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ABSTRACT: The discovery of the adipocyte hormone leptin completely changed our view of energy metabolism. In addition, the discovery of leptin rapidly progressed to clinical development. After a decade of clinical studies, leptin appears not to be the magic bullet therapy for obesity; however, it has a robust role in rare human conditions characterized by its deficiency. Recent exciting work from the Unger laboratory suggests that leptin therapy may also have a potential role for the treatment of Type 1 diabetes. In this review we discuss the positive evidence why such an approach is worthwhile. In order to achieve this broad goal, we reviewed available literature and provided our interpretation of the evidence presented in the original research papers. The potential cautionary aspects of this novel approach will be discussed in an accompanying article.
Pediatric Diabetes 09/2011; 13(1):68-73. · 2.16 Impact Factor
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ABSTRACT: To describe and assess the effectiveness of a lifestyle intervention program (Met Fit) designed to treat the metabolic syndrome (MetSyn) in a cardiac rehabilitation setting.
Met Fit is a physician referred and patient pay ($350) program consisting of 12 weekly sessions of 45 minutes of exercise and 45 minutes of education with target exercise recommendations of 150 to 200 minutes weekly and 5% loss in body weight using a Mediterranean-style diet. Primary outcomes are compliance with program recommendations and secondary outcomes effecting MetSyn components.
Patients (N = 126) were enrolled between June 2005 and July 2009 averaging 9 per class. Mean (SD) age was 51(12) years, body mass index 38(6.9) kg/m, high density lipoprotein-cholesterol for men 37(9.4) mg/dL and women 46(10) mg/dL, glucose 121(39) mg/dL, and homeostatic model assessment of insulin resistance 7.2(6.1). For the 93 (73.8%) patients for whom there was complete data, mean weight loss was 6.2(6.9) lbs, [corrected] 63.4% lost at least 4 lbs, [corrected] and 19.4% lost more than 5% of weight. Significant reductions were observed in the waist circumference and body fat, and systolic and diastolic blood pressure. Triglycerides decreased significantly in both diabetics and nondiabetics but glucose decreased significantly only in diabetics. At baseline, 51% had evidence of depression, which decreased to 24.7% at 12 weeks. At program completion, 18 patients (19.4%) no longer had the MetSyn and 39 (41.9%) lost at least 1 criterion (P < .0001).
A 12-week patient-pay lifestyle interventional program conducted in a cardiac rehabilitation setting can result in a highly significant benefit to patients with the MetSyn.
Journal of cardiopulmonary rehabilitation and prevention 07/2011; 31(5):282-9. · 1.69 Impact Factor
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ABSTRACT: An International Expert Committee made recommendations for using the hemoglobin A(₁C) (A1C) assay as the preferred method for the diagnosis of diabetes in nonpregnant individuals. A concentration of at least 6.5% was considered as diagnostic. It is the aim of this study to compare the sensitivity of A1C with that of plasma glucose concentrations in subjects with early diabetes or impaired glucose tolerance (IGT). We chose 2 groups of subjects who had A1C not exceeding 6.4%. The first group of 89 subjects had family histories of diabetes (MODY or type 2 diabetes mellitus) and had oral glucose tolerance test (OGTT) and A1C determinations. They included 36 subjects with diabetes or IGT and 53 with normal OGTT. The second group of 58 subjects was screened for diabetes in our Diabetes Clinic by fasting plasma glucose, 2-hour plasma glucose, or OGTT and A1C; and similar comparisons were made. Subjects with diabetes or IGT, including those with fasting hyperglycemia, had A1C ranging from 5.0% to 6.4% (mean, 5.8%). The subjects with normal OGTT had A1C of 4.2% to 6.3% (mean, 5.4%), or 5.5% for the 2 groups. The A1C may be in the normal range in subjects with diabetes or IGT, including those with fasting hyperglycemia. Approximately one third of subjects with early diabetes and IGT have A1C less than 5.7%, the cut point that the American Diabetes Association recommends as indicating the onset of risk of developing diabetes in the future. The results of our study are similar to those obtained by a large Dutch epidemiologic study. If our aim is to recognize early diabetic states to apply effective prophylactic procedures to prevent or delay progression to more severe diabetes, A1C is not sufficiently sensitive or reliable for diagnosis of diabetes or IGT. A combination of A1C and plasma glucose determinations, where necessary, is recommended for diagnosis or screening of diabetes or IGT.
