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Department of Medicine and Clinical Science (K.E., T.K., M.H., H.M., F.M., N.K., T.T., H.C., T.M., T.H., K.H., Y.O., K.N.), Kyoto University Graduate School of Medicine, and Department of Clinical Trial Management (M.F.), Translational Research Center, Kyoto University Hospital, Kyoto 606-8507, Japan; and Amgen Inc. (A.M.D.), Thousand Oaks, California 91319
Address all correspondence and requests for reprints to: Ken Ebihara or Kazuwa Nakao, Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: Kebihara{at}kuhp.kyoto-u.ac.jp or Nakao{at}kuhp.kyoto-u.ac.jp.
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Abstract |
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Methods: Seven Japanese patients with generalized lipodystrophy, two acquired and five congenital type, were treated with the physiological replacement dose of recombinant leptin during an initial 4-month hospitalization followed by outpatient follow-up for up to 36 months.
Results: The leptin-replacement therapy with the twice-daily injection dramatically improved fasting glucose (mean ± SE, 172 ± 20 to 120 ± 12 mg/dl, P < 0.05) and triglyceride levels (mean ± SE, 700 ± 272 to 260 ± 98 mg/dl, P < 0.05) within 1 wk. The leptin-replacement therapy reduced insulin resistance evaluated by euglycemic clamp method and augmented insulin secretion at glucose tolerance test with different responses between acquired and congenital types. Improvement of the fatty liver was also observed. The efficacy and safety of the once-daily injection were comparable to those of the twice-daily injection. The leptin-replacement therapy ameliorated macro- and microalbuminuria and showed no deterioration of neuropathy and retinopathy of these patients. The leptin-replacement therapy is beneficial to diabetic complications and lipodystrophic ones. Two patients developed antileptin antibodies but not neutralizing antibodies. The therapy was well tolerated, and its effects were maintained for up to 36 months without any notable adverse effects such as hypoglycemia, high blood pressure, or reduction of bone mineral density.
Conclusions: The present study demonstrates the efficacy and safety of the long-term leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Generalized lipodystrophy is a heterogeneous group of diseases characterized by a profound deficiency of adipose tissue (9) and is commonly associated with severe insulin-resistant diabetes, hypertriglyceridemia, and fatty liver (10, 11). In lipoatrophic patients, these metabolic abnormalities develop as a consequence of decreased mass of the adipose tissue (12, 13, 14), and consequently, plasma leptin concentrations are markedly reduced (15). We and others demonstrated that the leptin administration or transgenic overexpression of leptin reverses the metabolic abnormalities in different mouse models of lipodystrophy, indicating that the metabolic abnormalities in lipoatrophic patients are caused mainly by a shortage of leptin (16, 17). Recently, the 4-month leptin-replacement therapy with twice-daily injection protocol was reported to improve glucose and lipid metabolism in nine female patients with lipodystrophy in the United States (18).
In the present study, we evaluated the efficacy and safety of long-term leptin-replacement therapy on seven Japanese patients with generalized lipodystrophy.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Eligible criteria were according to the study protocol of the National Institutes of Health (18). We evaluated seven patients with generalized lipodystrophy including two patients with acquired generalized lipodystrophy (AGL) and five patients with congenital generalized lipodystrophy (CGL). Patients with CGL were further analyzed for mutations in either seipin (19) or 1-acylglycerol-3-phosphate O-acyltransferase2 (AGPAT2) genes (20). Table 1
summarizes the baseline clinical characteristics of seven patients treated in the present study.
