|
| |
 |
| REVIEW ARTICLE |
|
| Year : 2012 | Volume
: 16
| Issue : 9 | Page : 549-555 |
|
Leptin therapy, insulin sensitivity, and glucose homeostasis
Gilberto Paz-Filho, Claudio Mastronardi, Ma-Li Wong, Julio Licinio
Department of Translational Medicine, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia
| Date of Web Publication | 4-Jan-2013 |
Correspondence Address:
Gilberto Paz-Filho
The John Curtin School of Medical Research, The Australian National University, Garran Rd, Building 131, Acton ACT, 0200
Australia
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/2230-8210.105571
 Abstract | | |
Glucose homeostasis is closely regulated not only by insulin, but also by leptin. Both hormones act centrally, regulating food intake and adiposity in humans. Leptin has several effects on the glucose-insulin homeostasis, some of which are independent of body weight and adiposity. Those effects of leptin are determined centrally in the hypothalamus and peripherally in the pancreas, muscles and liver. Leptin has beneficial effects on the glucose-insulin metabolism, by decreasing glycemia, insulinemia and insulin resistance. The understanding of the effects of leptin on the glucose-insulin homeostasis will lead to the development of leptin-based therapies against diabetes and other insulin resistance syndromes. In these review, we summarize the interactions between leptin and insulin, and their effects on the glucose metabolism. Keywords: Diabetes, glucose, insulin, insulin resistance, leptin
How to cite this article:
Paz-Filho G, Mastronardi C, Wong ML, Licinio J. Leptin therapy, insulin sensitivity, and glucose homeostasis. Indian J Endocr Metab 2012;16, Suppl S3:549-55 |
How to cite this URL:
Paz-Filho G, Mastronardi C, Wong ML, Licinio J. Leptin therapy, insulin sensitivity, and glucose homeostasis. Indian J Endocr Metab [serial online] 2012 [cited 2021 Mar 1];16, Suppl S3:549-55. Available from: https://www.ijem.in/text.asp?2012/16/9/549/105571 |
| Introduction | |  |
Leptin is the most abundant hormone produced by adipocytes. It has structural homology with the cytokines of the long-chain helical family that includes interleukin (IL)-6, IL-11, IL-12, and oncostatin M, and therefore is part of the adipokines family. Leptin regulates food intake and energy expenditure, and has also multiple actions in the endocrine and immune systems, including fertility, bone formation, tissue remodeling, and inflammation. [1]
Within the endocrine system, leptin regulates the circadian rhythms of the gonadotropic, thyrotrophic and adrenal axes. It also plays key roles in the regulation of glucose homeostasis and insulin sensitivity, independent of actions on food intake, energy expenditure or body weight. [2]
In this review, we present evidence for leptin's actions on the glucose-insulin homeostasis, and highlight its current and future applications for treating disorders of the glucose-insulin homeostasis.
| Molecular Aspects of Leptin | | |
Leptin is a protein of high molecular mass (16 kDa). [3] Its levels are correlated with fat mass, [4] and the increase in human or rodent fat masses due to genetic manipulation or environmental induction causes an increase in leptin levels. [5] Several metabolic and hormonal factors influence the synthesis and secretion of leptin in the body, such as cytokines, cortisol, catecholamines, fatty acids, glucose, and insulin. [6]
There are at least four different isoforms of the leptin receptor in humans : O0 b-Ra, Ob-Rb, and Ob-Rc (membrane-anchored), and Ob-Re (soluble); these are all products of alternatively spliced forms of the Ob-R gene. [7] The membrane-anchored isoforms have identical extracellular, ligand-binding and transmembrane domains, with different lengths of the intracellular domain. [7] The isoform Ob-Rb contains a long cytoplasmic region containing several motifs required for signal transduction and capable of activating the JAK-STAT signal transduction pathway. [8],[9] Ob-Ra is regarded as the leptin transporter across the blood-brain barrier and leptin degrader. [10] The secreted soluble isoform (Ob-Re) lacks both the intracellular and transmembrane domains, and serves as plasmatic leptin-binding protein. [11] These isoforms are involved in mediating leptin's actions in the brain and in peripheral organs. [12] Two other isoforms have not been identified in humans : O0 b-Rd has been identified in mice and Ob-Rf, in rats only. [13]
The transduction of leptin's signals is mediated by known pathways, namely Janus kinase-signal transducer and activator of transcription (JAK-STAT), extracellular signal-regulated kinase (ERK)-1/2, phosphatidylinositol-3-kinase (PI3K), and AMP-activated protein kinase (AMPK). The AMPK pathway is particularly involved in preventing insulin resistance, in part by inhibiting pathways that antagonize insulin signaling. [14],[15] Intracellular mechanisms are activated to down-regulate leptin's actions, mediated mainly by the suppressor of cytokine signaling 3 (SOCS3). [16] and protein tyrosine phosphatase 1B (PTP1B), [17] which are implicated in the mechanisms of leptin resistance. [18]
The most important function of leptin is the regulation of energy expenditure and food intake, due to its actions on the arcuate nucleus of the hypothalamus. In this area, leptin binds to its receptors, which are expressed in two different neuronal populations : t0 he ones that express agouti-related peptide (AgRP) and neuropeptide Y (NPY), and those that express the peptide cocaine and amphetamine-related transcript (CART) and the large precursor peptide pro-opiomelanocortin (POMC). Leptin exerts anorexigenic effects by inhibiting the AgRP/NPY neurons and by stimulating the POMC/CART neurons. Several other effects have been attributed to leptin, mostly from studies with leptin-deficient animal and human models.
