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Epidemiological studies suggest that insulin resistance accelerates progression of age-based cognitive impairment, which neuroimaging has linked to brain glucose hypometabolism. As cellular inputs, ketones increase Gibbs free energy change for ATP by 27% compared to glucose. Here we test whether dietary changes are capable of modulating sustained functional communication between brain regions (network stability) by changing their predominant dietary fuel from glucose to ketones. We first established network stability as a biomarker for brain aging using two large-scale (n = 292, ages 20 to 85 y; n = 636, ages 18 to 88 y) 3 T functional MRI (fMRI) datasets. To determine whether diet can influence brain network stability, we additionally scanned 42 adults, age < 50 y, using ultrahigh-field (7 T) ultrafast (802 ms) fMRI optimized for single-participant-level detection sensitivity. One cohort was scanned under standard diet, overnight fasting, and ketogenic diet conditions. To isolate the impact of fuel type, an independent overnight fasted cohort was scanned before and after administration of a calorie-matched glucose and exogenous ketone ester (D-β-hydroxybutyrate) bolus. Across the life span, brain network destabilization correlated with decreased brain activity and cognitive acuity. Effects emerged at 47 y, with the most rapid degeneration occurring at 60 y. Networks were destabilized by glucose and stabilized by ketones, irrespective of whether ketosis was achieved with a ketogenic diet or exogenous ketone ester. Together, our results suggest that brain network destabilization may reflect early signs of hypometabolism, associated with dementia. Dietary interventions resulting in ketone utilization increase available energy and thus may show potential in protecting the aging brain.

Iron is essential to the cell. Both iron deficiency and overload impinge negatively on cardiac health. Thus, effective iron homeostasis is important for cardiac function. Ferroportin (FPN), the only known mammalian iron-exporting protein, plays an essential role in iron homeostasis at the systemic level. It increases systemic iron availability by releasing iron from the cells of the duodenum, spleen, and liver, the sites of iron absorption, recycling, and storage respectively. However, FPN is also found in tissues with no known role in systemic iron handling, such as the heart, where its function remains unknown. To explore this function, we generated mice with a cardiomyocyte-specific deletion ofFpn. We show that these animals have severely impaired cardiac function, with a median survival of 22 wk, despite otherwise unaltered systemic iron status. We then compared their phenotype with that of ubiquitous hepcidin knockouts, a recognized model of the iron-loading disease hemochromatosis. The phenotype of the hepcidin knockouts was far milder, with normal survival up to 12 mo, despite far greater iron loading in the hearts. Histological examination demonstrated that, although cardiac iron accumulates within the cardiomyocytes ofFpnknockouts, it accumulates predominantly in other cell types in the hepcidin knockouts. We conclude, first, that cardiomyocyte FPN is essential for intracellular iron homeostasis and, second, that the site of deposition of iron within the heart determines the severity with which it affects cardiac function. Both findings have significant implications for the assessment and treatment of cardiac complications of iron dysregulation.

