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Background There is some evidence that bariatric surgery patients who undergo the purely restrictive procedures, such as the gastric banding (GB) or the vertical banded gastroplasty surgery, do not meet the dietary reference intakes for several nutrients. Whether dietary counseling improves micronutrient and macronutrient intakes was examined in GB surgery patients. Methods Twenty-three GB surgery patients received dietary and behavioral counseling for 12 weeks to limit energy intake and improve nutrient intakes. Food intake was assessed by 3-day food record at baseline and 6 and 12 weeks. Postintervention data were available in 21 patients. Results At baseline, more than 50% of the subjects reported inadequate dietary intakes of 13 nutrients but overconsumption of sodium and percent energy from saturated and trans–fatty acids. Mixed-effects model for repeated measures revealed a significant reduction in energy (P = 0.0007), absolute protein (P = 0.04), cholesterol (P = 0.045), and potassium (P = 0.01) intake and an increase in vitamin K (P = 0.03) intake and percent energy from protein (P = 0.005) during the 12 weeks. The McNemar test showed a reduction in the proportion of the subjects with an inadequate intake of vitamin K (P = 0.008) but an increase in the proportion of the subjects with an inadequate intake of thiamin (P = 0.03) at 12 weeks. The proportion of the subjects who did not meet the nutrient requirements for the remaining 27 nutrients was generally high and remained unchanged. Conclusions Dietary intervention improved the intake of some nutrients in the GB surgery patients. However, most nutrient intake requirements remained unmet by many subjects. These results indicate that nutritional counseling beyond 12 weeks is warranted in GB surgery patients to improve their dietary nutrient intakes.

Familial partial lipodystrophy (FPLD), Dunnigan variety, is an autosomal dominant disorder characterized by marked loss of subcutaneous adipose tissue from the extremities and trunk but by excess fat deposition in the head and neck. The disease is frequently associated with profound insulin resistance, dyslipidemia, and diabetes. We have localized a gene for FPLD to chromosome 1q21-q23, and it has recently been proposed that nuclear lamin A/C is altered in FPLD, on the basis of a novel missense mutation (R482Q) in five Canadian probands. This gene had previously been shown to be altered in autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD-AD) and in dilated cardiomyopathy and conduction-system disease. We examined 15 families with FPLD for mutations in lamin A/C. Five families harbored the R482Q alteration that segregated with the disease phenotype. Seven families harbored an R482W alteration, and one family harbored a G465D alteration. All these mutations lie within exon 8 of the lamin A/C gene-an exon that has also been shown to harbor different missense mutations that are responsible for EDMD-AD. Mutations could not be detected in lamin A/C in one FPLD family in which there was linkage to chromosome 1q21-q23. One family with atypical FPLD harbored an R582H alteration in exon 11 of lamin A. This exon does not comprise part of the lamin C coding region. All mutations in FPLD affect the globular C-terminal domain of the lamin A/C protein. In contrast, mutations responsible for dilated cardiomyopathy and conduction-system disease are observed in the rod domain of the protein. The FPLD mutations R482Q and R482W occurred on different haplotypes, indicating that they are likely to have arisen more than once.

Recently, great progress has been made towards understanding the molecular basis of body fat regulation. Identification of mutations in several genes in spontaneous monogenic animal models of obesity and development of transgenic models have indicated the physiological roles of many genes in the regulation of body fat distribution. In humans, mutations in leptin, leptin receptor, prohormone convertase 1 (PC1), pro-opiomelanocortin (POMC), melanocortin 4-receptor (MC4-R), and peroxisome proliferator-activated receptor (PPAR) γ2 genes have been described in patients with severe obesity. Most of these obesity disorders exhibit a distinct phenotype with varying degrees of hypothalamic and pituitary dysfunction and a recessive inheritance, whereas MC4-R mutation has a nonsyndromic phenotype with dominant inheritance. These mutations suggest the critical role of central signaling systems composed of leptin/leptin receptor and α-melanocyte stimulating hormone/MC4-R in human energy homeostasis. Although the genetic basis of monogenic disorders of body fat distribution, such as congenital generalized lipodystrophy and familial partial lipodystrophy, Dunnigan variety, is still unknown, the genes for these have recently been localized to chromosomes 9q34 and 1q21-22, respectively. The advances in our knowledge of the phenotypic manifestations and underlying molecular mechanisms of genetic body fat disorders may lead to better treatment and prevention of obesity and other disorders of adipose tissue in the future.—Chen, D., and A. Garg. Monogenic disorders of obesity and body fat distribution. J. Lipid Res. 1999. 40: 1735–1746.

It has been proposed that excessive insulin resistance in Asian Indians living in urban areas or migrated to western countries is responsible for the higher incidence of type 2 diabetes and coronary heart disease observed in this population. To evaluate whether Asian Indians are more insulin resistant than Caucasians and to define the role of generalized and truncal adiposity, we performed hydrodensitometry, skinfold measurements, and euglycemic-hyperinsulinemic clamps in 21 healthy Asian Indian men and 23 Caucasian men of similar age and body fat content. The glucose disposal rate (Rd) was significantly lower in the Asian Indians than in the Caucasians (3.7+/-1.3 vs. 5.3+/-2.0 mg/min x kg lean body mass, respectively; P = 0.003). Despite similar total body fat content, Asian Indians had higher truncal adiposity than Caucasians (sum of truncal skinfolds, 117+/-37 and 92.4+/-38 mm, respectively). In both Asian Indians and Caucasians, the insulin sensitivity index (Rd/plasma insulin concentrations) was inversely correlated with both total body fat (r = -0.49; P

We validate the use of1H magnetic resonance spectroscopy (MRS) to quantitatively differentiate between adipocyte and intracellular triglyceride (TG) stores by monitoring the TG methylene proton signals at 1.6 and 1.4 ppm, respectively. In two animal models of intracellular TG accumulation, intrahepatic and intramyocellular TG accumulation was confirmed histologically. Consistent with the histological changes, the methylene signal intensity at 1.4 ppm increased in both liver and muscle, whereas the signal at 1.6 ppm was unchanged. In response to induced fat accumulation, the TG concentration in liver derived from1H MRS increased from 0 to 44.9 ± 13.2 μmol/g, and this was matched by increases measured biochemically (2.1 ± 1.1 to 46.1 ± 10.9 μmol/g). Supportive evidence that the methylene signal at 1.6 ppm in muscle is derived from investing interfascial adipose tissue was the finding that, in four subjects with generalized lipodystrophy, a disease characterized by absence of interfacial fat, no signal was detected at 1.6 ppm; however, a strong signal was seen at 1.4 ppm. An identical methylene chemical shift at 1.4 ppm was obtained in human subjects with fatty liver where the fat is located exclusively within hepatocytes. In experimental animals, there was a close correlation between hepatic TG content measured in vivo by1H MRS and chemically by liver biopsy [ R = 0.934; P 1H MRS measurement of intracellular TG, including that within myocytes, is feasible at 1.5-T field strengths and is comparable in accuracy to biochemical measurement. In addition, in mixed tissue such as muscle, the method is clearly advantageous in differentiating between TG from contaminating adipose tissue compared with intramyocellular lipids.

Familial partial lipodystrophy, Dunnigan type (FPLD), is a rare autosomal dominant genetic disorder characterized by gradual loss of sc fat from the extremities, commencing at the time of puberty. Excess fat deposition may occur in the face and neck area. Limited information is available about adipose tissue distribution in patients with FPLD. To investigate whether there is a unique pattern of fat distribution in both affected men and women with FPLD, we performed whole-body magnetic resonance imaging in one male and three female patients from two pedigrees. Magnetic resonance imaging studies confirmed the clinical findings of near-total absence of sc fat from all extremities. Reduction in sc adipose tissue from the truncal area was more prominent anteriorly than posteriorly. Increased fat stores were observed in the neck and face. Intermuscular adipose tissue in the extremities and pelvic area were subjectively increased. Intraabdominal and intrathoracic adipose tissue was not reduced. Bone marrow fat, as well as mechanical adipose tissue, was present in normal amounts. The pattern of fat distribution in the male and females was similar. We conclude that FPLD results in a characteristic absence of sc fat from the extremities, with preservation of intermuscular fat stores.

