Reducing insulin via conditional partial gene ablation in adults reverses diet-induced weight gain.

Excess circulating insulin is associated with obesity in humans and in animal models. However, the physiologic causality of hyperinsulinemia in adult obesity has rightfully been questioned because of the absence of clear evidence that weight loss can be induced by acutely reversing diet-induced hyperinsulinemia. Herein, we describe the consequences of inducible, partial insulin gene deletion in a mouse model in which animals have already been made obese by consuming a high-fat diet. A modest reduction in insulin production/secretion was sufficient to cause significant weight loss within 5 wk, with a specific effect on visceral adipose tissue. This result was associated with a reduction in the protein abundance of the lipodystrophy gene polymerase I and transcript release factor ( Ptrf; Cavin) in gonadal adipose tissue. RNAseq analysis showed that reduced insulin and weight loss also associated with a signature of reduced innate immunity. This study demonstrates that changes in circulating insulin that are too fine to adversely affect glucose homeostasis nonetheless exert control over adiposity.-Page, M. M., Skovsø, S., Cen, H., Chiu, A. P., Dionne, D. A., Hutchinson, D. F., Lim, G. E., Szabat, M., Flibotte, S., Sinha, S., Nislow, C., Rodrigues, B., Johnson, J. D. Reducing insulin via conditional partial gene ablation in adults reverses diet-induced weight gain.

CD34 regulates the skeletal muscle response to hypoxia.

Chronic obstructive pulmonary disease (COPD) can sometimes be associated with skeletal muscle atrophy. Hypoxemic episodes, which occur during disease exacerbation and daily physical activity, are frequent in COPD patients. However, the link between hypoxemia and muscle atrophy remains unclear, along with mechanisms of muscle hypoxic stress response. Myogenic progenitors (MPs) and fibro/adipogenic progenitors (FAPs) express CD34 and participate to muscle mass maintenance. Although there is evidence linking CD34 expression and muscle repair, the link between CD34 expression, muscle wasting and the hypoxic stress observed in COPD has never been studied. Using a 2-day model of exposure to hypoxic conditions, we investigated the impact of hypoxia on skeletal muscle wasting and function, and elucidated the importance of CD34 expression in that response. A 2-day exposure to hypoxic conditions induces muscle atrophy, which was significantly worse in Cd34-/- mice compared to wild type (WT). Moreover, the lack of CD34 expression negatively impacts the maximal strength of the extensor digitorum longus muscle in response to hypoxia. Following exposure to hypoxic conditions, FAPs (which support MPs differentiation and myogenesis) are significantly lower in Cd34-/- mice compared to WT animals while the expression of myogenic regulatory factors and degradation factors (Atrogin) are similar. CD34 expression is important in the maintenance of muscle mass and function in response to hypoxic stress. These results highlight a new potential role for CD34 in muscle mass maintenance in hypoxic stress such as observed in COPD.

Proteostasis and ageing: insights from long-lived mutant mice.

The global increase in life expectancy is creating significant medical, social and economic challenges to current and future generations. Consequently, there is a need to identify the fundamental mechanisms underlying the ageing process. This knowledge should help develop realistic interventions capable of combatting age-related disease, and thus improving late-life health and vitality. While several mechanisms have been proposed as conserved lifespan determinants, the loss of proteostasis - where proteostasis is defined here as the maintenance of the proteome - appears highly relevant to both ageing and disease. Several studies have shown that multiple proteostatic mechanisms, including the endoplasmic reticulum (ER)-induced unfolded protein response (UPR), the ubiquitin-proteasome system (UPS) and autophagy, appear indispensable for longevity in many long-lived invertebrate mutants. Similarly, interspecific comparisons suggest that proteostasis may be an important lifespan determinant in vertebrates. Over the last 20 years a number of long-lived mouse mutants have been described, many of which carry single-gene mutations within the growth-hormone, insulin/IGF-1 or mTOR signalling pathways. However, we still do not know how these mutations act mechanistically to increase lifespan and healthspan, and accordingly whether mechanistic commonality occurs between different mutants. Recent evidence supports the premise that the successful maintenance of the proteome during ageing may be linked to the increased lifespan and healthspan of long-lived mouse mutants.

Filtration performance, fit test and side effects of respiratory personal protective equipment following decontamination: Observations for user safety and comfort.

