Physiological Increase in Plasma Leptin Markedly Inhibits Insulin Secretion In Vivo

Cases, Jane A.; Gabriely, Ilan; Xi, Hui; Yang, Xiao Man; Michaeli, Tamar; Fleischer, Norman; Rossetti, Luciano; Barzilai, Nir

doi:10.2337/diabetes.50.2.348

Cited by 110 publications

(75 citation statements)

References 37 publications

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“…35 Leptin receptors have been demonstrated on the β-pancreatic cell, 36 and in animal studies acute physiologic increases in leptin significantly inhibited glucose stimulated insulin secretion in a dose-dependent manner. 37 Plasma levels of leptin, adequate to significantly suppress insulin, are found in mild obesity 38 and patients with IGT. 39 Furthermore, leptin is associated with features of the metabolic syndrome such as IGT and controls nor between OSA patients with and without IGT.…”

Section: Neuropeptides and Impaired Glucose Tolerancementioning

confidence: 99%

Lack of Association Between Impaired Glucose Tolerance and Appetite Regulating Hormones in Patients with Obstructive Sleep Apnea

Patterson¹,

Twigg²,

Vazir³

et al. 2011

Journal of Clinical Sleep Medicine

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Study Objectives: Understanding the etiologic mechanisms underlying impaired glucose tolerance in obstructive sleep apnea (OSA) would assist development of therapies against this comorbidity. We hypothesized that in patients with OSA impaired glucose tolerance (IGT) would be associated with elevated levels of hormones associated with appetite regulation (leptin, ghrelin, neuropeptide Y [NPY] and peptide tyrosine-tyrosine [PYY]). Method: We studied 68 OSA patients (mean AHI 22 events/h) and 37 age and weight matched healthy controls recruited by advertisement. All participants received a standardized evening meal, attended polysomnography and an oral glucose tolerance test (OGTT) on waking. Hormones were measured in blood taken before sleep (22:30) and at the start of the OGTT. Results: Impaired glucose tolerance was present in 54% of patients and 32% of controls (p = 0.05). The only differences between groups was that leptin was signifi cantly higher at 22:30 in OSA patients compared to controls (9.6 ng/L vs 7.9 ng/L, p = 0.05). OSA patients had marginally elevated plasma NPY levels at 22:30 (56.6 [52, 67] S C I E N T I F I C I N v E S T I G A T I O N SU ntreated obstructive sleep apnea (OSA) is associated with insulin resistance, 1,2 and some studies suggest that treatment with CPAP improves glucose control, 3,4 although this was not found in a randomized controlled trial of diabetics with sleep apnea. 5 The observation that established type 2 diabetics cannot improve glucose control when their OSA is treated with CPAP, emphasizes the importance of understanding the pathophysiology of insulin resistance associated with OSA.One mechanism linking OSA with impaired glucose tolerance could be sympathetic nerve activity which is a recognized phenomenon in OSA 6 ; indeed it has previously been hypothesized that this process is responsible for the elevated leptin levels seen in newly diagnosed OSA patients. 7 Consistent with this sibutramine, a serotonin and noradrenaline reuptake inhibitor, was able to improve insulin resistance in OSA independent of visceral fat. 8 Moreover two studies raise the hypothesis that hormones involved in appetite regulation could contribute to impaired glucose tolerance. Broglio et al. 9 demonstrated that ghrelin administered to healthy subjects simultaneously with glucose, resulted in a transient decrease of insulin concentration that was coupled with signifi cant increase in glucose levels. In addition it has been reported that IR is associated with increased plasma leptin concentration independent of the body fat. 10 Consistent with this hypothesis, previous studies have reported that OSA is independently associated with neuroendocrine dysregulation; in fact OSA has been reported to be bRIEF SUMMARY Current knowledge/Study Rationale: Impaired glucose tolerance is a common and important co-morbidity of obstructive sleep apnea yet its pathogenesis, beyond the shared etiology of obesity is unknown. Here we tested the hypothesis that OSA might induce increases of appetite regulating h...