| Leptin Deficiency | | |
Among mice that are leptin-deficient (ob/ob) or leptin-resistant (db/db, due to mutations in the leptin receptor gene causing lack of leptin signaling), hyperphagia is a constant and obesity, a hallmark. This adipocyte-derived hormone regulates nutritional status by controlling both energy intake and energy expenditure. In the absence of leptin, rodents and humans alike suffer from massive obesity with a voracious appetite and a blunted metabolic rate. [19],[20],[21],[22] Subjects with very low plasma leptin concentrations have large body weight gains over relatively short periods of time. [23]
Leptin-deficient mice (ob/ob) carry a spontaneous missense mutation in their leptin gene. They are severely obese due to hyperphagia and blunted metabolic rate. They also have dyslipidemia, hypercortisolism, low levels of growth hormone, central hypothyroidism, hypogonadotropic hypogonadism, and cellular immune deficiency. [19],[20],[21],[22],[24] In the leptin deficient ob/ob mouse model, obese phenotype is prevented and reversed by the administration of exogenous leptin. [18]
In humans, leptin deficiency can be observed in several conditions, such as lipodystrophy syndromes, anorexia nervosa, hypothalamic amenorrhea, and congenital leptin deficiency. For over 13 years, our group has been evaluating phenotypic findings and the effects of leptin replacement in four unique leptin-deficient adults from a consanguineous extended Turkish family. [25],[26] These individuals have a Mendelian recessive mutation in the leptin gene, consisting of a C→T substitution in codon 105 of this gene, resulting in an Arg→Trp replacement in the mature protein. [26]
Physiological doses of recombinant methionyl human leptin (r-metHuLeptin, Metreleptin® , Amylin Pharmaceuticals, USA, 0.02-0.04 mg/kg/day) were initiated on the leptin-deficient individuals being assessed by our group at ages 5 (boy), 27 (male), 30 and 40 (females). Treatment led to significant improvements in weight, endocrine function and behavior. [27] Leptin replacement was lifesaving, as eight members of this family with severe early-onset obesity, whom we presume to have been leptin-deficient, died during childhood due to infections. By evaluating leptin-deficient patients while on leptin replacement, and after brief periods of leptin withdrawal, we have observed that leptin regulates the circadian rhythms of cortisol, thyroid stimulating hormone, luteinizing hormone and follicle-stimulating hormone. In the brain, leptin controls energy balance and body weight, and plays a role in neurogenesis and brain function. Leptin enhances immune response, and regulates inflammation, coagulation, fibrinolysis, and platelet aggregation. [25],[26] Within the adipoinsular axis, we have observed that leptin decreases insulin and glucose levels. [28] In its absence, insulin sensitivity is markedly increased due to rapid weight gain (discussed with more detail ahead). [29],[30]
| Leptin and the Adipoinsular Axis | | |
The adipose tissue plays an important role in total energy homeostasis. [31] Glucose and lipid metabolism are regulated by complex interactions that occur within the adipoinsular axis. Insulin acutely stimulates lipogenesis while decreasing lipolysis, [32] whereas leptin exerts opposite effects. [14],[33] Abnormal accumulation of triglycerides in non-adipose tissues, caused by the upregulation of lipogenesis, leads to a deleterious state known as lipotoxicity. [34] Lipotoxicity is characterized as the accumulation of triglycerides in the surrounding hepatocytes and is thought to be a major contributor to islet cell transplantation failure in diabetics. [35],[36],[37],[38] Lipotoxicity also contributes to the increase in insulin resistance. Given that leptin is thought to oppose insulin action by decreasing hepatocyte lipogenesis, leptin administration may result in decreased lipotoxicity, being useful for the treatment of lipodystrophy syndromes. [39] However, when used for treating obesity-associated non-alcoholic fatty liver disease, leptin might instead promote insulin resistance, fibrosis, and hepatocellular carcinoma. [40]
Leptin and insulin play key metabolic roles. A majority of the studies suggest that leptin decreases insulin synthesis and secretion by pancreatic beta cells, and increases insulin hepatic extraction. [41],[42],[43],[44] As a result, insulin delivery is reduced by leptin. [28] This so-called adipoinsular axis is part of a leptin-mediated inhibitory feedback on insulin secretion in order to decrease adipogenesis. Leptin also decreases hepatic glucose production, increases insulin sensitivity, and decreases glucagon levels. Insulin, in turn, also plays a role in stimulating leptin production and secretion in the adipose tissue. [44] [Table 1] summarizes the effects of leptin.
Hypothalamic insulin and leptin signaling play a crucial role in the regulation of glucose homeostasis and in the development of insulin resistance. [45] Centrally, insulin modulates hepatic glucose production, skeletal muscle glycogen synthesis, brown adipose tissue thermogenesis, and white adipose tissue lipolysis. Central leptin, in turn, regulates hepatic gluconeogenesis and insulin sensitivity, skeletal-muscle lipid oxidation and glucose uptake/utilization, brown adipose tissue glucose uptake and white adipose tissue lipolysis, and insulin secretion. [46],[47] These effects seem to be mediated by the autonomic regulation of skeletal muscle, liver, pancreas and adipose tissues. [48] In the hypothalamus, the leptin signaling PI3K pathway plays an important role in decreasing peripheral insulin resistance, as central leptin improved tolerance to glucose, increased PGC1 alpha expression, and regulated AKT, AMPK, ACC and JAK2 phosphorylation in the soleus muscle of rats fed with regular chow. [49] In untreated diabetic mice, hypoleptinemia caused by decreased fat mass leads to severe insulin resistance, which is reversed by leptin replacement, [50] giving support to the usefulness of leptin in the treatment of diabetes.
