Phenotypic Differences Among Familial Partial Lipodystrophy Due to LMNA or PPARG Variants.

Context: Despite several reports of familial partial lipodystrophy (FPLD) type 2 (FPLD2) due to heterozygous LMNA variants and FPLD3 due to PPARG variants, the phenotypic differences among them remain unclear. Objective: To compare the body fat distribution, metabolic parameters, and prevalence of metabolic complications between FPLD3 and FPLD2. Methods: A retrospective, cross-sectional comparison of patients from 2 tertiary referral centers-UT Southwestern Medical Center and the National Institute of Diabetes and Digestive and Kidney Diseases. A total of 196 females and 59 males with FPLD2 (age 2-86 years) and 28 females and 4 males with FPLD3 (age 9-72 years) were included. The main outcome measures were skinfold thickness, regional body fat by dual-energy X-ray absorptiometry (DXA), metabolic variables, and prevalence of diabetes mellitus and hypertriglyceridemia. Results: Compared with subjects with FPLD2, subjects with FPLD3 had significantly increased prevalence of hypertriglyceridemia (66% vs 84%) and diabetes (44% vs 72%); and had higher median fasting serum triglycerides (208 vs 255 mg/dL), and mean hemoglobin A1c (6.4% vs 7.5%). Compared with subjects with FPLD2, subjects with FPLD3 also had significantly higher mean upper limb fat (21% vs 27%) and lower limb fat (16% vs 21%) on DXA and increased median skinfold thickness at the anterior thigh (5.8 vs 11.3 mm), calf (4 vs 6 mm), triceps (5.5 vs 7.5 mm), and biceps (4.3 vs 6.8 mm). Conclusion: Compared with subjects with FPLD2, subjects with FPLD3 have milder lipodystrophy but develop more severe metabolic complications, suggesting that the remaining adipose tissue in subjects with FPLD3 may be dysfunctional or those with mild metabolic disease are underrecognized.

Diagnostic Value of Anthropometric Measurements for Familial Partial Lipodystrophy, Dunnigan Variety.

CONTEXT: Familial partial lipodystrophy, Dunnigan variety (FPLD2) is a rare autosomal dominant disorder resulting from LMNA causal variants, which is characterized by loss of subcutaneous fat from the extremities and predisposition to metabolic complications. The diagnostic value of various anthropometric measurements for FPLD2 remains unknown. OBJECTIVE: To determine specificity and sensitivity of anthropometric measurements for the diagnosis of FPLD2. METHODS: We measured skinfold thickness and regional body fat by dual energy X-ray absorptiometry (DXA) in 50 adult females and 6 males with FPLD2 at UT Southwestern and compared their data with the sex- and age-matched controls from the National Health and Nutrition Examination Survey (NHANES) 1999-2010. We further compared data from 1652 unaffected females from the Dallas Heart Study and 23 females with FPLD2 from the National Institutes of Health with the NHANES data. RESULTS: The DXA-derived lower limb fat (%) had the best specificity (0.995) and sensitivity (1.0) compared with the upper limb fat, truncal fat, the ratio of lower limb to truncal fat, and triceps skinfold thickness for adult females with FPLD2. The lower limb fat below 1st percentile of NHANES females had a false-positive rate of 0.0054 and a false negative rate of 0. The diagnostic value of anthropometric parameters could not be determined for males with FPLD2 due to small sample size. CONCLUSIONS: The lower limb fat (%) is the best objective anthropometric measure for diagnosing FPLD2 in females. Women with below the 1st percentile lower limb fat should undergo genetic testing for FPLD2, especially if they have metabolic complications.

Very Severe Hypertriglyceridemia in a Large US County Health Care System: Associated Conditions and Management.

