Clinical effects of long-term metreleptin treatment in patients with lipodystrophy

ObjectiveTo evaluate the long-term clinical effect of treatment with metreleptin (an analogue of human leptin) on glycemic and lipid abnormalities and markers of hepatic steatosis in patients with inherited or acquired lipodystrophy.MethodsFifty-five patients (36 with generalized lipodystrophy and 19 with partial lipodystrophy) with at least 1 of 3 metabolic abnormalities (diabetes mellitus, fasting triglyceride level ≥ 200 mg/dL, and insulin resistance) and low leptin levels received subcutaneous injections of metreleptin once or twice daily in an ongoing clinical trial at the National Institutes of Health.ResultsAt baseline, hemoglobin A_1c-8.5% ± 2.1% (mean ± standard deviation [SD])-and triglycerides—479 ± 80 mg/dL (geometric mean ± standard error [SE])-were substantially elevated. Robust and sustained reductions in both variables were evident for the observed patient population during a 3-year metreleptin treatment period (-2.1% ± 0.5% [mean ± SE] and -35.4% ± 13.7% [mean ± SE], respectively). Mean alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were elevated at baseline (100 ± 120 U/L and 71 ± 77 U/L [mean ± SD], respectively) and decreased by -45 ± 19 U/L and -33 ± 14 U/L (mean ± SE), respectively, during the 3-year metreleptin treatment period. Improvements in hemoglobin A_1c, triglycerides, ALT, and AST were more pronounced in the subsets of patients having elevated levels at baseline. The most notable adverse events observed in this patient population were likely attributable to underlying metabolic abnormalities or comorbidities.ConclusionMetreleptin treatment substantially reduced glycemic variables, triglycerides, and liver enzymes (ALT and AST) and demonstrated durability of response throughout a 3-year treatment period. These results support metreleptin as a potential treatment for certain metabolic disorders (for example, diabetes mellitus and hypertriglyceridemia) associated with lipodystrophy. (Endocr Pract. 2011;17:922-932)     

Syndromic Insulin Resistance: Models for the Therapeutic Basis of the Metabolic Syndrome and Other Targets of Insulin Resistance

ObjectiveTo investigate the link between insulin resistance and the metabolic syndrome how to develop treatment approaches.MethodsWe present 3 cases of extreme syndromic insulin resistance: lipodystrophy, autoantibodies to the insulin receptor, and mutations in the insulin receptor gene, with accompanying discussion of pathophysiology and treatment.ResultsIn lipodystrophy, insulin resistance is a direct consequence of leptin deficiency, and thus leptin replacement reverses metabolic syndrome abnormalities, including diabetes and hypertriglyceridemia. The insulin “receptoropathies,” including autoantibodies to the insulin receptor and insulin receptor gene mutations, are characterized by extreme insulin resistance and ovarian hyperandrogenism, without dyslipidemia or fatty liver disease. Autoantibodies to the insulin receptor can be treated using an immunosuppressive paradigm adapted from treatment of other autoimmune and neoplastic conditions. Leptin treatment has shown some success in treating hyperglycemia in patients with insulin receptor gene mutations. Treatment for this condition remains inadequate, and novel therapies that bypass insulin receptor signaling, such as enhancers of brown adipose tissue, are needed.ConclusionsWe present a clinical approach to the treatment of syndromic insulin resistance. The study of rare diseases that replicate the metabolic syndrome, with clear-cut pathophysiology, promotes understanding of novel physiology and development of targeted therapies that may be applicable to the broader population with obesity, insulin resistance, and diabetes. (Endocr Pract. 2012; 18:763-771)     

Clinical Classification and Treatment of Congenital and Acquired Lipodystrophy

ObjectiveTo 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.MethodsThis 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 lipodystrophy not related to human immunodeficiency virus (HIV) infection, in light of the additional scope required to cover HIV-related lipodystrophy.ResultsCongenital 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 receptorg), 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.ConclusionLipodystrophy 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. (Endocr Pract. 2010;16:310-323)     

Efficacy and Safety of Pioglitazone in Treatment of a Patient with an Atypical Partial Lipodystrophy Syndrome