It has been shown that direct action of insulin and leptin on the POMC neurons is required to maintain normal glucose homeostasis. [51] In Ob-R deficient mice, restoring leptin receptor expression only at POMC neurons normalizes blood glucose and ameliorates hepatic insulin resistance, hyperglucagonemia, and dyslipidemia, independent of changes in body weight. [2] It has been calculated that 42% of leptin's hypoglycemic action is independent of weight reduction. [52] The effects of leptin can be explained by its actions in increasing hypothalamic insulin sensitivity. [53]
However, it has also been demonstrated that leptin ameliorates hyperglycemia by suppressing hepatic glucose production and by increasing tissue glucose uptake, independent of insulin. [54]
Another potential mechanism by which leptin ameliorates glucose levels is the increase in IGF binding protein 2 (IGFBP2) level, which reduces blood glucose in wild-type and diabetic mice, and potently suppresses hepatic glucose production, as well as genes involved in hepatic gluconeogenesis and fatty acid synthesis. [55]
More recently, the bone has been implicated in the control of energy homeostasis. Osteocalcin is a marker of bone formation that is synthesized and secreted by the osteoblasts. Osteocalcin increases insulin expression and insulin sensitivity in animals, and mice that lack osteocalcin are glucose intolerant. [56] It has been shown that the inhibition of insulin secretion exerted by leptin is partly mediated by leptin's effect on inhibiting the metabolic activity of osteocalcin: leptin stimulates the sympathetic tone, which in turn stimulates the expression of Esp, a gene that inhibits osteocalcin. [57] In humans, osteocalcin has been associated negatively with insulin resistance, and leptin has been correlated negatively with osteocalcin levels both in cross-sectional and longitudinal analyses. [58] Therefore, obesity may lead to insulin resistance through a leptin-mediated suppression of osteocalcin. However, the stimulatory role of osteocalcin on pancreatic insulin secretion has been questioned by studies showing that elevated osteocalcin is associated with suppressed blood insulin. Wild-type, ob/ob and non-obese, diabetic insulinopenic Akita mice submitted to a single intracerebroventricular (icv) injection of recombinant adeno-associated virus vector encoding leptin gene (rAAV-lep) showed increased blood osteocalcin levels, and decreased insulin levels. This suggests that the inhibitory effect of leptin on insulin secretion is limited by high circulating levels of osteocalcin, or that the osteocalcin stimulatory and insulin inhibitory effects are mediated by independent central leptin feedback mechanisms. [59]
Leptin plays a significant part in the pathophysiology of insulin resistance related to obesity. Leptin replacement reverses insulin resistance and diabetes in mice homozygous for mutations of the ob gene, [60] in aP2-nSREBP-1 c mice with moderate fat deficiency, [61] and in severely lipoatrophic A-ZIP/F-1 mice. [62] In non-obese diabetic (NOD) mice, leptin therapy alone or combined with low-dose insulin reverses the catabolic state through suppression of hyperglucagonemia, mimics the anabolic actions of insulin, and normalizes hemoglobin A1c. In contrast with insulin, leptin lowers lipogenic and cholesterologenic transcription factors and reduces plasma and tissue lipids. [63],[64] Therefore, leptin and insulin may become a potential combination therapy for type 1 diabetes, but there are concerns regarding hypoglycemia. [65]
Intracerebroventricular infusion of leptin improved hyperglycemia, hyperglucagonemia, hyperketonemia, and polyuria caused by insulin deficiency in NOD mice, [63] independent of hepatic signaling. [65] Therefore, leptin may improve insulin resistance not only by decreasing body weight and fat mass, but also by activating insulin-sensitive tissues such as the adipose tissue and liver. The activation of the JAK-STAT, PI3K, and AMPK pathways, which overlap with those of insulin, contributes to the leptin-mediated decrease in insulin resistance. [66] However, other in vitro and in vivo studies are contradictory, suggesting that leptin may in fact increase insulin resistance. [41],[67],[68],[69]
Gene therapy through icv injection of recombinant adeno-associated virus vector encoding the leptin gene (rAAV-lep) has been shown to normalize glucose levels in animal models of diabetes type 1 and 2, by stimulating glucose disposal, by increasing energy expenditure from peripheral organs such as brown adipose tissue, by improving insulin sensitivity, and by suppressing pancreatic insulin secretion in diabetes type 2 models. Besides being a potentially safe and effective antidiabetic therapy, these results clearly demonstrate that leptin regulates the glucose-insulin homeostasis in the hypothalamus, independent of its peripheral actions. [70],[71]
In humans, leptin levels are correlated with adiposity. [72] Moreover, leptin is positively correlated with insulin resistance, independently of body weight or adiposity, both in normoglycaemic and in diabetic patients. [73],[74] In obese patients with type 2 diabetes, metreleptin administration did not alter body weight or circulating inflammatory markers but reduced HbA1c marginally, from 8.01±0.93% to 7.96±1.12% (P = 0.03). [75] In addition, treatment did not have weight loss-independent, clinically important effects on insulin sensitivity in those patients. [76]