OBJECTIVE: While facing personal protective equipment (PPE) shortages during the COVID-19 pandemic, several institutions looked to PPE decontamination and reuse options. This study documents the effect of two hydrogen peroxide treatments on filtration efficiency and fit tests as well as the side effects for volunteers after the decontamination of N95 filtering facepiece respirators (FFRs). We also propose an efficient and large-scale treatment protocol that allows for the traceability of this protective equipment in hospitals during PPE shortages. METHODS: The effects of low-temperature hydrogen peroxide sterilization and hydrogen peroxide vapor (HPV) on two FFR models (filtration, decontamination level, residual emanation) were evaluated. Ten volunteers reported comfort issues and side effects after wearing 1h FFRs worn and decontaminated up to five times. RESULTS: The decontamination process does not negatively affect FFR efficiency, but repeated use and handling tend to lead to damage, limiting the number of times FFRs can be reused. Moreover, the recommended 24-h post-treatment aeration does not sufficiently eliminate residual hydrogen peroxide. Prolonged aeration time increased user comfort when using decontaminated FFRs. CONCLUSIONS: HPV and low-temperature hydrogen peroxide sterilization seem to be appropriate treatments for FFR decontamination when the PPE is reused by the same user. PPE decontamination and reuse methods should be carefully considered as they are critical for the comfort and safety of healthcare workers.

Dietary methylmercury and fatty acids affect the lipid metabolism of adipose tissue and liver in rainbow trout.

Methylmercury (MeHg) is a pervasive environmental contaminant in aquatic ecosystems that can reach elevated concentrations in fish of high trophic levels, such as salmonids. The present study aims at investigating the individual and combined impacts of dietary MeHg and fatty acids on lipid metabolism in juvenile rainbow trout (Oncorhynchus mykiss) with a focus on two key organs, adipose tissue and liver. MeHg and fatty acids are both known to act on energy homeostasis although little is known about their interplay on lipid metabolism in fish. Fish were fed diets enriched in linoleic acid (LA, 18:2 n-6), α-linolenic acid (ALA, 18:3 n-3), eicosapentaenoic acid (EPA, 20:5 n-3) or docosahexaenoic acid (DHA, 22:6 n-3) for ten weeks, with the addition of MeHg to the diets during the last six weeks (0, 2.4 or 5.5 mg MeHg/kg dry matter). LA and ALA are polyunsaturated fatty acids (PUFA) typical of plant-derived oils whereas EPA and DHA are n-3 long chain PUFA largely found in fish oil, all used in feed formulation in aquaculture. The results showed that the LA-enriched diet induced a higher whole-body lipid content compared to the three other diets. On the contrary, the addition of MeHg led to a significant reduction of the whole-body lipid content, regardless of the diet. Interestingly, the adipocytes were larger both in presence of LA, compared to EPA and DHA, or MeHg, indicating a lipogenic effect of these two compounds. No effect was, however, observed on lipid accumulation per gram of adipose tissue. The fatty acid composition of adipose tissue and liver was significantly modified by the dietary lipids, reflecting both the fatty acid composition of the diets and the high bioconversion capacity of the rainbow trout. Exposure to MeHg selectively led to a release of n-6 PUFA from the hepatic membranes of fish fed the LA-enriched diet, showing a disruption of the pathways using n-6 PUFA. This study highlights the significant impact of MeHg exposure and dietary fatty acids on lipid metabolism in fish. Further investigation is needed to elucidate the underlying mechanisms and to explore the potential involvement of other organs.

Beyond the Lab: What We Can Learn about Cancer from Wild and Domestic Animals.

Cancer research has benefited immensely from the use of animal models. Several genetic tools accessible in rodent models have provided valuable insight into cellular and molecular mechanisms linked to cancer development or metastasis and various lines are available. However, at the same time, it is important to accompany these findings with those from alternative or non-model animals to offer new perspectives into the understanding of tumor development, prevention, and treatment. In this review, we first discuss animals characterized by little or no tumor development. Cancer incidence in small animals, such as the naked mole rat, blind mole rat and bats have been reported as almost negligible and tumor development may be inhibited by increased defense and repair mechanisms, altered cell cycle signaling and reduced rates of cell migration to avoid tumor microenvironments. On the other end of the size spectrum, large animals such as elephants and whales also appear to have low overall cancer rates, possibly due to gene replicates that are involved in apoptosis and therefore can inhibit uncontrolled cell cycle progression. While it is important to determine the mechanisms that lead to cancer protection in these animals, we can also take advantage of other animals that are highly susceptible to cancer, especially those which develop tumors similar to humans, such as carnivores or poultry. The use of such animals does not require the transplantation of malignant cancer cells or use of oncogenic substances as they spontaneously develop tumors of similar presentation and pathophysiology to those found in humans. For example, some tumor suppressor genes are highly conserved between humans and domestic species, and various tumors develop in similar ways or because of a common environment. These animals are therefore of great interest for broadening perspectives and techniques and for gathering information on the tumor mechanisms of certain types of cancer. Here we present a detailed review of alternative and/or non-model vertebrates, that can be used at different levels of cancer research to open new perspectives and fields of action.

