Biomedical subjects

Vinaya Simha

Publications and source records attributed to Vinaya Simha.

9 recordsLinked to original sources

PubMed2006

Review: long-term impact of bariatric surgery on body weight, comorbidities, and nutritional status.

CONTEXT: The number of patients who undergo Roux-en-Y gastric bypass (RYGB) and gastric banding (GB) surgeries has increased dramatically over the past decade, yet the long-term impact of these surgeries on body weight, comorbidities, and nutritional status remains unclear, as do the mechanisms of weight regain. EVIDENCE ACQUISITION: The articles were found via PubMed searches. To review the impact of bariatric surgery on weight maintenance and comorbidities, only articles with a postoperative follow-up of 3 yr or longer were included. The articles on nutritional status had a follow-up of 12 months or longer. CONCLUSIONS: RYGB and GB surgeries lead to substantial weight loss in individuals with morbid obesity. However, significant weight regain occurs over the long term, and according to the only well-designed prospective controlled study, the improvement in comorbidities associated with weight loss mitigates in the long term on weight regain. There is some evidence from a retrospective study that RYGB surgery is associated with a modest decrease in long-term mortality. These results remain to be substantiated by well-designed, long-term, randomized and prospective controlled studies. The mechanisms that lead to weight regain need to be further examined and may include increase in energy intake due to enlargement of stoma and adaptive changes in the levels of gut and adipocyte hormones such as ghrelin and leptin, which regulate energy intake; decrease in physical activity; changes in energy expenditure; and other factors. In addition to weight regain, RYGB surgery is associated with frequent incidence of iron, vitamin B12, folate, calcium, and vitamin D deficiency, which requires regular supplementation and monitoring.

Bariatric Surgery↗

PubMed2006

Lipodystrophy: lessons in lipid and energy metabolism.

PURPOSE OF REVIEW: Lipodystrophies are rare inherited and acquired disorders characterized by the selective loss of adipose tissue. Despite marked phenotypic and genotypic heterogeneity, most lipodystrophic syndromes predispose to similar metabolic complications seen in patients with obesity, such as insulin resistance, diabetes mellitus, hepatic steatosis and dyslipidemia. The purpose of this review is to highlight the current understanding of the mechanisms underlying dyslipidemia in patients with lipodystrophies. RECENT FINDINGS: Marked hypertriglyceridemia and reduced levels of high-density lipoprotein cholesterol are commonly seen, and the severity of these metabolic abnormalities seems to be related to the extent of fat loss. The precise mechanisms by which the lack of adipose tissue causes hypertriglyceridemia remain unknown. Anecdotal kinetic studies in hyperglycemic patients with lipodystrophies have revealed accelerated lipolysis and increased free fatty acid turnover, which drives hepatic triglyceride and very low-density lipoprotein synthesis. Other mechanisms may also be involved in causing dyslipidemia and ectopic triglyceride accumulation in the liver and skeletal muscles that remain to be identified. SUMMARY: Understanding the pathophysiology of dyslipidemia in these rare disorders of lipodystrophies may offer insights into the normal role of adipocytes in maintaining metabolic homeostasis, and its disturbances in common forms of obesity.

Adipose Tissue↗

PubMed2003

Genetic and phenotypic heterogeneity in patients with mandibuloacral dysplasia-associated lipodystrophy.

Mandibuloacral dysplasia (MAD) is a phenotypically heterogeneous, rare autosomal recessive disorder characterized by mandibular and clavicular hypoplasia, acroosteolysis, delayed closure of cranial sutures, joint contractures, and mottled cutaneous pigmentation. Patients with MAD develop two patterns of lipodystrophy: type A pattern, with loss of sc fat from the extremities and normal or slight excess in the neck and truncal regions; and type B pattern, with a more generalized loss of sc fat involving the face, trunk, and extremities. Recently, affected patients from five consanguineous Italian pedigrees with partial lipodystrophy (type A) were reported to have a homozygous R527H mutation in LMNA (lamin A/C) gene. We carried out mutational analysis of LMNA in affected patients from six pedigrees. Affected patients from two pedigrees with type A lipodystrophy had the homozygous R527H mutation in LMNA. The other four affected subjects who had type B lipodystrophy did not have any mutation in the exons and splice site junctions of LMNA; RNA extracted from lymphoblasts of two of these patients also revealed normal sequence. In these four subjects, sequencing of other known genes implicated in lipodystrophies, i.e. AGPAT2, Seipin, and PPARG also revealed no substantial alterations. We conclude that MAD is a genetically and phenotypically heterogeneous disorder. Besides LMNA gene, other as yet unmapped loci could be linked to MAD.