Human studies evaluated the insulin-sensitizing effects of leptin replacement in patients with lipodystrophy. [77 ],[78],[79],[80 0] Humans with lipoatrophic disorders (exhibiting very low levels of leptin, increased insulin resistance and hyperinsulinemia) experienced a decrease in insulin resistance after treatment with r-metHuLeptin. [77],[78],[79],[80] Hemoglobin A1c reduced by 1.5% in a group of 48 patients with lipodystrophy treated with recombinant methionyl human leptin. [81] Those results may be biased because those patients lack adipose tissue, and have a presumably defective adipoinsular axis. Leptin-deficient humans therefore, provide a unique opportunity to evaluate the effects of leptin on insulin resistance. [82 ],[83],[80 4]
In a cohort of three leptin-deficient adults, we have previously observed that before treatment with metreleptin, all patients had high insulin and lipid levels. The older female was diabetic. [24],[27] Leptin replacement normalized serum lipids, insulin and glucose levels, and led to the resolution of type 2 diabetes. [27] Meal tolerance tests performed before and after leptin replacement showed increased insulin sensitivity (by 5.7-fold) and decreased insulin secretion (by 2-fold), while insulin hepatic extraction returned to rates close to normal. [28] Paradoxically, after leptin withdrawal, insulin sensitivity increased further, as measured by euglycemic hyperinsulinemic clamps [Figure 1]. [29] This might be attributed to the rapid gain in glucose-absorbing fat mass after leptin withdrawal. [30] The increase in insulin sensitivity when off leptin was clinically evident when the adult male developed severe hypoglycemia during an oral glucose tolerance test. | Figure 1: Euglycemic hyperinsulinemic clamps of leptin-defi cient patients while on leptin and after brief periods of leptin withdrawal (from Paz-Filho et al.[29]). Glucose infusion rates increased in eight out of nine times when leptin therapy was briefl y interrupted. The substantial weight gain after leptin withdrawal was responsible for acutely increasing insulin sensitivity
Click here to view |
| Conclusions | | |
Leptin and insulin share common effects in the control of food intake and energy metabolism. In the blood glucose homeostasis, both play important roles. Leptin and insulin directly regulate each other : 0 leptin inhibits insulin; insulin stimulates leptin synthesis and secretion. Leptin also increases insulin sensitivity, not only by decreasing adiposity and lipotoxicity, but also insulin-independent action, both centrally and peripherally. Leptin also decreases hepatic production of glucose, contributing to its glucose-lowering effects. The bone, through osteocalcin, also plays a role in regulating the glucose-insulin homeostasis [Figure 2]. | Figure 2: Interactions between fat, brain, pancreas and bone. Leptin activates the sympathetic tonus, which inhibits insulin secretion and stimulates Esp expression in the osteoblast (via stimulation of the adrenergic beta 2 receptor). Esp inhibits osteocalcin, decreasing insulin expression. Leptin inhibits pancreatic insulin. Insulin, in turn, stimulates leptin expression in the white adipose tissue. Adapted from Kieffer and Habener.[43] H: Hypothalamus
Click here to view |
In leptin-deficient humans, leptin therapy has been shown to determine remarkable effects, by increasing insulin sensitivity on the long term, by decreasing insulinemia, and ultimately by reversing type 2 diabetes in one previously diabetic patient. In lipodystrophic patients, leptin therapy also has positive metabolic effects. However, no clinically evident benefits have been observed in patients with type 2 diabetes. The effects of metreleptin in patients with type 1 diabetes are currently being evaluated in a clinical trial (ClinicalTrials.gov Identifier NCT01268644).
For the development of leptin-based therapies for treating diabetes and disorders that present insulin resistance, further human studies need to elucidate the effects of leptin on the glucose-insulin homeostasis, both in the leptin-sensitive and in the leptin-resistant milieus.[84]
| References | | |
| 1. | Kelesidis T, Kelesidis I, Chou S, Mantzoros CS. Narrative review : t0 he role of leptin in human physiology : e0 merging clinical applications. Ann Intern Med 2010;152:93-100. 
[PUBMED] |
| 2. | Berglund ED, Vianna CR, Donato J Jr, Kim MH, Chuang JC, Lee CE, et al. Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice. J Clin Invest 2012;122:1000-9.
[PUBMED] |
| 3. | Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995;269:543-6.
[PUBMED] |
| 4. | Maffei M, Halaas J, Ravussin E, Pratley R, Lee G, Zhang Y, et al. Leptin levels in human and rodent : m0 easurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1995;1:1155-61.
|
| 5. | Stunkard AJ, Harris JR, Pedersen NL, McClearn GE. The body-mass index of twins who have been reared apart. N Engl J Med 1990;322:1483-7.
[PUBMED] |
| 6. | Fried SK, Ricci MR, Russell CD, Laferrère B. Regulation of leptin production in humans. J Nutr 2000;130:3127S-31S.
|
| 7. | Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995;83:1263-71.
[PUBMED] |
| 8. | Fantuzzi G, Faggioni R. Leptin in the regulation of immunity, inflammation, and hematopoiesis. J Leukoc Biol 2000;68:437-46.
[PUBMED] |
| 9. | Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998;395:763-70.
[PUBMED] |
| 10. | Uotani S, Bjørbaek C, Tornøe J, Flier J. Functional properties of leptin receptor isoforms : i0 nternalization and degradation of leptin and ligand-induced receptor downregulation. Diabetes 1999;48:279-86.
|
| 11. | Di Yorio MP, Bilbao MG, Pustovrh MC, Prestifilippo JP, Faletti AG. Leptin modulates the expression of its receptors in the hypothalamic-pituitary-ovarian axis in a differential way. J Endocrinol 2008;198:355-66.
