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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin, the ob gene product, is produced by adipocytes, and it acts to decrease caloric intake and increase energy expenditure. To better understand the molecular mechanisms of hormone-regulated leptin synthesis and secretion, we assessed the ability of insulin and dexamethasone to acutely modulate ob gene expression and leptin secretion in rat adipocytes. Incubation of rat adipocytes with 100 nmol/l insulin for 2 h had no effect on ob mRNA levels, but it stimulated a twofold increase in leptin secretion. Dexamethasone (100 nmol/l) stimulated both a two- to fourfold increase in ob mRNA and a twofold increase in leptin secretion. Consonant with a posttranscriptional and transcriptional regulatory mechanism for insulin- and dexamethasone-stimulated leptin secretion, respectively, actinomycin D blocked dexamethasone-stimulated leptin secretion but did not affect insulin-stimulated leptin secretion. Cycloheximide treatment did not significantly affect ob mRNA accumulation, but it reduced total secreted leptin. Interestingly, however, insulin was still able to stimulate a twofold increase in leptin secretion. These data suggest that insulin, but not dexamethasone, is able to stimulate leptin secretion from a preexisting intracellular pool, although de novo protein synthesis is required for the full insulin-stimulated effect. Signaling pathways involved in leptin synthesis/secretion were also evaluated. The phosphatidylinositol 3-kinase inhibitor LY294002, the Map/Erk kinase inhibitor PD98059, and the immunosuppressant rapamycin had no effect on basal levels of leptin secretion. However, all three inhibitors markedly decreased both insulin- and dexamethasone-stimulated leptin secretion. These findings suggest a complex set of signaling pathways involved in mediating insulin- and dexamethasone-stimulated leptin synthesis and secretion.
Diabetes 1999 Feb
PMID:Regulation of ob gene expression and leptin secretion by insulin and dexamethasone in rat adipocytes. 1033 1

Leptin induces weight loss in rodents via its effects on food intake and energy expenditure. High-fat diets induce weight gain, but the mechanism is not well understood. Previous studies have not found an effect of dietary fat content on fasting leptin. There is a nocturnal increase of leptin, however, which is related to insulin responses to meals. We have reported that adipocyte glucose utilization is involved in insulin-induced leptin secretion in vitro. Accordingly, high-fat, low-carbohydrate (HF/LC) meals, which induce smaller insulin and glucose responses, would produce lower leptin concentrations than low-fat, high-carbohydrate (LF/HC) meals. Blood samples were collected every 30-60 min for 24 h from 19 normal-weight (BMI, 24.2 +/- 0.7 kg/m2; percent body fat = 31 +/- 1%) women on 2 days (10 days apart) during which the subjects were randomized to consume three isocaloric 730-kcal meals containing either 60/20 or 20/60% of energy as fat/carbohydrate. Overall insulin and glycemic responses (24-h area under the curve [AUC]) were reduced by 55 and 61%, respectively, on the HF/LC day (P < 0.0001). During LF/HC feeding, there were larger increases of leptin 4-6 h after breakfast (38 +/- 7%, P < 0.001) and lunch (78 +/- 14%, P < 0.001) than after HF/LC meals (both P < 0.02). During LF/HC feeding, leptin increased from a morning baseline of 10.7 +/- 1.6 ng/ml to a nocturnal peak of 21.3 +/- 1.3 ng/ml (change, 10.6 +/- 1.3 ng/ml; percent change, 123 +/- 16%; P < 0.0001). The amplitudes of the nocturnal rise of leptin and the 24-h leptin AUC were 21 +/- 8% (P < 0.005) and 38 +/- 12% (P < 0.0025) larger, respectively, on the LF/HC day. In summary, consumption of HF/LC meals results in lowered 24-h circulating leptin concentrations. This result may be a consequence of decreased adipocyte glucose metabolism. Decreases of 24-h circulating leptin could contribute to the weight gain during consumption of high-fat diets.
Diabetes 1999 Feb
PMID:High-fat meals reduce 24-h circulating leptin concentrations in women. 1033 10

