Chronic Exposure to Excess Nutrients Left-shifts the Concentration Dependence of Glucose-stimulated Insulin Secretion in Pancreatic β-Cells

Erion, Karel; Berdan, Charles A.; Burritt, Nathan E.; Corkey, Barbara E.; Deeney, Jude T.

doi:10.1074/jbc.m114.620351

Cited by 46 publications

(53 citation statements)

References 58 publications

(72 reference statements)

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“…A similar time course can be seen in the respiratory response of clonal insulinoma cells and human islets to acutely elevated glucose, with an initial doubling of respiration followed by a further increase over the subsequent 50 min (112,184,491). Much of the enhanced proton current is directed through the ATP synthase, rather than the endogenous proton leak, judged by the extent of oligomycin inhibition (FIGURE 3D) (112,147,184,427). To date, I am not aware of any detailed quantitative analysis of the ATPconsuming reactions in the ␤-cell cytosol.…”

Section: If the Effect Of Elevated [Ca 2ϩmentioning

confidence: 77%

“…Increasing glucose enhances whole cell NAD(P)H autofluorescence (FIGURE 4B) (112,147). Much of the signal is localized to the mitochondria in INS-1 832/13 cells (190), due in part to fluorescence enhancement caused by binding to proteins, including complex I.…”

Section: A Nadph/nadp ؉ Poolsmentioning

confidence: 99%

“…Basic "housekeeping" ATP turnover also responds to "⌬p," which stabilizes at a suboptimal level at which the restricted input corresponding to low glucose balances the sum of the two outputs (FIGURE 3Bi). Cell respirometry indicates that high glucose roughly doubles respiration (FIGURE 3C) (17,147,184,331). To model this, we double the rate of water inflow (FIGURE 3Bii), and as a result, the water level rises until the increased hydrostatic head has increased the two outflows sufficiently to balance in the input.…”

Section: Contracting Musclementioning

confidence: 99%

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The Pancreatic β-Cell: A Bioenergetic Perspective

Nicholls

2016

Physiological Reviews

123

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The pancreatic ␤-cell secretes insulin in response to elevated plasma glucose. This review applies an external bioenergetic critique to the central processes of glucose-stimulated insulin secretion, including glycolytic and mitochondrial metabolism, the cytosolic adenine nucleotide pool, and its interaction with plasma membrane ion channels. The control mechanisms responsible for the unique responsiveness of the cell to glucose availability are discussed from bioenergetic and metabolic control standpoints. The concept of coupling factor facilitation of secretion is critiqued, and an attempt is made to unravel the bioenergetic basis of the oscillatory mechanisms controlling secretion. The need to consider the physiological constraints operating in the intact cell is emphasized throughout. The aim is to provide a coherent pathway through an extensive, complex, and sometimes bewildering literature, particularly for those unfamiliar with the field.

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Section: If the Effect Of Elevated [Ca 2ϩmentioning

confidence: 77%

Section: A Nadph/nadp ؉ Poolsmentioning

confidence: 99%

Section: Contracting Musclementioning

confidence: 99%

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The Pancreatic β-Cell: A Bioenergetic Perspective

Nicholls

2016

Physiological Reviews

123

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“…These may include monogenic or polygenic defects that predispose to hyperinsulinemia, IR, more recently understood mechanisms such as inflammation by the immune system (48–51), susceptibility to environmental factors (37,51,52), or other physiological factors that increase demand on or otherwise damage β-cells such as elevated circulating lipids (37,53–55) (Fig. 2).…”

Section: β-Cell–centric Construct: a Potential Model For The Classifimentioning

confidence: 99%

“…Lifestyle modification is the starting point for intervention in prediabetes and DM as is normalization of dyslipidemia, given the links of prolonged lipid exposure with β-cell dysfunction (9,53–55). Our approach advocates intervention early in the process of β-cell dysfunction.…”

Section: β-Cell–centric Schema and Individualized Carementioning

confidence: 99%

The Time Is Right for a New Classification System for Diabetes: Rationale and Implications of the β-Cell–Centric Classification Schema

et al. 2016

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The current classification system presents challenges to the diagnosis and treatment of patients with diabetes mellitus (DM), in part due to its conflicting and confounding definitions of type 1 DM, type 2 DM, and latent autoimmune diabetes of adults (LADA). The current schema also lacks a foundation that readily incorporates advances in our understanding of the disease and its treatment. For appropriate and coherent therapy, we propose an alternate classification system. The β-cell–centric classification of DM is a new approach that obviates the inherent and unintended confusions of the current system. The β-cell–centric model presupposes that all DM originates from a final common denominator—the abnormal pancreatic β-cell. It recognizes that interactions between genetically predisposed β-cells with a number of factors, including insulin resistance (IR), susceptibility to environmental influences, and immune dysregulation/inflammation, lead to the range of hyperglycemic phenotypes within the spectrum of DM. Individually or in concert, and often self-perpetuating, these factors contribute to β-cell stress, dysfunction, or loss through at least 11 distinct pathways. Available, yet underutilized, treatments provide rational choices for personalized therapies that target the individual mediating pathways of hyperglycemia at work in any given patient, without the risk of drug-related hypoglycemia or weight gain or imposing further burden on the β-cells. This article issues an urgent call for the review of the current DM classification system toward the consensus on a new, more useful system.

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Avocatin B Protects Against Lipotoxicity and Improves Insulin Sensitivity in Diet‐Induced Obesity

Ahmed

Tcheng

Roma

et al. 2019

Molecular Nutrition Food Res

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ScopeThe effects of an avocado‐derived fatty acid oxidation (FAO) inhibitor, avocatin B (AvoB), on glucose and lipid metabolism in models of diet‐induced obesity (DIO) and in vitro models of lipotoxicity are evaluated. The safety of its oral consumption in humans is also determined.Methods and resultsMice are given high‐fat diets (HFD) for 8 weeks. Thereafter, AvoB or vehicle is administered orally twice weekly for 5 weeks. AvoB inhibits FAO which led to improved glucose tolerance, glucose utilization, and insulin sensitivity. AvoB's effects on metabolism under lipotoxic conditions are evaluated in vitro in pancreatic β‐islet cells and C2C12 myotubes. AvoB inhibits FAO and increases glucose oxidation, resulting in lowering of mitochondrial reactive oxygen species that improves insulin responsiveness in C2C12 myotubes and insulin secretion in INS‐1 (832/13) cells, respectively. A randomized, double‐blind, placebo‐controlled clinical trial in healthy human participants is conducted to assess the safety of AvoB consumption (50 mg or 200 mg per day for 60 days). AvoB is well‐tolerated and not associated with any dose‐limiting toxicity.ConclusionTherapeutic agents that are safe and effectively inhibit FAO and improve DIO‐associated pathologies are currently not available. AvoB's mechanism of action and favorable safety profile highlight its nutritional and clinical importance.

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Chronic Exposure to Excess Nutrients Left-shifts the Concentration Dependence of Glucose-stimulated Insulin Secretion in Pancreatic β-Cells

Cited by 46 publications

References 58 publications

The Pancreatic β-Cell: A Bioenergetic Perspective

The Pancreatic β-Cell: A Bioenergetic Perspective

The Time Is Right for a New Classification System for Diabetes: Rationale and Implications of the β-Cell–Centric Classification Schema

Avocatin B Protects Against Lipotoxicity and Improves Insulin Sensitivity in Diet‐Induced Obesity

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