Dietary Recommendations for Familial Hypercholesterolaemia: an Evidence-Free Zone

We have evaluated dietary recommendations for people diagnosed with familial hypercholesterolaemia (FH), a genetic condition in which increased low-density lipoprotein cholesterol (LDL-C) is associated with an increased risk for coronary heart disease (CHD). Recommendations for FH individuals have emphasised a low saturated fat, low cholesterol diet to reduce their LDL-C levels. The basis of this recommendation is the ‘diet-heart hypothesis’, which postulates that consumption of food rich in saturated fat increases serum cholesterol levels, which increases risk of CHD. We have challenged the rationale for FH dietary recommendations based on the absence of support for the diet-heart hypothesis, and the lack of evidence that a low saturated fat, low cholesterol diet reduces coronary events in FH individuals. As an alternative approach, we have summarised research which has shown that the subset of FH individuals that develop CHD exhibit risk factors associated with an insulin-resistant phenotype (elevated triglycerides, blood glucose, haemoglobin A1c (HbA1c), obesity, hyperinsulinaemia, high‐sensitivity C reactive protein, hypertension) or increased susceptibility to develop coagulopathy. The insulin-resistant phenotype, also referred to as the metabolic syndrome, manifests as carbohydrate intolerance, which is most effectively managed by a low carbohydrate diet (LCD). Therefore, we propose that FH individuals with signs of insulin resistance should be made aware of the benefits of an LCD. Our assessment of the literature provides the rationale for clinical trials to be conducted to determine if an LCD would prove to be effective in reducing the incidence of coronary events in FH individuals which exhibit an insulin-resistant phenotype or hypercoagulation risk.

Subversion of Systemic Glucose Metabolism As a Mechanism to Support the Growth of Leukemia Cells

Epidemiological studies indicate that obese populations have an increased risk for leukemia. However, the mechanism underlying this phenomenon remains unclear. In the current study, utilizing both murine AML models and human AML samples, we observe that AML pathogenesis leads to aberrancies in adipose tissue, pancreatic function, and gut/microbiome, all of which contribute to an insulin resistant phenotype. We demonstrate that through induction of insulin resistance, leukemic disease alters systemic metabolism and thereby redirects systemic glucose to be preferentially available to malignant cells. We found that insulin effect on leukemic mice was significantly impaired as shown by insulin tolerance tests (ITT) (Fig.1) as well as by reduced glucose utilization in both adipose and muscle tissues. Interestingly, glucose utilization in leukemia cells was not affected by insulin. Several mechanisms were found to underlie this insulin resistant phenotype. First, leukemia induced a high-level production of IGFBP1 from adipose tissue and led to a 100-fold increase in circulating IGFBP1, which impaired insulin sensitivity (Fig.1). Blocking IGFBP1 partially restored insulin sensitivity and reduced leukemic burden, whereas pretreating with IGFBP1 facilitated leukemic progression. Second, a 95% reduction in the gut-derived circulating serotonin led to a significant decrease in insulin secretion from pancreas in leukemic mice (Fig.2). Serotonin supplementation partially restored serum insulin levels and decreased leukemic burden by 50% (Fig.2). Finally, the profile of gut microbiota in leukemic mice was distinct from normal mice. Leukemia-associated microbiota functionally contributed to the insulin resistant phenotype and therefore promoted disease progression. Mechanistically, decreased productions of microbiota-derived short chain fatty acids (SCFAs) i.e. butyrate and propionate, were found in leukemic fecal materials and butyrate supplementation reduced leukemic burden by 50% (Fig.2). Of note, there was interplay between these mechanisms. For example, agents increasing insulin levels resulted in a decreased IGFBP1 production in leukemic mice. Further, leukemia-associated microbiota also contributed to the elevated IGFBP1 level and the reduced insulin level in leukemic mice. To test the therapeutic relevance of our findings, we combined serotonin supplementation with butyrate, and found this combination (hereafter termed 'Ser-Bu') reduced leukemic burden by 80% (Fig.3) and provided survival benefits. More importantly, multiple assays including PET-CT scanning (Fig.3), 3H-2-DG labeling, and 13C-NMR labeling were employed to demonstrate that Ser-Bu treatment increased glucose uptake/utilization in adipose and muscle tissues by 200% and 50% respectively and reduced glucose uptake/utilization in leukemia cells by 70% (Fig.3). Therefore, leukemia progression can be significantly attenuated solely by modulation of systemic glucose metabolism. To examine the human relevance of our findings, we analyzed serum samples from normal controls, MDS and AML patients and found that a 6-fold and a 14-fold increase of IGFBP1 in MDS and AML serum respectively compared to normal controls (Fig.4). Additionally, other insulin resistance indicators such as serum free fatty acids, inflammatory cytokines and serum Leptin and Resistin levels were all elevated in AML serum. An insulin resistant phenotype and elevated serum IGFBP1 were also observed in a primary human leukemia specimen xenograft model. Further, a 65% reduction in serotonin was found in AML serum compared to normal controls (Fig.4). Impressively, analyses of paired diagnostic, remission and relapsed BM specimens showed that IGFBP1 was decreased in remission samples and rebounded in the relapsed state, whereas serotonin level showed the opposite pattern (Fig.5). Together, these data support that an insulin resistant phenotype is also evident in AML patients. Collectively, our studies suggest that leukemic tumors gain a competitive advantage by co-opting multiple mechanisms to induce a diabetes-like physiological condition and thereby subvert systemic glucose metabolism to facilitate disease progression. Our studies demonstrate that restoration of normal glucose regulation may be a feasible strategy to suppress systemic growth of malignant cell types. Disclosures Pollyea: Gilead: Consultancy; Curis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Thin–fat insulin-resistant phenotype also present in South Asian neonates born in the Netherlands

Several studies have shown that South Asian neonates have a characteristic thin–fat insulin-resistant phenotype. The aim of our study was to determine whether this phenotype is also present in South Asians who have migrated to a Western country (the Netherlands). South Asian and white Dutch pregnant women were included in our study. After delivery, cord blood was collected and neonatal anthropometry was measured within 72 h. Compared with white Dutch mothers, South Asian mothers were younger (28.5 v. 32.2 years, P<0.001) and had a higher prepregnancy body mass index (25.1 v. 23.0, P=0.001). Gestational age at delivery was on average 4 days shorter in South Asians (274.9 v. 278.8, P=0.001). To compare the two groups of neonates, we calculated sex- and gestation-specific s.d. scores using the values for mean and s.d. obtained from the white Dutch subjects as a reference. All measurements were smaller in South Asian neonates, except for those of the skinfolds. The largest difference was found in abdominal circumference (s.d. score 1.39, 95% CI −1.76 to −1.01). Triceps and subscapular skinfolds were similar in both groups (triceps s.d. score −0.34, 95% CI −0.88 to +0.20 and subscapular s.d. score −0.03, 95% CI −0.31 to +0.25). South Asian neonates had higher cord plasma levels of triglycerides (0.40 v. 0.36, P=0.614), glucose (5.4 v. 4.8, P=0.079) and insulin (6.3 v. 4.0, P=0.051). However, these differences were not statistically significant. After adjustment for birth weight, the difference in insulin became statistically significant (P=0.001). We therefore conclude that the thin–fat insulin-resistant phenotype is also present in South Asian neonates in the Netherlands.