ObjectiveTo evaluate the effectiveness and safety of pioglitazone therapy in a patient with an atypical presentation of partial lipodystrophy.MethodsWe present a case report and review the associated literature to put this case in perspective and explain its atypical features.ResultsA 40-year-old woman was referred because of uncontrolled diabetes and dyslipidemia, despite receiving a total daily dose of insulin of 300 U and combination therapy with a statin and a fibrate. On examination, the patient was found to have substantial central and abdominal fat deposition in conjunction with slender arms and legs. The addition of pioglitazone to her therapeutic regimen resulted in a dramatic improvement in glycemic control and in the dyslipidemia. During approximately a 2-year period, the patient’s insulin dose was decreased and was ultimately discontinued. Considerable increases in weight and in waist circumference were observed during this period. Sequencing of candidate genes known to be associated with familial partial lipodystrophy, acquired partial lipodystrophy, and generalized lipodystrophy showed no genetic abnormalities. Magnetic resonance imaging confirmed the presence of significant visceral and subcutaneous abdominal fat deposition, in association with scant fat tissue in the extremities. Her weight decreased after discontinuation of the insulin therapy and institution of dietary counseling.ConclusionThiazolidinediones have been shown to be efficacious in syndromic lipodystrophies, such as familial partial lipodystrophy subtype 2. We report that these pharmaceutical agents may also help improve metabolic variables in atypical lipodystrophy syndromes with no obvious molecular basis. A pronounced weight gain might result from synergism between thiazolidinediones and insulin promoting adipogenesis, which diminished somewhat after discontinuation of insulin therapy. (Endocr Pract. 2007;13:656-661)     

Enhanced Weight Loss With Pramlintide/Metreleptin: An Integrated Neurohormonal Approach to Obesity Pharmacotherapy

The neurohormonal control of body weight involves a complex interplay between long‐term adiposity signals (e.g., leptin), and short‐term satiation signals (e.g., amylin). In diet‐induced obese (DIO) rodents, amylin/leptin combination treatment led to marked, synergistic, fat‐specific weight loss. To evaluate the weight‐lowering effect of combined amylin/leptin agonism (with pramlintide/metreleptin) in human obesity, a 24‐week, randomized, double‐blind, active‐drug‐controlled, proof‐of‐concept study was conducted in obese or overweight subjects (N = 177; 63% female; 39 ± 8 years; BMI 32.0 ± 2.1 kg/m²; 93.3 ± 13.2 kg; mean ± s.d.). After a 4‐week lead‐in period with pramlintide (180 µg b.i.d. for 2 weeks, 360 µg b.i.d. thereafter) and diet (40% calorie deficit), subjects achieving 2–8% weight loss were randomized 1:2:2 to 20 weeks of treatment with metreleptin (5 mg b.i.d.), pramlintide (360 µg b.i.d.), or pramlintide/metreleptin (360 µg/5 mg b.i.d.). Combination treatment with pramlintide/metreleptin led to significantly greater weight loss from enrollment to week 20 (?12.7 ± 0.9%; least squares mean ± s.e.) than treatment with pramlintide (?8.4 ± 0.9%; P < 0.001) or metreleptin (?8.2 ± 1.3%; P < 0.01) alone (evaluable, N = 93). The greater reduction in body weight was significant as early as week 4, and weight loss continued throughout the study, without evidence of a plateau. The most common adverse events with pramlintide/metreleptin were injection site events and nausea, which were mostly mild to moderate and decreased over time. These results support further development of pramlintide/metreleptin as a novel, integrated neurohormonal approach to obesity pharmacotherapy.     

Osteomalacia with Bone Marrow Fibrosis Due to Severe Vitamin D Deficiency After a Gastrointestinal Bypass Operation for Severe Obesity

