Priska Stahel

Polygenic Risk for Hypertriglyceridemia Can Mimic a Major Monogenic Mutation

Background: One in 1 million persons has monogenic, familial chylomicronemia that leads to marked hypertriglyceridemia (fasting plasma triglyceride levels>10 mmol/L [>885 mg/dL]), a defect associated with an increased risk for acute pancreatitis. Several genes, including LPL, APOC2, APOA5, LMF1, and GPIHBP1, can have large-effect mutations that are sufficient to cause the phenotype of hypertriglyceridemia when they are in a simple homozygous or compound heterozygous state (1). In contrast, more than 150 common-variant loci contribute modestly to perturbed lipid levels (2). To measure the joint effects of these loci on triglyceride levels, investigators developed the triglyceride polygenic risk score (3). This score is based on the 14 loci that most affect triglyceride levels and is calculated by adding the number of variant alleles. Because there are 2 alleles at each locus, the maximum score is 28. A triglyceride polygenic risk score of 14 represents the 50th percentile in the distribution of scores for persons with normal lipid levels, and a score of 18 represents the greater than 99th percentile based on gene sequences from 1000 persons. Therefore, most persons have at least 50% of the variant loci but still maintain normal triglyceride levels. Persons with elevated scores are genetically predisposed to moderate hypertriglyceridemia but are typically believed to require secondary factors to induce this condition, such as obesity, metabolic syndrome, pregnancy, heavy alcohol consumption, or use of some medications (1). Elevated low- and high-density lipoprotein cholesterol levels have separate polygenic risk scores (3). Objective: To show that a high polygenic risk for hypertriglyceridemia can mimic a major monogenic mutation, even without other causes of hypertriglyceridemia. Case Report: A 22-year-old man presented with severe hypertriglyceridemia despite overall excellent health, a high level of physical activity, healthy diet, body mass index of 25 kg/m2, and no other identifiable causes of this condition. He had fasting plasma lipid testing in light of an extensive family history of cardiovascular disease, and results revealed marked hypertriglyceridemia (11 mmol/L [973 mg/dL]) and markedly elevated total cholesterol levels (8 mmol/L [309 mg/dL]). A 3-day food diary documented minimal alcohol intake and showed no evidence that the patients diet was contributing to his lipid profile. Additional testing found normal thyroid, renal, and hepatic function. The patients lipid profile normalized with daily rosuvastatin, 20 mg/d, and fenofibrate, 145 mg/d. We sequenced 69 of the genes that were most likely to explain the patients lipid profile by using the LipidSeq panel on the MiSeq platform (Illumina) (2). We found no major mutations that are known to cause severe hypertriglyceridemia. The patients APOE genotype was E3/E2, and we noted no copy number variants. However, we did find many common polymorphisms that produced a triglyceride polygenic risk score of 19 (>99th percentile) and a low-density lipoprotein cholesterol polygenic risk score of 15 (maximum score, 20; 92nd percentile) (Table). Table. SNPs Used to Calculate the Patients LDL Cholesterol and Triglyceride Polygenic Risk Scores Discussion: When a young person presents with severe hypertriglyceridemia and a healthy lifestyle, the usual cause is 1 or more monogenic, high-effect mutations in the key genes that affect lipid metabolism. However, we believe that this patients severe hypertriglyceridemia should be attributed solely to his elevated polygenic risk score but recognize that it could be due to a gene that has yet to be characterized. This case highlights the need for physicians to consider a polygenic cause for patients with severe hypertriglyceridemia. This possibility should be evaluated using methods that screen for rare, large-effect variants and the common, small-effect polymorphisms that are used to calculate polygenic risk scores, such as the LipidSeq panel.

Effects of Intranasal Insulin on Triglyceride-Rich Lipoprotein Particle Production in Healthy Men.