Adolescent↗

PubMed2003

Phenotypic heterogeneity in body fat distribution in patients with congenital generalized lipodystrophy caused by mutations in the AGPAT2 or seipin genes.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive syndrome characterized by extreme paucity of adipose tissue since birth, acanthosis nigricans, severe insulin resistance, marked hypertriglyceridemia, and early-onset diabetes mellitus. Recently, we reported mutations in the 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) gene in CGL pedigrees linked to chromosome 9q34 (CGL1 subtype), and mutations in the Seipin gene were reported in pedigrees linked to chromosome 11q13 (CGL2 subtype). Whether the two subtypes have differences in body fat distribution has not been investigated. We, therefore, compared whole-body adipose tissue distribution by magnetic resonance imaging in 10 CGL patients, of whom seven (six females, one male) had CGL1 and three (two males, one female) had CGL2. Both subtypes had marked lack of metabolically active adipose tissue located at most sc, intermuscular, bone marrow, intraabdominal, and intrathoracic regions. Paucity of mechanical adipose tissue in the palms, soles, orbits, scalp, and periarticular regions was noted in CGL2, whereas it was well preserved in CGL1 patients. We conclude that CGL patients with Seipin mutations have a more severe lack of body fat, which affects both metabolically active and mechanical adipose tissue, compared with patients with mutations in the AGPAT2 gene.

1-Acylglycerol-3-Phosphate O-Acyltransferase↗

PubMed2003

Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue from birth. Recently, mutations in 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) and Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) genes were reported in pedigrees linked to chromosomes 9q34 and 11q13, respectively. There are limited data regarding phenotypic differences between the various subtypes of CGL. Furthermore, whether there are additional loci for CGL remains unknown. Therefore, we genotyped 45 pedigrees with CGL for AGPAT2 and BSCL2 loci and compared the phenotypes in the various subtypes. Twenty-six pedigrees harbored mutations, including seven novel variants, in the AGPAT2 gene, and 11 pedigrees harbored mutations in the BSCL2 gene, including five novel variants. Eight pedigrees had no substantial alterations in either gene. Of these, three informative pedigrees showed no linkage to markers spanning the AGPAT2 and BSCL2 loci, and in six of the affected subjects, the transcripts of AGPAT2 and BSCL2 were normal. All subtypes of CGL showed high prevalence of diabetes, hypertriglyceridemia, and acanthosis nigricans. However, patients with BSCL2 mutations had lower serum leptin levels, an earlier onset of diabetes, and higher prevalence of mild mental retardation compared with other subtypes. We conclude that besides AGPAT2 and BSCL2, there may be additional loci for CGL. The genetic heterogeneity in CGL patients is accompanied by phenotypic heterogeneity.

1-Acylglycerol-3-Phosphate O-Acyltransferase↗

PubMed2003

Effect of leptin replacement on intrahepatic and intramyocellular lipid content in patients with generalized lipodystrophy.

OBJECTIVE: To investigate whether leptin-induced improvements in glycemic control, hyperlipidemia, and insulin sensitivity in hypoleptinemic patients with generalized lipodystrophies are accompanied by reduction in intrahepatic and intramyocellular lipid (IMCL) accumulation. RESEARCH DESIGN AND METHODS: We examined the effects 8-10 months of subcutaneous leptin replacement therapy on insulin sensitivity, IMCL, and intrahepatic lipid content in two patients with acquired generalized lipodystrophy and one patient with congenital generalized lipodystrophy. All patients had extreme lack of body fat, low plasma leptin levels, and elevated serum triglycerides, but only two had diabetes. Insulin sensitivity was measured by a high-dose (0.2 IU/kg) insulin tolerance test, as well as by hyperinsulinemic-euglycemic glucose clamp studies in two patients. IMCL and intrahepatic lipid content were measured by (1)H magnetic resonance spectroscopy. All measurements were obtained before and during 2-10 months of leptin therapy. RESULTS: Glycemic control and lipoprotein levels markedly improved with leptin therapy in the two diabetic patients, and a slight improvement in lipoprotein levels was seen in the nondiabetic patients. Insulin stimulated glucose uptake during 60-120 min of the euglycemic clamp studies, and the rate of glucose disappearance during the insulin tolerance test nearly doubled with leptin therapy. As compared with the baseline period, after 8-10 months of leptin therapy, the mean intrahepatic lipid content was reduced by approximately 80% and the IMCL content was reduced by approximately 42%. CONCLUSIONS: Reduction in IMCL and intrahepatic lipid content may partly explain leptin-induced improvement in insulin sensitivity in patients with generalized lipodystrophy.