[PUBMED] |
| 12. | Blüher S, Mantzoros CS. Leptin in humans : l0 essons from translational research. Am J Clin Nutr 2009;89:991S-997S.
|
| 13. | Margetic S, Gazzola C, Pegg GG, Hill RA. Leptin : a0 review of its peripheral actions and interactions. Int J Obes Relat Metab Disord 2002;26:1407-33.
|
| 14. | Kahn BB, Alquier T, Carling D, Hardie DG. AMP-activated protein kinase : a0 ncient energy gauge provides clues to modern understanding of metabolism. Cell Metab 2005;1:15-25.
|
| 15. | Lim CT, Kola B, Korbonits M. AMPK as a mediator of hormonal signalling. J Mol Endocrinol 2010;44:87-97.
|
| 16. | Starr R, Willson TA, Viney EM, Murray LJ, Rayner JR, Jenkins BJ, et al. A family of cytokine-inducible inhibitors of signalling. Nature 1997;387:917-21.
|
| 17. | Myers MP, Andersen JN, Cheng A, Tremblay ML, Horvath CM, Parisien JP, et al. TYK2 and JAK2 are substrates of protein-tyrosine phosphatase 1B. J Biol Chem 2001;276:47771-4.
|
| 18. | Myers MG, Cowley MA, Münzberg H. Mechanisms of leptin action and leptin resistance. Annu Rev Physiol 2008;70:537-56.
|
| 19. | Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet 1998;18:213-5.
|
| 20. | Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997;387:903-8.
|
| 21. | Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999;341:879-84.
|
| 22. | Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:425-32.
|
| 23. | Ravussin E, Pratley RE, Maffei M, Wang H, Friedman JM, Bennett PH, et al. Relatively low plasma leptin concentrations precede weight gain in Pima Indians. Nat Med 1997;3:238-40.
|
| 24. | Ozata M, Ozdemir IC, Licinio J. Human leptin deficiency caused by a missense mutation : m0 ultiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J Clin Endocrinol Metab 1999;84:3686-95.
|
| 25. | Paz-Filho G, Mastronardi C, Delibasi T, Wong ML, Licinio J. Congenital leptin deficiency : d0 iagnosis and effects of leptin replacement therapy. Arq Bras Endocrinol Metabol 2010;54:690-7.
|
| 26. | Paz-Filho G, Wong ML, Licinio J. Ten years of leptin replacement therapy. Obes Rev 2011;12 :0 e315-23.
|
| 27. | Licinio J, Caglayan S, Ozata M, Yildiz BO, de Miranda PB, O'Kirwan F, et al. Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc Natl Acad Sci U S A 2004;101:4531-6.
|
| 28. | Andreev VP, Paz-Filho G, Wong ML, Licinio J. Deconvolution of insulin secretion, insulin hepatic extraction post-hepatic delivery rates and sensitivity during 24-hour standardized meals : t0 ime course of glucose homeostasis in leptin replacement treatment. Horm Metab Res 2009;41:142-51.
|
| 29. | Paz-Filho G, Esposito K, Hurwitz B, Sharma A, Dong C, Andreev V, et al. Changes in insulin sensitivity during leptin replacement therapy in leptin-deficient patients. Am J Physiol Endocrinol Metab 2008;295 : 0 e1401-8.
|
| 30. | Paz-Filho G, Esposito K, Hurwitz B, Sharma A, Dong C, Andreev V, et al. Leptin and insulin sensitivity : R0 eply to Oral and Burant. Am J Physiol Endocrinol Metab 2009;296:E1401-8.
|
| 31. | Fischer-Posovszky P, Wabitsch M, Hochberg Z. Endocrinology of adipose tissue-an update. Horm Metab Res 2007;39:314-21.
|
| 32. | Jaworski K, Sarkadi-Nagy E, Duncan RE, Ahmadian M, Sul HS. Regulation of triglyceride metabolism. IV. Hormonal regulation of lipolysis in adipose tissue. Am J Physiol Gastrointest Liver Physiol 2007;293 : G0 1-4.
|
| 33. | Ronti T, Lupattelli G, Mannarino E. The endocrine function of adipose tissue : a0 n update. Clin Endocrinol (Oxf) 2006;64:355-65.
|
| 34. | Unger RH, Clark GO, Scherer PE, Orci L. Lipid homeostasis, lipotoxicity and the metabolic syndrome. Biochim Biophys Acta 2010;1801:209-14.
|
| 35. | Bhargava R, Senior PA, Ackerman TE, Ryan EA, Paty BW, Lakey JR, et al. Prevalence of hepatic steatosis after islet transplantation and its relation to graft function. Diabetes 2004;53:1311-7.
|
| 36. | Cruz WS, Kwon G, Marshall CA, McDaniel ML, Semenkovich CF. Glucose and insulin stimulate heparin-releasable lipoprotein lipase activity in mouse islets and INS-1 cells. A potential link between insulin resistance and beta-cell dysfunction. J Biol Chem 2001;276:12162-8.
|
| 37. | Lupi R, Dotta F, Marselli L, Del Guerra S, Masini M, Santangelo C, et al. Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets : e0 vidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. Diabetes 2002;51:1437-42.