ObjectiveTo present 5 cases of bone biopsy-proven osteomalacia with marrow fibrosis (in 3 cases) after gastric bypass operation, review the relevant literature, and offer preventive strategies.MethodsWe summarize the clinical presentation, pertinent biochemical and radiologic data, and bone histomorphometric findings in 5 patients, encountered during a period of 17 years, in whom severe vitamin D deficiency developed after a gastrointestinal bypass surgical procedure for morbid obesity.ResultsFive patients (39 to 60 years of age) were seen for evaluation of metabolic bone disease not responding to “usual” therapy after a gastric bypass surgical procedure. All had generalized bone pain and tenderness, muscle weakness, stooping posture, difficulty walking, and waddling gait due to severe proximal muscle weakness for a period of 2 to 5 years. Diagnoses before the referral varied from arthritis and gout to vitamin D deficiency and osteoporosis despite highly suggestive biochemical or radiologic findings (or both) of osteomalacia in each patient, which was confirmed by bone biopsy. After therapy with pharmacologic doses of ergocalciferol (100,000 IU daily) and calcium carbonate (1 to 2.5 g daily), considerable improvements occurred in clinical symptoms and functional status, biochemical indices, bone mineral density, and bone histomorphometric features.ConclusionGastric bypass operations predispose patients to severe vitamin D deficiency and osteomalacia in the absence of pharmacologic doses of vitamin D therapy. In general, the current recommendations are grossly inadequate in this high-risk population, and the clinical presentation is both nonspecific and often misleading. Prospective long-term studies are needed to determine the appropriate vitamin D dose required to prevent osteomalacia in such patients. (Endocr Pract. 2009;15:528-533)     

Human Immunodeficiency Virus-Associated Lipodystrophy: An Objective Definition Based on Dual-Energy X-RAY Absorptiometry-Derived Regional Fat Ratios In A South Asian Population

ObjectiveTo develop an objective definition of human immunodeficiency virus (HIV)-associated lipodystrophy by using regional fat mass ratios and to assess the utility of anthropometric and skinfold measurements in the initial screening for lipodystrophy.MethodsMale patients between 25 and 50 years old with proven HIV infection (highly active antiretroviral therapy [HAART]-naïve subjects and those receiving successful HAART) were studied and compared with body mass index (BMI)-matched HIV-negative control subjects. Anthropometric variables, body composition, dual-energy x-ray absorptiometry findings, and metabolic variables were compared among the 3 study groups and between those patients with and those without lipodystrophy.ResultsTrunk fat/lower limb fat mass ratio > 2.28 identified 54.3% of patients with HIV receiving HAART as having lipodystrophy and had the highest odds ratio for predicting metabolic syndrome. The “clinical diagnosis of many false-positive and false-negative results. Triceps skinfold thickness (SFT)/BMI ratio ≤ 0.49 and abdominal SFT/triceps SFT ratio > 1.385 have good sensitivity but poor specificity in identifying lipodystrophy. In comparison with HAART-naïve patients with HIV, those receiving HAART had significantly higher insulin resistance, and a significantly greater proportion had impaired glucose tolerance and dyslipidemia. Among patients receiving HAART, those with lipodystrophy had a greater degree of insulin resistance, higher triglyceride levels, and lower levels of high-density lipoprotein cholesterol.ConclusionThe trunk fat/lower limb fat mass ratio in BMI-matched normal subjects can be used to derive cutoff values to define lipodystrophy objectively in HIV-infected patients. Defining lipodystrophy in this way is better than other methods of identifying those patients with increased cardiovascular risk. Triceps SFT/BMI and abdominal SFT/ triceps SFT ratios may be useful as screening tools in resource-poor settings. (Endocr Pract. 2012;18:158-169)     

Long-Term Stabilization Effects of Leptin on Brain Functions in a Leptin-Deficient Patient

Context

Congenital leptin deficiency, caused by a very rare mutation in the gene encoding leptin, leads to severe obesity, hyperphagia and impaired satiety. The only systemic treatment is the substitution with metreleptin leading to weight reduction based on hormonal changes. Several studies have also shown alterations in brain function after metreleptin therapy. In a previous study, we were able to show changes in homeostatic (hypothalamus) and reward-related brain areas (striatum, orbitofrontal cortex (OFC), substantia nigra/ventral tegmental area, amygdala) 3 days and 6 months after therapy start in a leptin-deficient adolescent girl. To further access the time course of functional brain activation changes, we followed the patient for 2 years after initiation of the therapy.

Design, Patient

Functional magnetic resonance imaging during visual stimulation with food (high- and low-caloric) and non-food pictures was performed 1 and 2 years after therapy start in the previously described patient.

Results

The comparison of ‘food vs. non-food’ pictures showed a stabilization of the long-term effects in the amygdala and in the OFC. Therefore, no significant differences were observed between 6 months compared to 12 and 24 months in these regions. Additionally, a reduction of the frontopolar cortex activity over the whole time span was observed. For the comparison of high- and low-caloric pictures, long-term effects in the hypothalamus showed an assimilating pattern for the response to the food categories whereas only acute effects after 3 months were observed in hedonic brain regions.