Posttranslational processing of preproghrelin encoded by the ghrelin (GHRL) gene is predicted to yield two peptides, ghrelin and obestatin, which have been proposed to have opposite actions on feeding behavior (1, 2). Although ghrelin increases food intake (1), obestatin has been shown to suppress it (2). This commentary focuses on the recent controversy about the role of obestatin as a hormone. The GHRL gene is predominantly expressed in the stomach in X/A-like cells (specialized oxyntic gland cells) but also at low levels in the duodenum, and the rest of the bowel, pancreas, pituitary, hypothalamus, kidney, and placenta (1, 3). The GHRL gene encodes a polypeptide containing 117 residues, called preproghrelin, which undergoes stepwise processing, including proteolysis and acylation, to form ghrelin (Fig. 1) (1, 4, 5). Based on bioinformatics, Zhang et al. (2) predicted that preproghrelin can also undergo additional processing at two potential proteolytic sites to form obestatin (Fig. 1). Purification of the immunoreactive obestatin from the rat stomach extract revealed the sequence to be consistent with the obestatin sequence deduced from rat preproghrelin cDNA. The investigators reported that synthetic obestatin, when injected ip (12.5–1000 nmol/kg) or intracerebroventricularly (8 nmol/kg), acutely suppressed food intake over 5 h in adult male mice in a dose-dependent fashion. Obestatin reduced gastric emptying and inhibited jejunal contractions acutely. In adult male rats, obestatin suppressed body weight gain over a 7-d period. The hormone was reported to bind to G protein-coupled receptor-39 (GPR39) (2). As often happens in highly competitive areas of science, many original findings have been challenged. First, three groups were unable to confirm the binding of obestatin to GPR39 (6–8). Second, the original investigators themselves could not reproduce the binding of obestatin to tissue homogenates or recombinant GPR39 (9). Thus, the receptor involved in action of obestatin remains unknown. Third, obestatin lacks specific binding at the blood-brain barrier and undergoes rapid degradation (10). Furthermore, many other laboratories failed to observe any significant effects of obestatin on food intake in animal models. In doses ranging from 12–1000 nmol/kg body weight ip or approximately 1.2–12 nmol/kg intracerebroventricularly, obestatin did not reduce food intake in adult mice or rats over 1–24 h or over 7–9 d (6, 11–17). In defense of their original findings, Zhang et al. (9) reported that obestatin, 750 nmol/kg ip, reduced food intake in mice when animals had access to food at precisely 15 min after injection. Recently, Lagaud et al. (18) also observed a mild, but significant reduction in food intake with 10–300 nmol/kg obestatin given ip to mice and rats; however, higher doses were ineffective. These authors also reported reduction in food intake and weight gain over a 7-d period with three times daily obestatin injections in mice (18). Nonetheless, in the hands of most of the investigators, obestatin has shown no effects on body weight. Obestatin does not affect secretion of any pituitary hormone or corticosterone in rat (17, 19); other investigators (20) have found little or no effects of obestatin on gastric or jejunal motility. Whether obestatin reduces thirst (16), promotes sleep (21), or affects memory and anxiety (22) remains to be confirmed. Serum obestatin levels did not change upon fasting or feeding in rats (2); but in mice, a slight reduction was seen upon fasting (14). In humans also no postprandial changes in serum obestatin levels have been noted (23). For a hormone proposed to affect food intake acutely, this lack of change in circulating concentrations postprandially is surprising. The intriguing feature of the preproghrelin protein is its proteolytic cleavage, such that during one processing step ghrelin is released, and with another, obestatin is released. Studies of animals lacking various prohormone convertases (PCs) suggest that PC1 is involved in processing of proghrelin to ghrelin as well as obestatin, although direct processing of proghrelin to obestatin was not evaluated (4). A recent study suggests that PC7 and furin may also be involved in ghrelin processing (5). These proteases recognize di-basic residues K-R or R-R and cleave the peptide bond carboxy terminal to the dibasic pair (24). They may also recognize monobasic residue cleavage sites, but the rules of engagement may be different or inefficient. Although the release of ghrelin after the initial removal of signal peptide involves a single cleavage, the release of obestatin requires cleavage at both the aminoand carboxy-terminus. The efficiency with which these two cleavages might occur is not clear because the proposed cleavage sites lack the more efficient dibasic Abbreviations: GHRL, Ghrelin (gene); GPR39, G protein-coupled receptor-39; PC, prohormone convertase.

Patients with diabetes mellitus have an increased risk for coronary artery disease due to hyperglycemia, hypertension, dyslipidemia, and other risk factors. The diabetic dyslipidemia in these patients is characterized by moderately high levels of (1) serum cholesterol and triglycerides; (2) small, dense low-density lipoprotein (LDL) particles; and (3) low high-density lipoprotein (HDL) cho-lesterol concentrations. Recent clinical trials have demonstrated the benefits of cholesterol-lowering therapy in both diabetic and nondiabetic patients, thus supporting aggressive treatment of diabetic dyslipidemia for coronary artery disease prevention. A 3-step approach is recommended for the treatment of diabetic dyslipidemia. First, modification of diet and lifestyle, including decreased intakes of cholesterol, cholesterol-raising fats, and total energy, and increased physical activity should be advised. Second, good glycemic control should be achieved with diet and hypoglycemic drugs, if needed. Third, lipid-lowering drugs should be used, if necessary. Non-HDL cholesterol levels, which include both very-low-density lipoprotein (VLDL) and LDL cholesterol, should be the target of cholesterol-lowering therapy. The use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (the "statins") has become the first-line drug therapy for diabetic dyslipidemia. Bile acid sequestrants are effective cholesterol-lowering agents in normotriglyceridemic patients with non-insulin-dependent diabetes mellitus (NIDDM). Patients with severe hypertriglyceridemia may require fibric acids or n-3 polyunsaturated fatty acids. Nicotinic acid worsens hyperglycemia; therefore, it should be avoided in most cases. The efficacy and safety of estrogen-replacement therapy in postmenopausal women with diabetes needs to be determined. The combination of two lipid-lowering agents may be appropriate for some NIDDM patients but should be used judiciously.

Two lines of investigation have provided important insights into dietary therapy of hypercholesterolemia. Studies have confirmed the efficacy of the US National Cholesterol Education Program Step II diet in lowering serum LDL-cholesterol concentrations and demonstrate that wide variability exists in responsiveness to this diet. Other studies indicate that, contrary to expectations, cholesterol raising saturated fatty acids are not limited to long-chain saturates, but also include medium-chain and very long-chain saturated fatty acids.

To develop a simplified but accurate method for determining the masses of various abdominal adipose tissue compartments, we studied the predictive value of masses of intraperitoneal, retroperitoneal, and subcutaneous abdominal adipose tissue determined on single axial abdominal magnetic resonance imaging (MRI) slices taken at various intervertebral levels from the 12th thoracic to 1st sacral vertebra (identified on a sagittal section) for the respective total masses of each compartment calculated from contiguous 10-mm thick MRI slices covering the entire abdomen in 49 men (26 without diabetes and 23 with non-insulin-dependent diabetes mellitus). The MRI slice at the intervertebral level between the lumbar (L) 2 and 3 vertebrae showed the highest and most consistent predictive value for all three compartments (R 2 = 0.85 for all). Furthermore, compared with other intervertebral levels, the L2-L3 level had a higher amount of intraperitoneal and retroperitoneal adipose tissue mass. We conclude that determining the masses of various abdominal adipose tissue compartments at the L2-L3 intervertebral level by MRI is an acceptably reliable and accurate method for studying abdominal adiposity in men.