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The study protocol was approved by the ethical committee of Kyoto University Graduate School of Medicine (approval number 331). Informed written consent was obtained from all subjects and their families. Recombinant methionyl human leptin (r-metHuLeptin) was provided by Amgen, Inc. (Thousand Oaks, CA). For the first year, r-metHuLeptin was administered as twice-daily sc injection (18). The physiological replacement dose was estimated to be 0.02 mg/kg·d for men, 0.03 mg/kg·d for girls under 18 yr of age, and 0.04 mg/kg·d for women on the basis of information provided by Amgen. Patient 1 was treated with 100% of the replacement dose for the entire period. Patient 2 was treated with 100% for the first and second month and 200% thereafter. Patients 3–7 were treated with 50% for the first month, 100% for the second month, and 200% thereafter. All patients were evaluated as inpatients for the first 4 months. After discharge, patients attended local clinics for every leptin injection, and all of the leptin injections were done by medical doctors because self-injection of r-metHuLeptin, which was not approved as a drug, was not permitted in Japan. Each patient had been prescribed a diet of fixed calories indicated in Table 1
beginning at least 2 months before the initiation of leptin-replacement therapy, and this was not altered throughout the therapy. The dose of antidiabetic and lipid-lowering drugs was tapered or the treatment discontinued as needed. After 12 months of twice-daily leptin treatment, we reduced the dosing frequency to once daily without change of total daily dose. At present, total duration of leptin-replacement therapy was 36 months for patient 1 and 2, 24 months for patient 3, 18 months for patient 4, 8 months for patient 5, and 2 months for patients 6 and 7.
Biochemical analysis
Plasma leptin levels were determined by the immunoassay (Linco, St. Charles, MO). Plasma glucose, serum triglycerides, total cholesterol, alanine aminotransferase, aspartate aminotransferase, and serum and urine creatinine levels were determined according to standard methods with the use of automated equipment. Glycosylated hemoglobin (HbA1c) levels were measured by ion-exchange HPLC. Serum insulin levels were determined by immunoassays (Shibayagi Co., Ltd., Gunma, Japan). Urine albumin excretion was assayed with a human albumin ELISA kit (Sanko Junyaku Co., Ltd., Tokyo, Japan). Antibodies to leptin in serum was tested with the use of a solid-phase RIA, and the potential neutralizing effects of antibodies on leptin bioactivity were assessed in an in vitro bioassay developed by Amgen (Thousand Oaks, CA) (21).
Procedures
Body fat and whole-body bone mineral density were determined by dual-energy x-ray absorptiometry (QDR-2000; Hologic Inc., Bedford, MA). The oral glucose tolerance test (75 g) was performed after an overnight fast. In patients under insulin therapy, insulin injection was stopped from the previous night. The 
values of plasma glucose (PG) levels and serum insulin (IRI) levels were calculated by the sum of the values at 0, 30, 60, 90, 120, and 180 min after administration. Insulin action on glucose uptake in peripheral tissues was evaluated using the hyperinsulinemic-euglycemic glucose clamp technique (22). Fatty liver was diagnosed by both ultrasound and computed tomography (CT) imaging. Liver volume was calculated with the use of CT imaging. Lipid contents of liver and skeletal muscle were determined by magnetic resonance imaging performed on a 1.5-T system (Magnetom Symphony; Siemens Medical System, Erlangen, Germany). The signal intensity of the same region on both the in-phase image (Iin) and the out-of-phase image (Iout) was measured. The fat index (FI) was defined by the following formulae: FI = (Iin– Iout) / Iin. Tissue lipid content was calculated using FI as previously reported (23).
Statistical analysis
Data were expressed as the mean ± SE. Comparison between baseline data and data obtained at various times was assessed by ANOVA and completed by Fisher’s probable least-significant difference test, as required.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Three of five CGL patients were homozygous for the same nonsense mutation (R275X) of the seipin gene as we previously reported (Table 1) (24). The remaining CGL patients had neither seipin nor AGPAT2 gene mutation (24, 25). All the patients had markedly decreased body fat, hypoleptinemia, and uncontrolled diabetes with high fasting glucose levels and HbA1c levels, despite the diet and exercise therapy and the use of oral antidiabetic drugs or insulin. Their age of onset and duration of diabetes are also summarized in Table 1. Three of seven patients had marked fasting hypertriglyceridemia at the level above 1000 mg/dl. The mean ± SE of the total cholesterol level was 233 ± 18 mg/dl. Five patients were diagnosed to have fatty liver, and their ratios of liver to spleen (L/S ratio) for CT attenuation values were under 0.95. Four of seven patients had elevated urine albumin excretion (>30 mg/d), and two of them had macroalbuminuria (>300 mg/d). All the patients showed normal blood pressure (mean ± SE, 110 ± 4/61 ± 5 mm Hg) and bone mineral density (mean ± SE, 1.11 ± 0.08 g/cm2).
