Paper - Confronting myths: relative and absolute requirements of dietary carbohydrates and glucose as metabolic fuels. - 2024
Paper - Confronting myths: relative and absolute requirements of dietary carbohydrates and glucose as metabolic fuels. - 2024
TLDR: People don't need carbohydrates, ketosis isn't dangerous.
It is pertinent to briefly discuss the enduring misconception that glucose itself represents an “absolutely essential”, “universal fuel” in human physiology, which requires nuanced definition and gradation, but has been perpetuated verbatim and may have been incorporated into the physiology education of currently practicing healthcare professionals [1-7].
We must first address the distinction between endogenous and exogenous sources of glucose. Clinical trials and epidemiological studies of very low to zero carbohydrate diets support the statement of the US National Academies of Sciences that “the lower limit of dietary carbohydrate compatible with life apparently is zero, provided that adequate amounts of protein and fat are consumed” [8-11]. Even so, despite seemingly safe and increasingly popular, the long-term effects of a truly “zero” carbohydrate diet (without micronutrient supplementation) are difficult to ascertain through controlled experimentation, being only inferred from evolutionary biology, observational studies, and mechanistic data [12-14]. With this caveat, it has now been clearly established in large cohorts of patients, both adult and pediatric, that the oral intake of carbohydrates can be chronically very low (< 5-10% of total daily energy), as long as essential micronutrients are obtained from the underlying food selection and/or supplementation [15-18].
During fasting or in the absence of dietary carbohydrates, a steady-state euglycemia will be maintained in a low but physiological range via hepatic and renal gluconeogenesis from endogenous sources, such as lactate, fatty acids (glycerol), gluconeogenic amino acids and odd chain fatty acids [19-21]. From an evolutionary perspective, a minimal threshold of gluconeogenesis was preserved even after indefinite periods of fasting, questioning whether glucose itself is essential [22, 23]. It was not until the seminal work of Cahill et al. corroborating the remarkable metabolic flexibility of human physiology that the absolute requirements of glucose under compensatory ketosis could be quantified [24]. Drenick et al. demonstrated that, after a 2-month fast in obese subjects, insulin stimulation failed to precipitate hypoglycemic reactions with plasma glucose as low as 9 mg/dl (0.5 mM) [25]. During prolonged fasting, blood glucose levels below 30 mg/dL (1.70 mM) have been sustained continuously for several months without adverse effects [22, 23]. It is apparent that glucose requirements can be significantly displaced by fat-derived fuels, assuming a gradual period of ketogenic adaptation proportional to the degree of glucose depletion [26, 27]. Most human tissues require at least 1 to 4 weeks of strict KD adherence for the effective upregulation of ketone body metabolism, a process that can be accelerated through water-only fasting [28-30]. Without ketogenic adaptation, glucose is indeed the “primary metabolic fuel”, as evidenced by hypoglycemic reactions after accidental secretagogue or insulin overdose in diabetic patients following carbohydrate-rich diets, even under conditions of diabetic ketoacidosis [31-33].
Many clinicians fear ketosis due to confusion with diabetic ketoacidosis, defined by the triad of excessive ketogenesis, metabolic acidosis and concomitant hyperglycemia [34]. A low level of ketones (e.g., < 0.5 mM) prior to initiating carbohydrate restriction indicates that the individual is likely not deficient in insulin and therefore not at risk for ketoacidosis [35]. Clinicians may wish to monitor serum bicarbonate during the early stages of ketogenic adaptation. Ketoacidosis does not occur unless ketones coexist with hyperglycemia and decreasing bicarbonate levels, indicating insulin insufficiency (not to be confused with insulin suppression via carbohydrate restriction, which in turn increases insulin sensitivity, as indicated by lower insulin requirements for euglycemia) [36].
In the context of KMT, evolutionary competition for the limited nutrient supply between the tumor and normal tissues may be potentiated [37]. It is important to clarify that the uninterrupted maintenance of very low glucose levels (< 3 mM) is not realistically achievable for most patients following isocaloric KDs and typically requires prolonged fasting or pharmacological interventions. Fortunately, the anti-tumoral benefits of KMT are hypothesized to arise from pleiotropic regulation of energy sensing and growth signaling pathways (PI3K, AKT, AMPK/mTOR, PGC-1α), inflammation, angiogenesis, and autophagy, not solely as the result of reduced glucose availability with compensatory ketosis, which simply serves as a surrogate marker for successful clinical implementation [38-43].
Ok, this isn't a whole paper by itself, its an appendix of Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma But its so well written, it deserves to be highlighted.
Full Original Paper here: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-024-03775-4#Sec31 - Supplementary Material 1 - Appendix 1 - Warning - It's a docx document.
The image in the post is from Resistance to Symptomatic Insulin Reactions after Fasting which is reference 35.