The current American Diabetes Association guidelines for nutrition recommend a moderate increase in monounsaturated fats and a reduced intake of carbohydrate in patients with diabetes in whom high-carbohydrate diets deteriorate glycemic control and lipoprotein levels. High-fat diets, however, are believed to promote obesity, and some investigators may have reservations recommending such diets. This review thus investigates the role of diet composition in promoting obesity or achieving weight loss and its implications in patients with diabetes. Epidemiological studies show some evidence that fat intake is more importantly related to body weight than carbohydrate intake, but conclusions are weak because confounding variables, such as physical activity, smoking, and energy intake, were generally not controlled for. Metabolic studies under isoenergic conditions report no change in energy balance when fat intake is increased, but report a negative fat balance with substantial increase carbohydrate intake. During overfeeding, excess fat intake is stored as fat, whereas excess carbohydrate is mostly oxidized in the short term but can lead to substantial gain in fat stores because of reduced fat oxidation and considerable de novo lipogenesis in the long term. Spontaneous energy intake, however, is higher on an unrestricted high-fat diet compared with a high-carbohydrate diet, but the long-term effects are not known. Weight-loss intervention studies show that a hypocaloric high-carbohydrate diet is not associated with more weight loss than a high-fat hypocaloric diet. In conclusion, a high-monounsaturated fat diet to control glycemic control and lipoprotein levels in patients with diabetes should not affect weight loss or maintenance, provided that energy intake is carefully controlled.

OBJECTIVE Islet amyloidosis may be one mechanism for pancreatic islet β-cell loss that is associated with the development of NIDDM. However, the question remains whether chronic overstimulation of insulin and islet amyloid polypeptide (IAPP) secretion in states of insulin resistance could lead to formation of islet amyloidosis and hence NIDDM in some patients. We studied pancreatic islet pathology in congenital generalized lipodystrophy, a genetic syndrome of extreme insulin resistance that may provide some clues. RESEARCH DESIGN AND METHODS Our patient was a 24-year-old African-American woman with congenital generalized lipodystrophy. Severe acanthosis nigricans was noted in her since age 6. At ages 12 and 16, normal and impaired glucose tolerances, respectively, were noted on oral glucose tolerance tests but were accompanied by extreme fasting and post-prandial hyperinsulnemia. Overt diabetes developed at age 18 and she required ∼180 U of insulin daily. Immediately after an accidental death at age 24, an autopsy was performed. Pancreatic histology was studied in detail using routine methods and immunohistochemical techniques. RESULTS Some scarring of the pancreas as a result of previous episodes of acute pancreatitis was observed. Severe amyloidosis was noted in 89% of the islets, sparing those that were rich in pancreatic polypeptide-secreting cells. Amyloid deposits stained intensely on immunostaining with antibodies against amylin. Marked paucity of β-cells was evident. The ratio of β- to α-cells was reduced to 1:1 (normal ratio ∼ 4:1). CONCLUSIONS These observations suggest that chronic presence of extreme insulin resistance may induce premature and severe islet amyloidosis as well as β-cell atrophy.

Lipodystrophies, heterogeneous acquired or inherited disorders characterized by the selective loss of adipose tissue, predispose affected patients to insulin resistance and its attendant complications. This review focuses on the clinical features, underlying pathogenetic mechanisms, and management of various types of acquired and inherited lipodystrophies.

This study was carried out to identify and define lipoprotein abnormalities in patients with noninsulin-dependent diabetes mellitus (NIDDM) who do not have clinical elevations of cholesterol or triglycerides. Thirty-four male patients with mild NIDDM and normolipidemia (plasma cholesterolor = 240 mg/dl and triglyceridesor = 250 mg/dl) were compared with 35 healthy male normolipidemic subjects. The two groups had similar age and body mass index. Measurements in the two groups included concentrations and chemical composition of lipoproteins and sizing of low-density lipoprotein (LDL) particles. The patients with NIDDM, compared to control subjects, had two distinct lipoprotein abnormalities: first a significantly reduced level of high-density lipoprotein (HDL) cholesterol (mean +/- S.D., 35 +/- 8 mg/dl vs. 41 +/-10 mg/dl, respectively; P = 0.006), and second, a high cholesterol-to-apolipoprotein (apo) B ratio both in a very low density lipoprotein (VLDL) + intermediate density lipoprotein (IDL) fraction (mean +/- S.D.; 3.2 +/- 0.8 vs. 2.8 +/- 0.9, respectively; P = 0.02) and in LDL fraction (mean +/- S.D.; 1.61 +/- 0.11 vs. 1.52 +/- 0.13, respectively; P = 0.003). Increased cholesterol content in LDL was mainly due to free cholesterol. No differences were detected between the two groups in the frequency of LDL pattern A (major LDL peak255 A) and pattern B (major LDL peakor = 255 A). However, a higher frequency of LDL pattern B was found in NIDDM patients with low plasma total triglyceride concentrations (150 mg/dl) compared to the to the control subjects (45% vs. 7%, P = 0.02). Thus in normolipidemic patients with mild NIDDM, the major lipoprotein abnormalities were a low level of HDL cholesterol and compositional changes in LDL and VLDL + IDL fractions. Compositional abnormalities included enrichment of apo B-containing lipoproteins with cholesterol. These lipoprotein abnormalities could have atherogenic potential in patients with mild NIDDM and normolipidemia.

Monoacylglycerol acyltransferase 1 (Mogat1) catalyzes the conversion of monoacylglycerols (MAG) to diacylglycerols (DAG), the precursor of several physiologically important lipids such as phosphatidylcholine, phosphatidylethanolamine and triacylglycerol (TAG). Expression of Mogat1 is tissue restricted and it is highly expressed in the kidney, stomach and adipose tissue but minimally in the normal adult liver. To understand the transcriptional regulation of Mogat1, we characterized the mouse and human Mogat1 promoters in human kidney proximal tubule-2 (HK-2) cells. In-silico analysis revealed several peroxisome proliferator response element (PPRE) binding sites in the promoters of both human and mouse Mogat1. These sites responded to all three peroxisome proliferator activated receptor (PPAR) isoforms such that their respective agonist or antagonist activated or inhibited the expression of Mogat1. PPRE site mutagenesis revealed that sites located at -592 and -2518 are very effective in decreasing luciferase reporter gene activity. Chromatin immunoprecipitation (ChIP) assay using PPARα antibody further confirmed the occupancy of these sites by PPARα. While these assays revealed the core promoter elements necessary for Mogat1 expression, there are additional elements required to regulate its tissue specific expression. Chromosome conformation capture (3C) assay revealed additional cis-elements located ~10-15 kb upstream which interact with the core promoter. These chromosomal regions are responsive to both PPARα agonist and antagonist.