Comparative evaluation of Panther Fusion and real-time PCR for detection of Burkholderia pseudomallei in spiked human blood.

Introduction. Melioidosis is an infection that most commonly presents with bacteraemia. Culture-based laboratory methods can result in a significant delay to organism identification. Molecular diagnostic techniques have a high sensitivity and rapid time to diagnosis. A decreased time to diagnosis is likely to improve patient outcomes. Aim. To compare the Panther Fusion automated molecular instrument to an in-house method for the detection of Burkholderia pseudomallei directly from spiked human whole-blood samples. Results. The in-house method detected 11/12 (92 %) samples with a B. pseudomallei concentration of 2.5-4.5×102 c.f.u. ml-1. The Panther was less reliable, detecting only 8/14 (75 %) samples with a similar bacterial concentration. The Panther was able to detect 12/12 (100 %) spiked blood culture-positive samples. Conclusion. The direct detection of B. pseudomallei from patient blood on presentation to a healthcare facility will significantly decrease time to diagnosis. We describe an in-house real-time PCR method with the lowest reported limit of detection to date. Due to lower sensitivity, the Panther Fusion would be best used as a diagnostic method directly from a positive blood culture.

The Catechins Profile of Green Tea Extracts Affects the Antioxidant Activity and Degradation of Catechins in DHA-Rich Oil.

This study investigated the effect of the catechins profile on the antioxidant activity of green tea extracts (GTEs) by comparing the antioxidant activity of an EGC-rich GTE (GTE1, catechin content: 58% EGC, 30.1% EGCG, 7.9% EC, and 3.9% ECG) and an EGCG-rich GTE (GTE2, catechin content: 60.6% EGCG, 17.7% EGC, 11.8% ECG, and 9.8% EC) in a DHA-rich oil. The effects of the individual catechins (EGC, EC, EGCG, and ECG) and reconstituted catechins mixtures (CatMix), prepared to contain the same amount of major catechins as in the GTEs, were also measured. All treatments (GTE1, CatMix1, GTE2, CatMix2, EGC250, EC250, EGCG250, and ECG250), each containing epistructured catechins at a concentration of 250 ppm, as well as the control (oil with no added antioxidant), were stored at 30 °C for 21 days with sampling intervals of 7 days. The antioxidant activity was assessed by measuring the peroxide value (PV) and p-anisidine value (p-AV) of oils. Changes in fatty acid content and catechins content were also monitored. Both GTEs enhanced the oxidative stability of the DHA-rich oil, but GTE1 demonstrated a stronger antioxidant activity than GTE2. No significant difference was observed between the PV of treatments with GTE1 and CatMix1 during storage, whereas the PV of oil with GTE2 was significantly higher than that with CatMix2 after 21 days. Among the individual catechins, EGC was the strongest antioxidant. Overall, the antioxidant activities of the extracts and catechins were observed in the decreasing order GTE1 ≈ EGC250 ≈ CatMix1 > GTE2 > EGCG250 ≈ CatMix2 > ECG250 > EC250. A significant change in fatty acid content was observed for the control and EC250 samples, and the catechins were most stable in GTE1-supplemented oil. Our results indicate that the EGC-rich GTE is a more potent antioxidant in DHA-rich oil than the EGCG-rich GTE.

Punicic Acid Triggers Ferroptotic Cell Death in Carcinoma Cells.

Plant-derived conjugated linolenic acids (CLnA) have been widely studied for their preventive and therapeutic properties against diverse diseases such as cancer. In particular, punicic acid (PunA), a conjugated linolenic acid isomer (C18:3 c9t11c13) present at up to 83% in pomegranate seed oil, has been shown to exert anti-cancer effects, although the mechanism behind its cytotoxicity remains unclear. Ferroptosis, a cell death triggered by an overwhelming accumulation of lipid peroxides, has recently arisen as a potential mechanism underlying CLnA cytotoxicity. In the present study, we show that PunA is highly cytotoxic to HCT-116 colorectal and FaDu hypopharyngeal carcinoma cells grown either in monolayers or as three-dimensional spheroids. Moreover, our data indicate that PunA triggers ferroptosis in carcinoma cells. It induces significant lipid peroxidation and its effects are prevented by the addition of ferroptosis inhibitors. A combination with docosahexaenoic acid (DHA), a known polyunsaturated fatty acid with anticancer properties, synergistically increases PunA cytotoxicity. Our findings highlight the potential of using PunA as a ferroptosis-sensitizing phytochemical for the prevention and treatment of cancer.