CONTEXT: Patients with very severe hypertriglyceridemia (triglyceride levels ≥2000 mg/dL; 22.6 mmol/L) require aggressive treatment. However, little research exists on the underlying etiologies and management of very severe hypertriglyceridemia. OBJECTIVE: We hypothesized (i) very severe hypertriglyceridemia in adults is mostly associated with secondary causes and (ii) most patients with very severe hypertriglyceridemia lack appropriate follow-up and treatment. DESIGN: We queried electronic medical records at Parkland Health and Hospital Systems for lipid measurements in the year 2016 and identified patients with serum triglyceride levels ≥2000 mg/dL (22.6 mmol/L). We extracted data on demographics, underlying causes, lipid-lowering therapy, and follow-up. RESULTS: One hundred sixty-four serum triglyceride measurements were ≥2000 mg/dL (22.6 mmol/L) in 103 unique patients. Of these, 60 patients were admitted to the hospital (39 for acute pancreatitis). Most were Hispanic (79%). The major conditions associated with very severe hypertriglyceridemia included uncontrolled diabetes mellitus (74%), heavy alcohol use (10%), medication use (7%), and hypothyroidism (2%). Two patients were known to have monogenic causes of hypertriglyceridemia. After the index measurement of triglycerides ≥2000 mg/dL (22.6 mmol/L), the use of triglyceride-lowering drugs increased, most prominently the use of fish oil supplements, which increased by 80%. However, in follow-up visits, hypertriglyceridemia was addressed in only 50% of encounters, and serum triglycerides were remeasured in only 18%. CONCLUSION: In summary, very severe hypertriglyceridemia was quite prevalent (∼0.1% of all lipid measurements) in our large county health care system, especially in Hispanic men. Most cases were related to uncontrolled diabetes mellitus, and follow-up monitoring was inadequate.

Regional Body Fat Changes and Metabolic Complications in Children With Dunnigan Lipodystrophy-Causing LMNA Variants.

CONTEXT: Familial partial lipodystrophy, Dunnigan variety (FPLD2) is a rare autosomal-dominant disorder due to heterozygous missense lamin A/C (LMNA) mutations. Subjects with FPLD2 gradually lose fat from the upper and lower extremities but gain fat in the face and neck around puberty. However, the precise onset of body fat changes and metabolic complications during childhood remains unknown. OBJECTIVE: To compare metabolic parameters and regional body fat in children with FPLD2 with the sex- and age-matched controls from the National Health and Nutrition Examination Survey (NHANES) 2005 to 2010. METHODS: We measured fasting serum triglycerides, glucose, and skinfold thicknesses in all children (aged 1 to 18 years) harboring FPLD2-causing LMNA mutations and determined regional body fat by dual-energy X-ray absorptiometry in those aged ≥8 years. RESULTS: Thirty-two affected females and 14 males participated. The lower limb fat in all affected females, except one, was below or equal to the first percentile and in two affected males was below the fifth percentile for NHANES. One female subject with FPLD2 followed from age 6 to 16 years revealed marked loss of extremity fat much before thelarche. Serum triglycerides were higher in females with FPLD2 aged 7 to 18 years compared with controls (median 208 vs 70 mg/dL; P < 0.0001) and showed inverse correlation with extremity skinfolds. Serum triglycerides in males with FPLD2 were not significantly different than controls. CONCLUSIONS: The onset of fat loss from the extremities, especially in girls with FPLD2, occurs well before the onset of puberty. High serum triglycerides are seen in young females with FPLD2 with severe loss of fat from the extremities.

Comparison of nutrient intakes in South Asians with type 2 diabetes mellitus and controls living in the United States.

AIMS: Despite having a high risk for type 2 diabetes mellitus (T2DM), little is known about the relationship between nutrient intakes and T2DM in South Asians (SA) in the U.S. In addition, the available data are limited to a few macronutrients and collected using subjective measures. Therefore, we compared macro- and micro-nutrient intakes of SA migrants with and without T2DM using an objective measure. METHODS: SA in the U.S. with T2DM (n = 44) and controls (n = 33) reported their dietary intake using image-assisted dietary assessment method. They took pictures of all foods/drinks consumed on two weekdays and one weekend day. Age, gender distribution, and body mass index were similar across the two groups. RESULTS: SA with T2DM, as compared to controls, consumed less total energy (mean difference: 499 kcal/d; p < .0001), linoleic acid (3.6 g/d; p = .003), dietary fiber (8.6 g/d; p < .0001), vitamin A (262 µg/d; p = .003), vitamin E (2.7 mg/d; p = .007), calcium (133 mg/d; p = .01), magnesium (116 mg/d; p < .0001), zinc (1.4 mg/d; p = .004), potassium (754 mg/d; p < .0001), and ß-carotene (1761 µg/d; p = .03). SA with T2DM, as compared to controls, were significantly more likely not to meet the requirements for linoleic acid, dietary fiber, vitamin E, calcium, magnesium, zinc, and potassium (p < .05). CONCLUSIONS: SA with T2DM, compared to controls, consume less total energy and have lower consumption of many nutrients associated with reduced risk of T2DM. Dietary interventions to reduce risk for T2DM are warranted in SA.