The present study investigated whether a predisposition to high frequency of small, dense low density lipoproteins (LDL) could be an additional coronary risk factor in migrant Asian Indians. Ninety-three normolipidemic (fasting plasma cholesterol levelsor = 240 mg/dl and triglyceride levelsor = 250 mg/dl) adult Asian Indian men residing in the U.S. were compared to a group of 59 Caucasian men for the prevalence of LDL electrophoretic patterns A and B (size of major LDL peakor = 255 A for LDL pattern A and255 A for LDL pattern B). Compared to the Caucasians, the Asian Indians had larger LDL size (mean +/- SD; 260.1 +/- 12.8 A vs 267.7 +/- 11.4 A, respectively; p = 0.0002), an increased frequency of LDL pattern A (59% vs 85%, respectively) and a lower frequency of LDL pattern B (41% vs 15%, respectively) (p = 0.0005). The difference in LDL size in the two study groups persisted after adjusting for the various confounding variables, such as age, plasma triglycerides, high-density lipoprotein cholesterol and dietary habits. We conclude that compared to Caucasians, Asian Indian men have larger LDL particles and a lower prevalence of LDL phenotype B in the presence of normolipidemia. Therefore, we exclude a genetic predisposition to atherogenic LDL phenotype as a factor contributing to the high incidence of coronary heart disease in migrant Asian Indians.

The relative impacts of regional and generalized adiposity on insulin sensitivity have not been fully defined. Therefore, we investigated the relationship of insulin sensitivity (measured using hyperinsulinemic, euglycemic clamp technique with [3-3H]glucose turnover) to total body adiposity (determined by hydrodensitometry) and regional adiposity. The latter was assessed by determining subcutaneous abdominal, intraperitoneal, and retroperitoneal fat masses (using magnetic resonance imaging) and the sum of truncal and peripheral skinfold thicknesses. 39 healthy middle-aged men with a wide range of adiposity were studied. Overall, the intraperitoneal and retroperitoneal fat constituted only 11 and 7% of the total body fat. Glucose disposal rate (Rd) and residual hepatic glucose output (rHGO) values during the 40 mU/m2.min insulin infusion correlated significantly with total body fat (r = -0.61 and 0.50, respectively), subcutaneous abdominal fat (r = -0.62 and 0.50, respectively), sum of truncal skinfold thickness (r = -0.72 and 0.57, respectively), and intraperitoneal fat (r = -0.51 and 0.44, respectively) but not to retroperitoneal fat. After adjusting for total body fat, the Rd and rHGO values showed the highest correlation with the sum of truncal skinfold thickness (partial r = -0.40 and 0.33, respectively). We conclude that subcutaneous truncal fat plays a major role in obesity-related insulin resistance in men, whereas intraperitoneal fat and retroperitoneal fat have a lesser role.

Type I hyperlipoproteinemia (T1HLP) usually presents with extreme hypertriglyceridemia, recurrent episodes of acute pancreatitis, lipemia retinalis, and cutaneous eruptive xanthomas. We report a unique 10-year-old male of Indian origin who presented in neonatal period with transient obstructive jaundice and xanthomas in the pancreas and kidneys. Serum triglycerides stabilized with extremely low-fat diet although he subsequently developed pancreatic atrophy. Extreme hypertriglyceridemia failed to respond to treatment with fenofibrate, fish oil, and orlistat. Whole-exome sequencing of the parents and patient was performed. Copy number variation analysis revealed a large deletion in chromosome 8 containing the entire GPIHBP1, which was confirmed by Sanger sequencing to be 54,623 bp deletion. Review of the literature revealed a slightly higher maximum triglyceride levels in those with homozygous null vs missense mutations suggesting severe disease in those with nonfunctional vs dysfunctional GPIHBP1 protein. Visceral xanthomas and pancreatic atrophy can be part of the spectrum of clinical features in patients with T1HLP. We highlight the need to perform copy number variations analysis of whole-exome sequencing data for finding disease-causing variants. There is also an urgent need to develop novel targeted therapies for patients with T1HLP.

The observation that different patterns of adipose tissue distribution are associated with different metabolic abnormalities, has recently given new impetus to research in obesity. Due to several methodologic problems, however, many aspects of regional excess of adipose tissue are still poorly understood. Among them, the causes and the metabolic consequences of regional adiposity are particularly important. Heterogeneity in adipose tissue distribution may be determined by a combination of genetic and hormonal causes. Both factors may determine differences in metabolism of various adipose tissue compartments primarily by regulating LPL production, storage and release of triacylglycerols, and aromatization of androgens. Furthermore, changes in adipocyte sensitivity to hormones such as, sex steroids, glucocorticoids, insulin and adrenergic hormones may also regulate fat distribution in various adipose tissue compartments. The metabolic heterogeneity of adipose tissue from various compartments, particularly the differences between the "portal" and subcutaneous adipose tissues, may account for several metabolic abnormalities associated with "upper body adiposity". However, no direct evidence is available to confirm this hypothesis. Recent advances in the methodology to study adipose tissue distribution (mainly CT and MRI) may provide the necessary tools to evaluate the true impact of adiposity in various compartments on intermediary metabolism and to identify a "morbid" adipose tissue compartment. These observations may help in designing better therapeutic strategies targeted towards regional adiposity and its metabolic complications.

Background— Autosomal dominant hypercholesterolemia (ADH), characterized by elevated plasma levels of low-density lipoprotein (LDL)-cholesterol, is caused by variants in at least 3 different genes: LDL receptor ( LDLR ), apolipoprotein B-100, and proprotein convertase subtilisin-like kexin type 9. There is paucity of data about the molecular basis of ADH among ethnic groups other than those of European or Japanese descent. Here, we examined the molecular basis of ADH in a multiethnic patient cohort from lipid clinics in a large, urban US city. Methods and Results— A total of 38 men and 53 women, aged 22 to 76 years, met modified Simon-Broome criteria for ADH and were screened for mutations in the exons and consensus splice sites of LDLR , and in selected exons of apolipoprotein B-100 and proprotein convertase subtilisin-like kexin type 9. Deletions and duplications of LDLR exons were detected with multiplex ligation-dependent probe amplification. Heterozygous variants in LDLR were identified in 30 patients and in apolipoprotein B-100 in 1 patient. The remaining 60 patients (65%) had unexplained ADH. A higher proportion of blacks (77%) than either non-Hispanic whites (57%) or Hispanics (53%) had unexplained ADH. Compared with patients with LDLR variants, those with unexplained ADH had lower levels of LDL-cholesterol (292±47 mg/dL versus 239±42 mg/dL, respectively; P P =0.003). Conclusions— Our findings suggest that additional loci may contribute to ADH, especially in understudied populations such as blacks.

The evaluation of adipose tissue distribution has become an essential component of investigations on the complications of obesity. However, a major limitation is lack of methodology for accurate estimation of adipose tissue mass in the different regions of the body. Therefore, we have tested the accuracy and precision of magnetic resonance imaging (MRI) as a method to measure adipose tissue mass in regions of the body not accessible with standard anthropometric methods. The mass of subcutaneous and intraabdominal adipose tissue estimated by MRI was compared with that obtained by direct weighing of the same adipose tissue compartments after dissection in human cadavers. MRI was performed on three unembalmed cadavers (two males, one female) who were subsequently dissected to isolate intraperitoneal, retroperitoneal, and subcutaneous adipose tissues. These same components were delineated by MRI. The results of the two methods were highly congruent. For the various compartments, the mean of the difference between the two methods was only 0.076 kg (95% confidence interval + 0.005 kg and + 0.147 kg). The “limits of agreement” between the two techniques were -0.066 kg and +0.218 kg. Multiple repeated estimates of mass of adipose tissue compartments were made to determine reproducibility of the MRI measurement; the coefficient of variation for repeated measures was below 14%. The results of this study show that MRI is an accurate and precise technique to evaluate adipose tissue mass in subcutaneous and intraabdominal compartments. Furthermore, MRI was found to be a valid method to separately evaluate the mass of intraabdominal subcompartments of intraperitoneal and retroperitoneal adipose tissue.