The mouse ob gene encodes leptin, an adipocyte hormone that regulates body weight and energy expenditure. Leptin has potent metabolic effects on fat and glucose metabolism. A mutation of the ob gene results in mice with severe hereditary obesity and diabetes that can be corrected by treatment with the hormone. In lean mice, leptin acutely increases glucose metabolism in an insulin-independent manner, which could account, at least in part, for some of the antidiabetic effect of the hormone. To investigate further the acute effect of leptin on glucose metabolism in insulin-resistant obese diabetic mice, leptin (40 ng x g(-1) x h(-1)) was administered intravenously for 6 h in C57Bl/6J ob/ob mice. Leptin increased glucose turnover and stimulated glucose uptake in brown adipose tissue (BAT), brain, and heart with no increase in heart rate. A slight increase in all splanchnic tissues was also noticed. Conversely, no increase in skeletal muscle or white adipose tissue (WAT) glucose uptake was observed. Plasma insulin concentration increased moderately but neither glucose, glucagon, thyroid hormones, growth hormone, nor IGF-1 levels were different from phosphate-buffered saline-infused C57Bl/6J ob/ob mice. In addition, leptin stimulated hepatic glucose production, which was associated with increased glucose-6-phosphatase activity. Conversely, PEPCK activity was rather diminished. Interestingly, hepatic insulin receptor substrate (IRS)1-associated phosphatidylinositol 3-kinase activity was slightly elevated, but neither the content of glucose transporter GLUT2 nor the phosphorylation state of the insulin receptor and IRS-1 were changed by acute leptin treatment. Hepatic lipid metabolism was not stimulated during the acute leptin infusion, since the content of triglycerides, glycerol, and citrate was unchanged. These findings suggest that in ob/ob mice, the antidiabetic antiobesity effect of leptin could be the result of a profound alteration of glucose metabolism in liver, BAT, heart, and consequently, glucose turnover. Insulin resistance of skeletal muscle and WAT, while not affected by acute leptin treatment, could also be corrected in the long term and account for some of leptin's antidiabetic effects.
Diabetes 1999 Jun
PMID:Acute intravenous leptin infusion increases glucose turnover but not skeletal muscle glucose uptake in ob/ob mice. 1034 14

The adipocyte hormone leptin reduces food intake in normal animals. During uncontrolled type 1 diabetes, plasma leptin levels fall, whereas food intake increases. To test the hypothesis that low leptin levels contribute to diabetic hyperphagia, we investigated the effect on food intake of replacement of leptin at basal plasma concentrations for 7 days in Long-Evans rats with uncontrolled diabetes induced by streptozotocin (STZ). One group of STZ diabetic rats received saline (STZ + Sal) (n = 11), while the other group (STZ + Lep) (n = 15) received a subcutaneous infusion of recombinant rat leptin (100 microg x kg(-1) x day(-1)) via osmotic minipumps. A nondiabetic control group (Con) (n = 11) received saline only. In the STZ + Sal group, plasma leptin levels decreased by 75% (P < 0.05) from 2.4+/-0.5 on the day before STZ/citrate buffer vehicle (Veh) injection (day 0) to 0.6+/-0.2 ng/ml on day 7. In contrast, plasma leptin levels on days 3-7 were comparable to pretreatment values in both the STZ + Lep group (day 0: 2.6+/-0.4 vs. day 7: 2.5+/-0.3 ng/ml, NS) and the Con group (day 0: 3.8+/-0.4 vs. day 7: 2.9+/-1.0 ng/ml, NS). In the STZ + Sal group, daily food intake increased gradually to values 43% above basal by day 7 (day 0: 24+/-2 to day 7: 33+/-3 g, P < 0.05), whereas food intake did not increase in either the STZ + Lep group (day 0: 24+/-1 vs. day 7: 21+/-2 g, NS), or the Con group (day 0: 23+/-1 vs. day 7: 23+/-2 g). Plasma glucose levels exceeded nondiabetic control values (7.7+/-0.2 mmol/l) in both diabetic groups, but were lower in the STZ + Lep group (17.2+/-1.8 mmol/l) than in the STZ + Sal group (24.3+/-1.1 mmol/l, P < 0.05). To determine if sensitivity to leptin-induced anorexia was affected by STZ treatment, a second experiment was performed in which the effect of intracerebroventricular leptin injection (at doses of 0.35, 1.0, or 3.5 microg) on food intake was measured 10 days after STZ or Veh treatment. Leptin suppressed both 4- and 24-h food intake in the two groups to an equal extent at every dose (by 15, 22, and 35%, respectively). These findings support the hypothesis that the effect of uncontrolled diabetes to lower leptin levels contributes to diabetic hyperphagia and that this effect is not due to altered leptin sensitivity.
Diabetes 1999 Jun
PMID:Low plasma leptin levels contribute to diabetic hyperphagia in rats. 1034 16

