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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.

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.

Preservation of beta cell against apoptosis is one of the therapeutic benefits of the glucagon-like peptide-1 (GLP1) antidiabetic mimetics for preserving the functional beta cell mass exposed to diabetogenic condition including proinflammatory cytokines. The mitogen activated protein kinase 10 also called c-jun amino-terminal kinase 3 (JNK3) plays a protective role in insulin-secreting cells against death caused by cytokines. In this study, we investigated whether the JNK3 expression is associated with the protective effect elicited by the GLP1 mimetic exendin 4. We found an increase in the abundance of JNK3 in isolated human islets and INS-1E cells cultured with exendin 4. Induction of JNK3 by exendin 4 was associated with an increased survival of INS-1E cells. Silencing of JNK3 prevented the cytoprotective effect of exendin 4 against apoptosis elicited by culture condition and cytokines. These results emphasize the requirement of JNK3 in the antiapoptotic effects of exendin 4.

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.

Locally in Far Hills, you may recognize the brand-new Punch Kettlebell Gym co-owners and certified personal trainers, Valerie Pawlowski and Shari Sperandio, best known for establishing the New Jersey Adventure Fitness Boot Camp with a reputation for inspiring people to have fun while participating in a fantastic workout.

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 additional author support information was erroneously omitted from the Supplementary Information. This has been corrected online.The additional author support information was erroneously omitted from the Supplementary Information. This has been corrected online.

The root nodule symbiosis of plants with nitrogen-fixing bacteria impacts global nitrogen cycles and food production but is restricted to a subset of genera within a single clade of flowering plants. To explore the genetic basis for this scattered occurrence, we sequenced the genomes of ten plant species covering the diversity of nodule morphotypes, bacterial symbionts and infection strategies. In a genome-wide comparative analysis of a total of 37 plant species, we discovered signatures of multiple independent loss-of-function events in the indispensable symbiotic regulator NODULE INCEPTION (NIN) in ten out of 13 genomes of non-nodulating species within this clade. The discovery that multiple independent losses shaped the present day distribution of nitrogen-fixing root nodule symbiosis in plants reveals a phylogenetically wider distribution in evolutionary history and a so far underestimated selection pressure against this symbiosis.