High compliance of leptin-replacement therapy
All of the leptin injections were done by medical doctors. For the initial 4 months, all the patients received 100% of scheduled leptin injections as inpatients. After discharge, patients attended local clinics for every leptin injection and received over 98% as outpatients thereafter.
Achievement of physiological replacement of leptin
At any dose, peak plasma levels occurred 2 h after the leptin injection. The peak plasma leptin levels at the doses of 50, 100, and 200% under the protocol of twice-daily injections were 4.05 ± 0.19, 9.80 ± 1.70, 18.95 ± 1.58 (mean ± SE) ng/ml, respectively. The peak plasma leptin level of the 400% dose under the protocol of once-daily injections was 34.48 ± 2.11 (mean ± SE) ng/ml. Thus, the elevations of plasma leptin level were dose dependent, and physiological replacement was achieved as expected.
Rapid effects on glucose and triglyceride levels
The fasting plasma glucose levels decreased day by day in all the patients, and a significant reduction was achieved within 7 d (mean ± SE, 172 ± 20 mg/dl at baseline vs. 120 ± 12 mg/dl after 7 d, P < 0.05) (Table 2). By 4 months, all the patients, except patient 6, were able to discontinue all of the antidiabetic drugs (Table 1). Patient 6 could reduce the dose of the antidiabetic drug by 2 months.
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). Lipid-lowering drugs of patient 4 were able to be discontinued by 4 months. Glucose tolerance tests
As shown in Fig. 1A, the mean plasma glucose levels in response to the oral 75-g glucose load were dramatically improved already at 1 month and were maintained at 2 and 4 months in all patients. The insulin levels were distinctly low before the treatment in both AGL and CGL patients (Fig. 1, B and C). The changes after the initiation of the leptin-replacement therapy of serum insulin levels showed a marked contrast between AGL and CGL patients. Glucose-induced insulin secretion was dramatically improved already at 1 month in AGL patients (Fig. 1B), whereas no apparent improvement in insulin secretion was observed even after 4 months of the therapy in CGL patients (Fig. 1C). To evaluate the ability of insulin secretion, we calculated the values of IRI/PG in a 75-g oral glucose tolerance test. The values of IRI/PG were substantially increased at 1 month in two AGL patients, and additional increases were observed at 2 and 4 months, whereas those in five CGL patients remained unchanged even after 4 months of the therapy (Fig. 1D).
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The glucose infusion rates during the hyperinsulinemic-euglycemic clamp study were distinctly low at baseline in all the patients (mean ± SE, 2.5 ± 0.3 mg/kg·min; range, 1.60–3.6 mg/kg·min). The increase of glucose infusion rate was observed but not statistically significant at 1 month on the treatment (mean ± SE, 3.7 ± 0.3 mg/kg·min, P = 0.062 vs. at baseline). A significant increase was achieved at 2 months (mean ± SE, 4.4 ± 0.4 mg/kg·min, P < 0.01 vs. at baseline) and an additional increase was observed at 4 months (mean ± SE, 5.6 ± 1.0 mg/kg·min, P < 0.001 vs. at baseline). By contrast to insulin secretion, no apparent difference between AGL and CGL patients was observed on the changes of insulin sensitivity.
In patient 4, the hyperinsulinemic-euglycemic clamp study was performed at 10 d. A substantial increase of glucose infusion rate was detected already at 10 d (2.52 mg/kg·min at baseline and 4.63 mg/kg·min at 10 d) and again at 1 month (4.59 mg/kg·min), which was comparable to that at 4 months (5.06 mg/kg·min).
