Leptin rapidly suppresses insulin release from insulinoma cells, rat and human islets and, in vivo, in mice.

Kulkarni, Rohit; Wang, Zhi Li; Wang, Ren Ming; Hurley, James; Smith, David M.; Ghatei, Mohammad A.; Withers, Dominic J.; Gardiner, James; Bailey, Clifford J.; Bloom, Stephen R.

doi:10.1172/jci119818

Cited by 284 publications

(233 citation statements)

References 55 publications

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“…Previous studies have shown leptin to decrease basal insulin secretion from the pancreatic islets 34 and down-regulates insulin gene transcription. 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.…”

Section: Neuropeptides and Impaired Glucose Tolerancementioning

confidence: 92%

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: 92%

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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“…In normal fed mice a decrease in plasma insulin and associated rise in glucose were observed after leptin administration (159,160), while infusion of leptin to fasted rats reduced both glucose and insulin (161). This seems to be due to effects on insulin action as well as on insulin release.…”

Section: Effect Of Leptin On Insulin Secretionmentioning

confidence: 94%

Human leptin: from an adipocyte hormone to an endocrine mediator

2000

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Leptin is a mainly adipocyte-secreted protein that was discovered 5 years ago. Most of the research following this discovery focused on the role of leptin in body weight regulation, aiming to illuminate the pathophysiology of human obesity. However, more and more data are emerging that leptin is not only important in the regulation of food intake and energy balance, but that it also has a function as a metabolic and neuroendocrine hormone. It is now clear that it is especially involved in glucose metabolism, as well as in normal sexual maturation and reproduction. Besides this, interactions with the hypothalamic±pituitary±adrenal, thyroid and GH axes and even with haematopoiesis and the immune system have also been described. It has been shown that leptin secretion by the adipocyte is partly regulated by other hormones, such as insulin, cortisol, and sex steroids, mainly testosterone. Also, other hormones like thyroid hormone and GH are possibly involved in leptin synthesis. Leptin itself exerts effects on different endocrine axes, mainly on the hypothalamic±pituitary±gonadal axis and on insulin metabolism, but also on the hypothalamic±pituitary±adrenal, thyroid and GH axes.Leptin may thus be considered a new endocrine mediator, besides its obvious role in body weight regulation.

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“…Suppression of insulin secretion and gene transcription by leptin in the obese range has also been demonstrated in human pancreatic islets. 15,17 It should be noted, however, that not all studies have reported inhibitory effects of leptin on insulin secretion. Thus, Shimizu et al, 24 and Tanizawa et al, 25 have actually shown stimulation of insulin secretion by leptin at a physiological range of concentrations, in HIT-T15 and MIN-6 cells, respectively.…”

Section: Inhibition Of Insulin Transcription By Tnfa and Leptinmentioning

confidence: 99%

TNFα and leptin inhibit basal and glucose-stimulated insulin secretion and gene transcription in the HIT-T15 pancreatic cells

Tsiotra¹,

Tsigos²,

Raptis

2001

Int J Obes

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BACKGROUND: Tumor necrosis factor a (TNFa), a cytokine produced at in¯ammatory sites and in adipose tissue, is known primarily for its detrimental effects on insulin action. There is evidence to suggest that TNFa may also in¯uence b-cell function. Leptin is another adipose tissue-derived hormone that might also act on b-cells. OBJECTIVE: We explored the independent and combined effects of TNFa and leptin upon basal and glucose-stimulated insulin transcription and secretion in the HIT-T15 pancreatic b cell line. METHODS: Cells were cultured for 40 h in the presence of near-normal basal (7 mM) or high (16.7 mM) glucose and treated with either TNFa (1, 10 and 50 ngaml) or leptin (10, 50 and 100 ngaml) or both together. Insulin concentrations were measured by radioimmunoassay. Insulin mRNA levels were evaluated by a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) method, after normalization with b-actin mRNA. RESULTS: TNFa signi®cantly suppressed basal and glucose-stimulated insulin secretion and proinsulin mRNA transcription in a dose-dependent manner, an effect that was more powerful in the presence of high glucose. Leptin also inhibited dosedependent insulin mRNA and protein at both glucose concentrations, but did not appear to further potentiate the suppressive effects of TNFa. CONCLUSION: TNFa suppresses both basal and glucose-stimulated insulin transcription and secretion in HIT-T15 cells, an effect that is enhanced signi®cantly by high glucose. Leptin also independently inhibits basal and glucose-stimulated insulin secretion and transcription but does not modify TNFa effects. These effects might contribute to the abnormalities of glucose metabolism that characterize conditions of increased TNFa andaor leptin production.

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Leptin rapidly suppresses insulin release from insulinoma cells, rat and human islets and, in vivo, in mice.

Cited by 284 publications

References 55 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

Human leptin: from an adipocyte hormone to an endocrine mediator

TNFα and leptin inhibit basal and glucose-stimulated insulin secretion and gene transcription in the HIT-T15 pancreatic cells

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