Conclusion

This follow-up study shows that the long lasting benefit of metreleptin therapy is also associated with activation changes in homeostatic, hedonic and frontal control regions in congenital leptin deficiency.     

Correlation of Symptoms with Vitamin D Deficiency and Symptom Response to Cholecalciferol Treatment: a Randomized Controlled Trial

ObjectiveTo examine the association of symptoms with vitamin D deficiency and symptom response to cholecalciferol treatment in a randomized, double-blind, placebo-controlled trial.MethodsAdult primary care patients in Duluth, Minnesota, were screened for vitamin D deficiency in February 2007. Participants completed questionnaires pertaining to a variety of symptoms, vitamin D intake, and selected medical conditions. Patients with mild to moderate vitamin D deficiency (25-hydroxyvitamin D [25(OH)D], 10-25 ng/mL) participated in a randomized controlled trial (RCT) of vitamin D replacement and its effect on symptoms. Participants were randomly assigned to receive 50000 units of cholecalciferol (vitamin D₃) weekly or placebo for 8 weeks. Patients with severe vitamin D deficiency (25[OH]D < 10 ng/mL) were treated in an unblinded fashion, and symptoms were reevaluated post treatment.ResultsA total of 610 patients underwent initial screening, and 100 patients with mild to moderate vitamin D deficiency participated in the RCT. Thirty-eight severely deficient patients were treated in an unblinded fashion. On initial screening, 46.2% of participants were deficient in vitamin D. Self-reported vitamin D supplementation, milk intake, celiac disease, gastric bypass, and chronic pancreatitis were predictive of vitamin D status. Severely deficient participants reported increased musculoskeletal symptoms, depression (including seasonal), and higher (worse) scores on a fibromyalgia assessment questionnaire. In the RCT, the treated group showed significant improvement in fibromyalgia assessment scores (P = 0.03), whereas the placebo-treated participants did not. Severely deficient patients did not show symptom improvement over the 8-week trial period or when followed up 1 year later.ConclusionsCompared with participants in the placebo group, patients in the treatment group showed mild short-term improvement in the overall fibromyalgia impact score, but did not show significant improvement in most musculoskeletal symptoms or in activities of daily living. (Endocr Pract. 2009;15:203-212)     

Metformin-Responsive Classic Salt-Losing Congenita L Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency: a Case Report

ObjectiveTo study the effect of adding metformin to standard steroid replacement therapy in a patient with classic salt-losing congenital adrenal hyperplasia due to 21- hydroxylase deficiency with suboptimal biochemical and clinical control.MethodsWe present the clinical and laboratory findings before and after the addition of metformin to the therapeutic regimen of the study patient.ResultsA 17-year-old girl had been diagnosed as a neonate with classic salt-losing congenital adrenal hyperplasia caused by 21-hydroxylase deficiency (CYP21A2 deficiency). She was treated with hydrocortisone, 20 mg in the morning and 10 mg at bedtime, and fludrocortisone, 50 mcg daily. While on steroid replacement, she maintained normal serum electrolytes, glucose, blood pressure, and external genitalia, but she continued to express clinical features of obesity, hirsutism, amenorrhea, and acanthosis nigricans. Elevated laboratory measurements included the following: fasting 17-hydroxyprogesterone, 3410 ng/dL; total testosterone, 326 ng/dL; and androstenedione, 390 ng/dL. She was initiated on metformin, 500 mg twice daily after meals. After 3 months, the patient lost 2 kg, amenorrhea resolved, 17-hydroxyprogesterone decreased to 1539 ng/dL, total testosterone decreased to 163 ng/dL, and androstenedione levels remained unchanged.ConclusionsMetformin, an agent known to reduce insulin resistance, further suppressed the 17-hydroxyprogesterone concentration in a patient with classic congenital adrenal hyperplasia on steroid replacement therapy. Metformin may improve clinical and biochemical outcomes in classic congenital adrenal hyperplasia without the risk of iatrogenic Cushing syndrome. (Endocr Pract. 2008;14:889-891)     

Leptin and adiponectin, but not IL18, are related with insulin resistance in treated HIV-1-infected patients with lipodystrophy