Patients with insulin-dependent diabetes mellitus (IDDM) are at an increased risk for coronary heart disease. Factors that may enhance the risk include dyslipidemia, hypertension, and hyperglycemia. Until recently, the importance of dyslipidemia in IDDM was ignored because the prevalence of high cholesterol levels was similar to that in the nondiabetic population. However, unique abnormalities in the composition and metabolism of lipoproteins may occur in IDDM patients. Management of IDDM patients, therefore, should include control of dyslipidemia as well as control of hyperglycemia and hypertension. The therapeutic goals for serum cholesterol reduction in IDDM patients should be lower than that for nondiabetic patients, and the goals for children should be even lower than those for adults. Both very-low-density lipoprotein and low-density lipoprotein (LDL) levels should be the targets for therapeutic interventions and not just the LDL alone. Because of the unique features of dyslipidemia in IDDM patients, the therapeutic options may not be the same as that for nondiabetic patients. Hyperglycemia should be controlled by matching daily energy intake and activity with appropriately timed doses of insulin. The diets should be low in saturated fats and cholesterol. If dyslipidemia persists despite diet and hyperglycemia management, drug therapy may be initiated. For IDDM children > or = 10 years of age with elevated LDL-cholesterol levels, the first-line therapy should be bile acid sequestrants. For adults with IDDM, bile acid sequestrants also may be the drugs of choice, particularly for normotriglyceridemic patients. Nicotinic acid therapy should be avoided. Among other drugs, hydroxymethyl-glutaryl coenzyme A reductase inhibitors may be preferable for patients with elevated LDL cholesterol and borderline hypertriglyceridemia. Fibric acid derivatives should be used for markedly hypertriglyceridemic patients. The role of probucol for dyslipidemia in IDDM patients is not clear.

Congenital generalized lipodystrophy is an autosomal recessive disorder characterized by marked paucity of adipose tissue, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis and early onset of diabetes. We report several different mutations of the gene (AGPAT2) encoding 1-acylglycerol-3-phosphate O-acyltransferase 2 in 20 affected individuals from 11 pedigrees of diverse ethnicities showing linkage to chromosome 9q34. The AGPAT2 enzyme catalyzes the acylation of lysophosphatidic acid to form phosphatidic acid, a key intermediate in the biosynthesis of triacylglycerol and glycerophospholipids. AGPAT2 mRNA is highly expressed in adipose tissue. We conclude that mutations in AGPAT2 may cause congenital generalized lipodystrophy by inhibiting triacylglycerol synthesis and storage in adipocytes.

Leptin replacement therapy improves metabolic complications in patients with lipodystrophy and severe hypoleptinemia (SH), but whether the response is related to the degree of hypoleptinemia remains unclear.The aim of the study was to compare efficacy of leptin therapy in familial partial lipodystrophy, Dunnigan variety (FPLD) patients with SH (serum leptin7th percentile of normal) vs. those with moderate hypoleptinemia (MH; serum leptin in 7th to 20th percentiles).We conducted an open-label, parallel group, observational study in 14 SH (mean±sd, serum leptin, 1.9±1.1 ng/ml) and 10 MH (serum leptin, 5.3±1.0 ng/ml) women with FPLD.Patients received 0.08 mg/kg·d of metreleptin by twice daily sc injections for 6 months.The primary outcome variable was change in fasting serum triglycerides. Other secondary variables were fasting plasma glucose and insulin, insulin sensitivity, hemoglobin A1c, and hepatic triglyceride content.Median fasting serum triglycerides decreased from 228 to 183 mg/dl in the SH group (P=0.04) and from 423 to 339 mg/dl in the MH group (P=0.02), but with no difference between the groups (P value for interaction=0.96). Hepatic triglyceride levels similarly declined significantly from 8.8 to 4.9% in the SH group and from 23.7 to 9.2% in the MH group (P value for interaction=0.9). Loss of body weight and body fat occurred in both groups. Fasting glucose, insulin, glucose tolerance, and hemoglobin A1c levels did not change. K value on insulin tolerance test improved slightly in the SH group (0.98 to 1.24%; P=0.01), but not in the MH group (1.1 to 1.27%; P=0.4).Metreleptin replacement therapy is equally effective in FPLD patients with both SH and MH in reducing serum and hepatic triglyceride levels, but did not improve hyperglycemia.

CONTEXT: Lipodystrophies are heterogeneous, genetic or acquired disorders characterized by selective loss of body fat and predisposition to insulin resistance. The extent of fat loss determines the severity of associated metabolic complications such as diabetes mellitus, hypertriglyceridemia, and hepatic steatosis. EVIDENCE ACQUISITION AND SYNTHESIS: Both original and review articles were found via PubMed search reporting on clinical features and management of various types of lipodystrophies and were integrated with the author's knowledge of the field. CONCLUSION: The autosomal recessive congenital generalized lipodystrophy and autosomal dominant familial partial lipodystrophy (FPL) are the two most common types of genetic lipodystrophies. Mutations in AGPAT2, BSCL2, CAV1, and PTRF have been reported in congenital generalized lipodystrophy and in LMNA, PPARG, AKT2, and PLIN1 in FPL. CIDEC is the disease gene for autosomal recessive, FPL and LMNA and ZMPSTE24 for autosomal recessive, mandibuloacral dysplasia-associated lipodystrophy. Recently, an autosomal recessive autoinflammatory lipodystrophy syndrome was reported to be due to PSMB8 mutation. Molecular genetic bases of many rare forms of genetic lipodystrophies remain to be elucidated. The most prevalent subtype of acquired lipodystrophy currently occurs with prolonged duration of protease inhibitor-containing, highly-active antiretroviral therapy in HIV-infected patients. The acquired generalized and partial lipodystrophies are mainly autoimmune in origin and display complement abnormalities. Localized lipodystrophies occur due to drug or vaccine injections, pressure, panniculitis, and other unknown reasons. The current management includes cosmetic surgery and early identification and treatment of metabolic and other complications with diet, exercise, hypoglycemic drugs, and lipid-lowering agents.

Weight regain is a problem among many bariatric surgery patients. Whether a high-volume exercise program (HVEP), a strategy to limit weight regain, is feasible in these patients is unknown. The feasibility of an HVEP in obese post-bariatric-surgery patients was determined by randomizing 33 Roux-en-Y gastric bypass (RYGB) and gastric banding (GB) surgery patients with a mean BMI of 41 ± 6 kg/m2 to an HVEP or control group for 12 weeks. The HVEP group was instructed to expend ≥ 2,000 kcal/week in moderate-intensity exercise. All patients were counseled to limit energy intake. Treatment effect was assessed by repeated measures analysis. During the last 4 weeks of the study, 53% of the HVEP group expended ≥ 2,000 kcal/week and 82% expended ≥ 1,500 kcal/week. Step count, reported time spent and energy expended during moderate physical activity, maximal oxygen consumption relative to weight, and incremental area under the postprandial blood glucose curve were significantly improved over 12 weeks in the HVEP group compared to controls (group-by-week effect: P = 0.009-0.03). Both groups reported significant improvement in some quality-of-life scales. Changes in weight, energy and macronutrient intake, resting energy expenditure (REE), fasting lipids and glucose, and fasting and postprandial insulin concentrations were not different between the two groups. HVEP is feasible in about 50% of the patients and enhances physical fitness and reduces postprandial blood glucose in bariatric surgery patients.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near total absence of body fat since birth with predisposition to insulin resistance, diabetes, hypertriglyceridemia, and hepatic steatosis. Three CGL loci, AGPAT2, BSCL2, and CAV1, have been identified previously. Recently, mutations in polymerase I and transcript release factor (PTRF) were reported in five Japanese patients presenting with myopathy and CGL (CGL4). We report novel PTRF mutations and detailed phenotypes of two male and three female patients with CGL4 belonging to two pedigrees of Mexican origin (CGL7100 and CGL178) and one pedigree of Turkish origin (CGL180). All patients had near total loss of body fat and congenital myopathy manifesting as weakness, percussion-induced muscle mounding, and high serum creatine kinase levels. Four of them had hypertriglyceridemia. Three of them had atlantoaxial instability. Two patients belonging to CGL178 pedigree required surgery for pyloric stenosis in the first month of life. None of them had prolonged QT interval on electrocardiography but both siblings belonging to CGL7100 had exercise-induced ventricular arrhythmias. Three of them had mild acanthosis nigricans but had normal glucose tolerance. Two of them had hepatic steatosis. All patients had novel null mutations in PTRF gene. In conclusion, mutations in PTRF result in a novel phenotype that includes generalized lipodystrophy with mild metabolic derangements, myopathy, cardiac arrhythmias, atlantoaxial instability, and pyloric stenosis. It is unclear how mutations in PTRF, which plays an essential role in formation of caveolae, affect a wide variety of tissues resulting in a variable phenotype. (C) 2010 Wiley-Liss, Inc.

