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The addition of glucagon delivery to a closed-loop system with automated exercise detection reduces hypoglycemia in physically active adults with type 1 diabetes.

We previously presented evidence that proliferative human islet precursor cells may be derived in vitro from adult islets by epithelial-to-mesenchymal transition (EMT) and show here that similar fibroblast-like cells can be derived from mouse islets. These mouse cell populations exhibited changes in gene expression consistent with EMT. Both C-peptide and insulin mRNAs were undetectable in expanded cultures of mouse islet-derived precursor cells (mIPCs). After expansion, mIPCs could be induced to migrate into clusters and differentiate into hormone-expressing islet-like aggregates. Although early morphological changes suggesting EMT were observed by time-lapse microscopy when green fluorescent protein-labeled beta cells were placed in culture, the expanded precursor cell population was not fluorescent. Using two mouse models in which beta cells were permanently made either to express alkaline phosphatase or to have a deleted M 3 muscarinic receptor, we provide evidence that mIPCs in long term culture are not derived from beta cells.Investigators worldwide are conducting pre-clinical research aimed at employing in vitro systems to generate large numbers of islets of Langerhans (or beta cells) (1,2). Although beta cells proliferate in vivo (3) and in vitro (4), well-differentiated beta cells do not proliferate rapidly in vitro. Therefore, islet (or beta cell) precursor cells are being studied for this purpose based on the concept that undifferentiated precursor cells can be expanded exponentially and then induced to differentiate into islet-like cells. We (5-7) and others (8-12) have derived islet precursor cells from adult human islet preparations. However, insights into the processes involved in derivation, expansion and differentiation of these human precursor cells are limited. Assuming conservation across species, similar precursor cells derived from nonhuman islets could be used to study these processes further. For example, transgenic or knockout mice could be used to delineate signal transduction pathways involved in proliferation and differentiation of precursor cells and thereby identify targets for regulation by drugs.We provided evidence previously that precursor cells from human islets may be derived by in vitro epithelial-to-mesenchymal transition (EMT) of insulin-expressing cells (5). The origin of these cells was uncertain because individual human insulin-expressing cells could not be identified and followed in culture. In this report, transgenic mice are used for this purpose. We demonstrate that cells similar to human islet-derived precursor cells (IPCs) (5) can be derived from preparations of mouse islets. Like human IPCs (hIPCs), these cells can proliferate for over 20 doublings and after expansion can be differentiated into clusters of hormone-expressing Corresponding Author: Marvin C. Gershengorn, Scientific Director, NIDDK, National Institutes of Health, 50 South Drive, Bethesda, MD 20892-8029, USA, Tel: 301-451-6305, Fax: 301-480-4214, E-mail: marving@intra.niddk.nih.gov Publisher's...

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Background: Fear of exercise related hypoglycemia is a major reason why people with type 1 diabetes (T1D) do not exercise. There is no validated prediction algorithm that can predict hypoglycemia at the start of aerobic exercise. Methods: We have developed and evaluated two separate algorithms to predict hypoglycemia at the start of exercise. Model 1 is a decision tree and model 2 is a random forest model. Both models were trained using a meta-data set based on 154 observations of in-clinic aerobic exercise in 43 adults with T1D from 3 different studies that included participants using sensor augmented pump therapy, automated insulin delivery therapy, and automated insulin and glucagon therapy. Both models were validated using an entirely new validation data set with 90 exercise observations collected from 12 new adults with T1D. Results: Model 1 identified two critical features predictive of hypoglycemia during exercise: heart rate and glucose at the start of exercise. If heart rate was greater than 121 bpm during the first 5 min of exercise and glucose at the start of exercise was less than 182 mg/dL, it predicted hypoglycemia with 79.55% accuracy. Model 2 achieved a higher accuracy of 86.7% using additional features and higher complexity. Conclusions: Models presented here can assist people with T1D to avoid exercise related hypoglycemia. The simple model 1 heuristic can be easily remembered (the 180/120 rule) and model 2 is more complex requiring computational resources, making it suitable for automated artificial pancreas or decision support systems.