Leptin has been shown to improve insulin sensitivity and glucose metabolism in normoinsulinemic healthy or obese rodents. It has not been determined whether leptin may act independently of insulin in regulating energy metabolism in vivo. The present study was designed to examine the effects of leptin treatment alone on glucose metabolism in insulin-deficient streptozotocin (STZ)-induced diabetic rats. Four groups of STZ-induced diabetic rats were studied: 1) rats treated with recombinant methionine murine leptin subcutaneous infusion with osmotic pumps for 12-14 days (LEP; 4 mg x kg(-1) x day(-1), n = 10); 2) control rats infused with vehicle (phosphate-buffered saline) for 12-14 days (VEH; n = 10); 3) pair-fed control rats given a daily food ration matching that of LEP rats for 12-14 days (PF; n = 8); and 4) rats treated with subcutaneous phloridzin for 4 days (PLZ; 0.4 g/kg twice daily, n = 10). Phloridzin treatment normalizes blood glucose without insulin and was used as a control for the effect of leptin in correcting hyperglycemia. All animals were then studied with a hyperinsulinemic-euglycemic clamp (6 mU x kg(-1) x min(-1). Our study demonstrates that leptin treatment in the insulin-deficient diabetic rats restored euglycemia, minimized body weight loss due to food restriction, substantially improved glucose metabolic rates during the postabsorptive state, and restored insulin sensitivities at the levels of the liver and the peripheral tissues during the glucose clamp. The effects on glucose turnover are largely independent of food restriction and changes in blood glucose concentration, as evidenced by the minimal improvement of insulin action and glucose turnover parameters in the PF and PLZ groups. Our results suggest that the antidiabetic effects of leptin are achieved through both an insulin-independent and an insulin-sensitizing mechanism.
Diabetes 1999 Jul
PMID:Leptin restores euglycemia and normalizes glucose turnover in insulin-deficient diabetes in the rat. 1038 59

Leptin acts as an adipocyte-derived blood-borne satiety factor that can increase glucose metabolism. To elucidate the therapeutic implications of leptin for obesity-associated diabetes, we crossed transgenic skinny mice overexpressing leptin (Tg/+), which we have developed recently, and lethal yellow KKAy mice (Ay/+), a genetic model for obesity-diabetes syndrome, and examined the metabolic phenotypes of F1 animals. At 6 weeks of age, plasma leptin concentrations in Tg/+ mice with the Ay allele (Tg/+:Ay/+) were significantly higher than those in Ay/+ mice. Although no significant differences in body weight were noted among Tg/+:Ay/+ mice, Ay/+ mice, and their wild-type lean littermates (+/+), glucose and insulin tolerance tests revealed increased glucose tolerance and insulin sensitivity in Tg/+:Ay/+ compared with Ay/+ mice. However, at 12 weeks of age, when plasma leptin concentrations in Ay/+ mice were comparable to those in Tg/+:Ay/+ mice, Tg/+:Ay/+ mice developed obesity-diabetes syndrome similar to that of Ay/+ mice. Body weights of 12-week-old Tg/+:Ay/+ and Ay/+ mice were reduced to those of +/+ mice by a 3-week food restriction; when plasma leptin concentrations remained high in Tg/+:Ay/+ mice but were markedly reduced in Ay/+ and +/+ mice, glucose tolerance and insulin sensitivity in Tg/+:Ay/+ mice were markedly improved as compared with Ay/+ and +/+ mice. The present study demonstrates that hyperleptinemia can delay the onset of impaired glucose metabolism and accelerate the recovery from diabetes during caloric restriction in Tg/+:Ay/+ mice, thereby suggesting the potential usefulness of leptin in combination with a long-term caloric restriction for the treatment of obesity-associated diabetes.
Diabetes 1999 Aug
PMID:Glucose metabolism and insulin sensitivity in transgenic mice overexpressing leptin with lethal yellow agouti mutation: usefulness of leptin for the treatment of obesity-associated diabetes. 1042 81

Leptin is an adipocyte-derived blood-borne satiety factor that acts directly on the hypothalamus, thereby regulating food intake and energy expenditure. We have demonstrated that the hypothalamic arcuate nucleus (Arc) is a primary site of the satiety effect of leptin (Neurosci Lett 224:149-152, 1997). To explore the hypothalamic pathway of sympathetic activation of leptin, we examined the effects of a single intravenous or intracerebroventricular injection of recombinant human leptin on catecholamine secretion in rats. We also examined the effects of direct microinjection of leptin into the ventromedial hypothalamus (VMH), Arc, paraventricular nucleus (PVN), and dorsomedial hypothalamus (DMH) in rats. To further assess whether sympathetic activation of leptin is mediated via the VMH, we also examined the effects of a single intravenous injection of leptin in VMH-lesioned rats. A single injection of leptin (0.25-1.0 mg i.v./rat or 0.5-2.0 pg i.c.v./rat) increased plasma norepinephrine (NE) and epinephrine (EPI) concentrations in a dose-dependent manner. Plasma NE and EPI concentrations were increased significantly when leptin was injected directly into the VMH but were unchanged when injected into the Arc, PVN, and DMH. Plasma NE and EPI concentrations were unchanged in VMH-lesioned rats that received a single intravenous injection of leptin. The present study provides evidence that a leptin-induced increase in catecholamine secretion is mediated primarily via the VMH and suggests the presence of distinct hypothalamic pathways mediating the satiety effect and sympathetic activation of leptin.
Diabetes 1999 Sep
PMID:Sympathetic activation of leptin via the ventromedial hypothalamus: leptin-induced increase in catecholamine secretion. 1048 Jun 9