OBJECTIVE To study effects of high carbohydrate intake on hyperglycemia, islet functions, and plasma lipoproteins in patients with NIDDM. RESEARCH DESIGN AND METHODS An attempt was made to induce hyperglycemia in 10 men with NIDDM by feeding them an isocaloric high-carbohydrate diet (65% of energy as simple carbohydrates [31% as glucose] and 20% as fat) for 28 days in a metabolic ward. Response to the high-carbohydrate diet was compared with that of feeding a diet rich in monounsaturated fat (45% of energy as fat [31% as monounsaturated fat] and 38% as carbohydrates) for 28 days in a cross-over manner. Islet functions were assessed by evaluating plasma glucose, insulin, C-peptide and glucagon responses to standard meal tolerance tests on days 0, 14, 21, and 28 of each dietary period. Fasting plasma lipoproteins were determined during the last week of each dietary period. RESULTS The high-carbohydrate diet caused significant but modest accentuation of hyperglycemia, particularly in patients with moderately severe diabetes mellitus, whereas no change was observed with the high-monounsaturated fatty-acid diet. Accentuation of hyperglycemia was accompanied by an increase in plasma glucagon levels, but no significant change in insulin and C-peptide responses. In 1 patient, feeding the high-carbohydrate diet for 68 days produced marked hyperglycemia and caused definite suppression of insulin and C-peptide responses along with an increase in glucagon levels. Compared with the high-monounsaturated fat diet, the high-carbohydrate diet also raised plasma triglyceride and VLDL cholesterol concentrations. CONCLUSIONS High-carbohydrate diets may cause accentuation of hyperglycemia and a rise in plasma glucagon levels in NIDDM patients. High-carbohydrate diets also adversely affect lipoproteins and therefore may not be desirable in all NIDDM patients.

Previous studies indicate that diets rich in digestible carbohydrates improve glucose tolerance in nondiabetic individuals, but may worsen glycemic control in NIDDM patients with moderately severe hyperglycemia. The effects of such high-carbohydrate diets on glucose metabolism in patients with mild NIDDM have not been studied adequately. This study compares responses to an isocaloric high-carbohydrate diet (60% of total energy from carbohydrates) and a low-carbohydrate diet (35% of total energy from carbohydrates) in 8 men with mild NIDDM. Both diets were low in saturated fatty acids, whereas the low-carbohydrate diet was rich in monounsaturated fatty acids. The two diets were matched for dietary fiber content (25 g/day). All patients were randomly assigned to receive first one and then the other diet, each for a period of 21 days, in a metabolic ward. Compared with the low-carbohydrate diet, the high-carbohydrate diet caused a 27.5% increase in plasma triglycerides and a similar increase in VLDL-cholesterol levels; it also reduced levels of HDL cholesterol by 11%. Plasma glucose and insulin responses to identical standard breakfast meals were studied on days 4 and 21 of each period, and these did not differ significantly between the two diets. At the end of each period, a euglycemic hyperinsulinemic glucose clamp study with simultaneous infusion of [3-3H]glucose revealed no significant changes in hepatic insulin sensitivity; and peripheral insulin-mediated glucose disposal remained unchanged (14.7 ± 1.4 vs. 16.5 ± 2.3 μM · kg−1 · min−1 on the high-carbohydrate and low-carbohydrate diets, respectively). We conclude that in patients with mild NIDDM, high-carbohydrate diets do not improve glycemic control nor insulin sensitivity, and they raise plasma triglyceride and VLDL-cholesterol concentrations and reduce HDL-cholesterol levels, which may not be desirable.

Patients with diabetes mellitus are at increased risk of morbidity and mortality from macrovascular disease manifesting as coronary heart disease, cerebrovascular accidents, and peripheral vascular disease. Increased frequency of dyslipidemia, hyperglycemia, obesity, hypertension, and associated nephropathy may contribute to accelerated atherogenesis in diabetic patients. Therefore, besides intensive control of hyperglycemia, management of dyslipidemia, hypertension, and obesity should also be emphasized in diabetic patients. Those who smoke should be strongly encouraged to quit smoking. Besides attempts to achieve normal levels of plasma lipoproteins, consideration also should be given to normalization of compositional abnormalities of various lipoproteins in patients with diabetes mellitus. The therapeutic goals for cholesterol reduction should be lower in diabetic patients than nondiabetic subjects. The first step is to achieve good metabolic control of diabetes mellitus by diet, exercise, and weight reduction and, if needed, with sulfonylureas or insulin therapy. Because most of the patients with insulin-dependent diabetes mellitus achieve normal levels of plasma lipoproteins with intensive insulin therapy, lipid-lowering medications are rarely needed. In patients with non-insulin-dependent diabetes mellitus, however, dyslipidemia often persists despite good glycemic control. Lipid-lowering medications should be considered in such patients. Because nicotinic acid can cause marked deterioration in glycemic control, and bile acid-binding resins may accentuate hypertriglyceridemia, these agents are less desirable for use by diabetic patients. Inhibitors of hydroxymethylglutaryl coenzyme A reductase may be preferred in patients with elevated LDL cholesterol and mild hypertriglyceridemia. For diabetic patients with marked hypertriglyceridemia, however, fibric acid derivatives should be the drug of choice.

Congenital generalized lipodystrophy (CGL) is a rare genetic disease with extreme paucity of fat from birth which is believed to be generalized, involving the whole body. Affected patients are characterized by severe insulin resistance. Sites of adipose tissue distribution in patients with CGL have not been studied systematically. Therefore, the fat distribution in three women (17-20 yr old) with CGL was investigated. Determination of body composition by underwater volume displacement suggested the complete absence of body fat (range, -3 to -7%; normal, 15-25%). Whole body magnetic resonance imaging, however, detected fat in particular anatomical sites, namely in orbits, palms and soles, and periarticular and epidural regions. Some fat was also localized in the tongue, breasts, vulva, and buccal area. Fat in other subcutaneous areas, intraabdominal and intrathoracic regions, and bone marrow was essentially absent. Thus, patients with CGL do not have a complete absence of body fat; of interest, fat is present in those sites where adipose tissue may be serving mainly a mechanical function. Patients with CGL, therefore, provided a unique opportunity to identify the various sites of localization of "mechanical" adipose tissue in the human body. Our study suggests that the genetic defect in CGL results in poor growth and development of metabolically active adipose tissue, whereas mechanical adipose tissue is well preserved.