Leptin, adiponectin and IL18 are adipokines related with obesity, insulin resistance and dyslipidemia in the general population. Treated HIV-1-infected patients with lipodystrophy may develop insulin resistance and proatherogenic dyslipidemia. We assessed the relationship between plasma adipokine levels, adipokine genetics, lipodystrophy and metabolic disturbances. Plasma leptin, adiponectin and IL18 levels were assessed in 446 individuals: 282 HIV-1-infected patients treated with antiretroviral drugs (132 with lipodystrophy and 150 without) and 164 uninfected controls (UC). The LEP2410A>G, LEPRQ223R, ADIPQ276G>T, ADIPOR2-Intron5A>G and IL18-607C>A polymorphisms were validated by sequencing. Leptin levels were higher in UC than in HIV-1-infected, either with or without lipodystrophy (p<0.001 for both comparisons) and were lower in patients with lipodystrophy compared with those without lipodystrophy (p=0.006). In patients with lipodystrophy, leptin had a positive correlation with insulin and with HOMA-IR. Adiponectin levels were non-significantly different in UC and HIV-1-infected patients. Patients with lipodystrophy had lower adiponectin levels than non-lipodystrophy subjects (p<0.001). In patients with lipodystrophy, adiponectin was negatively correlated with insulin, HOMA-IR and triglycerides. Plasma IL18 levels were higher in HIV-1-infected patients compared with UC (p<0.001), and no differences were found according to the presence of lipodystrophy. In patients with lipodystrophy there was a negative correlation between IL18 levels and LDLc. Genetic analyses indicated no significant associations with lipodystrophy nor with insulin resistance or with lipid abnormalities. In conclusion, HIV-1-infected patients have reduced plasma leptin levels. This reduction is magnified in patients with lipodystrophy whose adiponectin levels were lower than that of non-lipodystrophy subjects. Plasma IL18 levels are increased in infected patients irrespective of the presence of lipodystrophy. The polymorphisms assessed are not associated with lipodystrophy or metabolic disturbances in treated HIV-1-infected patients.     

Leptin treatment reduces body fat but does not affect lean body mass or the myostatin-follistatin-activin axis in lean hypoleptinemic women

Animal studies in vivo indicate that leptin treatment in extremely leptin-sensitive ob/ob mice reduces body weight exclusively by reducing fat mass and that it increases muscle mass by downregulating myostatin expression. Data from human trials are limited. Therefore, we aimed at characterizing the effects of leptin administration on fat mass, lean body mass, and circulating regulators of muscle growth in hypoleptinemic and presumably leptin-sensitive human subjects. In an open-label, single-arm trial, seven lean, strenuously exercising, amenorrheic women with low leptin concentrations (≤5 ng/ml) were given recombinant methionyl human leptin (metreleptin; 0.08 mg·kg(-1)·day(-1)) for 10 wk. In a separate randomized, double-blind, placebo-controlled trial, seven women were given metreleptin (initial dose: 0.08 mg·kg(-1)·day(-1) for 3 mo, increased thereafter to 0.12 mg·kg(-1)·day(-1) if menstruation did not occur), and six were given placebo for 9 mo. Metreleptin significantly reduced total body fat by an average of 18.6% after 10 wk (P < 0.001) in the single-arm trial and by 19.5% after 9 mo (placebo subtracted; P for interaction = 0.025, P for metreleptin = 0.004) in the placebo-controlled trial. There were no significant changes in lean body mass (P ≥ 0.33) or in serum concentrations of myostatin (P ≥ 0.35), follistatin (P ≥ 0.30), and activin A (P ≥ 0.20) whether in the 10-wk trial or the 9-mo trial. We conclude that metreleptin administration in lean hypoleptinemic women reduces fat mass exclusively and does not affect lean body mass or the myostatin-follistatin-activin axis.     

