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The prevalence of diabetes and its worldwide co-morbidities is escalating. Therefore, the number of users of therapeutic peptides including insulin analogs and glucagon-like peptide 1 receptor agonists (GLP-1RAs), will unavoidably increase in the coming years. However, access to these two antidiabetic classes remains limited in some countries due to their high cost. Even when available, their long-term therapeutic efficiency is often compromised by challenges in sustained treatment adherence, mainly resulting from their mode of administration through repeated subcutaneous injections. This repeated invasive delivery not only affects patient comfort but also complicates long-term disease management and monitoring. Therefore, there is an urgent need to improve the accessibility, affordability, and long-term patient adherence to insulin and GLP-1RAs. In this review, we highlight as promising alternatives the potential of plants and microalgae to serve as host organisms, as well as the use of their polysaccharides as drug carriers, for the production of low-cost and non-invasive antidiabetic drugs.

Diabetes poses major economic, social, and public health challenges in all countries worldwide. Besides cardiovascular disease and microangiopathy, diabetes is a leading cause of foot ulcers and lower limb amputations. With the continued rise of diabetes prevalence, it is expected that the future burden of diabetes complications, early mortality, and disabilities will increase. The diabetes epidemic is partly caused by the current lack of clinical imaging diagnostic tools, the timely monitoring of insulin secretion and insulin-expressing cell mass (beta (β)-cells), and the lack of patients’ adherence to treatment, because some drugs are not tolerated or invasively administrated. In addition to this, there is a lack of efficient topical treatment capable of stopping the progression of disabilities, in particular for treating foot ulcers. In this context, polymer-based nanostructures garnered significant interest due to their tunable physicochemical characteristics, rich diversity, and biocompatibility. This review article emphasizes the last advances and discusses the prospects in the use of polymeric materials as nanocarriers for β-cell imaging and non-invasive drug delivery of insulin and antidiabetic drugs in the management of blood glucose and foot ulcers.

Elevated plasma concentration of the pro-atherogenic oxidized low density lipoprotein cholesterol (LDL) triggers adverse effects in pancreatic beta-cells and is associated with type 2 diabetes. Here, we investigated whether the endoplasmic reticulum (ER) stress is a key player coupling oxidative stress to beta-cell dysfunction and death elicited by human oxidized LDL. We found that human oxidized LDL activates ER stress as evidenced by the activation of the inositol requiring 1α, and the elevated expression of both DDIT3 (also called CHOP) and DNAJC3 (also called P58IPK) ER stress markers in isolated human islets and the mouse insulin secreting MIN6 cells. Silencing of Chop and inhibition of ER stress markers by the chemical chaperone phenyl butyric acid (PBA) prevented cell death caused by oxidized LDL. Finally, we found that oxidative stress accounts for activation of ER stress markers induced by oxidized LDL. Induction of Chop/CHOP and p58IPK/P58IPK by oxidized LDL was mimicked by hydrogen peroxide and was blocked by co-treatment with the N-acetylcystein antioxidant. As a conclusion, the harmful effects of oxidized LDL in beta-cells requires ER stress activation in a manner that involves oxidative stress. This mechanism may account for impaired beta-cell function in diabetes and can be reversed by antioxidant treatment.

Unveiling the key pathways underlying postnatal beta-cell proliferation can be instrumental to decipher the mechanisms of beta-cell mass plasticity to increased physiological demand of insulin during weight gain and pregnancy. Using transcriptome and global Serine Threonine Kinase activity (STK) analyses of islets from newborn (10 days old) and adult rats, we found that highly proliferative neonatal rat islet cells display a substantially elevated activity of the mitogen activated protein 3 kinase 12, also called dual leucine zipper-bearing kinase (Dlk). As a key upstream component of the c-Jun amino terminal kinase (Jnk) pathway, Dlk overexpression was associated with increased Jnk3 activity and was mainly localized in the beta-cell cytoplasm. We provide the evidence that Dlk associates with and activates Jnk3, and that this cascade stimulates the expression of Ccnd1 and Ccnd2, two essential cyclins controlling postnatal beta-cell replication. Silencing of Dlk or of Jnk3 in neonatal islet cells dramatically hampered primary beta-cell replication and the expression of the two cyclins. Moreover, the expression of Dlk,Jnk3,Ccnd1 and Ccnd2 was induced in high replicative islet beta cells from ob/ob mice during weight gain, and from pregnant female rats. In human islets from non-diabetic obese individuals, DLK expression was also cytoplasmic and the rise of the mRNA level was associated with an increase of JNK3,CCND1andCCND2 mRNA levels, when compared to islets from lean and obese patients with diabetes. In conclusion, we find that activation of Jnk3 signalling by Dlk could be a key mechanism for adapting islet beta-cell mass during postnatal development and weight gain.

Improvement of insulin secretion by pancreatic β-cells and preservation of their mass are the current challenges that future antidiabetic drugs should meet for achieving efficient and long-term glycemic control in patients with type 2 diabetes (T2D). The successful development of glucagon-like peptide 1 (GLP-1) analogues, derived from the saliva of a lizard from the Helodermatidae family, has provided the proof of concept that antidiabetic drugs directly targeting pancreatic β-cells can emerge from venomous animals. The literature reporting on the antidiabetic effects of medicinal plants suggests that they contain some promising active substances such as polyphenols and alkaloids, which could be active as insulin secretagogues and β-cell protectors. In this review, we discuss the potential of several polyphenols, alkaloids and venom peptides from snake, frogs, scorpions and cone snails. These molecules could contribute to the development of new efficient antidiabetic medicines targeting β-cells, which would tackle the progression of the disease.