Familial hypobetalipoproteinemia, a syndrome associated with low plasma cholesterol levels, can be caused by apoB gene mutations. We identified a healthy 42-year-old man whose total plasma cholesterol level was 80 mg/dl. His plasma very low density lipoprotein (VLDL) contained a unique truncated apoB species, apoB-83, in addition to the normal B apolipoproteins, apoB-100 and apoB-48. Virtually no apoB-83 was detectable in his low density lipoprotein (LDL). From the subject's kindred, we identified nine other hypocholesterolemic subjects whose VLDL contained apoB-83. A tendency for cholelithiasis was noted in the apoB-83 heterozygotes, particularly in the older individuals. From the apparent size of apoB-83 on SDS-polyacrylamide gels and its reactivity with apoB-specific monoclonal antibodies, we estimated that it would contain approximately 3700-3800 amino acids. DNA sequencing of apoB genomic clones from two affected individuals revealed that apoB-83 was caused by a C----A transversion in exon 26 of the apoB gene (apoB cDNA nucleotide 11458). This mutation converts Ser-3750 (TCA) into a premature stop codon (TAA) and creates a unique MseI restriction endonuclease site. Thus, a single nucleotide transversion in the apoB gene results in a unique truncated apoB species, apoB-83, and the clinical syndrome of familial hypobetalipoproteinemia.

Context: Hutchinson-Gilford progeria syndrome (HGPS) and mandibuloacral dysplasia are well-recognized allelic autosomal dominant and recessive progeroid disorders, respectively, due to mutations in lamin A/C (LMNA) gene. Heterozygous LMNA mutations have also been reported in a small number of patients with a less well-characterized atypical progeroid syndrome (APS). Objective: The objective of the study was to investigate the underlying genetic and molecular basis of the phenotype of patients presenting with APS. Results: We report 11 patients with APS from nine families, many with novel heterozygous missense LMNA mutations, such as, P4R, E111K, D136H, E159K, and C588R. These and previously reported patients now reveal a spectrum of clinical features including progeroid manifestations such as short stature, beaked nose, premature graying, partial alopecia, high-pitched voice, skin atrophy over the hands and feet, partial and generalized lipodystrophy with metabolic complications, and skeletal anomalies such as mandibular hypoplasia and mild acroosteolysis. Skin fibroblasts from these patients when assessed for lamin A/C expression using epifluorescence microscopy revealed variable nuclear morphological abnormalities similar to those observed in patients with HGPS. However, these nuclear abnormalities in APS patients could not be rescued with 48 h treatment with farnesyl transferase inhibitors, geranylgeranyl transferase inhibitors or trichostatin-A, a histone deacetylase inhibitor. Immunoblots of cell lysates from fibroblasts did not reveal prelamin A accumulation in any of these patients. Conclusions: APS patients have a few overlapping but some distinct clinical features as compared with HGPS and mandibuloacral dysplasia. The pathogenesis of clinical manifestations in APS patients seems not to be related to accumulation of mutant farnesylated prelamin A.

Familial partial lipodystrophy, Dunnigan variety, is a rare autosomal dominant disorder caused by missense mutations in LMNA gene. Individuals are predisposed to insulin resistance and its complications, including features of polycystic ovary syndrome.A 27-year-old Hispanic woman presented with oligomenorrhea and hirsutism. Examination revealed cushingoid facies, significant hirsutism, acanthosis nigricans, and a lean body habitus. Metabolic testing identified diabetes mellitus, dyslipidemia, and steatohepatitis. A diagnosis of familial partial lipodystrophy, Dunnigan variety, was confirmed by the detection of a heterozygous p.Arg482Trp (c.1444CT) missense mutation in the lamin A/C (LMNA) gene. Subsequently, seven female relatives were diagnosed with familial partial lipodystrophy, Dunnigan variety, four of whom had menstrual irregularities.Familial partial lipodystrophy, Dunnigan variety, can present with features similar to polycystic ovary syndrome. Diagnosis is critical because the metabolic complications of the disorder have significant morbidity.

OBJECTIVE High levels of dietary fiber, especially soluble fiber, are recommended to lower serum cholesterol levels and improve glycemic control in patients with type 2 diabetes. It is not clear, however, how high levels of fiber affect mineral balance. RESEARCH DESIGN AND METHODS In a randomized crossover study, 13 patients with type 2 diabetes were fed a high-fiber (50 g total and 25 g soluble fiber) and a moderate-fiber (24 g total and 8 g soluble fiber) diet of the same energy, macronutrient, calcium, magnesium, and phosphorus content for 6 weeks each. Intestinal calcium absorption was determined by fecal recovery of 47Ca. Stool weight and mineral content were assessed during 3 days, and 24-h urinary mineral content and serum chemistry were assessed over 5 days at the end of each phase. The results were compared by repeated-measures ANOVA. RESULTS Compared with the moderate-fiber diet, the high-fiber diet increased stool weight (165 ± 53 vs. 216 ± 63 g/day, P = 0.02) and reduced 24-h urinary calcium (3.3 ± 1.7 vs. 2.4 ± 1.2 mmol/day, P = 0.003) and phosphorus (29.2 ± 5.5 vs. 26.0 ± 3.2 mmol/day, P = 0.003) excretion and serum calcium concentration (2.33 ± 0.06 vs. 2.29 ± 0.07 mmol/l, P = 0.04). Calcium absorption, stool calcium, magnesium, and phosphorus content and serum phosphorus concentration were not significantly different with the two diets. CONCLUSIONS A high-fiber diet rich in soluble fiber has a small impact on calcium and phosphorus balance in subjects with type 2 diabetes. It may be prudent to ensure adequate intake of calcium and other minerals in individuals consuming a high-fiber diet.

The hypotriglyceridemic action of omega-3 (n-3) fatty acids is attributed primarily to reduction in hepatic triglyceride synthesis and reduced secretion of very-low-density lipoproteins (VLDLs). However, increased catabolism of triglyceride-rich lipoproteins was reported and could be due to increased availability of peripheral lipoprotein lipase (LPL) or hepatic lipase (HL). In this study plasma lipoproteins and postheparin activities of LPL and HL were determined in 12 patients with primary hypertriglyceridemia before and during isocaloric substitution of omega-3 fatty acids (10 g/d) for 4 wk. Omega-3 polyunsaturates resulted in 53% and 61% reductions in plasma triglyceride and VLDL-cholesterol concentrations, respectively (P less than 0.0001). However, low-density-lipoprotein (LDL)-cholesterol concentrations increased by 26% (P less than 0.001). Activities of postheparin LPL and HL essentially remained the same. Thus, in patients with primary hypertriglyceridemia, reduction in plasma triglyceride concentrations and increase in LDL-cholesterol concentrations mediated by omega-3 polyunsaturates seem to occur without an increase in LPL or HL activities.

Background Long-term antiretroviral therapy (ART) is associated with lipodystrophy, peripheral neuropathy, lactic acidosis, and myopathy. Blepharoptosis, without prior ART association, is usually caused by age-associated involutional ptosis, but it is also seen in mitochondrial myopathies with external ophthalmoplegia, cardiac conduction disturbances, and neurological impairments. Methods Patients presented over a 2-year period. Four patients underwent surgical blepharoptosis repair. Results Five human immunodeficiency virus type 1-infected patients (median age, 50 years; range, 46-53 years) who were receiving ART presented with severe blepharoptosis; 2 of these 5 also presented with external ophthalmoplegia. Findings included decreased palpebral fissure height (median, 6.5 mm; normal height, 9 mm), mildly impaired levator function (median, 10 mm; normal, >13 mm), and markedly decreased marginal reflex distance (median, 0.5 mm; normal, 4 mm). A greater advancement of the levator aponeurosis was required during surgical repair, a finding consistent more with myogenic than with involutional blepharoptosis. All patients had severe lipodystrophy, which preceded blepharoptosis by a median interval of 4.7 years (range, 2.8-5.7 years). Four patients also presented with peripheral neuropathy and metabolic abnormalities before the onset of blepharoptosis, and 3 had cardiac conduction disturbances. Patients received ART for a median of 7.8 years (range, 4.9-11.2 years), thymidine analogue-containing ART for a median of 7.1 years (range, 1.2-7.9 years), and protease inhibitor-containing ART for a median of 7.1 years (range, 4.9-8.9 years). Conclusions We report the novel findings of blepharoptosis and external ophthalmoplegia in patients who are receiving ART. Ptosis was preceded by lipodystrophy with long-term use of both thymidine-analogue- and protease inhibitor-containing ART. The findings are most consistent with myogenic ptosis in a generalized mitochondrial myopathy syndrome. Clinicians should also be watchful for other potential myopathic ptosis-associated complications, including proximal weakness, dysphagia, deafness, and cardiac conduction disturbances.