Objective— Insulin administered directly into the brain acutely suppresses hepatic glucose production and triglyceride-rich lipoprotein (TRL) secretion in rodents. In addition, intranasally administered insulin, which selectively raises cerebrospinal fluid insulin concentration, suppresses hepatic glucose production in humans; however, its effect on TRL secretion in humans has not previously been examined. In this study, we examined whether intranasal insulin, administered at a dose that has previously been shown to suppress hepatic glucose production, modulates TRL particle secretion by the liver and intestine in humans. Approach and Results— Nine healthy, normolipidemic, and normoglycemic men participated in a study consisting of 2 randomized study arms. Subjects received intranasal lispro insulin (40 IU) or placebo. Because intranasal insulin results in a rapid and transient increase in systemic insulin concentration after administration, we matched systemic insulin concentrations in the 2 study arms by infusing lispro insulin intravenously for 30 minutes together with intranasal placebo administration. Apo (apolipoprotein) B100–containing (hepatically derived) and apoB48-containing (intestinally derived) TRL lipoprotein particle turnover were measured for the ensuing 10 hours under pancreatic clamp conditions and constant fed state, using stable isotope enrichment techniques and multicompartmental modeling. Under these experimental conditions, no significant effects of intranasal insulin versus placebo on TRL apoB100 or B48 concentrations, fractional catabolic rates, or production rates were observed. Conclusions— Insulin delivered intranasally at a dose that has been shown to raise cerebrospinal fluid insulin concentration and suppress hepatic glucose production does not affect TRL particle production by the liver and intestine in healthy men. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT03141827.

Evaluation of the specific effects of intranasal glucagon on glucose production and lipid concentration in healthy men during a pancreatic clamp

To investigate the specific effects of intranasal glucagon (ING) on plasma glucose, endogenous glucose production (EGP) and lipid concentration.

The Atherogenic Dyslipidemia Complex and Novel Approaches to Cardiovascular Disease Prevention in Diabetes

Despite the effectiveness of low-density lipoprotein (LDL)-lowering strategies for the treatment of diabetic dyslipidemia, significant residual risk of atherosclerotic cardiovascular disease remains. Residual risk might in part be explained by lipid abnormalities that go beyond LDL cholesterol elevation, collectively termed the atherogenic dyslipidemia complex (ADC), consisting of hypertriglyceridemia, elevated small dense LDL particles, reduced high-density lipoprotein cholesterol, and high-density lipoprotein particle numbers, increased remnant lipoproteins, and postprandial hyperlipidemia. In this review, we briefly discuss the pathophysiology of the typical dyslipidemia that occurs in insulin-resistant states including obesity, the metabolic syndrome, and type 2 diabetes. Lipid-modifying strategies including lifestyle modification, ezetimibe, statins, fibrates, niacin, and cholesteryl ester transfer protein inhibitors in treating ADC are discussed. With the advent of novel therapies involving antisense oligonucleotides and monoclonal antibodies, new targets can be specifically downregulated to potentially promote lipoprotein clearance or suppress production. We review novel approaches currently undergoing clinical testing and we speculate on their suitability for use in treating ADC for the prevention of atherosclerotic cardiovascular disease. In addition, future targets that might be considered for therapeutic development are discussed.

Recent Advances in Triacylglycerol Mobilization by the Gut

Dietary lipid absorption and lipoprotein secretion by the gut are important in maintaining whole-body energy homeostasis and have significant implications for health and disease. The processing of dietary lipids, including storage within and subsequent mobilization and transport from enterocyte cytoplasmic lipid droplets or other intestinal lipid storage pools (including the secretary pathway, lamina propria and lymphatics) and secretion of chylomicrons, involves coordinated steps that are subject to various controls. This review summarizes recent advances in our understanding of the mechanisms that underlie lipid storage and mobilization by small intestinal enterocytes and the intestinal lymphatic vasculature. Therapeutic targeting of lipid processing by the gut may provide opportunities for the treatment and prevention of dyslipidemia, and for improving health status.

Phenotypic and genetic analysis of an adult cohort with extreme obesity

Context:Adult extreme obesity (EO) is a growing health concern. The prevalence of known obesity associated co-morbidities namely cardio-metabolic and neuro-psychiatric disease in EO is not fully established. The contribution of pathogenic genetic variants, previously implicated in early childhood onset obesity, to adult EO is also not established.Objective:We undertook phenotypic and genetic analysis of adult patients with extreme obesity (EO, BMIu2009>u200950). Specifically, we assessed the prevalence of eating disorders, cardio-metabolic, and neuro-psychiatric disease and the presence of pathogenic variants in known monogenic obesity genes.Design:A total of 55 patients with EO from a single site bariatric surgery referral program were assessed for the presence of eating disorders, cardio-metabolic, and neuro-psychiatric disease. The 54 obese (O) patients with a BMIu2009<u200950 from the same program were identified for phenotypic comparison. The 45 EO patients underwent whole exome sequencing to identify deleterious variants in known monogenic obesity genes.Outcomes:(1) Presence of eating disorders, cardio-metabolic, and neuro-psychiatric disease in EO compared to O. (2) Onset of obesity in the EO group. (3) Presence of deleterious variants in genes previously implicated in monogenic obesity in the EO group.Results:The EO group had higher prevalence of lifetime neuro-psychiatric disease (67.3% vs. 37%, pu2009=u20090.001) and sleep apnea (74.6% vs. 51.9%, pu2009=u20090.01) but lower prevalence of type 2 diabetes (30.1% vs. 50%, pu2009=u20090.045) compared to O. There were no significant differences in binge eating, dyslipidemia, hypertension, and cardiac disease. In the EO group, we found previously unreported singleton variants in NTRK2 (pS667W, bio-informatically predicted to be deleterious) and BDNF (pE23K). No previously confirmed loss of function variants in monogenic obesity genes were found.Conclusions:Adults with EO have significantly increased prevalence of neuro-psychiatric disease and a possibly lower burden of type 2 diabetes compared to less obese patients. Known monogenic causes of obesity were not highly prevalent in this cohort. Further studies are warranted to confirm these preliminary findings.

