This was a interesting cross over study! So in the graph P1 is a year of ketosis, P2 is carb loading to the UK dietary recommendations for 21 days, and P3 is a return to ketosis. So this is different from most studies where people are slowly adapting to keto, here we have long term ketosis adapting to carbs in a short window.

Notes:

Carbohydrate restriction (CR) and fasting have been shown to extend lifespan

Chronic insulin secretion and signalling, driven by dietary sources of glucose, leads to hyperinsulinaemia and/or insulin resistance, and consequently chronic diseases which decrease healthspan by accelerating cellular growth and division whilst impeding apoptosis and promoting production of inflammatory cytokines.

Fasting mimicking diets (FMD), including ketogenic diets, upregulate beta-oxidation, ketogenesis and ketolysis, enhance mitophagy, increase mitochondrial biogenesis, and alter gene expression, promoting oxidative stress responses and cell survival

Repeated bolus glucose excursions chronically stimulate bolus insulin synthesis and release, and over time downregulate ketogenesis enzyme expression, leading to chronic hypoketonaemia

2.1. Suppression of Ketosis Increases BMI and Fat Mass

ha! Usually we see it from the other side.

2.5. Suppression of Ketosis Is Associated with Increases in Inflammatory Liver Markers

Together, these data indicate that the participants were indeed highly fat-adapted and, even with the introduction of carbohydrates into their diet, their bodies reverted to beta-oxidation and ketolysis during periods of fasting… This suggests that metabolic flexibility is maintained in long-term habitual ketosis in metabolically healthy individuals.

I would speculate after 3 months of adaptation you lose any benefit from having formally been adapted to ketosis and fat burning. The metabolic flexibility referenced here is just a OGTT response (so yes the body will still make insulin on demand).

Across all three phases, in two different metabolic states (ketosis vs. glucose fuelling), participants’ RQ values were indicative of individuals that were metabolically healthy; interestingly, their values were superior to observations previously made in high performance athletes

Just being in long term ketosis has superior RQ then carb athletes!

Considering that our cohort is exclusively female, it is imperative to recognise, for global population health, the pressing importance of focusing on diabetes, hyperinsulinaemia (insulin may be inside reference ranges; however, chronic hypoketonaemia may indicate an individual’s hyperinsulinaemia threshold), obesity, and breast cancer. Given their widespread prevalence [65,66,67,68], understanding the intricate links between these conditions is critical in order to prevent occurrence and to improve outcomes. Our participant data show that long-term NK reduces fasting insulin, IGF-1, and glucose. This data adds to existing evidence that sustaining a lifestyle which promotes ketosis is an effective modality for the prevention and management of both type 1 and type 2 diabetes [69].

A great position to take in general.

This pattern may be incorrectly labelled as a lack of sensitivity to insulin; on the contrary, this is the sum of the exogenous glucose from the OGTT, plus hepatic glucose output, which does not abate from the one-time glucose bolus.

This is with reference to “slowness” of a insulin response to a big glucose bolus, which just means in a fat adapted environment the pancreas doesn’t keep a big reserve of insulin ready to go, and the response is delayed while more insulin is produced.

This suggests that maintaining a long-term metabolic phenotype 1 profile may aid in maintaining a healthier healthspan and lifespan.

i.e. keto

These data indicate that consumption of a carbohydrate diet that suppresses ketosis for 21 days results in limited de novo ketogenesis, even following a 12 h fasting period, indicating adaptive changes and likely downregulation of cellular ketogenesis enzymes and activities.

The more insulin rises with food the more ketones are suppressed in the body even while sleeping.

Our findings suggest that suppressing ketosis may impose some degree of oxidative stress and inflammation on the liver, leading to increased GGT levels.

The lack of ketones may be stressing the liver, this is a viewpoint we wouldn’t see using a standard population which is carb adapted doing 21 days of keto… I’m glad they did this cross over study.

This indicates that the relatively short period of carbohydrate fuelling is a sufficient time to elevate the concentrations of these growth factors in a way that cannot be fully recovered in 21 days after returning to ketosis.

This is a bit sad, losing ketones is quick and building them back up is slow. That is ok, we still see improvments even in 21 days. We know from other sources about 3 months is a good ballpark adaptation window.

Women with diabetes have been shown to exhibit poorer outcomes for breast cancer compared to their non-diabetic counterparts…Consistent with these findings, in vitro research has shown that treating cancer cells, particularly breast and pancreatic, with high levels of glucose initiates molecular alterations such as phosphorylation of EGFR, which promotes their proliferation

We covered Seyfried’s work before, but it’s very sad - the glucose rich diet can directly feed and accelerate cancer.

Beyond direct cellular growth effects, the hyperglycaemic state appears to compromise the body’s innate anti-tumour defences, notably by inhibiting neutrophil mobilisation, thereby granting tumour cells an immunological escape route and enhancing their metastatic capabilities

Given that VEGF, EGF, and MCP-1 are often elevated in many cancers [142,143,144,145], KMT may be an effective way to support the action of certain cancer therapies, along with using the glucose-ketone index (GKI) calculator to measure therapeutic efficacy in metabolic management of brain cancers and likely other cancers [146]. Furthermore, KMT may be an effective stand-alone therapy for cancer. There have, indeed, been various human studies indicating that a ketogenic diet is tolerable for individuals with cancer [147], but also effective in reducing tumour burden and symptomatic disease [148]. Tumour cells are not well adapted to metabolising ketones, but instead predominantly depend on glucose for fuelling [149]. Limiting glucose availability for tumours by adapting into ketosis may therefore create a metabolically unfavourable environment for tumour growth, whilst also reducing insulin and IGF-1′s growth and division stimulating signals [150]. The data presented here indicate that long-term ketosis is safe in healthy populations; well-designed clinical trials would elucidate the value of such an approach in cancer therapy.

The good news is these trials are already underway for glioblastomas now.

Recently, it has been shown in a large cohort study that a diet with a high proportion of carbohydrates significantly increases the risk of CVD [154].

Ohh, i think i’ll read this paper next.

We therefore propose that the reduced concentration of BHB, accompanied by higher concentrations of insulin and IGF-1, may confer increased risk of morbidity and mortality over time, potentially increasing biological ageing rate.

Evolutionary evidence suggests that ancestral populations were predominantly adapted to patterns of intermittent and time-restricted feeding, as opposed to continuous nutritional intake, rich in farinaceous and sucrose carbohydrates that stimulate bolus insulin secretion.

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Great paper, I love the “lets take keto as the baseline” approach.