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Section: Neuropeptides and Impaired Glucose Tolerancementioning

confidence: 99%

Lack of Association Between Impaired Glucose Tolerance and Appetite Regulating Hormones in Patients with Obstructive Sleep Apnea

Patterson¹,

Twigg²,

Vazir³

et al. 2011

Journal of Clinical Sleep Medicine

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“…Thus, O'Doherty et al (42) demonstrated that an acute infusion of leptin does not increase PDE3B activity in rat liver. Furthermore, Cases et al (43) determined that leptin suppression of insulin secretion in vivo is not blocked by milrinone, a PDE3B inhibitor. However, it should be noted that inhibition of PDE3B in the hypothalamus suppresses the effects of leptin on food intake (25), suggesting that a requirement for PDE3B activity for leptin action may be process-and tissue-specific.…”

Section: Figmentioning

confidence: 99%

Impaired Activation of Phosphatidylinositol 3-Kinase by Leptin Is a Novel Mechanism of Hepatic Leptin Resistance in Diet-induced Obesity

Huang

Dedousis

Bhatt

et al. 2004

Journal of Biological Chemistry

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Obesity is associated with the development of leptin resistance. However, the effects of leptin resistance on leptin-regulated metabolic processes and the biochemical defects that cause leptin resistance are poorly understood. We have addressed in rats the effect of dietinduced obesity (DIO), a situation of elevated tissue lipid levels, on the well described lipid-lowering effect of leptin in liver, an action that is proposed to be important for the prevention of tissue lipotoxicity and insulin resistance. In addition, we have addressed the role of phosphatidylinositol 3-kinase (PI 3-kinase) in mediating the acute effects of leptin on hepatic lipid levels in lean and DIO animals. A 90-min leptin (ϳ10 ng/ml) perfusion of isolated livers from lean animals decreased triglyceride levels by 42 ؎ 5% (p ‫؍‬ 0.006). However, leptin concentrations ranging from ϳ10 to ϳ90 ng/ml had no effect on triglyceride levels in livers from DIO animals. The acute lipid-lowering effect of leptin on livers from lean animals was mediated by a PI 3-kinase-dependent mechanism, because wortmannin and LY294002, the PI 3-kinase inhibitors, blocked the effects of leptin on hepatic triglyceride levels and leptin increased liver PI 3-kinase activity by 183 ؎ 6% (p ‫؍‬ 0.003) and insulin receptor substrate 1 tyrosine phosphorylation by 185 ؎ 30% (p ‫؍‬ 0.02) in the absence of PI 3-kinase inhibitors. Contrary to the effects of leptin in lean livers, leptin did not activate PI 3-kinase in livers from DIO rats. These data present evidence for a role for 1) leptin resistance in contributing to the excessive accumulation of tissue lipid in obesity, 2) PI 3-kinase in mediating the acute lipid-lowering effects of leptin in liver, and 3) defective leptin activation of PI 3-kinase as a novel mechanism of leptin resistance.Human obesity and diet-induced obesity in rodents are associated with the development of leptin resistance (1-3). However, despite substantial progress, our understanding of the consequences of leptin resistance for the metabolic actions of leptin and the molecular defects causing leptin resistance remains vague. Metabolic abnormalities arising from defective leptin action are most clear in leptin-deficient states caused by leptin gene mutations or lipodystrophy in humans or rodents. These states are characterized by hyperlipidemia, excessive storage of lipid in tissues such as liver and skeletal muscle, and insulin resistance, defects that are markedly improved by administration of leptin (4 -8). Similar effects on lipid metabolism and/or insulin sensitivity are obtained in normal rodents with acute (9, 10) or prolonged (11-13) hyperleptinemia. In the ZDF rat characterized by non-functional leptin receptors and obesity, elevated hepatic lipid levels are reduced by adenovirusmediated expression of functional wild-type leptin receptors in liver (14), whereas administration of leptin to gold-thioglucosetreated mice that lack hypothalamic leptin function decreases hepatic lipogenesis (15). Taken together, these studies demonstrate potent l...

