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Emerging evidence suggests that "leanness" and good metabolic health markers may predict larger increases in LDL cholesterol (LDL-C) in response to carbohydrate restriction. Specifically, a recent cohort study demonstrated an inverse association between BMI and LDL-C change among individuals on carbohydrate-restricted diets and identified a subgroup of "Lean Mass Hyper-Responders" (LMHR) who exhibit exceptional increases in LDL-C, in the context of low triglycerides and high HDL-C. We present the case of one subject, LM, who adopted a ketogenic diet for management of ulcerative colitis. He subsequently experienced an increase in LDL-C from 95 to 545 mg/dl, at peak, in association with HDL-C >100 mg/dl and triglycerides ~40 mg/dl, typical of the emergent LMHR phenotype. Assessments of LM's dietary intake, lipid panels, and BMI are consistent with prior data and suggest that the LMHR phenomenon is not dependent on saturated fat intake but inversely associates with BMI changes. Finally, computed tomography angiography conducted on LM after over 2 years of hypercholesterolemia revealed no evidence of calcified or non-calcified plaque.

When lean people adopt carbohydrate-restricted diets (CRDs), they may develop a lipid profile consisting of elevated LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C) with low triglycerides (TGs). The magnitude of this lipid profile correlates with BMI such that those with lower BMI exhibit larger increases in both LDL-C and HDL-C. The inverse association between BMI and LDL-C and HDL-C change on CRD contributed to the discovery of a subset of individuals-termed Lean Mass Hyper-Responders (LMHR)-who, despite normal pre-diet LDL-C, as compared to non-LMHR (mean levels of 148 and 145 mg/dL, respectively), exhibited a pronounced hyperlipidemic response to a CRD, with mean LDL-C and HDL-C levels increasing to 320 and 99 mg/dL, respectively, in the context of mean TG of 47 mg/dL. In some LMHR, LDL-C levels may be in excess of 500 mg/dL, again, with relatively normal pre-diet LDL-C and absent of genetic findings indicative of familial hypercholesterolemia in those who have been tested. The Lipid Energy Model (LEM) attempts to explain this metabolic phenomenon by positing that, with carbohydrate restriction in lean persons, the increased dependence on fat as a metabolic substrate drives increased hepatic secretion and peripheral uptake of TG contained within very low-density lipoproteins (VLDL) by lipoprotein lipase, resulting in marked elevations of LDL-C and HDL-C, and low TG. Herein, we review the core features of the LEM. We review several existing lines of evidence supporting the model and suggest ways to test the model's predictions.

The adoption of carbohydrate-restrictive diets to improve health is increasing in popularity, but there is a dearth of research on individuals who choose to severely restrict or entirely exclude carbohydrates. The present study investigated the beliefs and experiences of individuals following a diet that severely limits, or entirely excludes, dietary carbohydrates, colloquially known as a 'zero-carb' diet, for at least 6 months. Zero-carb dieters (n = 170) recruited via a social networking site completed an online qualitative survey prompting them to discuss their motives, rationale, and experiences of following a low-carb diet. Transcripts of participants' responses were analyzed using inductive thematic analysis. Results revealed that participants' decision to follow a zero-carb diet was driven by health concerns and benefits. Participants expressed a strong social identity and belongingness to online zero-carb communities. Participants reported strong intentions to follow the diet indefinitely. Shortcomings of the diet centered on experienced stigma; lack of support from healthcare providers and significant others; limited access to, and high cost of, foods; and limited scientific data on the diet. Further research into the benefits and shortcomings of zero-carb diets across settings and populations is warranted, and guidelines for healthcare professionals on how to support individuals following a zero-carb diet are needed.

The confluence of basic cell biochemistry, epidemiological and anthropologic evidence points to high dietary carbohydrate and the associated disruption of the glucose-insulin axis as causes of the current increase in metabolic disorders, metabolic syndrome, hypertension and cardiovascular disease. This hyperinsulinemic state likely contributes, as well, to an increased mutagenic microenvironment, with increased risk for cancer. This critical review discusses these risks in their historical and evolutionary context. The evidence supports the benefits of lowering the glycemic load of the diet as a preventive measure against the development of cancer.