- Interleukin-6 Reduces β-Cell Oxidative Stress by Linking Autophagy With the Antioxidant Response. [Journal Article]
- DDiabetes 2018 May 21
- Production of reactive oxygen species (ROS) is a key instigator of β-cell dysfunction in diabetes. The pleiotropic cytokine IL-6 has previously been linked to β-cell autophagy but has not been studie...
Production of reactive oxygen species (ROS) is a key instigator of β-cell dysfunction in diabetes. The pleiotropic cytokine IL-6 has previously been linked to β-cell autophagy but has not been studied in the context of β-cell antioxidant response. We used a combination of animal models of diabetes and analysis of cultured human islets and rodent β-cells to study how IL-6 influences antioxidant response. We show that IL-6 couples autophagy to antioxidant response to reduce β-cell and human islet ROS. β cell-specific loss of IL-6 signaling in vivo renders mice more susceptible to oxidative damage and cell death by the selective β-cell toxins streptozotocin and alloxan. IL-6-driven ROS reduction is associated with an increase in the master antioxidant factor NRF2, which rapidly translocates to the mitochondria to decrease mitochondrial activity and stimulate mitophagy. IL-6 also initiates a robust transient drop in cellular cAMP, likely contributing to the stimulation of mitophagy for ROS mitigation. Our findings suggest that coupling autophagy to antioxidant response in the β cell leads to stress adaptation that can reduce cellular apoptosis. These findings have implications for β-cell survival under diabetogenic conditions and present novel targets for therapeutic intervention.
- Mechanisms Responsible for Metabolic Improvements of Bariatric Surgeries. [Journal Article]
- DDiabetes 2018; 67(6):1043-1044
- Immune Recognition of β-Cells: Neoepitopes as Key Players in the Loss of Tolerance. [Journal Article]
- DDiabetes 2018; 67(6):1035-1042
- Prior to the onset of type 1 diabetes, there is progressive loss of immune self-tolerance, evidenced by the accumulation of islet autoantibodies and emergence of autoreactive T cells. Continued autoi...
Prior to the onset of type 1 diabetes, there is progressive loss of immune self-tolerance, evidenced by the accumulation of islet autoantibodies and emergence of autoreactive T cells. Continued autoimmune activity leads to the destruction of pancreatic β-cells and loss of insulin secretion. Studies of samples from patients with type 1 diabetes and of murine disease models have generated important insights about genetic and environmental factors that contribute to susceptibility and immune pathways that are important for pathogenesis. However, important unanswered questions remain regarding the events that surround the initial loss of tolerance and subsequent failure of regulatory mechanisms to arrest autoimmunity and preserve functional β-cells. In this Perspective, we discuss various processes that lead to the generation of neoepitopes in pancreatic β-cells, their recognition by autoreactive T cells and antibodies, and potential roles for such responses in the pathology of disease. Emerging evidence supports the relevance of neoepitopes generated through processes that are mechanistically linked with β-cell stress. Together, these observations support a paradigm in which neoepitope generation leads to the activation of pathogenic immune cells that initiate a feed-forward loop that can amplify the antigenic repertoire toward pancreatic β-cell proteins.
- In This Issue of Diabetes. [Editorial]
- DDiabetes 2018; 67(6):1033-1034
- Liraglutide Modulates Appetite and Body Weight Via GLP-1R-Expressing Glutamatergic Neurons. [Journal Article]
- DDiabetes 2018 May 18
- Glucagon-like peptide-1 receptor (GLP-1R) agonists are FDA-approved weight loss drugs. Despite their widespread use, the sites of action through which GLP-1R agonists (GLP1RAs) impact appetite and bo...
Glucagon-like peptide-1 receptor (GLP-1R) agonists are FDA-approved weight loss drugs. Despite their widespread use, the sites of action through which GLP-1R agonists (GLP1RAs) impact appetite and body weight are still not fully understood. Here, we determined whether GLP-1Rs in either GABAergic or glutamatergic neurons are necessary for the acute and chronic effects of the GLP1RA liraglutide on food intake, visceral illness, body weight and neural network activation. We found that mice lacking GLP-1Rs in vGAT-expressing GABAergic neurons responded identically to controls in all parameters measured, whereas deletion of GLP-1Rs in vGlut2-expressing glutamatergic neurons eliminated liraglutide-induced weight loss and visceral illness and severely attenuated its effects on feeding. Concomitantly, deletion of GLP-1Rs from glutamatergic neurons completely abolished the neural network activation observed after liraglutide administration. We conclude that liraglutide activates a dispersed but discrete neural network to mediate its physiological effects, and that these effects require GLP-1R expression on glutamatergic but not GABAergic neurons.
- Prostaglandin F2α Facilitates Hepatic Glucose Production Through CaMKIIγ/p38/FoxO1-Signaling Pathway in Fasting and Obesity. [Journal Article]
- DDiabetes 2018 May 17
- CONCLUSIONS: FP mediated hepatic gluconeogenesis via the CaMKIIγ/p38/FoxO1-signaling pathway, indicating that the FP receptor might be a promising therapeutic target for type 2 diabetes.
- Strength in Numbers: Opportunities for Enhancing the Development of Effective Treatments for Type 1 Diabetes-The TrialNet Experience. [Journal Article]
- DDiabetes 2018 May 16
- The early to mid-1980s were an inflection point in the history of type 1 diabetes research. Two landmark events occurred: the initiation of immune-based interventions seeking to prevent type 1 diabet...
