is limited by issues such as penetrance [ 33 ], or confounded by conflicting preclinical functional data reviewed in [ 34 ].
Missing type 2 diabetes heritability may also be linked to a role for epigenetic DNA modifications and non-coding RNAs as key players in the pathogenesis of type 2 diabetes.
Epigenetic DNA modifications, such as DNA methylation and histone acetylation, are strictly regulated to maintain optimal tissue-specific gene expression profiles. However, epigenetic modifications can be altered based on environmental cues, such as exercise, diet and the intrauterine environment, which can modify the risk for type 2 diabetes.
For example, altered DNA methylation patterns have been reported for functionally important genes in islets, skeletal muscle and adipose tissues in type 2 diabetic vs non-diabetic donors [ 35 , 36 , 37 ]. One locus KCNQ1 was found for which methylation predicts a causal pathway to type 2 diabetes, as opposed to being the result of disease [ 39 ].
Post-transcriptional gene silencing also responds to microRNAs miRNAs , which are 20—25 nucleotide non-coding RNAs. One miRNA can influence the expression of several targets, or conversely, several miRNAs can regulate expression of a single gene.
miRNAs regulate critical components of GSIS in the beta cell [ 40 , 41 ] and also skeletal muscle mitochondrial biogenesis and insulin signalling by targeting genes such as PI3K and GLUT4 also known as SLC2A4 [ 42 ].
Inhibition of miRNA and miRNA has been shown to significantly enhance insulin sensitivity [ 43 ]. Long non-coding RNAs lncRNAs , which are more than nucleotides long, are also emerging as important factors in type 2 diabetes.
BetaLinc1 beta cell long intergenic non-coding RNA 1 has been shown to be important for islet beta cell formation and function in mice [ 44 ].
Hence, exploiting miRNA and lncRNA targets is an active area of type 2 diabetes research, although it remains unknown whether there are miRNA and lncRNA targets that can multitask to address beta cell dysfunction and insulin resistance in a coordinated fashion.
Small extracellular vesicles, often called exosomes 50— nm in diameter , carry miRNAs, other nucleic acids and proteins. They are secreted by cells and could be involved in cell-to-cell communication and inter-organ crosstalk in beta cells and insulin-responsive tissues [ 45 ].
In humans physical exercise significantly enhances release of exosomes into the circulation [ 46 ]. While most mechanistic data captured to date are preclinical, provocative data from high fat diet-fed mice suggest that exosomes derived from skeletal muscle modulate the gene expression and proliferation rates of clonal beta cells, and that miR is a key signalling factor in the exosomes [ 45 ].
Moreover, adipose tissue macrophage-derived exosomes containing miRNAs from obese mice caused insulin resistance in lean mice; this effect was attributed to increased expression of miR in adipose tissue macrophages from the obese mice [ 47 ].
Conversely, exosomes from lean mice improved glucose tolerance in obese mice [ 47 ]. Harnessing the potential of cell—cell communication by exosomes could represent a new delivery tool for therapeutic agents.
This review highlights the importance of understanding type 2 diabetes pathogenesis from a multi-tissue angle and points out that strategies focused on improving insulin sensitivity could be crucial for beta cell health in the treatment of type 2 diabetes. Conventional medications are largely insufficient to attain long-term remission of type 2 diabetes, with some commonly causing unwanted effects such as weight gain and hypoglycaemia.
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J Extracell Vesicles
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