Green Tea Extract Enhances the Oxidative Stability of DHA-Rich Oil.

Docosahexaenoic acid (DHA) is one of the most important omega-3 polyunsaturated fatty acids, with proven health-promoting properties. However, oils with a very high content in DHA (DHAO) are extremely susceptible to oxidation, which affects shelf stability and limits incorporation in food products. Green tea extracts (GTE) are potential candidates for the protection of these oils, but their use in such oils has not been previously reported. This study investigated the effect of GTE (160 ppm, 400 ppm, 1000 ppm) and α-tocopherol (80 ppm, 200 ppm, 500 ppm) on the oxidative stability of a DHAO over a 9-week storage at 30 °C. The oxidative status was monitored during storage by the measurement of peroxide value (PV) and p-anisidine value (p-AV). Changes in eicosapentaenoic acid (EPA) and DHA content, as well as in catechins and tocopherol contents, were also evaluated. The addition of GTE enhanced the oxidative stability of DHAO by reducing the formation of peroxides and secondary oxidation products, whereas α-tocopherol had no significant effect on the PV of oil during storage but led to a significantly higher p-AV. The EPA and DHA content of DHAO was stable in GTE-supplemented samples whereas a decrease was observed in the control and α-tocopherol-supplemented samples. GTE also delayed the degradation of tocopherols initially present in the oil, while catechins resulting from the addition of GTE decreased progressively during the storage period.

Lack of Differences in Inflammation and T Cell-Mediated Function between Young and Older Women with Obesity.

Both obesity and aging are associated with dysregulated immune and inflammatory responses. There is limited knowledge, however, on differences in the immune system between young and older adults with obesity. The goal of this study was to compare circulating inflammatory cytokines and T cell-mediated immune response between young and older women with obesity. Twenty-three young (23-43 years) and 21 older (60-83 years) women with obesity were recruited at the Weight and Wellness Center at Tufts Medical Center. Circulating inflammatory cytokines (CRP, IL-6, and IL-1ß) and ex vivo indicators of T cell-mediated immune function were compared between the groups. Older women with obesity had significantly fewer circulating CD3+, CD8+, CD19+, and natural killer T (NKT) cells compared to young women with obesity (p = 0.016, p < 0.0001, p = 0.0003, and p < 0.0001, respectively). However, with few exceptions, there was no significant difference in inflammation markers or stimulated lymphocyte proliferation and cytokine production by peripheral blood mononuclear cells between young and older participants. These findings are in contrast to those previously reported in young and old subjects with healthy weight and call for further investigation into the impact of obesity on premature aging of the immune system.

In vitro measurement of DNA base excision repair in isolated mitochondria.

Mitochondrial DNA (mtDNA) is in relatively close proximity to reactive oxygen species (ROS) arising from spontaneous superoxide formation during respiration. As a result, it sustains oxidative damage that may include base modifications, base loss, and strand breaks. mtDNA replication past sites of oxidative damage can result in the introduction of mutations. mtDNA mutations are associated with various human diseases and can manifest as loss of bioenergetic function. DNA repair processes exist in mitochondria from apparently all metazoans. A fully functional DNA base excision repair (BER) pathway is present in mitochondria of vertebrates. This pathway is catalyzed by a number of DNA glycosylases, an AP endonuclease, polymerase gamma, and a DNA ligase. This chapter outlines the step-by-step protocols for isolating mitochondrial fractions, from a number of different model organisms, of sufficient purity to allow mtDNA repair activities to be measured. It details in vitro assays for the measurement of BER enzyme activities in lysates prepared from isolated mitochondria.

Intracellular antioxidant enzymes are not globally upregulated during hibernation in the major oxidative tissues of the 13-lined ground squirrel Spermophilus tridecemlineatus.