Excess of body fat, or obesity, is a major health problem and confers a higher risk of cardiovascular and metabolic disorders such as diabetes, hypertension, and coronary heart disease. Leptin is an adipocyte-derived satiety factor that plays an important role in the regulation of energy homeostasis, and its synthesis and secretion are markedly increased in obese subjects. To explore the metabolic consequences of an increased amount of leptin on a long-term basis in vivo, we generated transgenic skinny mice with elevated plasma leptin concentrations comparable to those in obese subjects. Overexpression of leptin in the liver has resulted in complete disappearance of white and brown adipose tissue for a long period of time in mice. Transgenic skinny mice exhibit increased glucose metabolism accompanied by the activation of insulin signaling in the skeletal muscle and liver. They also show small-sized livers with a marked decrease in glycogen and lipid storage. The phenotypes are in striking contrast to those of recently reported animal models of lipoatrophic diabetes and patients with lipoatrophic diabetes with reduced amount of leptin. The present study provides evidence that leptin is an adipocyte-derived antidiabetic hormone in vivo and suggests its pathophysiologic and therapeutic implications in diabetes.
Diabetes 1999 Sep
PMID:Increased glucose metabolism and insulin sensitivity in transgenic skinny mice overexpressing leptin. 1048 Jun 14

Leptin (OB protein) is an important signal in the regulation of energy balance. Leptin levels correlate with adiposity, but also decrease acutely with caloric restriction and increase with refeeding. The brain is an established critical site of leptin function, yet little is known about leptin concentrations in the central nervous system relative to plasma levels, psychiatric diagnoses, and other endocrine parameters. Therefore, using a novel ultrasensitive leptin assay, we explored relationships of human plasma and cerebrospinal fluid (CSF) leptin levels to body mass index, smoking, posttraumatic stress disorder diagnosis, and levels of dopamine, monoamine metabolites, beta-lipotropin, glucocorticoid, and thyroid and cytokine hormones. A strong linear relation between CSF and plasma leptin levels in the am (r = 0.63; P < 0.002) and afternoon (r = 0.90; P < 0.0001) was revealed. CSF and plasma leptin concentrations decreased during a 12- to 20-h period of fasting. A strong association was found between plasma leptin and CSF dopamine levels (r = 0.74; P < 0.01) as well as between CSF leptin levels and urinary free cortisol (r = 0.73; P < 0.01). Both of these parameters covaried with leptin independently of adiposity, as estimated by body mass index. Implications for leptin transport, regulation, and its potential role in therapeutic strategies for obesity and diabetes are discussed.
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PMID:Cerebrospinal fluid and plasma leptin measurements: covariability with dopamine and cortisol in fasting humans. 1052 99

Leptin, an ob gene product, has been shown to suppress food intake by regulating hypothalamic neuromodulators. The present study was designed to examine the involvement of brain histamine in leptin-induced feeding suppression. A bolus infusion of 1.0 microg leptin into the rat third cerebroventricle (i3vt) elevated the turnover rate of hypothalamic neuronal histamine (P < 0.05) as assessed by pargyline-induced accumulation of tele-methylhistamine (t-MH), a major metabolite of histamine. No remarkable change in the mRNA expression of histidine decarboxylase (HDC), a histamine-synthesizing enzyme, was observed in the hypothalamus after i3vt infusion of leptin. These results indicate that leptin increases histamine turnover by affecting the posttranscriptional process of HDC formation or histamine release per se. As expected, concomitant suppression in 24-h cumulative food intake was also observed after infusion of leptin. Systemic depletion of brain histamine levels by pretreatment with an intraperitoneal injection of 224 micromol/kg alpha-fluoromethylhistidine (FMH), a suicide inhibitor of HDC, attenuated the leptin-induced feeding suppression by 50.7% (P < 0.05). This attenuation of feeding suppression was mimicked by the i3vt infusion of 2.24 micromol/kg FMH before leptin treatment (P < 0.05). In addition, concentrations of hypothalamic histamine and t-MH were lowered in diabetic (db/db) mice, which are known to be deficient in leptin receptors (P < 0.05 vs. lean littermates for each amine), although the amine levels were higher in diet-induced obese rats (P < 0.05 for each amine). Leptin-deficient obese mice (ob/ob) showed lower histamine turnover (P < 0.05 vs. lean littermates), which recovered after leptin infusion. Thus, a growing body of results points to an important role for the hypothalamic histamine neurons in the central regulation of feeding behavior controlled by leptin.
Diabetes 1999 Dec
PMID:Hypothalamic neuronal histamine as a target of leptin in feeding behavior. 1058 Apr 15


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