Hepcidin is the master regulator of systemic iron homeostasis. Derived primarily from the liver, it inhibits the iron exporter ferroportin in the gut and spleen, the sites of iron absorption and recycling respectively. Recently, we demonstrated that ferroportin is also found in cardiomyocytes, and that its cardiac-specific deletion leads to fatal cardiac iron overload. Hepcidin is also expressed in cardiomyocytes, where its function remains unknown. To define the function of cardiomyocyte hepcidin, we generated mice with cardiomyocyte-specific deletion of hepcidin, or knock-in of hepcidin-resistant ferroportin. We find that while both models maintain normal systemic iron homeostasis, they nonetheless develop fatal contractile and metabolic dysfunction as a consequence of cardiomyocyte iron deficiency. These findings are the first demonstration of a cell-autonomous role for hepcidin in iron homeostasis. They raise the possibility that such function may also be important in other tissues that express both hepcidin and ferroportin, such as the kidney and the brain. Many proteins inside cells require iron to work properly, and so this mineral is an essential part of the diets of most mammals. However, because too much iron in the body is also bad for health, mammals possess several proteins whose role is to maintain the balance of iron. Two proteins in particular, called hepcidin and ferroportin, are thought to be important in this process. Some ferroportin is found in the cells that line the gut (where iron is absorbed into the body) and is required to release this iron into the bloodstream. It is also found in the spleen, which is where iron is removed from old red blood cells so that it can be recycled. The liver produces hepcidin to control when ferroportin is active in the gut and spleen. Both hepcidin and ferroportin are also found in heart cells. In 2015, a study reported that that heart ferroportin plays an important role in heart activity. However, it was not clear what role hepcidin plays in this organ. Now, Lakhal-Littleton et al. – including many of the researchers from the previous work – have genetically engineered mice such that they specifically lacked heart hepcidin, or had a version of ferroportin in their heart that does not respond to hepcidin. The experiments show that these changes caused fatal heart failure in the mice because ferroportin releases iron from heart cells in an uncontrolled manner. Lakhal-Littleton et al. were able to prevent heart failure by injecting the animals with iron directly into the bloodstream. These findings show that hepcidin produced outside the liver has a role in controlling the levels of iron in the body’s organs. Other organs such as the brain, kidney and placenta all have their own forms of hepcidin and ferroportin; further work could investigate the roles of these proteins. Finally, another challenge for the future will be to test whether new drugs that are being developed to block or mimic hepcidin from the liver have the potential to treat heart conditions in humans.

As the prevalence of Alzheimer disease (AD) continues to rise unabated, new models have been put forth to improve our understanding of this devastating condition. Although individual models may have their merits, integrated models may prove more valuable. Indeed, the reliable failures of monotherapies for AD, and the ensuing surrender of major drug companies, suggests that an integrated perspective may be necessary if we are to invent multifaceted treatments that could ultimately prove more successful. In this review article, we discuss the Wnt/Glycogen Synthase Kinase 3β (GSK3β), α-synuclein, and type 3 diabetes hypotheses of AD, and their deep interconnection, in order to foster the integrative thinking that may be required to reach a solution for the coming neurological epidemic.

Type 2 diabetes mellitus (T2DM) is associated with coronary microvascular dysfunction in the absence of obstructive coronary artery disease (CAD). Cardiovascular magnetic resonance (CMR) T1-mapping at rest and during adenosine stress can assess coronary vascular reactivity. We hypothesised that the non-contrast T1 response to vasodilator stress will be altered in patients with T2DM without CAD compared to controls due to coronary microvascular dysfunction. Thirty-one patients with T2DM and sixteen matched healthy controls underwent CMR (3 T) for cine, rest and adenosine stress non-contrast T1-mapping (ShMOLLI), first-pass perfusion and late gadolinium enhancement (LGE) imaging. Significant CAD (>50% coronary luminal stenosis) was excluded in all patients by coronary computed tomographic angiography. All subjects had normal left ventricular (LV) ejection and LV mass index, with no LGE. Myocardial perfusion reserve index (MPRI) was lower in T2DM than in controls (1.60 ± 0.44 vs 2.01 ± 0.42; p = 0.008). There was no difference in rest native T1 values (p = 0.59). During adenosine stress, T1 values increased significantly in both T2DM patients (from 1196 ± 32 ms to 1244 ± 44 ms, p < 0.001) and controls (from 1194 ± 26 ms to 1273 ± 44 ms, p < 0.001). T2DM patients showed blunted relative stress non-contrast T1 response (T2DM: ΔT1 = 4.1 ± 2.9% vs. controls: ΔT1 = 6.6 ± 2.6%, p = 0.007) due to a blunted maximal T1 during adenosine stress (T2DM 1244 ± 44 ms vs. controls 1273 ± 44 ms, p = 0.045). Patients with well controlled T2DM, even in the absence of arterial hypertension and significant CAD, exhibit blunted maximal non-contrast T1 response during adenosine vasodilatory stress, likely reflecting coronary microvascular dysfunction. Adenosine stress and rest T1 mapping can detect subclinical abnormalities of the coronary microvasculature, without the need for gadolinium contrast agents. CMR may identify early features of the diabetic heart phenotype and subclinical cardiac risk markers in patients with T2DM, providing an opportunity for early therapeutic intervention.