|
| 38. | Wajchenberg BL. Beta-cell failure in diabetes and preservation by clinical treatment. Endocr Rev 2007;28:187-218.
|
| 39. | Oral EA, Chan JL. Rationale for leptin-replacement therapy for severe lipodystrophy. Endocr Pract 2010;16:324-33.
|
| 40. | Polyzos SA, Kountouras J, Zavos C, Deretzi G. The potential adverse role of leptin resistance in nonalcoholic fatty liver disease : a0 hypothesis based on critical review of the literature. J Clin Gastroenterol 2011;45:50-4.
|
| 41. | Ceddia RB, Koistinen HA, Zierath JR, Sweeney G. Analysis of paradoxical observations on the association between leptin and insulin resistance. FASEB J 2002;16:1163-76.
|
| 42. | Covey SD, Wideman RD, McDonald C, Unniappan S, Huynh F, Asadi A, et al. The pancreatic beta cell is a key site for mediating the effects of leptin on glucose homeostasis. Cell Metab 2006;4:291-302.
|
| 43. | Kieffer TJ, Habener JF. The adipoinsular axis : e0 ffects of leptin on pancreatic beta-cells. Am J Physiol Endocrinol Metab 2000;278 :E0 1-E14.
|
| 44. | Seufert J. Leptin effects on pancreatic beta-cell gene expression and function. Diabetes 2004;53 :S0 152-8.
|
| 45. | Morton GJ, Schwartz MW. Leptin and the central nervous system control of glucose metabolism. Physiol Rev 2011;91:389-411.
|
| 46. | Marino JS, Xu Y, Hill JW. Central insulin and leptin-mediated autonomic control of glucose homeostasis. Trends Endocrinol Metab 2011;22:275-85.
|
| 47. | Sánchez-Lasheras C, Könner AC, Brüning JC. Integrative neurobiology of energy homeostasis-neurocircuits, signals and mediators. Front Neuroendocrinol 2010;31:4-15.
|
| 48. | Park S, Ahn IS, Kim da S. Central infusion of leptin improves insulin resistance and suppresses beta-cell function, but not beta-cell mass, primarily through the sympathetic nervous system in a type 2 diabetic rat model. Life Sci 2010;86:854-62.
|
| 49. | Roman EA, Reis D, Romanatto T, Maimoni D, Ferreira EA, Santos GA, et al. Central leptin action improves skeletal muscle AKT, AMPK, and PGC1 alpha activation by hypothalamic PI3K-dependent mechanism. Mol Cell Endocrinol 2010;314:62-9.
|
| 50. | German JP, Wisse BE, Thaler JP, Oh-I S, Sarruf DA, Ogimoto K, et al. Leptin deficiency causes insulin resistance induced by uncontrolled diabetes. Diabetes 2010;59:1626-34.
|
| 51. | Hill JW, Elias CF, Fukuda M, Williams KW, Berglund ED, Holland WL, et al. Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell Metab 2010;11:286-97.
|
| 52. | Schwartz MW, Baskin DG, Bukowski TR, Kuijper JL, Foster D, Lasser G, et al. Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice. Diabetes 1996;45:531-5.
|
| 53. | Koch C, Augustine RA, Steger J, Ganjam GK, Benzler J, Pracht C, et al. Leptin rapidly improves glucose homeostasis in obese mice by increasing hypothalamic insulin sensitivity. J Neurosci 2010;30:16180-7.
|
| 54. | German JP, Thaler JP, Wisse BE, Oh-I S, Sarruf DA, Matsen ME, et al. Leptin activates a novel CNS mechanism for insulin-independent normalization of severe diabetic hyperglycemia. Endocrinology 2011;152:394-404.
|
| 55. | Hedbacker K, Birsoy K, Wysocki RW, Asilmaz E, Ahima RS, Farooqi IS, et al. Antidiabetic effects of IGFBP2, a leptin-regulated gene. Cell Metab 2010;11:11-22.
|
| 56. | Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, et al. Endocrine regulation of energy metabolism by the skeleton. Cell 2007;130:456-69.
|
| 57. | Hinoi E, Gao N, Jung DY, Yadav V, Yoshizawa T, Kajimura D, et al. An Osteoblast-dependent mechanism contributes to the leptin regulation of insulin secretion. Ann N Y Acad Sci 2009;1173 1 :E0 20-30.
|
| 58. | Reinehr T, Roth CL. A new link between skeleton, obesity and insulin resistance : r0 elationships between osteocalcin, leptin and insulin resistance in obese children before and after weight loss. Int J Obes (Lond) 2010;34:852-8.
|
| 59. | Kalra SP, Dube MG, Iwaniec UT. Leptin increases osteoblast-specific osteocalcin release through a hypothalamic relay. Peptides 2009;30:967-73.
|
| 60. | Muzzin P, Eisensmith RC, Copeland KC, Woo SL. Correction of obesity and diabetes in genetically obese mice by leptin gene therapy. Proc Natl Acad Sci U S A 1996;93:14804-8.
|
| 61. | Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 1999;401:73-6.
|
| 62. | Gavrilova O, Marcus-Samuels B, Leon LR, Vinson C, Reitman ML. Leptin and diabetes in lipoatrophic mice. Nature 2000;403:850.
|
| 63. | Fujikawa T, Chuang JC, Sakata I, Ramadori G, Coppari R. Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice. Proc Natl Acad Sci U S A 2010;107:17391-6.