Metabolism: clinical and experimental 01/2011; 60(1):86-91. · 2.59 Impact Factor
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AJP Endocrinology and Metabolism 03/2009; 296(2):E394-5, author reply E396. · 4.75 Impact Factor
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ABSTRACT: To examine leptin's role in human appetite regulation, we studied recombinant methionyl human leptin's effects on satiation and satiety in a model of leptin insufficiency, lipodystrophy. Eight females with hypoleptinemia and lipodystrophy were given sc injections of A-100 (maximal dose, 200% of that predicted to normalize serum leptin) for 4 months. Satiation and satiety were determined before and again during leptin treatment. Satiation was measured as the time to voluntary cessation of eating from a standardized food array after a 12-h fast. Satiety was determined as the time to hunger sufficient to consume a full meal after consumption of a standardized preload. During leptin treatment, satiation time decreased (41.2 +/- 18.2 to 19.5 +/- 10.6 min; P = 0.01), satiety time increased (62.9 +/- 64.8 to 137.8 +/- 91.6 min; P = 0.04), energy consumed to produce satiation decreased (2034 +/- 405 to 1135 +/- 432 kcal or 8.5 +/- 1.7 to 4.7 +/- 1.8 MJ; P < 0.01), and the amount of food desired in the postabsorptive state decreased (P < 0.02). Ghrelin concentrations also decreased during leptin administration (284.3 +/- 127.9 to 140.6 +/- 104.5 pmol/liter; P < 0.002). We conclude that increased leptin in patients with lipodystrophy results in less caloric, shorter, more satiating meals and longer-lived satiety. These data support the hypothesis that leptin plays an important, permissive role in human appetite regulation.
Journal of Clinical Endocrinology & Metabolism 09/2004; 89(9):4258-63. · 6.50 Impact Factor
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ABSTRACT: To review evidence supporting the hypothesis that metabolic manifestations of lipodystrophy result from leptin deficiency and that leptin replacement may be a viable treatment for generalized lipodystrophy.
This review results from the authors' collective clinical experience and a comprehensive MEDLINE search of the English-language literature (1998 to 2009) on "leptin and lipodystrophy."
Severe lipodystrophy syndromes are characterized by loss of subcutaneous adipose tissue and thus a relative deficiency of the adipocyte-secreted hormone leptin. Several small, nonrandomized, open-label trials in a composite total of more than 100 patients with severe lipodystrophy not related to human immunodeficiency virus infection have evaluated the efficacy and safety of recombinant human methionyl leptin (metreleptin) therapy. Variables observed to improve after treatment with metreleptin include glycemic control, insulin sensitivity, plasma triglycerides, caloric intake, liver volume and lipid content, intramyocellular lipid content, and neuroendocrine and immunologic end points. In these studies, metreleptin treatment was well tolerated. Typical daily replacement doses for metreleptin were 0.06 to 0.08 mg/kg for female patients and 0.04 mg/kg for male patients, administered by subcutaneous injection twice daily. Although metreleptin is not yet approved for routine clinical use, it is available by means of expanded access provisions for patients with severe lipodystrophy and associated metabolic abnormalities.
Evidence published in the medical literature indicates that treating severe lipodystrophy as a leptin deficiency syndrome can improve the metabolic outcomes in affected patients.
Endocrine Practice 16(2):324-33. · 2.49 Impact Factor
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ABSTRACT: To review the initial clinical manifestations of congenital and acquired lipodystrophy syndromes, discuss novel classifications associated with genetic mutations, and assess currently available therapeutic options for patients with lipodystrophy.
This review is the result of the authors' collective clinical experience and a comprehensive MEDLINE literature search on the English-language literature published between January 1966 and October 2009 on "lipodystrophy." This review focuses primarily on severe dystrophy not related to human immunodeficiency virus (HIV) infection, in light of the additional scope required to cover HIV-related lipodystrophy.
Congenital lipodystrophy syndromes are characterized by a paucity of adipose tissue and classified on the basis of the extent of fat loss and heritability Paradoxically, they are associated with metabolic abnormalities often found in obese patients, including insulin resistance, diabetes, and severe hypertriglyceridemia. Patients with severe forms of lipodystrophy are also deficient in adipokines such as leptin, which may contribute to metabolic abnormalities. The search for molecular defects has revealed a role for genes that affect adipocyte differentiation (for example, peroxisome proliferator-activated receptor gamma), lipid droplet morphology (seipin, caveolin-1), or lipid metabolism (AGPAT2). Others (lamin A/C) are known to be associated with completely different diseases. There are also acquired forms of lipodystrophy that are thought to occur primarily attributable to autoimmune mechanisms. Recently, recombinant leptin has emerged as a useful therapy.
Lipodystrophy syndromes have advanced our understanding of the physiologic role of adipose tissue and allowed identification of key molecular mechanisms involved in adipocyte differentiation. Novel therapeutic strategies are being developed on the basis of the pathophysiologic aspects of these syndromes.
Endocrine Practice 16(2):310-23. · 2.49 Impact Factor
