Revision of cyrtandra (gesneriaceae) in the marquesas islands.

During the preparation of the Vascular Flora of the Marquesas Islands three new species of Cyrtandra (Gesneriaceae) have come to light and are described herein: C. uapouensis W. L. Wagner & Lorence, C. uahukaensis W. L. Wagner & Lorence, and C. kenwoodii W. L. Wagner & A. J. Wagner. Amended descriptions of the eight previously described Marquesan species are also provided as well as a key to the species. With the description of these the new species Cyrtandra in the Marquesas Islands consists of 11 species, six of which have been included in recent molecular phylogenetic studies of Pacific Cyrtandra, and appear to have arisen from one original introduction. If the other five species are members of this Marquesas clade then Cyrtandra would represent the largest lineage of Marquesas vascular plants. Psychotria is largest genus in the Marquesas Islands with 13 species, but is thought to consist of three separate lineages.

Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults.

Genetic mutations in the leptin pathway can be a cause of human obesity. It is still unknown whether leptin can be effective in the treatment of fully established morbid obesity and its endocrine and metabolic consequences in adults. To test the hypothesis that leptin has a key role in metabolic and endocrine regulation in adults, we examined the effects of human leptin replacement in the only three adults identified to date who have genetically based leptin deficiency. We treated these three morbidly obese homozygous leptin-deficient adult patients with recombinant human leptin at low, physiological replacement doses in the range of 0.01-0.04 mg/kg for 18 months. Patients were hypogonadal, and one of them also had type 2 diabetes mellitus. We chose the doses of recombinant methionyl human leptin that would achieve normal leptin concentrations and administered them daily in the evening to model the normal circadian variation in endogenous leptin. The mean body mass index dropped from 51.2 +/- 2.5 (mean +/- SEM) at baseline to 26.9 +/- 2.1 kg/m2 after 18 months of treatment, mainly because of loss of fat mass. We document here that leptin replacement therapy in leptin-deficient adults with established morbid obesity results in profound weight loss, increased physical activity, changes in endocrine function and metabolism, including resolution of type 2 diabetes mellitus and hypogonadism, and beneficial effects on ingestive and noningestive behavior. These results highlight the role of the leptin pathway in adults with key effects on the regulation of body weight, gonadal function, and behavior.

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.

Effect of leptin replacement on pituitary hormone regulation in patients with severe lipodystrophy.

Leptin is important in regulating energy homeostasis. Severe lipodystrophy is associated with leptin deficiency and insulin resistance, hypertriglyceridemia, and hepatic steatosis. Leptin deficiency is also associated with abnormalities of the pituitary hormones in rodent models and patients with congenital absence of leptin. We inquired whether similar abnormalities are seen in patients with lipodystrophy and whether replacement of leptin will make an impact on the regulation of pituitary hormones. Seven female patients (aged 15-42 yr, all diabetic) with lipodystrophy and serum leptin levels less than 4 mg/liter were treated with recombinant methionyl-human leptin (recombinant leptin) in physiological doses in an open-labeled study. The following parameters were evaluated before and at 4 months of leptin treatment: menstrual history, pelvic ultrasonogram, LHRH, TRH, and CRH tests. While on recombinant leptin, mean serum leptin concentration increased from 1.3 +/- 0.3 mg/liter to 11.1 +/- 2.5 mg/liter. Only one of five patients who had intact reproductive systems was cycling normally before leptin therapy, and all five had normal menses by the fourth month of leptin therapy. Serum E2 concentrations increased (110 +/- 44 pmol/liter vs. 546 +/- 247 pmol/liter, P = 0.002), serum T concentrations decreased (3.5 +/- 3.0 nmol/liter vs. 1.3 +/- 0.7 nmol/liter, P = 0.055), and the attenuated LH response to LHRH was corrected with therapy. Serum T(3) and free T(4) were in the normal range before leptin therapy and did not change. However, serum TSH concentrations fell from 2.2 +/- 1.1 microU/ml to 1.2 +/- 0.7 microU/ml (P < 0.001). The percent increase in TSH following TRH administration was similar before (560%) and at 4 months (580%) of leptin therapy. The mean nonstimulated ACTH and cortisol concentrations were, respectively, 6.0 +/- 3.4 pmol/liter and 680 +/- 280 nmol/liter before leptin and did not change after 4 months of therapy (4.2 +/- 1.2 pmol/liter, P = 0.11 and 453 +/- 142 nmol/liter, P = 0.13, respectively). The ACTH and cortisol responses to CRH stimulation were normal both before and after therapy. Leptin replacement improved menstrual abnormalities and low E2 levels and corrected the attenuated LH response to LHRH in a group of young women with lipodystrophy and leptin deficiency. These results add to the growing body of evidence that metabolic signals such as leptin play a role in neuroendocrine regulation.

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.