|
| 64. | Wang MY, Chen L, Clark GO, Lee Y, Stevens RD, Ilkayeva OR, et al. Leptin therapy in insulin-deficient type I diabetes. Proc Natl Acad Sci U S A 2010;107:4813-9.
|
| 65. | Denroche HC, Levi J, Wideman RD, Sequeira RM, Huynh FK, Covey SD, et al. Leptin therapy reverses hyperglycemia in mice with streptozotocin-induced diabetes, independent of hepatic leptin signaling. Diabetes 2011;60:1414-23.
|
| 66. | Dardeno TA, Chou SH, Moon HS, Chamberland JP, Fiorenza CG, Mantzoros CS. Leptin in human physiology and therapeutics. Front Neuroendocrinol 2010;31:377-93.
|
| 67. | Cohen B, Novick D, Rubinstein M. Modulation of insulin activities by leptin. Science 1996;274:1185-8.
|
| 68. | Müller G, Ertl J, Gerl M, Preibisch G. Leptin impairs metabolic actions of insulin in isolated rat adipocytes. J Biol Chem 1997;272:10585-93.
|
| 69. | Sweeney G, Keen J, Somwar R, Konrad D, Garg R, Klip A. High leptin levels acutely inhibit insulin-stimulated glucose uptake without affecting glucose transporter 4 translocation in l6 rat skeletal muscle cells. Endocrinology 2001;142:4806-12.
|
| 70. | Kalra SP. Pivotal role of leptin-hypothalamus signaling in the etiology of diabetes uncovered by gene therapy : a0 new therapeutic intervention? Gene Ther 2011;18:319-25.
|
| 71. | Kalra SP. Central leptin gene therapy ameliorates diabetes type 1 and 2 through two independent hypothalamic relays; a benefit beyond weight and appetite regulation. Peptides 2009;30:1957-63.
|
| 72. | Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996;334:292-5.
|
| 73. | Haffner SM, Miettinen H, Mykkänen L, Karhapää P, Rainwater DL, Laakso M. Leptin concentrations and insulin sensitivity in normoglycemic men. Int J Obes Relat Metab Disord 1997;21:393-9.
|
| 74. | Fischer S, Hanefeld M, Haffner SM, Fusch C, Schwanebeck U, Köhler C, et al. Insulin-resistant patients with type 2 diabetes mellitus have higher serum leptin levels independently of body fat mass. Acta Diabetol 2002;39:105-10.
|
| 75. | Moon HS, Matarese G, Brennan AM, Chamberland JP, Liu X, Fiorenza CG, et al. Efficacy of metreleptin in obese patients with type 2 diabetes : c0 ellular and molecular pathways underlying leptin tolerance. Diabetes 2011;60:1647-56.
|
| 76. | Mittendorfer B, Horowitz JF, DePaoli AM, McCamish MA, Patterson BW, Klein S. Recombinant human leptin treatment does not improve insulin action in obese subjects with type 2 diabetes. Diabetes 2011;60:1474-7.
|
| 77. | Ebihara K, Kusakabe T, Hirata M, Masuzaki H, Miyanaga F, Kobayashi N, et al. Efficacy and safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy. J Clin Endocrinol Metab 2007;92:532-41.
|
| 78. | Javor ED, Cochran EK, Musso C, Young JR, Depaoli AM, Gorden P. Long-term efficacy of leptin replacement in patients with generalized lipodystrophy. Diabetes 2005;54:1994-2002.
|
| 79. | Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med 2002;346:570-8.
|
| 80. | Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu C, et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 2002;109:1345-50.
|
| 81. | Chong AY, Lupsa BC, Cochran EK, Gorden P. Efficacy of leptin therapy in the different forms of human lipodystrophy. Diabetologia 2010;53:27-35.
|
| 82. | Dulloo AG, Stock MJ, Solinas G, Boss O, Montani JP, Seydoux J. Leptin directly stimulates thermogenesis in skeletal muscle. FEBS Lett 2002;515:109-13.
|
| 83. | Kellerer M, Koch M, Metzinger E, Mushack J, Capp E, Häring HU. Leptin activates PI-3 kinase in C2C12 myotubes via janus kinase-2 (JAK-2) and insulin receptor substrate-2 (IRS-2) dependent pathways. Diabetologia 1997;40:1358-62.
|
| 84. | Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Müller C, Carling D, et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 2002;415:339-43.