Effects of intranasal insulin on endogenous glucose production in insulin-resistant men

The effects of intranasal insulin on the regulation of endogenous glucose production (EGP) in individuals with insulin resistance were assessed in a single‐blind, crossover study. Overweight or obese insulin‐resistant men (n = 7; body mass index 35.4 ± 4.4 kg/m2, homeostatic model assessment of insulin resistance 5.6 ± 1.6) received intranasal spray of either 40 IU insulin lispro or placebo in 2 randomized visits. Acute systemic spillover of intranasal insulin into the circulation was matched with a 30‐minute intravenous infusion of insulin lispro in the nasal placebo arm. EGP was assessed under conditions of a pancreatic clamp with a primed, constant infusion of glucose tracer. Under these experimental conditions, compared with placebo, intranasal administration of insulin did not significantly affect plasma glucose concentrations, EGP or glucose disposal in overweight/obese, insulin‐resistant men, in contrast to our previous study, in which an equivalent dose of intranasal insulin significantly suppressed EGP in lean, insulin‐sensitive men. Insulin resistance is probably associated with impairment in centrally mediated insulin suppression of EGP.

Control of intestinal lipoprotein secretion by dietary carbohydrates

PURPOSE OF REVIEWnDyslipidemia is a major risk factor for atherosclerotic cardiovascular disease (CVD). Lipoproteins secreted by the intestine can contribute to dyslipidemia and may increase risk for CVD. This review focuses on how dietary carbohydrates can impact the production of chylomicrons, thereby influencing plasma concentrations of triglycerides and lipoproteins.nnnRECENT FINDINGSnHypercaloric diets high in monosaccharides can exacerbate postprandial triglyceride concentration. In contrast, isocaloric substitution of monosaccharides into mixed meals has no clear stimulatory or inhibitory effect on postprandial triglycerides. Mechanistic studies with oral ingestion of carbohydrates or elevation of plasma glucose have demonstrated enhanced secretion of chylomicrons. The mechanisms underlying this modulation remain largely unknown but may include enhanced intestinal de novo lipogenesis and mobilization of intestinally stored lipids.nnnSUMMARYnThe studies reviewed here have implications for dietary recommendations regarding refined carbohydrate intake and prevention of CVD.

Oral Glucose Mobilizes Triglyceride Stores from the Human Intestine

Background & Aims The small intestine regulates plasma triglyceride (TG) concentration. Within enterocytes, dietary TGs are packaged into chylomicrons (CMs) for secretion or stored temporarily in cytoplasmic lipid droplets (CLDs) until further mobilization. We and others have shown that oral and intravenous glucose enhances CM particle secretion in human beings, however, the mechanisms through which this occurs are incompletely understood. Methods Two separate cohorts of participants ingested a high-fat liquid meal and, 5 hours later, were assigned randomly to ingest either a glucose solution or an equivalent volume of water. In 1 group (N = 6), plasma and lipoprotein TG responses were assessed in a randomized cross-over study. In a separate group (N = 24), duodenal biopsy specimens were obtained 1 hour after ingestion of glucose or water. Ultrastructural and proteomic analyses were performed on duodenal biopsy specimens. Results Compared with water, glucose ingestion increased circulating TGs within 30 minutes, mainly in the CM fraction. It decreased the total number of CLDs and the proportion of large-sized CLDs within enterocytes. We identified 2919 proteins in human duodenal tissue, 270 of which are related to lipid metabolism and 134 of which were differentially present in response to glucose compared with water ingestion. Conclusions Oral glucose mobilizes TGs stored within enterocyte CLDs to provide substrate for CM synthesis and secretion. Future studies elucidating the underlying signaling pathways may provide mechanistic insights that lead to the development of novel therapeutics for the treatment of hypertriglyceridemia.