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“…13,14 Physiological increase in plasma leptin has been shown to significantly inhibit glucose-stimulated insulin secretion in vivo and to determine insulin resistance. 15 Plasma leptin concentration usually reflects the total amount of fat present in the body, and lower plasma leptin levels have been reported consistently among weight-losing patients. 16,17 The results of our study show that significant reduction of leptin levels occur early after gastric bypass when BMI is still in the morbidly obese range.…”

Section: The Role Of Leptinmentioning

confidence: 99%

The Early Effect of the Roux-en-Y Gastric Bypass on Hormones Involved in Body Weight Regulation and Glucose Metabolism

Rubino¹,

Gautier²,

Gentileschi³

et al. 2004

Annals of Surgery

582

372

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Objective: To evaluate the early effect of Roux-en-Y (RYGB) gastric bypass on hormones involved in body weight regulation and glucose metabolism. Significant Background Data: The RYGB is an effective bariatric procedure for which the mechanism of action has not been elucidated yet. Reports of hormonal changes after RYGB suggest a possible endocrine effect of the operation; however, it is unknown whether these changes are the cause or rather the effect of surgically induced weight loss. We speculated that if the mechanism of action of the RYGB involves an endocrine effect, then hormonal changes should occur early after surgery, prior to substantial body weight changes. Methods: Ten patients with a mean preoperative body mass index (BMI) of 46.2 kg/m 2 (40 -53 kg/m 2 ) underwent laparoscopic RYGB. Six patients had type 2 diabetes treated by oral hypoglycemic agents. Preoperatively and 3 weeks following surgery, all patients were tested for fasting glucose, insulin, glucagon, insulinlike growth factor 1 (IGF-1), leptin, gastric inhibitory polypeptide (GIP), glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK), adrenocorticotropic hormone (ACTH), corticosterone, and neuropeptide Y (NPY). Results: Changes in mean BMI were rather minimal (43.2 kg/m 2 ; P ϭ not significant), but there was a significant decrease in blood glucose (P ϭ 0.005), insulin (P ϭ 0.02), IGF-1 (P Ͻ 0.05), leptin (P ϭ 0.001), and an increase in ACTH levels (P ϭ 0.01). The other hormones were not significantly changed by surgery. All the 6 diabetic patients had normal glucose and insulin levels and did not require medications after surgery. The RYGB reduced GIP levels in diabetic patients (P Ͻ 0.01), whereas no changes in GIP levels were found in nondiabetics. Conclusions: Roux-en-Y gastric bypass determines considerable hormonal changes before significant BMI changes take place. These results support the hypothesis of an endocrine effect as the possible mechanism of action of RYGB. S urgery represents the most effective therapeutic modality for morbid obesity.1,2 Interestingly, the Roux-en-Y gastric bypass (RYGB), a procedure that includes the creation of a small proximal gastric pouch and the bypass of the duodenum and proximal jejunum from the transit of food, not only determines permanent reduction of excess body weight, but also induces resolution of type 2 diabetes mellitus in more than 80% of morbidly obese patients. 3Body weight is the result of complex physiologic mechanisms that control food intake and energy expenditure. Regulation of body weight involves several systems such as the adipose tissue, 4 the hypothalamus, 5 and the adrenal glands, 6 which are linked by neural and hormonal signals. Recent investigations have identified several key molecules that regulate food intake, including ghrelin, neuropeptide Y (NPY), 7 and melanocortins 8 and have focused on the relationship between obesity and leptin levels. The effectiveness of gastric bypass in inducing remarkable weight loss and control of diabetes represents an "experimental mod...

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Physiological Increase in Plasma Leptin Markedly Inhibits Insulin Secretion In Vivo

Cited by 110 publications

References 37 publications

Lack of Association Between Impaired Glucose Tolerance and Appetite Regulating Hormones in Patients with Obstructive Sleep Apnea

Lack of Association Between Impaired Glucose Tolerance and Appetite Regulating Hormones in Patients with Obstructive Sleep Apnea

Impaired Activation of Phosphatidylinositol 3-Kinase by Leptin Is a Novel Mechanism of Hepatic Leptin Resistance in Diet-induced Obesity

The Early Effect of the Roux-en-Y Gastric Bypass on Hormones Involved in Body Weight Regulation and Glucose Metabolism

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