β-Hydroxybutyrate improves β-cell mitochondrial function and survival

Sampson, MaryJane; Lathen, Daniel R.; Dallon, Blake W.; Draney, Carrie; Ray, Jason D.; Kener, Kyle B.; Parker, Brian A.; Gibbs, Jonathan L.; Gropp, Jarom S.; Tessem, Jeffery S.; Bikman, Benjamin T.

doi:10.4102/jir.v2i1.25

Cited by 4 publications

(5 citation statements)

References 44 publications

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“…Recent study supported these results about anti-oxidant properties of βOHB 25). βOHB also improves mitochondrial function and increases ATP production in pancreatic beta cells and neuronal cells 26)27). In line with these findings, we found that βOHB increased intracellular ATP levels and restored mitochondrial dysfunction in cardiomyocytes (Figure 3E and F).…”

Section: Discussionsupporting

confidence: 89%

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Cardioprotective Potential of an SGLT2 Inhibitor Against Doxorubicin-Induced Heart Failure

Cho

Jang

et al. 2019

Korean Circ J

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Background and ObjectivesRecent studies have shown that sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of heart failure (HF)-associated hospitalization and mortality in patients with diabetes. However, it is not clear whether SGLT2 inhibitors have a cardiovascular benefit in patients without diabetes. We aimed to determine whether empagliflozin (EMPA), an SGLT2 inhibitor, has a protective role in HF without diabetes.MethodsCardiomyopathy was induced in C57BL/6J mice using intraperitoneal injection of doxorubicin (Dox). Mice with HF were fed a normal chow diet (NCD) or an NCD containing 0.03% EMPA. Then we analyzed their phenotypes and performed in vitro experiments to reveal underlying mechanisms of the EMPA's effects.ResultsMice fed NCD with EMPA showed improved heart function and reduced fibrosis. In vitro studies showed similar results. Phloridzin, a non-specific SGLT inhibitor, did not show any protective effect against Dox toxicity in H9C2 cells. SGLT2 inhibitor can cause increase in blood ketone levels. Beta hydroxybutyrate (βOHB), which is well known ketone body associated with SGLT2 inhibitor, showed a protective effect against Dox in H9C2 cells and in Dox-treated mice. These results suggest elevating βOHB might be a convincing mechanism for the protective effects of SGLT2 inhibitor.ConclusionsSGLT2 inhibitors have a protective effect in Dox-induced HF in mice. This implied that SGLT2 inhibitor therapy could be a good treatment strategy even in HF patients without diabetes.

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Section: Discussionsupporting

confidence: 89%

“…Several studies support our findings about the cardioprotective role of βOHB. Ketone bodies are effective energy source of failing heart and increase survival in aging mice 26)28). Exogenous βOHB infusion protects ischemic injury in heart by reducing ROS and enhancing adenosine trisphosphate production 29).…”

Section: Discussionmentioning

confidence: 99%

Cardioprotective Potential of an SGLT2 Inhibitor Against Doxorubicin-Induced Heart Failure

Cho

Jang

et al. 2019

Korean Circ J

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“…Cells and tissue were prepared for mitochondrial respiration as described previously [ 35 , 36 , 37 , 38 ] before being transferred to respirometer chambers using the Oroboros O2K oxygraph (Oroboros, Innsbruck, Austria). Electron flow through complex I was supported by glutamate + malate (10 mM and 2 mM, respectively) to determine leak oxygen consumption (GM L ).…”

Section: Methodsmentioning

confidence: 99%

β-Hydroxybutyrate Elicits Favorable Mitochondrial Changes in Skeletal Muscle

Parker

Walton

Carr

et al. 2018

IJMS

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The clinical benefit of ketosis has historically and almost exclusively centered on neurological conditions, lending insight into how ketones alter mitochondrial function in neurons. However, there is a gap in our understanding of how ketones influence mitochondria within skeletal muscle cells. The purpose of this study was to elucidate the specific effects of β-hydroxybutyrate (β-HB) on muscle cell mitochondrial physiology. In addition to increased cell viability, murine myotubes displayed beneficial mitochondrial changes evident in reduced H2O2 emission and less mitochondrial fission, which may be a result of a β-HB-induced reduction in ceramides. Furthermore, muscle from rats in sustained ketosis similarly produced less H2O2 despite an increase in mitochondrial respiration and no apparent change in mitochondrial quantity. In sum, these results indicate a general improvement in muscle cell mitochondrial function when β-HB is provided as a fuel.

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“…It may be the case that the down regulation of the rapid insulin release may not be wholly pathological if one considers it as a means to reduce any excess insulin signal on the liver to inhibit glycogenolysis. However, this is hypothetical and it is more likely that mitochondrial damage results in the pathological changes that impair the first phase rapid insulin response after a glucose bolus in T2DM patients, and this, in turn, contributes to a pathological feedforward progression of increases in fasting basal insulin levels [29,50,55,126].…”

Section: An Alternative Hypothesis: Insulin's Main Role Is To Regulate Beta-hydroxybutyrate Synthesismentioning

confidence: 99%

Metabolic Phenotypes and Step by Step Evolution of Type 2 Diabetes: A New Paradigm

et al. 2021

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Unlike bolus insulin secretion mechanisms, basal insulin secretion is poorly understood. It is essential to elucidate these mechanisms in non-hyperinsulinaemia healthy persons. This establishes a baseline for investigation into pathologies where these processes are dysregulated, such as in type 2 diabetes (T2DM), cardiovascular disease (CVD), certain cancers and dementias. Chronic hyperinsulinaemia enforces glucose fueling, depleting the NAD+ dependent antioxidant activity that increases mitochondrial reactive oxygen species (mtROS). Consequently, beta-cell mitochondria increase uncoupling protein expression, which decreases the mitochondrial ATP surge generation capacity, impairing bolus mediated insulin exocytosis. Excessive ROS increases the Drp1:Mfn2 ratio, increasing mitochondrial fission, which increases mtROS; endoplasmic reticulum-stress and impaired calcium homeostasis ensues. Healthy individuals in habitual ketosis have significantly lower glucagon and insulin levels than T2DM individuals. As beta-hydroxybutyrate rises, hepatic gluconeogenesis and glycogenolysis supply extra-hepatic glucose needs, and osteocalcin synthesis/release increases. We propose insulin’s primary role is regulating beta-hydroxybutyrate synthesis, while the role of bone regulates glucose uptake sensitivity via osteocalcin. Osteocalcin regulates the alpha-cell glucagon secretory profile via glucagon-like peptide-1 and serotonin, and beta-hydroxybutyrate synthesis via regulating basal insulin levels. Establishing metabolic phenotypes aids in resolving basal insulin secretion regulation, enabling elucidation of the pathological changes that occur and progress into chronic diseases associated with ageing.

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β-Hydroxybutyrate improves β-cell mitochondrial function and survival

Cited by 4 publications

References 44 publications

Cardioprotective Potential of an SGLT2 Inhibitor Against Doxorubicin-Induced Heart Failure

Cardioprotective Potential of an SGLT2 Inhibitor Against Doxorubicin-Induced Heart Failure

β-Hydroxybutyrate Elicits Favorable Mitochondrial Changes in Skeletal Muscle

Metabolic Phenotypes and Step by Step Evolution of Type 2 Diabetes: A New Paradigm

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