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Neuroprotective effects of ketones
Neuroprotection is the mechanisms and strategies that, once implemented, may lead to salvage, recovery or regeneration of the nervous system. Ketones may have a neuroprotective effect (see Figure Figure1).1). Ketones represent an alternative fuel for both the normal and the injured brain .
There is now an impressive body of literature implicating insulin and insulin signaling in successful aging and longevity. New information from in vivo and in vitro studies concerning insulin and insulin receptors has extended our understanding of the physiological role of insulin in the brain. However, the relevance of these to aging and longevity remains to be elucidated. Here, we review advances in our understanding of the physiological role of insulin in the brain, how insulin gets into the brain, and its relevance to aging and longevity. Furthermore, we examine possible future therapeutic applications and implications of insulin in the context of available models of delayed and accelerated aging.
The Effect of Medium Chain Triglycerides on Time to Nutritional Ketosis and Symptoms of Keto-Induction in Healthy Adults: A Randomised Controlled Clinical Trial
Medium chain triglycerides (MCTs) are ketogenic and might reduce adverse effects of keto-induction and improve time to ketosis and the tolerability of very low carbohydrate diets. This study investigates whether MCT supplementation improves time to nutritional ketosis (NK), mood, and symptoms of keto-induction. We compared changes in beta-hydroxybutyrate (BOHB), blood glucose, symptoms of keto-induction, and mood disturbance, in 28 healthy adults prescribed a ketogenic diet, randomised to receive either 30 ml of MCT, or sunflower oil as a control, three times per day, for 20 days. The primary outcome measured was the achievement of NK (≥0.5 mmol·L−1 BOHB). Participants also completed a daily Profile of Mood States and keto-induction symptom questionnaire. MCT resulted in higher BOHB at all time points and faster time to NK, a result that failed to reach significance. Symptoms of keto-induction resulted from both diets, with a greater magnitude in the control group, except for abdominal pain, which occurred with greater frequency and severity in the MCT-supplemented diet. There was a possibly beneficial effect on symptoms by MCT, but the effect on mood was unclear. Based on these results, MCTs increase BOHB compared with LCT and reduce symptoms of keto-induction. It is unclear whether MCTs significantly improve mood or time to NK. The trial was registered by the Australia New Zealand Clinical Trial Registry ACTRN12616001099415.
Obesity is a causal factor of type 2 diabetes (T2D); however, people without obesity (including lean, normal weight, or overweight) may still develop T2D. Non-obese T2D is prevalent in Asia and also frequently occurs in Europe. Recently, multiple evidences oppose the notion that either obesity or central obesity (visceral fat accumulation) promotes non-obese T2D. Several factors such as inflammation and environmental factors contribute to non-obese T2D. According to the data derived from gene knockout mice and T2D clinical samples in Asia and Europe, the pathogenesis of non-obese T2D has been unveiled recently. MAP4K4 downregulation in T cells results in enhancement of the IL-6+ Th17 cell population, leading to insulin resistance and T2D in both human and mice. Moreover, MAP4K4 single nucleotide polymorphisms and epigenetic changes are associated with T2D patients. Interactions between MAP4K4 gene variants and environmental factors may contribute to MAP4K4 attenuation in T cells, leading to non-obese T2D. Future investigations of the pathogenesis of non-obese T2D shall lead to development of precision medicine for non-obese T2D.
This remains one of the most in depth interview with Dr Valter Longo.
This is essential still 2 main types with sub groups.
Type 1 - Insulin deficient
Type 2 - Insulin resistant
Diabetic heart is characterized by failure of insulin to increase glucose uptake and increasingly relies on free fatty acids (FFAs) as a source of fuel in animal models. However, it is not well known how cardiac energy metabolism is altered in diabetic hearts in humans. We examined cardiac fuel metabolism in the diabetics as compared to non-diabetics who underwent cardiac catheterization for heart diseases.
Cardiac uptakes of carbohydrate (glucose, lactate and pyruvate) were decreased, whereas those of total ketone bodies and β-hydroxybutyrate were increased in the diabetics as compared to the non-diabetics in humans. Ketone bodies therefore are utilized as an energy source partially replacing glucose in the human diabetic heart.
In the normal heart, fatty acids and glucose are the major fuels, while lactic acids, ketone bodies and amino acids play minor roles [, , ]. The normal heart has a substantial amount of metabolic flexibility that allows it to switch back and forth between fatty acid and carbohydrate oxidation, depending on the workload of the heart, the energy substrate supply, and hormonal and nutritional states [, , ].