Drug-induced lipotoxicity: Lipodystrophy associated with HIV-1 infection and antiretroviral treatment

A subset of HIV-1-infected patients undergoing antiretroviral treatment develops a lipodystrophy syndrome. It is characterized by loss of peripheral subcutaneous adipose tissue (face, limbs, buttocks), visceral fat accumulation, and, in some cases, lipomatosis, especially in the dorsocervical area. In addition, these patients show metabolic alterations reminiscent of the metabolic syndrome, particularly dyslipidemia and insulin resistance. These alterations lead to enhanced cardiovascular risk in patients and favor the development of diabetes. Although a complex combination of HIV-1 infection and drug treatment-related events triggers the syndrome, lipotoxicity appears to contribute to the development of the syndrome. Active lipolysis in subcutaneous fat, combined with impaired fat storage capacity in the subcutaneous depot, drive ectopic deposition of lipids, either in the visceral depot or in nonadipose sites. Both hepatic steatosis and increased lipid content in skeletal muscle take place and surely contribute to systemic metabolic alterations, especially insulin resistance. Pancreatic function may also be affected by the exposure to high levels of fatty acids; together with direct effects of antiretroviral drugs, this may contribute to impaired insulin release and a prodiabetic state in the patients. Addressing lipotoxicity as a pathogenic actor in the lipodystrophy syndrome should be considered in strategies for treating and/or preventing the morphological alterations and systemic metabolic disturbances associated with lipodystrophy.     

Clinical Effects of Sodium-Glucose Transporter Type 2 Inhibitors in Patients With Partial Lipodystrophy

ObjectiveSevere insulin resistance syndromes, such as lipodystrophy, lead to diabetes, which is challenging to control. This study explored the safety and efficacy of sodium-glucose cotransporter 2 inhibitors (SGLT2is) in a series of 12 patients with severe insulin resistance due to partial lipodystrophy.MethodsA retrospective chart review of the safety (N = 22) and efficacy (N = 12) of SGLT2is in patients with partial lipodystrophy was conducted at our institution. The efficacy outcomes included hemoglobin A1C level, insulin dose, fasting plasma glucose level, C-peptide level, lipid profile, 24-hour urinary glucose excretion, estimated glomerular filtration rate, and blood pressure before and after 12 months of SGLT2i treatment.ResultsThe hemoglobin A1C level decreased after SGLT2i treatment (at baseline: 9.2% ± 2.0% [77.0 ± 21.9 mmol/mol]; after 12 months: 8.4% ± 1.8% [68.0 ± 19.7 mmol/mol]; P = .028). Significant reductions were also noted in systolic (P = .011) and diastolic blood pressure (P = .013). There was a trend toward a decreased C-peptide level (P = .071). The fasting plasma glucose level, lipid level, and estimated glomerular filtration rate remained unchanged. The adverse effects included extremity pain, hypoglycemia, diabetic ketoacidosis (in a patient who was nonadherent to insulin), pancreatitis (in a patient with prior pancreatitis), and fungal infections.ConclusionSGLT2is reduced the hemoglobin A1C level in patients with partial lipodystrophy, with a similar safety profile compared with that in patients with type 2 diabetes. After individual consideration of the risks and benefits of SGLT2is, these may be considered a part of the treatment armamentarium for these rare forms of diabetes, but larger trials are needed to confirm these findings.     

Endocrine Disturbances in Empty Sella Syndrome: Case Reports and Review of Literature

ObjectiveTo report 5 cases of empty sella syndrome (ESS) manifesting with various degrees of pituitary dysfunction.MethodsWe describe the initial manifestations in 5 patients with primary ESS and in previous cases of ESS reported in the English language literature.ResultsReview of our recent medical records identified 5 patients referred for evaluation of pituitary deficiencies in whom ESS was diagnosed. Glucocorticoid replacement was required in 3 patients, 2 of whom presented initially with symptoms of severe glucocorticoid deficiency. In each case, magnetic resonance imaging of the brain demonstrated an empty sella.ConclusionOur cases suggest that endocrine abnormalities are not rare as the initial manifestation of ESS and that, contrary to many studies in the literature, the endocrine abnormalities may be quite severe. (Endocr Pract. 2005;11:120-124)     

Continuous Subcutaneous Pramlintide Infusion Therapy In Patients With Type 1 Diabetes: Observations From A Pilot Study