The early to mid-1980s were an inflection point in the history of type 1 diabetes research. Two landmark events occurred: the initiation of immune-based interventions seeking to prevent type 1 diabetes and the presentation of an innovative model describing the disorder's natural history. Both formed the basis for hundreds of subsequent studies designed to achieve a dramatic therapeutic goal-a means to prevent and/or reverse type 1 diabetes. However, the need to screen large numbers of individuals and prospectively monitor them using immunologic and metabolic tests for extended periods of time suggested such efforts would require a large collaborative network. Hence, the National Institutes of Health formed the landmark Diabetes Prevention Trial-Type 1 (DPT-1) in the mid-1990s, an effort that led to Type 1 Diabetes TrialNet. TrialNet studies have helped identify novel biomarkers; delineate type 1 diabetes progression, resulting in identification of highly predictable stages defined by the accumulation of autoantibodies (stage 1), dysglycemia (stage 2), and disease meeting clinical criteria for diagnosis (stage 3); and oversee numerous clinical trials aimed at preventing disease progression. Such efforts pave the way for stage-specific intervention trials with improved hope that a means to effectively disrupt the disorder's development will be identified.
- Membrane-Initiated Estrogen Receptor Signaling Mediates Metabolic Homeostasis via Central Activation of Protein Phosphatase 2A. [Journal Article]
- DDiabetes 2018 May 15
- Women gain weight and their diabetes risk increases as they transition through menopause; these changes can in part be reversed by hormone therapy. However, the underlying molecular mechanisms mediat...
Women gain weight and their diabetes risk increases as they transition through menopause; these changes can in part be reversed by hormone therapy. However, the underlying molecular mechanisms mediating these effects are unknown. A novel knock-in mouse line with the selective blockade of the membrane-initiated estrogen receptor (ER) pathway was employed, and we found that the lack of this pathway precipitated excessive weight gain and glucose intolerance independent of food intake, and that this was accompanied by impaired adaptive thermogenesis and reduced physical activity. Notably, the central activation of protein phosphatase (PP) 2A improved metabolic disorders induced by the lack of membrane-initiated ER signaling. Furthermore, the anti-obesity effect of estrogen replacement in a murine menopause model was abolished by central PP2A inactivation. These findings define a critical role for membrane-initiated ER signaling in metabolic homeostasis via the central action of PP2A.
- Activation of Nrf2 is Required for Normal and ChREBPα-Augmented Glucose-Stimulated β-Cell Proliferation. [Journal Article]
- DDiabetes 2018 May 15
- Patients with both major forms of diabetes would benefit from therapies that increase β-cell mass. Glucose is a natural mitogen that drives adaptive β-cell mass expansion by promoting β-cell prolifer...
Patients with both major forms of diabetes would benefit from therapies that increase β-cell mass. Glucose is a natural mitogen that drives adaptive β-cell mass expansion by promoting β-cell proliferation. We previously demonstrated that carbohydrate response element binding protein (ChREBPα) is required for glucose-stimulated β-cell proliferation, and that overexpression of ChREBPα amplifies the proliferative effect of glucose. Here we found that ChREBPα reprogrammed anabolic metabolism to promote proliferation. Remarkably, ChREBPα increased mitochondrial biogenesis, oxygen consumption rates, and ATP production. The augmented proliferation by ChREBPα required the presence of ChREBPβ. Importantly, ChREBPα increased the expression and activity of Nrf2, initiating antioxidant and mitochondrial biogenic programs. The induction of Nrf2 was required for ChREBPα-mediated mitochondrial biogenesis, as well as glucose-stimulated and ChREBPα-augmented β-cell proliferation. Confirming the importance of this pathway, overexpression of Nrf2 was sufficient to drive human β-cell proliferation in vitro Our results reveal a novel pathway necessary for β-cell proliferation that may be exploited for therapeutic β-cell regeneration.
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- The Ceramide Transporter CERT is Involved in Muscle Insulin Signaling Defects Under Lipotoxic Conditions. [Journal Article]
- DDiabetes 2018 May 14
- One main mechanism of insulin resistance (IR), a key feature of type-2 diabetes, is the accumulation of saturated fatty acids (FA) in muscles of obese and type-2 diabetic patients. Understanding the ...
One main mechanism of insulin resistance (IR), a key feature of type-2 diabetes, is the accumulation of saturated fatty acids (FA) in muscles of obese and type-2 diabetic patients. Understanding the mechanism underlying lipid-induced IR is therefore a crucial challenge. Saturated FA are metabolized into lipid-derivatives called ceramides and their accumulation plays a central role in the development of muscle IR. Ceramides are produced in the endoplasmic reticulum (ER) and transported to the Golgi through a transporter called CERT, where they are converted into different sphingolipid species. We show here that CERT protein expression is reduced in all insulin resistance models studied due to a caspase-dependent cleavage. Inhibiting CERT activity in vitro potentiates the deleterious action of lipotoxicity on insulin signaling whereas overexpression of CERT in vitro or in vivo increases muscle ceramide content and improves insulin signaling. In addition, inhibition of caspase activity prevents ceramide-induced insulin signaling defects in C2C12 muscle cells. Altogether, these results demonstrate the importance of a physiological ER to Golgi ceramide traffic to preserve muscle cell insulin signaling and identifies CERT as a major actor in this process.