Effects on fatty liver
Five of seven patients were diagnosed to have apparent fatty liver. The L/S ratios of CT attenuation value in five of seven patients were 0.74 ± 0.10 (mean ± SE) (Table 1). The L/S ratio of CT attenuation value in these patients improved from 0.74 ± 0.10 (mean ± SE) to 1.09 ± 0.06 (mean ± SE) by 2 months and further improved thereafter. Consistent with this, in these patients, the alanine aminotransferase level decreased from 80.5 ± 24.2 to 32.3 ± 4.6 U/liter (mean ± SE), and the ASL level decreased from 42.3 ± 11.1 to 21.5 ± 4.3 U/liter (mean ± SE) by 2 months, and these values were also further improved thereafter. The liver volume also decreased in all patients who had fatty liver at baseline (mean ± SE, 1.88 ± 0.12 l at baseline to 1.50 ± 0.10 l at the end of the second month).
In patient 4, measurements of tissue lipid content were performed using magnetic resonance imaging before and after 3 and 10 d and 1, 2, and 4 months of the leptin-replacement therapy. At baseline, lipid content in her liver was clearly increased (29.0%), whereas that in her skeletal muscle was not increased (4.3%). After the leptin-replacement therapy, a distinct change of lipid content in the liver was not detected at 3 and 10 d (31.5 and 28.4%, respectively), but a substantial and gradual decrease was detected at 1 month and again at 2 and 4 months (23.5, 17.5, and 9.6%, respectively). On the other hand, in the skeletal muscle, no distinct change of lipid content was detected even at 4 months (4.2%).
Metabolic controls after discharge for 8 months
After the initial 4 months of hospitalization, the patients were continuously followed as outpatients on the protocol of twice-daily injection. Their fasting glucose levels (Fig. 2A), HbA1c levels (Fig. 2B), glucose infusion rates during the hyperinsulinemic-euglycemic clamp study (Fig. 2C), triglyceride levels (Fig. 2D), total cholesterol levels (Fig. 2E), and liver volumes (Fig. 2F) at 8 and 12 months were almost unchanged when compared with those at 4 months, the end of the hospitalization.
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After 12 months of twice-daily leptin injection, the treatment protocol was altered to once-daily dosing without change of total daily dose in patient 1–4. The alteration of leptin injection protocol did not affect the plasma glucose levels before breakfast, lunch, and dinner in four patients (Fig. 3, A–C). Consistent with these results, HbA1c (Fig. 2B) levels and results of the 75-g oral glucose tolerance test (data not shown) in these patients did not change after the protocol alteration. Likewise, glucose infusion rates during the hyperinsulinemic-euglycemic clamp study, triglyceride levels, total cholesterol levels, and liver volumes were unchanged after the alteration of the treatment protocol (Fig. 2, C–F).
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The duration of leptin-replacement therapy was 36 months for patients 1 and 2, 24 months for patient 3, and 18 months for patient 4. The fasting plasma glucose levels and HbA1c levels were well controlled throughout the therapy period (Fig. 2, A and B). The improved glucose infusion rates during the hyperinsulinemic-euglycemic clamp study, decreased triglyceride and total cholesterol levels, and liver volumes after 4 months of leptin-replacement therapy as inpatients were well controlled throughout the therapy period (Fig. 2, C–F).
Antileptin antibodies
Patients 2 and 3, both CGL patients, showed elevations of basal plasma leptin levels, 75.0 and 42.4 ng/ml at the end of the 12th month, respectively. We detected antileptin antibodies in both patients. Antibodies from these patients did not neutralize the action of leptin at all in a bioassay.
Diabetes and other complications
All seven patients had normal renal functions at baseline; however, two patients had microalbuminuria (>30 mg/d), and two patients had macroalbuminuria (>300 mg/d) (Table 1). In addition, five of seven patients had elevated creatinine clearance (mean ± SE, 206.5 ± 22.0 ml/min·1.73 m2) at the level above 125 ml/min·1.73 m2. After the initiation of leptin-replacement therapy, urine albumin excretion of patients 1 and 3 with microalbuminuria began to decrease gradually within 1 month and was normalized within 2 months (Fig. 4A). Macroalbuminuria of patients 4 and 6 was also regressed to microalbuminuria within 3 and 1 month, respectively (Fig. 4B). In parallel, the creatinine clearance of the five patients with glomerular hyperfiltration significantly decreased to 129.5 ± 24.5 ml/min·1.73 m2 (mean ± SE) for the 4-month leptin-replacement therapy (P < 0.05). These beneficial effects of leptin on urine albumin excretion and glomerular hyperfiltration were stable for up to 36 months.