Adolescent↗

PubMed2002

Leptin-replacement therapy for lipodystrophy.

BACKGROUND: The adipocyte hormone leptin is important in regulating energy homeostasis. Since severe lipodystrophy is associated with leptin deficiency, insulin resistance, hypertriglyceridemia, and hepatic steatosis, we assessed whether leptin replacement would ameliorate this condition. METHODS: Nine female patients (age range, 15 to 42 years; eight with diabetes mellitus) who had lipodystrophy and serum leptin levels of less than 4 ng per milliliter (0.32 nmol per milliliter) received recombinant methionyl human leptin (recombinant leptin). Recombinant leptin was administered subcutaneously twice a day for four months at escalating doses to achieve low, intermediate, and high physiologic replacement levels of leptin. RESULTS: During treatment with recombinant leptin, the serum leptin level increased from a mean (+/- SE) of 1.3 +/- 0.3 ng per milliliter to 11.1 +/- 2.5 ng per milliliter (0.1 +/- 0.02 to 0.9 +/- 0.2 nmol per milliliter). The absolute decrease in the glycosylated hemoglobin value was 1.9 percent (95 percent confidence interval, 1.1 to 2.7 percent; P=0.001) in the eight patients with diabetes. Four months of therapy decreased average triglyceride levels by 60 percent (95 percent confidence interval, 43 to 77 percent; P<0.001) and liver volume by an average of 28 percent (95 percent confidence interval, 20 to 36 percent; P=0.002) in all nine patients and led to the discontinuation of or a large reduction in antidiabetes therapy. Self-reported daily caloric intake and the measured resting metabolic rate also decreased significantly with therapy. Overall, recombinant leptin therapy was well tolerated. CONCLUSIONS: Leptin-replacement therapy improved glycemic control and decreased triglyceride levels in patients with lipodystrophy and leptin deficiency. Leptin deficiency contributes to the insulin resistance and other metabolic abnormalities associated with severe lipodystrophy.

Adolescent↗

PubMed2002

Effect of subcutaneous leptin replacement therapy on bone metabolism in patients with generalized lipodystrophy.

The adipocyte-derived hormone leptin, which plays an important role in energy homeostasis, has been suggested to have an influence on bone development and remodeling. However, it is not clear from animal studies whether leptin is a stimulator or an inhibitor of bone growth. Cross-sectional studies in humans suggest that serum leptin levels are positively associated with bone mineral density (BMD), but these observations are not consistent, and whether this relationship is independent of obesity remains unclear. We therefore examined the effect of sc leptin administration on BMD and markers of bone turnover in two women, one with congenital generalized lipodystrophy and the other with acquired generalized lipodystrophy. Both patients had regular menstrual cycles. At baseline, the BMD for both patients, measured at the lumbar spine and total hip, was within 1 SD of the peak bone mass. There was no significant change in BMD in both patients after 16-18 months of leptin therapy. Similarly, concentrations of serum osteocalcin and bone-specific alkaline phosphatase or urinary excretion of deoxypyridinoline and N-telopeptides remained unchanged after 6-8 months of leptin therapy, suggesting no effects of leptin on osteoblastic or osteoclastic activity. Our preliminary data suggest that sc leptin replacement in hypoleptinemic patients with generalized lipodystrophy has no effect on the mature adult skeleton.

Absorptiometry, Photon↗

PubMed2002

Body fat distribution and metabolic derangements in patients with familial partial lipodystrophy associated with mandibuloacral dysplasia.

Mandibuloacral dysplasia (MAD) is a rare autosomal recessive disorder that is characterized by mandibular and clavicular hypoplasia, acroosteolysis, delayed closure of cranial sutures, joint contractures, and mottled cutaneous pigmentation. It is also associated with partial lipodystrophy, but the pattern of fat loss has not been well characterized. We studied body fat distribution in two male and two female patients with MAD by anthropometry, dual energy x-ray absorptiometry, and magnetic resonance imaging. Blood glucose and insulin responses during an oral glucose tolerance test and fasting serum lipoproteins were determined. Three of the four subjects had loss of sc fat from the extremities with normal or slight excess in the neck and truncal regions (termed type A pattern). In contrast, one patient had generalized loss of sc fat involving the face, trunk, and extremities (type B pattern). All of the patients had normal glucose tolerance but had fasting and postprandial hyperinsulinemia suggestive of insulin resistance. Elevated serum triglycerides with low high-density lipoprotein cholesterol levels were noted in three subjects. We conclude that familial partial lipodystrophy associated with MAD presents with two types of body fat distribution patterns, both of which are associated with insulin resistance and its metabolic complications.

Absorptiometry, Photon↗