ObjectiveTo investigate the efficacy and safety of continuous (basal-bolus) subcutaneous pramlintide infusion (CSPI) in patients with type 1 diabetes mellitus.MethodsA 16-week, open-label, single-arm pilot study enrolled 11 patients (mean ± SD values: age, 39.9 ± 4.0 years; hemoglobin A1c, 8.20% ± 0.60%; weight, 92.3 ± 18.4 kg; body mass index, 29.7 ± 5.1 kg/m²) with longterm type 1 diabetes mellitus (20.7 ± 1.3 years; duration of pump therapy, 9.5 ± 6.0 years). Pramlintide basal infusion was begun with continuous subcutaneous infusion at 9 μg/h. After 3 days, premeal bolus doses of pramlintide were initiated at 15 μg and titrated to 60 μg per meal. Basal and bolus insulin doses were reduced 10% on initiation of CSPI and adjusted thereafter as needed to prevent hypoglycemia.ResultsAfter 16 weeks of pramlintide therapy, mean ± SD hemoglobin A1c decreased to 7.85% ± 0.74% (-0.35%). The fasting glucose level declined from 198.2 ± 66.9 mg/dL to 135.8 ± 63.9 mg/dL. The mean weight decreased to 91.8 ± 20.1 kg (-0.5 kg) at week 12. The daily bolus insulin requirement decreased 20%; daily basal insulin was unchanged (27.7 ± 11.7 U). All patients experienced mild postprandial hypoglycemia, but no severe hypoglycemia was reported. Three of the 11 study participants experienced mild initial nausea, but all patients successfully titrated bolus doses to 60 μg within 3 weeks.ConclusionIn this pilot study of 11 patients with type 1 diabetes using insulin pumps, CSPI seemed safe and well tolerated, did not alter pramlintide pharmacokinetic variables, and reduced fasting glucose levels. Larger studies of this method for pramlintide administration seem warranted. (Endocr Pract. 2009;15:689-695)     

Severe Insulin Resistance and Hypertriglyceridemia After Childhood Total Body Irradiation

ObjectiveTo characterize the metabolic phenotype of 2 cases of normal weight young women who developed type 2 diabetes (T2D), severe insulin resistance (insulin requirement >200 units/day), marked hypertriglyceridemia (>2000 mg/dL), and hepatic steatosis beginning 9 years after undergoing total body irradiation (TBI) and bone marrow transplantation for childhood cancer.MethodsFasting plasma glucose, insulin, free fatty acids (FFAs), leptin, adiponectin, resistin, TNFα, and IL-6 were measured in each case and in 8 healthy women; Case 1 was also assessed after initiating pioglitazone. Coding regions and splice junctions of PPARG, LMNA, and AKT2 were sequenced in Case 1 and of PPARG in Case 2 to evaluate for familial partial lipodystrophies. Genotyping of APOE was performed in Case 1 to rule out type III hyperlipoproteinemia.ResultsBoth cases had elevated plasma levels of insulin, leptin, resistin, and IL-6, high-normal to elevated TNFα, and low to low-normal adiponectin in keeping with post-receptor insulin resistance and adipose tissue inflammation. Case 1 experienced a biochemical response to pioglitazone. No causative mutations for partial lipodystrophies or type III hyperlipoproteinemia were identified.ConclusionThough metabolic derangements have previously been reported in association with TBI, few cases have described insulin resistance and hypertriglyceridemia as severe as that seen in our patients. We speculate that early childhood TBI may impede adipose tissue development leading to metabolic complications from an attenuated ability of adipose tissue to accommodate caloric excess, and propose that this extreme metabolic syndrome be evaluated for as a late complication of TBI. (Endocr Pract. 2013;19:51-58)     

Leptin Activates Hepatic 5′-AMP-activated Protein Kinase through Sympathetic Nervous System and α1-Adrenergic Receptor: A POTENTIAL MECHANISM FOR IMPROVEMENT OF FATTY LIVER IN LIPODYSTROPHY BY LEPTIN*

Leptin is an adipocyte-derived hormone that regulates energy homeostasis. Leptin treatment strikingly ameliorates metabolic disorders of lipodystrophy, which exhibits ectopic fat accumulation and severe insulin-resistant diabetes due to a paucity of adipose tissue. Although leptin is shown to activate 5′-AMP-activated protein kinase (AMPK) in the skeletal muscle, the effect of leptin in the liver is still unclear. We investigated the effect of leptin on hepatic AMPK and its pathophysiological relevance in A-ZIP/F-1 mice, a model of generalized lipodystrophy. Here, we demonstrated that leptin activates hepatic AMPK through the central nervous system and α-adrenergic sympathetic nerves. AMPK activities were decreased in the fatty liver of A-ZIP/F-1 mice, and leptin administration increased AMPK activities in the liver as well as in skeletal muscle with significant reduction in triglyceride content. Activation of hepatic AMPK with A769662 also led to a decrease in hepatic triglyceride content and blood glucose levels in A-ZIP/F-1 mice. These results indicate that the down-regulation of hepatic AMPK activities plays a pathophysiological role in the metabolic disturbances of lipodystrophy, and the hepatic AMPK activation is involved in the therapeutic effects of leptin.     