The advent of hyperpolarized ¹³C magnetic resonance (MR) has provided new potential for the real-time visualization of in vivo metabolic processes. The aim of this work was to use hyperpolarized [1-¹³C]pyruvate as a metabolic tracer to assess noninvasively the flux through the mitochondrial enzyme complex pyruvate dehydrogenase (PDH) in the rat heart, by measuring the production of bicarbonate (H¹³CO[Formula: see text]), a byproduct of the PDH-catalyzed conversion of [1-¹³C]pyruvate to acetyl-CoA. By noninvasively observing a 74% decrease in H¹³CO[Formula: see text] production in fasted rats compared with fed controls, we have demonstrated that hyperpolarized ¹³C MR is sensitive to physiological perturbations in PDH flux. Further, we evaluated the ability of the hyperpolarized ¹³C MR technique to monitor disease progression by examining PDH flux before and 5 days after streptozotocin induction of type 1 diabetes. We detected decreased H¹³CO[Formula: see text] production with the onset of diabetes that correlated with disease severity. These observations were supported by in vitro investigations of PDH activity as reported in the literature and provided evidence that flux through the PDH enzyme complex can be monitored noninvasively, in vivo, by using hyperpolarized ¹³C MR.

Routine exercise is thought to be among the only disease-modifying treatments for Parkinson's disease; however, patients' progressive loss of physical ability limits its application. Therefore, we sought to investigate whether a ketone ester drink, which has previously been shown to enhance endurance exercise performance in elite athletes, could also improve performance in persons with Parkinson's disease. 14 patients, aged 40-80 years, with Hoehn and Yahr stage 1-2 Parkinson's disease. A randomized, placebo-controlled, crossover study in which each participant was administered a ketone ester drink or an isocaloric carbohydrate-based control drink on separate occasions prior to engaging in a steady state cycling test at 80 rpm to assess endurance exercise performance. The primary outcome variable was length of time participants could sustain a therapeutic 80 rpm cadence. Secondary, metabolic outcomes measures included cardiorespiratory parameters as well as serum β-hydroxybutyrate, glucose, and lactate. The ketone ester increased the time that participants were able to sustain an 80 rpm cycling cadence by 24 ± 9% ( = 0.027). Correspondingly, the ketone ester increased β-hydroxybutyrate levels to >3 mmol/L and decreased respiratory exchange ratio, consistent with a shift away from carbohydrate-dependent metabolism. Ketone ester supplementation improved endurance exercise performance in persons with Parkinson's disease and may, therefore, be useful as an adjunctive therapy to enhance the effectiveness of exercise treatment for Parkinson's disease.

Iron deficiency impairs skeletal muscle metabolism. The underlying mechanisms are incompletely characterised, but animal and human experiments suggest the involvement of signalling pathways co-dependent upon oxygen and iron availability, including the pathway associated with hypoxia-inducible factor (HIF). We performed a prospective, case–control, clinical physiology study to explore the effects of iron deficiency on human metabolism, using exercise as a stressor. Thirteen iron-deficient (ID) individuals and thirteen iron-replete (IR) control participants each underwent 31 P-magnetic resonance spectroscopy of exercising calf muscle to investigate differences in oxidative phosphorylation, followed by whole-body cardiopulmonary exercise testing. Thereafter, individuals were given an intravenous (IV) infusion, randomised to either iron or saline, and the assessments repeated ~ 1 week later. Neither baseline iron status nor IV iron significantly influenced high-energy phosphate metabolism. During submaximal cardiopulmonary exercise, the rate of decline in blood lactate concentration was diminished in the ID group (P = 0.005). Intravenous iron corrected this abnormality. Furthermore, IV iron increased lactate threshold during maximal cardiopulmonary exercise by ~ 10%, regardless of baseline iron status. These findings demonstrate abnormal whole-body energy metabolism in iron-deficient but otherwise healthy humans. Iron deficiency promotes a more glycolytic phenotype without having a detectable effect on mitochondrial bioenergetics.