The callipyge mutation causes postnatal muscle hypertrophy in heterozygous lambs that inherit a paternal callipyge allele (+/CLPG). Our hypothesis was that the up-regulation of one or both of the affected paternally expressed genes (DLK1 or PEG11) initiates changes in biochemical and physiological pathways in skeletal muscle to induce hypertrophy. The goal of this study was to identify changes in gene expression during the onset of muscle hypertrophy to identify the pathways that are involved in the expression of the callipyge phenotype. Gene expression was analysed in longissimus dorsi total RNA from lambs at 10, 20, and 30 days of age using the Affymetrix Bovine Expression Array. An average of 40.6% of probe sets on the array was detected in sheep muscle. Data were normalized and analysed using a two-way anova for genotype and age effects with a false discovery rate of 0.10. From the anova, 13 genes were significant for the effect of genotype and 13 were significant for effect of age (P < 0.10). No significant age-by-genotype interactions were detected (P > 0.10). Of the 13 genes indicating an effect of genotype, quantitative PCR assays were developed for all of them and tested on a larger group of animals from 10 to 200 days of age. Nine genes had significantly elevated transcript levels in callipyge lambs. These genes included phosphofructokinase, a putative methyltransferase protein, a cAMP phosphodiesterase, and the transcription factor DNTTIP1.

Glycemic control is the mainstay of preventing diabetes complications at the expense of increased risk of hypoglycemia. Severe hypoglycemia negatively impacts the quality of life of patients with type 1 diabetes and can lead to morbidity and mortality. Currently available glucagon emergency kits are effective at treating hypoglycemia when correctly used, however use is complicated especially by untrained persons. Better formulations and devices for glucagon treatment of hypoglycemia are needed, specifically stable liquid glucagon. Out of the scope of this review, other potential uses of stable liquid glucagon include congenital hyperinsulinism, post-bariatric surgery hypoglycemia, and insulinoma induced hypoglycemia. In the 35 years since Food and Drug Administration (FDA) approval of the first liquid stable human recombinant insulin, we continue to wait for the glucagon counterpart. For mild hypoglycemia, a commercially available liquid stable glucagon would enable more widespread implementation of mini-dose glucagon use as well as glucagon in dual hormone closed-loop systems. This review focuses on the current and upcoming pharmaceutical uses of glucagon in the treatment of type 1 diabetes with an outlook on stable liquid glucagon preparations that will hopefully be available for use in patients in the near future.

OBJECTIVE To assess the efficacy and feasibility of a dual-hormone (DH) closed-loop system with insulin and a novel liquid stable glucagon formulation compared with an insulin-only closed-loop system and a predictive low glucose suspend (PLGS) system. RESEARCH DESIGN AND METHODS In a 76-h, randomized, crossover, outpatient study, 23 participants with type 1 diabetes used three modes of the Oregon Artificial Pancreas system: 1) dual-hormone (DH) closed-loop control, 2) insulin-only single-hormone (SH) closed-loop control, and 3) PLGS system. The primary end point was percentage time in hypoglycemia (&lt;70 mg/dL) from the start of in-clinic aerobic exercise (45 min at 60% VO2max) to 4 h after. RESULTS DH reduced hypoglycemia compared with SH during and after exercise (DH 0.0% [interquartile range 0.0–4.2], SH 8.3% [0.0–12.5], P = 0.025). There was an increased time in hyperglycemia (&gt;180 mg/dL) during and after exercise for DH versus SH (20.8% DH vs. 6.3% SH, P = 0.038). Mean glucose during the entire study duration was DH, 159.2; SH, 151.6; and PLGS, 163.6 mg/dL. Across the entire study duration, DH resulted in 7.5% more time in target range (70–180 mg/dL) compared with the PLGS system (71.0% vs. 63.4%, P = 0.044). For the entire study duration, DH had 28.2% time in hyperglycemia vs. 25.1% for SH (P = 0.044) and 34.7% for PLGS (P = 0.140). Four participants experienced nausea related to glucagon, leading three to withdraw from the study. CONCLUSIONS The glucagon formulation demonstrated feasibility in a closed-loop system. The DH system reduced hypoglycemia during and after exercise, with some increase in hyperglycemia.