Hibernating mammals exhibit oxidative stress resistance in brain, liver and other tissues. In many animals, cellular oxidative stress resistance is associated with enhanced expression of intracellular antioxidant enzymes. Intracellular antioxidant capacity may be upregulated during hibernation to protect against oxidative damage associated with the ischemia-reperfusion that occurs during transitions between torpor and arousal. We tested the hypothesis that the 13-lined ground squirrel (Spermophilus tridecemlineatus), upregulates intracellular antioxidant enzymes in major oxidative tissues during hibernation. The two major intracellular isoforms of superoxide dismutase (MnSOD and CuZnSOD), which catalyze the first step in superoxide detoxification, were quantified in heart, brain and liver tissue using immunodetection and an in-gel activity assay. However, no differences in SOD protein expression or activity were found between active and hibernating squirrels. Measurements of glutathione peroxidase and glutathione reductase, which catalyze hydrogen peroxide removal, were not broadly upregulated during hibernation. The activity of catalase, which catalyzes an alternative hydrogen peroxide detoxification pathway, was higher in heart and brain of torpid squirrels, but lower in liver. Taken together, these data do not support the hypothesis that hibernation is associated with enhanced oxidative stress resistance due to an upregulation of intracellular antioxidant enzymes in the major oxidative tissues.

How using a logic model refined our program to ensure success.

When a program does not produce expected changes in the outcomes of interest, program staff must understand why before making programmatic decisions. One mechanism for doing so is the logic model. This article describes how using one such logic model (the ATM approach) was used to improve areas of program planning and implementation. The key components include interviewing stakeholders to identify antecedent conditions to the problem of interest that are placed in a summary map and then prioritizing those conditions to address with program activities. Although the logic modeling process was helpful in making programmatic improvements, there were also several unintended benefits of engaging in the process including: providing a framework for planning and evaluation, helping the program operate more effectively and efficiently, and providing a common language among program staff and the evaluators.

Molecular mechanisms of oxidative stress resistance induced by resveratrol: Specific and progressive induction of MnSOD.

trans-Resveratrol (3,4',5-trihydroxystilbene; RES), a polyphenol found in particularly high concentrations in red wine, has recently attracted intense interest for its potentially beneficial effects on human health. Here, we report the effects of long-term exposure to micromolar concentrations of RES on antioxidant and DNA repair enzyme activities in a human cell line (MRC-5). RES had either no effect on, or reduced the activities of glutathione peroxidase, catalase and CuZn superoxide dismutase (SOD), in treatments lasting up to 2 weeks. RES failed to induce activities of the DNA base excision repair enzymes apurinic/apyrimidinic endonuclease and DNA polymerase beta. However, it dramatically and progressively induced mitochondrial MnSOD expression and activity. Two weeks exposure to RES increased MnSOD protein level 6-fold and activity 14-fold. Thus, long-term exposure of human cells to RES results in a highly specific upregulation of MnSOD, and this may be an important mechanism by which it elicits its effects in human cells.

Mild Suppression of Hyperinsulinemia to Treat Obesity and Insulin Resistance.

Insulin plays roles in lipid uptake, lipolysis, and lipogenesis, in addition to controlling blood glucose levels. Excessive circulating insulin is associated with adipose tissue expansion and obesity, yet a causal role for hyperinsulinemia in the development of mammalian obesity has proven controversial, with many researchers suggesting it as a consequence of insulin resistance. Recently, evidence that specifically reducing hyperinsulinemia can prevent and reverse obesity in animal models has been presented. Our experiments, and others in this field, question the current dogma that hyperinsulinemia is a response to obesity and/or insulin resistance. In this review, we discuss preclinical evidence in the context of the broader literature and speculate on the possibility of clinical translation of alternative approaches for treating obesity.

Common and unique transcriptional responses to dietary restriction and loss of insulin receptor substrate 1 (IRS1) in mice.

Dietary restriction (DR) is the most widely studied non-genetic intervention capable of extending lifespan across multiple taxa. Modulation of genes, primarily within the insulin/insulin-like growth factor signalling (IIS) and the mechanistic target of rapamycin (mTOR) signalling pathways also act to extend lifespan in model organisms. For example, mice lacking insulin receptor substrate-1 (IRS1) are long-lived and protected against several age-associated pathologies. However, it remains unclear how these particular interventions act mechanistically to produce their beneficial effects. Here, we investigated transcriptional responses in wild-type and IRS1 null mice fed an ad libitum diet (WTAL and KOAL) or fed a 30% DR diet (WTDR or KODR). Using an RNAseq approach we noted a high correlation coefficient of differentially expressed genes existed within the same tissue across WTDR and KOAL mice and many metabolic features were shared between these mice. Overall, we report that significant overlap exists in the tissue-specific transcriptional response between long-lived DR mice and IRS1 null mice. However, there was evidence of disconnect between transcriptional signatures and certain phenotypic measures between KOAL and KODR, in that additive effects on body mass were observed but at the transcriptional level DR induced a unique set of genes in these already long-lived mice.