Elevated levels of cardiac mitochondrial uncoupling protein 3 (UCP3) and decreased cardiac efficiency (hydraulic power/oxygen consumption) with abnormal cardiac function occur in obese, diabetic mice. To determine whether cardiac mitochondrial uncoupling occurs in non-genetic obesity, we fed rats a high fat diet (55% kcal from fat) or standard laboratory chow (7% kcal from fat) for 3 weeks, after which we measured cardiac function in vivo using cine MRI, efficiency in isolated working hearts and respiration rates and ADP/O ratios in isolated interfibrillar mitochondria; also, measured were medium chain acyl-CoA dehydrogenase (MCAD) and citrate synthase activities plus uncoupling protein 3 (UCP3), mitochondrial thioesterase 1 (MTE-1), adenine nucleotide translocase (ANT) and ATP synthase protein levels. We found that in vivo cardiac function was the same for all rats, yet oxygen consumption was 19% higher in high fat-fed rat hearts, therefore, efficiency was 21% lower than in controls. We found that mitochondrial fatty acid oxidation rates were 25% higher, and MCAD activity was 23% higher, in hearts from rats fed the high fat diet when compared with controls. Mitochondria from high fat-fed rat hearts had lower ADP/O ratios than controls, indicating increased respiratory uncoupling, which was ameliorated by GDP, a UCP3 inhibitor. Mitochondrial UCP3 and MTE-1 levels were both increased by 20% in high fat-fed rat hearts when compared with controls, with no significant change in ATP synthase or ANT levels, or citrate synthase activity. We conclude that increased cardiac oxygen utilisation, and thereby decreased cardiac efficiency, occurs in non-genetic obesity, which is associated with increased mitochondrial uncoupling due to elevated UCP3 and MTE-1 levels.

Background Interventions that induce ketosis simultaneously lower blood glucose and the explanation for this phenomenon is unknown. Additionally, the glucose‐lowering effect of acute ketosis is greater in people with type 2 diabetes (T2D). On the contrary, L‐alanine is a gluconeogenic substrate secreted by skeletal muscle at higher levels in people with T2D and infusing of ketones lower circulating L‐alanine blood levels. In this study, we sought to determine whether supplementation with L‐alanine would attenuate the glucose‐lowering effect of exogenous ketosis using a ketone ester (KE). Methods This crossover study involved 10 healthy human volunteers who fasted for 24 h prior to the ingestion of 25 g of d‐β‐hydroxybutyrate (βHB) in the form of a KE drink (ΔG®) on two separate visits. During one of the visits, participants additionally ingested 2 g of L‐alanine to see whether L‐alanine supplementation would attenuate the glucose‐lowering effect of the KE drink. Blood L‐alanine, L‐glutamine, glucose, βHB, free fatty acids (FFA), lactate and C‐peptide were measured for 120 min after ingestion of the KE, with or without L‐alanine. Findings The KE drinks elevated blood βHB concentrations from negligible levels to 4.52 ± 1.23 mmol/L, lowered glucose from 4.97 ± SD 0.39 to 3.77 ± SD 0.40 mmol/L, and lowered and L‐alanine from 0.56 ± SD 0.88 to 0.41 ± SD 0.91 mmol/L. L‐alanine in the KE drink elevated blood L‐Alanine by 0.68 ± SD 0.15 mmol/L, but had no significant effect on blood βHB, L‐glutamine, FFA, lactate, nor C‐peptide concentrations. By contrast, L‐alanine supplementation significantly attenuated the ketosis‐induced drop in glucose from 28% ± SD 8% to 16% ± SD 7% (p < .01). Conclusions The glucose‐lowering effect of acutely elevated βHB is partially due to βHB decreasing L‐alanine availability as a substrate for gluconeogenesis. This was crossover study involved two separate visits for 10 healthy human volunteers who fasted for 24 h prior to the ingestion of 25 g of d‐β‐hydroxybutyrate (βHB) monoester (ΔG®). During one of the visits, participants ingested 2 g of L‐alanine. Blood L‐alanine, L‐glutamine, glucose, βHB, free fatty acids (FFA), lactate and C‐peptide were measured. Demonstrating that ketosis induces hypoglycemia, in part, by limiting L‐alanine availability for gluconeogenesis.