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Five of seven patients had moderate to severe acanthosis nigricans at baseline, but the acanthosis nigricans was improved in five patients after the leptin-replacement therapy.
Four of five female patients who were of reproductive age had hypogonadotropic amenorrhea at baseline as previously reported (26, 27) but resumed and sustained normal menses after the initiation of the leptin therapy. In an 11-yr-old girl, the menarche was observed after 12 months of the leptin therapy.
All the patients indicated an improvement in feeling of satisfaction after a meal within 1 or 2 d after the initiation of leptin therapy. This effect was sustained throughout the leptin therapy. For the first 4 months, a tendency of body weight reduction was observed in all the patients, but this change was not significant (mean ± SE, 40.9 ± 3.5 to 38.1 ± 3.1 kg, P = 0.55). After the first 4 months, the body weight was almost unchanged throughout the leptin therapy.
Adverse effects
We carefully observed blood pressure in the patients. At baseline, no patients showed hypertension (Table 1), and no distinct elevation of blood pressure was observed at any time throughout the therapy period (Fig. 4C).
No patients showed abnormal bone mineral density (Table 1). Whole-body bone mineral densities of the patients were unchanged for up to 36 months (Fig. 4D).
In all the patients, no other adverse effects of the leptin-replacement therapy including skin reactions at injection sites were detected for up to 36 months.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In previous reports, improvements of glucose and triglyceride levels, glucose tolerance, and insulin sensitivity were reported at 1 month (18, 25, 28). The present study clearly shows that significant reductions of fasting glucose levels are achieved within 7 d after the initiation of the leptin-replacement therapy, and substantial reductions of the triglyceride levels are also gained within 7 d (Table 2). These rapid and powerful effects of leptin-replacement therapy were further confirmed with the glucose tolerance test and hyperinsulinemic-euglycemic glucose clamp study performed after 7 or 10 d in patient 4. These rapid effects on glucose and lipid metabolism in the present study are comparable to the rapid effects of leptin administration in two different mouse models of generalized lipodystrophy (16, 17).
After 12 months of the twice-daily leptin treatment, we tried to alter the leptin injection protocol to a once-daily injection without change of total daily dose. This protocol alteration did not affect the controls of glucose and lipid metabolism, and these controls were maintained for up to 24 months (Figs. 2 and 3). These observations demonstrate that a once-daily leptin injection is sufficient to control glucose and lipid metabolism in patients with generalized lipodystrophy.
In the present study, we detected antileptin antibodies in two of four tested patients. Both of them were CGL patients, whereas we did not detect antileptin antibodies in AGL patients. This observation raises the possibility that antileptin antibodies more easily develop in CGL patients than AGL patients. Antibodies from both of our CGL patients did not neutralize the leptin action in vitro bioassay. In at least one child with congenital leptin deficiency, the transient appearance of neutralizing antibodies against leptin was reported (21). It is possible to speculate that neutralizing antibodies against leptin more easily develop in patients with congenital leptin deficiency than CGL patients, who have a little leptin levels.
The leptin-replacement therapy substantially ameliorated or did not worsen diabetic complications. Amelioration of proteinuria in the present study is consistent with our and other’s previous reports that leptin-replacement therapy significantly alleviates the glomerular injury and proteinuria of lipoatrophic diabetes in mice and humans (29, 30). Although we could not perform renal biopsies, it is highly likely that proteinuria observed in our patients is due to diabetic nephropathy because their proteinuria and hyperfiltration were evidently improved in parallel with the metabolic improvement. These findings indicate that leptin is useful to treat, at least, a certain type of diabetic nephropathy.
The leptin-replacement therapy did not induce elevation of blood pressure in any patients throughout the therapy period (Fig. 4C). We previously demonstrated that a high plasma leptin level that is 10 times of that in normal controls elevates blood pressure through the activation of the sympathetic nervous system in mice (31). It is highly likely that the leptin-replacement therapy at the physiological replacement dose does not affect blood pressure.
