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Pancreatic [beta] cells are specialized for coupling glucose metabolism to insulin peptide production and secretion. Acute glucose exposure robustly and coordinately increases translation of proinsulin and proteins required for secretion of mature insulin peptide. By contrast, chronically elevated glucose levels that occur during diabetes impair [beta] cell insulin secretion and have been shown experimentally to suppress insulin translation. Whether translation of other genes critical for insulin secretion is similarly downregulated by chronic high glucose is unknown. Here, we used high-throughput ribosome profiling and nascent proteomics in MIN6 insulinoma cells to elucidate the genome- wide impact of sustained high glucose on [beta] cell mRNA translation. Before induction of ER stress or suppression of global translation, sustained high glucose suppressed glucose-stimulated insulin secretion and downregulated translation of not only insulin, but also mRNAs related to insulin secretory granule formation, exocytosis, and metabolism-coupled insulin secretion. Translation of these mRNAs was also downregulated in primary rat and human islets following ex vivo incubation with sustained high glucose and in an in vivo model of chronic mild hyperglycemia. Furthermore, translational downregulation decreased cellular abundance of these proteins. Our study uncovered a translational regulatory circuit during [beta] cell glucose toxicity that impairs expression of proteins with critical roles in [beta] cell function., Introduction Diabetes results from failure of pancreatic [beta] cells to secrete sufficient insulin to regulate glucose homeostasis. Progressive decline in [beta] cell function occurs in the setting of hyperglycemia during [...]

BACKGROUND. In the Joslin Medalist Study (Medalists), we determined whether significant associations exist between [beta] cell function and pathology and clinical characteristics. METHODS. Individuals with type 1 diabetes (T1D) for 50 or more years underwent evaluation including HLA analysis, basal and longitudinal autoantibody (AAb) status, and [beta] cell function by a mixed-meal tolerance test (MMTT) and a hyperglycemia/ arginine clamp procedure. Postmortem analysis of pancreases from 68 Medalists was performed. Monogenic diabetes genes were screened for the entire cohort. RESULTS. Of the 1019 Medalists, 32.4% retained detectable C-peptide levels (>0.05 ng/mL, median: 0.21 ng/mL). In those who underwent a MMTT (n = 516), 5.8% responded with a doubling of baseline C-peptide levels. Longitudinally (n = 181, median: 4 years), C-peptide levels increased in 12.2% (n = 22) and decreased in 37% (n = 67) of the Medalists. Among those with repeated MMTTs, 5.4% (3 of 56) and 16.1% (9 of 56) had waxing and waning responses, respectively. Thirty Medalists with baseline C-peptide levels of 0.1 ng/mL or higher underwent the clamp procedure, with [HLA.sup.-]/[AAb.sup.-] and [HLA.sup.+]/[AAb.sup.-] Medalists being most responsive. Postmortem examination of pancreases from 68 Medalists showed that all had scattered insulin-positive cells; 59 additionally had few insulin-positive cells within a few islets; and 14 additionally had lobes with multiple islets with numerous insulin-positive cells. Genetic analysis revealed that 280 Medalists (27.5%) had monogenic diabetes variants; in 80 (7.9%) of these Medalists, the variants were classified as 'likely pathogenic' (rare exome variant ensemble learner [REVEL] >0.75). CONCLUSION. All Medalists retained insulin-positive [beta] cells, with many responding to metabolic stimuli even after 50 years of T1D. The Medalists were heterogeneous with respect to [beta] cell function, and many with [HLA.sup.+] diabetes risk alleles also had monogenic diabetes variants, indicating the importance of genetic testing for clinically diagnosed T1D. FUNDING. Funding for this work was provided by the Dianne Nunnally Hoppes Fund; the Beatson Pledge Fund; the NIH, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); and the American Diabetes Association (ADA)., Introduction Pancreatic [beta] cell depletion attributed to autoimmunity is the hallmark of type 1 diabetes (T1D). However, recent studies have shown that residual [beta] cells may exist despite very long-duration [...]

Diabetes constitutes a world-wide pandemic that requires searching for new treatments to halt its progression. Cellular senescence of pancreatic beta cells has been described as a major contributor to development and worsening of diabetes. The concept of reversibility of cellular senescence is critical as is the timing to take actions against this "dormant" senescent state. The reversal of cellular senescence can be considered as rejuvenation of the specific cell if it returns to the original "healthy state" and doesn't behave aberrantly as seen in some cancer cells. In rodents, treatment with senolytics and senomorphics blunted or prevented disease progression, however their use carry drawbacks. Modulators of cellular senescence is a new area of research that seeks to reverse the senescence. More research in each of these modalities should lead to new treatments to stop diabetes development and progression. [ABSTRACT FROM AUTHOR]

During progression to both types 1 and 2 diabetes (T1D, T2D), there is a striking loss of glucose-induced first-phase insulin release (FPIR), which is known to predict the onset of T1D. The contribution of reduced [beta] cell mass to the onset of hyperglycemia remains unclear. In this issue of the JCI, Mezza et al. report on their study of patients with pancreatic neoplasms before and after partial pancreatectomy to evaluate the impact of reduced [beta] cell mass on the development of diabetes. The authors found that reduced FPIR predicted diabetes when 50% of the pancreas was removed. These findings suggest that low or absent FPIR indicates that [beta] cell mass can no longer compensate for increased insulin needs. Notably, clinicians may use reduction of FPIR as a warning that progression to T2D is underway., The earliest stages of diabetes progression The loss of glucose-induced first-phase insulin release (FPIR) is a striking finding seen in the earliest stages of progression to diabetes (1-3). This FPIR [...]