Pancreatic beta-cell function and mass are markedly adaptive to compensate for the changes in insulin requirement observed during several situations such as pregnancy, obesity, glucocorticoids excess, or administration. This requires a beta-cell compensation which is achieved through a gain of beta-cell mass and function. Elucidating the physiological mechanisms that promote functional beta-cell mass expansion and that protect cells against death, is a key therapeutic target for diabetes. In this respect, several recent studies have emphasized the instrumental role of microRNAs in the control of beta-cell function. MicroRNAs are negative regulators of gene expression, and are pivotal for the control of beta-cell proliferation, function, and survival. On the one hand, changes in specific microRNA levels have been associated with beta-cell compensation and are triggered by hormones or bioactive peptides that promote beta-cell survival and function. Conversely, modifications in the expression of other specific microRNAs contribute to beta-cell dysfunction and death elicited by diabetogenic factors including, cytokines, chronic hyperlipidemia, hyperglycemia, and oxidized LDL. This review underlines the importance of targeting the microRNA network for future innovative therapies aiming at preventing the beta-cell decline in diabetes.

Elevation of the dietary saturated fatty acid palmitate contributes to the reduction of functional beta cell mass in the pathogenesis of type 2 diabetes. The diabetogenic effect of palmitate is achieved by increasing beta cell death through induction of the endoplasmic reticulum (ER) stress markers including activating transcription factor 3 (Atf3) and CAAT/enhancer-binding protein homologous protein-10 (Chop). In this study, we investigated whether treatment of beta cells with the MS-275, a HDAC1 and HDAC3 activity inhibitor which prevents beta cell death elicited by cytokines, is beneficial for combating beta cell dysfunction caused by palmitate. We show that culture of isolated human islets and MIN6 cells with MS-275 reduced apoptosis evoked by palmitate. The protective effect of MS-275 was associated with the attenuation of the expression of Atf3 and Chop. Silencing of HDAC3, but not of HDAC1, mimicked the effects of MS-275 on the expression of the two ER stress markers and apoptosis. These data point to HDAC3 as a potential drug target for preserving beta cells against lipotoxicity in diabetes.

Chronic intake of saturated free fatty acids is associated with diabetes and may contribute to the impairment of functional beta cell mass. Mitogen activated protein kinase 8 interacting protein 1 also called islet brain 1 (IB1) is a candidate gene for diabetes that is required for beta cell survival and glucose-induced insulin secretion (GSIS). In this study we investigated whether IB1 expression is required for preserving beta cell survival and function in response to palmitate. Chronic exposure of MIN6 and isolated rat islets cells to palmitate led to reduction of the IB1 mRNA and protein content. Diminution of IB1 mRNA and protein level relied on the inducible cAMP early repressor activity and proteasome-mediated degradation, respectively. Suppression of IB1 level mimicked the harmful effects of palmitate on the beta cell survival and GSIS. Conversely, ectopic expression of IB1 counteracted the deleterious effects of palmitate on the beta cell survival and insulin secretion. These findings highlight the importance in preserving the IB1 content for protecting beta cell against lipotoxicity in diabetes.

Type 2 diabetes (T2D) is closely linked with non-alcoholic fatty liver disease (NAFLD) and hepatic insulin resistance, but the involved mechanisms are still elusive. Using DNA methylome and transcriptome analyses of livers from obese individuals, we found that both hypomethylation at a CpG site in PDGFA (encoding platelet derived growth factor alpha) and PDGFA overexpression are associated with increased T2D risk, hyperinsulinemia, increased insulin resistance and increased steatohepatitis risk. Both genetic risk score studies and human cell modeling pointed to a causative impact of high insulin levels on PDGFA CpG site hypomethylation, PDGFA overexpression, and increased PDGF-AA secretion from liver. We found that PDGF-AA secretion further stimulates its own expression through protein kinase C activity and contributes to insulin resistance through decreased expression of both insulin receptor substrate 1 and of insulin receptor. Importantly, hepatocyte insulin sensitivity can be restored by PDGF-AA blocking antibodies, PDGF receptor inhibitors and by metformin opening therapeutic avenues. Conclusion: Therefore, in the liver of obese patients with T2D, the increased PDGF-AA signaling contributes to insulin resistance, opening new therapeutic avenues against T2D and NAFLD.

The gas-phase concentration at the material surface ( y 0 ) is pointed out in the literature as a key parameter to describe semivolatile organic compound (SVOC) emissions from materials. This is an important input data in predictive models of SVOC behavior indoors and risk exposure assessment. However, most of the existing measurement methods consist of determining emission rates and not y 0 and none allow on-site sampling. Hence, a new passive sampler was developed. It consists of a glass cell that is simply placed on the material surface until reaching equilibrium between material and air; y 0 is then determined by solid-phase microextraction (SPME) sampling and GC-MS analysis. The limits of detection are at the μg/m 3 level and relative standard deviations (RSD) below 10%. A variation of 11% between two sets of experiments involving different cell volumes confirmed the y 0 measurement. In addition, due to the ability of SVOCs to be sorbed on surfaces, the cell wall/air partition was assessed by determining the inner cell surface concentration of SVOCs, which is the concentration of SVOCs adsorbed on the glass, and the cell surface/air partition coefficient ( K glass ). The recovery yields of the SVOCs sorbed on the cell walls are strongly compound-dependent and comprise between 2 and 93%. The K glass coefficients are found to be lower than the stainless steel/air partition coefficient ( K ss ), showing that glass is suitable for the SVOC sampling. This innovative tool opens up promising perspectives in terms of identification of SVOC sources and quantification of their emissions indoors, and would significantly contribute to human exposure assessment. Graphical Abstract Passive sampling for the determination of SVOCs concentration at the material/air interface