Bone mineral density of the patients was within normal range at baseline and was unchanged during the therapy period for up to 36 months (Fig. 4D), consistent with the study reported previously (32). We also previously demonstrated that leptin is a powerful inhibitor of bone formation in mice (33). Although the present study indicates that the leptin-replacement therapy at the physiological replacement dose does not affect bone mineral density in humans, careful follow-up is necessary for young patients.
The effect of leptin on ß-cell function remains unclear. Leptin treatment decreased serum insulin levels in mouse models of lipodystrophy (16, 17) and human lipoatrophic patients in the United States (18). These decreases of insulin levels were explained by the reduction of glucose levels rather than the suppressive effect of leptin. Indeed, insulin levels peaked earlier in lipoatrophic patients in the United States, although their overall amounts of insulin secreted in response to the glucose load were less after the leptin therapy than at baseline (28). On the other hand, we here demonstrate that leptin-replacement therapy dramatically improves insulin secretion in Japanese AGL patients. Because glucose-lowering therapy often leads to the restoration of ß-cell function in patients with diabetes, this effect can be explained at least in part by the cancellation of glucotoxicity (34). The different responses of insulin secretion to leptin-replacement therapy between AGL and CGL patients could be accounted for by the different duration of diabetes. The impaired insulin responses to the glucose load in CGL patients suggests that their ß-cell functions were already exhausted before leptin-replacement therapy. Although whether leptin has an additional effect on ß-cell is unknown, we here demonstrate that leptin-replacement therapy is beneficial to the treatment of impaired ß-cell function.
The mechanisms through which leptin exerts its insulin-sensitizing actions are unclear at present. Fat accumulation in the insulin target organs, which causes so-called lipotoxicity, is considered to be one of the mechanisms for insulin resistance in patients with lipodystrophy (35). Because in patient 4 with AGL, the improvement of insulin sensitivity was observed before a substantial decrease of tissue lipid content in the liver and muscle, additional studies are necessary to clarify the relationship between insulin resistance and the tissue lipid content in humans.
Based on the effect of the leptin-replacement therapy, it is highly likely that leptin deficiency is the main cause of the metabolic abnormalities associated with lipodystrophy. However, the adipose tissue is recognized as the largest endocrine organ. Therefore, it is possible to speculate that these hormones other than leptin may be involved to some degree in the pathogenesis of lipoatrophic diabetes.
Using leptin-overexpressing transgenic skinny mice (8), we previously reported that leptin treatment is useful for treatment of not only lipoatrophic diabetes mice (17) but also other diabetic mice models (36, 37). These observations along with dramatic effects and safety of the leptin therapy in the present study indicate possible application of the leptin therapy to diabetes and its complications.
In summary, under strict control of lifestyle and an extremely high compliance of leptin injection, we demonstrate that the leptin-replacement therapy improves both insulin sensitivity and insulin secretion dramatically and rapidly improves glucose and lipid metabolism in patients with generalized lipodystrophy, and its effects are maintained for up to 36 months without any adverse effects. In addition, the leptin-replacement therapy is beneficial to diabetic complications and lipodystrophic ones. The once-daily leptin injection is sufficient to control glucose and lipid metabolism for a long time. It is concluded that leptin-replacement therapy is an effective and safe treatment for long-term improvement of glucose and lipid metabolism and complications in generalized lipodystrophy.
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Acknowledgments |
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Footnotes |
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Disclosure Statement: K.E., T.K., M.H., H.M., F.M., N.K., T.T., H.C., T.M., T.H., K.H., Y.O., M.F., and K.N. have nothing to disclose. A.M.D. is employed by Amgen Inc.
First Published Online November 21, 2006
Abbreviations: AGL, Acquired generalized lipodystrophy; CGL, congenital generalized lipodystrophy; CT, computed tomography; HbA1c, glycosylated hemoglobin; L/S, liver to spleen; r-metHuLeptin, recombinant methionyl human leptin.
Received July 17, 2006.
Accepted November 15, 2006.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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