A Prospective Trial of U500 Insulin Delivered by Omnipod in Patients With Type 2 Diabetes Mellitus and Severe Insulin Resistance

ObjectiveTo test the effectiveness and safety of U500 regular insulin delivered by continuous subcutaneous insulin infusion (CSII) via the Omnipod insulin delivery system in patients with uncontrolled type 2 diabetes mellitus and severe insulin resistance.MethodsIn this prospective, 1-year, proof-of-concept trial, patients with insulin-requiring type 2 diabetes who had a hemoglobin A1c level of 7.0% or higher and severe insulin resistance (average insulin requirement, 1.74 units of insulin per kilogram each day; range, 1.4 to 2.64 units of insulin per kilogram [average insulin dose, 196.4 units daily]) were identified at routine office visits at Mountain Diabetes and Endocrine Center in Asheville, North Carolina, between December 2007 and August 2008. All patients had been on intensive insulin therapy with or without oral agents for more than 3 months. All patients were switched from baseline failed therapy to U500 regular insulin by continuous subcutaneous insulin infusion via Omnipod. Effectiveness was assessed by hemoglobin A1c measurement and 72-hour continuous glucose monitoring at baseline and at weeks 13, 26, and, 52 and by treatment satisfaction assessed by the Insulin Delivery Rating System Questionnaire at baseline and at week 52 while on U500 via Omnipod.ResultsTwenty-one adults were enrolled (mean age, 54 years; mean duration of diabetes, 4 years; mean body mass index, 39.4 kg/m2; mean insulin requirement, 1.7 U/ kg per day; and mean hemoglobin A1c, 8.6%) whose previous treatment with U100 insulin regimens had failed. Twenty patients completed the study. Treatment with U500 insulin via Omnipod significantly reduced hemoglobin A1c by 1.23% (P < .001) and significantly increased the percentage of time spent in the blood glucose target range (70- 180 mg/dL) by 70.75% as assessed by continuous glucose monitoring (P < .001) without a significant increase in hypoglycemia. Patients were satisfied with treatment with U500 insulin via Omnipod, and 14 patients elected to remain on treatment at study completion.ConclusionsU500 insulin delivered subcutaneously continuously via Omnipod is a safe and effective method of insulin delivery in the very insulin-resistant type 2 diabetic population. (Endocr Pract. 2010;16:778-784)     

Therapeutic use of recombinant methionyl human leptin

Recombinant methionyl human leptin (r-metHuLeptin) was first used as a replacement therapy in patients bearing inactivating mutations in the leptin gene. In this indication, it was shown since 1999 to be very efficient in inducing a dramatic weight loss in rare children and adults with severe obesity due to the lack of leptin. These first clinical trials clearly showed that r-metHuLeptin acted centrally to reduce food intake, inducing loss of fat mass, and to correct metabolic alterations, immune and neuroendocrine defects. A few years later, r-metHuLeptin was also shown to reverse the metabolic complications associated with lipodystrophic syndromes, due to primary defects in fat storage, which induce leptin deficiency. The beneficial effects, which could be mediated by central and/or peripheral mechanisms, are thought to mainly involve the lowering effects of leptin on ectopic lipid storage, in particular in liver and muscles, reducing insulin resistance. Interestingly, r-metHuLeptin therapy also reversed the hypothalamic-pituitary-gonadal axis dysfunctions associated with hypothalamic amenorrhea. However, if r-metHuLeptin treatment has been shown to be dramatically efficient in leptin-deficient states, its very limited effect in inducing weight loss in common obese patients revealed that, in patients with adequate leptin secretion, mechanisms of leptin resistance and leptin tolerance prevent r-metHuLeptin from inducing any additional effects. This review will present the current data about the effects of r-metHuLeptin therapy in humans, and discuss the recent perspectives of this therapy in new indications.