Patients with “typical” type 2 diabetes are generally obese and display varying degrees of insulin resistance and insulin secretory defects. The onset of type 2 diabetes occurs mostly after the third decade of life, and these patients do not spontaneously develop ketosis or need insulin for survival. Many other patients present with “atypical” forms of type 2 diabetes; insulin resistance or insulin secretory defects occur owing to certain other specific etiologies. These include various genetic and acquired causes leading to adipose tissue disorders,β-cell dysfunction or impaired insulin action. Other endocrinopathies and drug therapy may also result in atypical diabetes. Lipodystrophies are characterized by selective loss of adipose tissue leading to excess fat accumulation in aberrant tissues such as the liver and muscle, which causes insulin resistance. Although the degree of fat loss and the resultant metabolic abnormalities varies among patients with the different types of lipodystrophies, diabetes in most lipodystrophic patients is characterized by marked insulin resistance and high insulin requirements. Maturity-onset Diabetes of the Young (MODY) is a group of heterogeneous forms of monogenic diabetes characterized by autosomal dominant inheritance, young age at onset and pancreatic β-cell dysfunction. Similarly, mutations or deletions in mitochondrial DNA also cause diabetes owing to β-cell dysfunction, which is maternally inherited, whereas insulin receptor mutations cause autosomal dominant or recessive syndromes of extreme insulin resistance such as type-A insulin resistance syndrome, Rabson-Mendenhall syndrome, and Leprechaunism. The clinical features and management of patients with these rare syndromes are distinct from those for patients with typical type 2 diabetes. Recognition of these patients is important, as it helps to tailor therapy based on the underlying pathophysiologic process. These syndromes have also greatly contributed to our understanding of glucose homeostasis and the pathogenesis of diabetes in general.

Caveolae are specialized plasma membrane microdomains appearing as 50- to 100-nm vesicular invaginations (1,2). These organelles were initially identified by Yamada (3) more than 50 yr ago and can be found individually or in clusters at the surface of several cell types, including adipocytes, endothelial cells, fibroblasts, and myocytes. These plasma membrane domains, often referred to as lipid rafts, are rich in cholesterol, glycosphingolipids, and signaling proteins, especially caveolins. Caveolins are major components of the caveolae, and three members of this family (caveolins 1, 2, and 3) have been identified.

Lipodystrophy is a disorder characterized by a loss of adipose tissue often accompanied by severe hypertriglyceridemia, insulin resistance, diabetes, and fatty liver. It can be inherited or acquired. The most severe inherited form is Berardinelli-Seip Congenital Lipodystrophy Type 2, associated with mutations in the BSCL2 gene. BSCL2 encodes seipin, the function of which has been entirely unknown. We now report the identification of yeast BSCL2 /seipin through a screen to detect genes important for lipid droplet morphology. The absence of yeast seipin results in irregular lipid droplets often clustered alongside proliferated endoplasmic reticulum (ER); giant lipid droplets are also seen. Many small irregular lipid droplets are also apparent in fibroblasts from a BSCL2 patient. Human seipin can functionally replace yeast seipin, but a missense mutation in human seipin that causes lipodystrophy, or corresponding mutations in the yeast gene, render them unable to complement. Yeast seipin is localized in the ER, where it forms puncta. Almost all lipid droplets appear to be on the ER, and seipin is found at these junctions. Therefore, we hypothesize that seipin is important for droplet maintenance and perhaps assembly. In addition to detecting seipin, the screen identified 58 other genes whose deletions cause aberrant lipid droplets, including 2 genes encoding proteins known to activate lipin, a lipodystrophy locus in mice, and 16 other genes that are involved in endosomal–lysosomal trafficking. The genes identified in our screen should be of value in understanding the pathway of lipid droplet biogenesis and maintenance and the cause of some lipodystrophies.

OBJECTIVE—The recommendations for dietary fats in patients with type 2 diabetes are based largely on the impact of fatty acids on fasting serum lipid and glucose concentrations. How fatty acids affect postprandial insulin, glucose, and triglyceride concentrations, however, remains unclear. The objective of this study was to study the effect of fatty acids on postprandial insulin, glucose, and triglyceride responses. RESEARCH DESIGN AND METHODS—Test meals rich in palmitic acid, linoleic acid, oleic acid, and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and containing 1,000 kcal each were administered in a randomized crossover design to 11 type 2 diabetic subjects. Serum insulin, glucose, and triglyceride concentrations were measured for 360 min. All subjects received an isoenergetic diet of constant composition throughout the study. RESULTS—According to repeated-measures ANOVA, the insulin (P = 0.0002) but not glucose (P = 0.10) response was significantly different between meals. The insulin response was lower to meals rich in oleic acid or EPA and DHA than to meals rich in palmitic acid or linoleic acid (P < 0.01). The triglyceride response did not reach statistical significance (P = 0.06) but tended to be lower with EPA and DHA than with the other fatty acids. Similar trends were seen for area under the curve (AUC) and incremental AUC for serum insulin and triglycerides, but the differences were not significant. CONCLUSIONS—In comparison with palmitic acid and linoleic acid, oleic acid or EPA and DHA may modestly lower insulin response in patients with type 2 diabetes without deteriorating the glucose response. EPA and DHA may also reduce the triglyceride response.

Most cells synthesize their glycerophospholipids and triglycerides (TG) to maintain the cellular integrity and to provide energy for cellular functions. The phospholipids are synthesized de novo in cells through an evolutionary conserved process involving serial acylations of glycerol-3-phosphate. Several isoforms of the enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) acylate lysophosphatidic acid at the sn-2 position to produce phosphatidic acid. We cloned a cDNA predicted to be an AGPAT isoform and designated it AGPAT9. The human AGPAT9 gene spans across 14 exons and encodes for a polypeptide of 534 amino acids. AGPAT9 is highly expressed in the lung and spleen, followed by leukocyte, omental adipose tissue, and placenta. In the Chinese Hamster Ovary (CHO), cell lysates overexpressing AGPAT9, we observed AGPAT activity but not the lysophosphatidylcholine acyltransferase activity. When AGPAT9 is coexpressed with AGPAT1 in CHO cells, both the isoforms localize to the endoplasmic reticulum (ER) and occupy the same ER domain as AGPAT1. Despite substitution of asparagine with proline in the NHX4D motif and arginine with cysteine in the EGTR motif, AGPAT9 retains AGPAT activity suggesting that residues asparagine and arginine in the NHX4D and EGTR motifs respectively are not essential for the enzymatic activity. Based on the X-ray crystallographic structure of a related acyltransferase, squash gpat, a model is proposed in which a hydrophobic pocket in AGPAT9 accommodates fatty acyl chains of both substrates in an orientation, whereas the HX4D motif participates in catalysis. Based on the activity and expression pattern of AGPAT9 in the lung and spleen, this novel isoform could be implicated in the biosynthesis of phospholipids and TG in these tissues.