The diabetic heart cannot use the glucose fully due to insulin resistance and may thereby be forced to switch almost exclusively to the fatty acids as a source of energy as demonstrated [, , ]. Diabetic heart has an increased lipid content or cardiac steatosis, which leads to oxidative stress and cardiac dysfunction, as compared to non-diabetic heart [, ]. However, it is not well known how myocardial substrate oxidation and metabolic flexibility are altered in the diabetic patients.
The present study shows that the plasma levels of FFAs, glucose, total ketone bodies, β-OHB, and acetoacetate were higher at the aortic root and that the myocardial uptakes of glucose, lactate and pyruvate were lower and those of total ketone bodies including β-OHB and acetoacetate were higher in the DM patients than the non-DM patients in the fasting state. There was however no difference in the myocardial uptake of FFAs between the DM and non-DM patients. These findings indicate that diabetic hearts switch partially from carbohydrates (glucose, lactate and pyruvate) to ketone bodies (ß-OHB and acetoacetate) but not to FFAs as energy sources in humans. It is likely that increased cardiac lipids with toxic intermediates such as diacylglycerol and ceramide compromise mitochondrial ATP production and increase oxidative stress, which result in suppression of further increase of cardiac FFA uptake even in the presence of impaired glucose oxidation in the established DM in humans [6. It is also possible that myocardial ischemia in the majority of the study patients may have altered FFA oxidation [, ]. Furthermore, ketone bodies are avidly taken up by the heart and compete with glucose or FFAs as cardiac energy substrates and suppress FFA uptake [, ]. Ketone bodies produce ATP more efficiently per molecule of oxygen consumed than glucose or FFAs and thereby increase cardiac efficiency and may thus be a “super fuel” for the heart [, , , ]. Recent evidence has shown that cardiac ketone oxidation is increased in the failing heart and it is likely that increased ketone oxidation can maintain cardiac energy supply in situation of limited energy production such as DM or heart failure [, , ].
There were no significant differences in the clinical characteristics between the DM and non-DM groups except the increased LV wall thickness and early diastolic dysfunction as indicated by the reduced LV e′ in the group DM (Table 2). These findings imply that the diabetic heart exhibits LV concentric remodeling with diastolic dysfunction and has an increased propensity for heart failure in agreement with previous studies [, , , , ]. The present study also shows that cardiac O2 uptake or consumption increases with plasma glucose levels. The present study also revealed that there was a significant positive correlation between the plasma BNP levels and the cardiac uptake of total ketone bodies, indicating that cardiac utilization of ketone bodies increase with deterioration of LV dysfunction [, , , , ].
The major focus of this Review is on the mechanisms of islet β cell failure in the pathogenesis of obesity-associated type 2 diabetes (T2D). As this demise occurs within the context of β cell compensation for insulin resistance, consideration is also given to the mechanisms involved in the compensation process, including mechanisms for expansion of β cell mass and for enhanced β cell performance. The importance of genetic, intrauterine, and environmental factors in the determination of “susceptible” islets and overall risk for T2D is reviewed. The likely mechanisms of β cell failure are discussed within the two broad categories: those with initiation and those with progression roles.
Numerous studies show that insulin resistance precedes the development of hyperglycemia in subjects that eventually develop T2D (2, S1). However, it is increasingly being realized that T2D only develops in insulin-resistant subjects with the onset of β cell dysfunction (3–6, S2).
The normal pancreatic β cell response to a chronic fuel surfeit and obesity-associated insulin resistance is compensatory insulin hypersecretion in order to maintain normoglycemia. T2D only develops in subjects that are unable to sustain the β cell compensatory response. Longitudinal studies of subjects that develop T2D show a rise in insulin levels in the normoglycemic and prediabetes phases that keep glycemia near normal despite the insulin resistance (β cell compensation), followed by a decline when fasting glycemia surpasses the upper limit of normal of 5.5 mM (β cell failure) (5) (Figure (Figure1).1). A longitudinal study in Pima Indians showed that β cell dysfunction was the major determinant of progression from normoglycemia to diabetes (7). Furthermore, the natural history of T2D entails progressive deterioration in β cell function (5), associated with loss of β cell mass due to apoptosis (8). Many affected persons that initially have adequate control of their disease with lifestyle changes alone eventually require insulin therapy in the later stage of the disease (Figure (Figure1).1). Less certain is the time point in T2D development when β cell dysfunction first appears. The recent evidence points to it being early, long before the onset of prediabetes, when glycemia is still classified as normal glucose tolerance (9, S3, S4).
This is a comprehensive 7 part powerpoint slides series on classifying diabetes base on beta-cells dysfunction.