Core histone genes of Giardia intestinalis: genomic organization, promoter structure, and expression.

BACKGROUND: Giardia intestinalis is a protist found in freshwaters worldwide, and is the most common cause of parasitic diarrhea in humans. The phylogenetic position of this parasite is still much debated. Histones are small, highly conserved proteins that associate tightly with DNA to form chromatin within the nucleus. There are two classes of core histone genes in higher eukaryotes: DNA replication-independent histones and DNA replication-dependent ones. RESULTS: We identified two copies each of the core histone H2a, H2b and H3 genes, and three copies of the H4 gene, at separate locations on chromosomes 3, 4 and 5 within the genome of Giardia intestinalis, but no gene encoding a H1 linker histone could be recognized. The copies of each gene share extensive DNA sequence identities throughout their coding and 5' noncoding regions, which suggests these copies have arisen from relatively recent gene duplications or gene conversions. The transcription start sites are at triplet A sequences 1-27 nucleotides upstream of the translation start codon for each gene. We determined that a 50 bp region upstream from the start of the histone H4 coding region is the minimal promoter, and a highly conserved 15 bp sequence called the histone motif (him) is essential for its activity. The Giardia core histone genes are constitutively expressed at approximately equivalent levels and their mRNAs are polyadenylated. Competition gel-shift experiments suggest that a factor within the protein complex that binds him may also be a part of the protein complexes that bind other promoter elements described previously in Giardia. CONCLUSION: In contrast to other eukaryotes, the Giardia genome has only a single class of core histone genes that encode replication-independent histones. Our inability to locate a gene encoding the linker histone H1 leads us to speculate that the H1 protein may not be required for the compaction of Giardia's small and gene-rich genome.

A causal role for hyperinsulinemia in obesity.

Insulin modulates the biochemical pathways controlling lipid uptake, lipolysis and lipogenesis at multiple levels. Elevated insulin levels are associated with obesity, and conversely, dietary and pharmacological manipulations that reduce insulin have occasionally been reported to cause weight loss. However, the causal role of insulin hypersecretion in the development of mammalian obesity remained controversial in the absence of direct loss-of-function experiments. Here, we discuss theoretical considerations around the causal role of excess insulin for obesity, as well as recent studies employing mice that are genetically incapable of the rapid and sustained hyperinsulinemia that normally accompanies a high-fat diet. We also discuss new evidence demonstrating that modest reductions in circulating insulin prevent weight gain, with sustained effects that can persist after insulin levels normalize. Importantly, evidence from long-term studies reveals that a modest reduction in circulating insulin is not associated with impaired glucose homeostasis, meaning that body weight and lipid homeostasis are actually more sensitive to small changes in circulating insulin than glucose homeostasis in these models. Collectively, the evidence from new studies on genetic loss-of-function models forces a re-evaluation of current paradigms related to obesity, insulin resistance and diabetes. The potential for translation of these findings to humans is briefly discussed.

Reduced Insulin Production Relieves Endoplasmic Reticulum Stress and Induces ß Cell Proliferation.

Pancreatic ß cells are mostly post-mitotic, but it is unclear what locks them in this state. Perturbations including uncontrolled hyperglycemia can drive ß cells into more pliable states with reduced cellular insulin levels, increased ß cell proliferation, and hormone mis-expression, but it is unknown whether reduced insulin production itself plays a role. Here, we define the effects of ∼50% reduced insulin production in Ins1(-/-):Ins2(f/f):Pdx1Cre(ERT):mTmG mice prior to robust hyperglycemia. Transcriptome, proteome, and network analysis revealed alleviation of chronic endoplasmic reticulum (ER) stress, indicated by reduced Ddit3, Trib3, and Atf4 expression; reduced Xbp1 splicing; and reduced phospho-eIF2α. This state was associated with hyper-phosphorylation of Akt, which is negatively regulated by Trib3, and with cyclinD1 upregulation. Remarkably, ß cell proliferation was increased 2-fold after reduced insulin production independently of hyperglycemia. Eventually, recombined cells mis-expressed glucagon in the hyperglycemic state. We conclude that the normally high rate of insulin production suppresses ß cell proliferation in a cell-autonomous manner.