Efficacy and Safety of Metreleptin Therapy in Patients With Type 1 Diabetes: A Pilot Study.

OBJECTIVE: To study the efficacy and safety of metreleptin therapy in patients with suboptimally controlled type 1 diabetes mellitus (T1DM). RESEARCH DESIGN AND METHODS: After a baseline period of 4 weeks, five female and three male patients with T1DM (mean age 33 years, BMI 23.8 kg/m2) received metreleptin (0.08 mg/kg/day in females and 0.04 mg/kg/day in males) subcutaneously twice daily for 20 weeks followed by an off-therapy period of 4 weeks. RESULTS: Metreleptin therapy did not lower HbA1c significantly compared with the baseline value (mean difference -0.19% [-2.0 mmol/mol] and -0.04% [-0.5 mmol/mol] at 12 and 20 weeks, respectively). Mean body weight reduced significantly by 2.6 and 4.7 kg (P = 0.003) and daily insulin dose by 12.6% and 15.0% at week 12 and 20 (P = 0.006), respectively. CONCLUSIONS: Metreleptin is safe but may not be efficacious in improving glycemic control in patients with T1DM, although it reduces body weight and daily insulin dose modestly.

US physician practices for diagnosing familial hypercholesterolemia: data from the CASCADE-FH registry.

BACKGROUND: In the US familial hypercholesterolemia (FH), patients are underidentified, despite an estimated prevalence of 1:200 to 1:500. Criteria to identify FH patients include Simon Broome, Dutch Lipid Clinic Network (DLCN), or Make Early Diagnosis to Prevent Early Deaths (MEDPED). The use of these criteria in US clinical practices remains unclear. OBJECTIVE: To characterize the FH diagnostic criteria applied by US lipid specialists participating in the FH Foundation's CASCADE FH (CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia) patient registry. METHODS: We performed an observational, cross-sectional analysis of diagnostic criteria chosen for each adult patient, both overall and by baseline patient characteristics, at 15 clinical sites that had contributed data to the registry as of September 8, 2015. A sample of 1867 FH adults was analyzed. The median age at FH diagnosis was 50 years, and the median pretreatment low-density lipoprotein cholesterol (LDL-C) value was 238 mg/dL. The main outcome was the diagnostic criteria chosen. Diagnostic criteria were divided into five nonexclusive categories: "clinical diagnosis," MEDPED, Simon Broome, DLCN, and other. RESULTS: Most adults enrolled in CASCADE FH (55.0%) received a "clinical diagnosis." The most commonly used formal criteria was Simon-Broome only (21%), followed by multiple diagnostic criteria (16%), MEDPED only (7%), DLCN only (1%), and other (0.5%), P < .0001. Of the patients with only a "clinical diagnosis," 93% would have met criteria for Simon Broome, DLCN, or MEDPED based on the data available in the registry. CONCLUSIONS: Our findings demonstrate heterogeneity in the application of FH diagnostic criteria in the United States. A nationwide consensus definition may lead to better identification, earlier treatment, and ultimately CHD prevention.

Upregulation of hepatic LDL transport by n-3 fatty acids in LDL receptor knockout mice.

We determined the effects of dietary n-6 and n-3 polyunsaturated fatty acids (PUFA) on parameters of plasma lipoprotein and hepatic lipid metabolism in LDL receptor (LDLr) knockout mice. Dietary n-3 PUFA decreased the rate of appearance and increased the hepatic clearance of IDL/LDL resulting in a marked decrease in the plasma concentration of these particles. Dietary n-3 PUFA increased the hepatic clearance of IDL/LDL through a mechanism that appears to involve apolipoprotein (apo)E but is independent of the LDLr, the LDLr related protein (LRP), the scavenger receptor B1, and the VLDLr. The decreased rate of appearance of IDL/VLDL in the plasma of animals fed n-3 PUFA could be attributed to a marked decrease in the plasma concentration of precursor VLDL. Decreased plasma VLDL concentrations were due in part to decreased hepatic secretion of VLDL triglyceride and cholesteryl esters, which in turn was associated with decreased concentrations of these lipids in liver. Decreased hepatic triglyceride concentrations in animals fed n-3 PUFA were due in part to suppression of fatty acid synthesis as a result of a decrease in sterol regulatory element binding protein-1 (SREBP-1) expression and processing. In conclusion, these studies indicate that n-3 PUFA can markedly decrease the plasma concentration of apoB-containing lipoproteins and enhance hepatic LDL clearance through a mechanism that does not involve the LDLr pathway or LRP.