|
[Figure 1], [Figure 2]
[Table 1]
| This article has been cited by | | 1 |
Type 2 diabetes and viral infection; cause and effect of disease |
|
| Tamara Turk Wensveen,Dora Gašparini,Dario Rahelic,Felix M. Wensveen | | Diabetes Research and Clinical Practice. 2021; 172: 108637 | | [Pubmed] | [DOI] | | | 2 |
A multidisciplinary weight loss intervention in obese adolescents with and without sleep-disordered breathing improves cardiometabolic health, whether SDB was normalized or not |
|
| Johanna Roche,Flavia Campos Corgosinho,Laurie Isacco,Karine Scheuermaier,Bruno Pereira,Valérie Gillet,Gustavo A. Moreira,Marcia Pradella-Hallinan,Sergio Tufik,Marco Túlio de Mello,Fabienne Mougin,Ana R. Dâmaso,David Thivel | | Sleep Medicine. 2020; | | [Pubmed] | [DOI] | | | 3 |
Current perspectives of oleic acid: Regulation of molecular pathways in mitochondrial and endothelial functioning against insulin resistance and diabetes |
|
| Kanwal Rehman,Kamran Haider,Komal Jabeen,Muhammad Sajid Hamid Akash | | Reviews in Endocrine and Metabolic Disorders. 2020; | | [Pubmed] | [DOI] | | | 4 |
Assessing insulin sensitivity and resistance in syndromes of severe short stature |
|
| Jaime Guevara-Aguirre,Enrique Teran,Daniela Lescano,Carolina Guevara,Alexandra Guevara,Jannette Saavedra,Patricio Procel,Clive Wasserfall,Antonio W.D. Gavilanes | | Growth Hormone & IGF Research. 2020; 53-54: 101339 | | [Pubmed] | [DOI] | | | 5 |
Elucidating the mechanisms by which disulfiram protects against obesity and metabolic syndrome |
|
| Michel Bernier,Dylan Harney,Yen Chin Koay,Antonio Diaz,Abhishek Singh,Devin Wahl,Tamara Pulpitel,Ahmed Ali,Vince Guiterrez,Sarah J. Mitchell,Eun-Young Kim,John Mach,Nathan L. Price,Miguel A. Aon,David G. LeCouteur,Victoria C. Cogger,Carlos Fernandez-Hernando,John O’Sullivan,Mark Larance,Ana Maria Cuervo,Rafael de Cabo | | npj Aging and Mechanisms of Disease. 2020; 6(1) | | [Pubmed] | [DOI] | | | 6 |
Endocrine-Disrupting Chemicals and Insulin Resistance in Children |
|
| Eleonora Rotondo,Francesco Chiarelli | | Biomedicines. 2020; 8(6): 137 | | [Pubmed] | [DOI] | | | 7 |
Acute effect of concurrent exercise on serum leptin and resistance insulin response in sedentary men |
|
| Bahram Abedi | | International Archives of Health Sciences. 2020; 7(1): 14 | | [Pubmed] | [DOI] | | | 8 |
The Impact of Glucose-Based or Lipid-Based Total Parenteral Nutrition on the Free Fatty Acids Profile in Critically Ill Patients |
|
| Pavel Skorepa,Ondrej Sobotka,Jan Vanek,Alena Ticha,Joao Fortunato,Jan Manak,Vladimir Blaha,Jan M. Horacek,Lubos Sobotka | | Nutrients. 2020; 12(5): 1373 | | [Pubmed] | [DOI] | | | 9 |
Discovery and preclinical efficacy of HSG4112, a synthetic structural analog of glabridin, for the treatment of obesity |
|
| Leo Sungwong Choi,In Geun Jo,Ku Suk Kang,Jeong Ho Im,Jiyoung Kim,Jinyoung Kim,Jin Wook Chung,Sang-Ku Yoo | | International Journal of Obesity. 2020; | | [Pubmed] | [DOI] | | | 10 |
Recent therapeutic trends and promising targets in triple negative breast cancer |
|
| Soo-Yeon Hwang,Seojeong Park,Youngjoo Kwon | | Pharmacology & Therapeutics. 2019; | | [Pubmed] | [DOI] | | | 11 |
n-3 polyunsaturated fatty acids provoke a specific transcriptional profile in rabbit adipose-derived stem cells in vitro |
|
| E?aterina Vackova,Darko Bosnakovski,Bodil Bjørndal,Penka Yonkova,Natalia Grigorova,Zhenya Ivanova,Georgi Penchev,Galina Simeonova,Lyuba Miteva,Anelya Milanova,Tatyana Vlaykova,Spaska Stanilova,Ivan Penchev Georgiev | | Journal of Animal Physiology and Animal Nutrition. 2019; | | [Pubmed] | [DOI] | | | 12 |
Interaction of Breast Cancer and Insulin Resistance on PD1 and TIM3 Expression in Peripheral Blood CD8 T Cells |
|
| Miriam Victoria Martín-Manzo,Carlos Lara,Cruz Vargas-de-Leon,Julio Carrero,Gloria Queipo,Miguel Fonseca-Sanchez,Nancy R. Mejia-Dominguez,David Kershenobich,Srinivas Mummidi,Alejandro Zentella-Dehesa,Joselin Hernandez | | Pathology & Oncology Research. 2019; | | [Pubmed] | [DOI] | | | 13 |
Effect of yerba mate and green tea on paraoxonase and leptin levels in patients affected by overweight or obesity and dyslipidemia: a randomized clinical trial |
|
| Guilherme Balsan,Lúcia Campos Pellanda,Grasiele Sausen,Thaís Galarraga,Denise Zaffari,Bruna Pontin,Vera Lúcia Portal | | Nutrition Journal. 2019; 18(1) | | [Pubmed] | [DOI] | | | 14 |
Appetite regulating hormones in first-episode psychosis: A systematic review and meta-analysis |
|
| Blazej Misiak,Francesco Bartoli,Filip Stramecki,Jerzy Samochowiec,Michal Lis,Justyna Kasznia,Konrad Jarosz,Bartlomiej Stanczykiewicz | | Neuroscience & Biobehavioral Reviews. 2019; 102: 362 | | [Pubmed] | [DOI] | | | 15 |
Leptin as a predictive marker for metabolic syndrome |
|
| Abhijit A. Ghadge,Amrita A. Khaire | | Cytokine. 2019; 121: 154735 | | [Pubmed] | [DOI] | | | 16 |
The effect of concurrent aerobic-resistance training on thyroid hormones, blood glucose hemostasis, and blood lipid indices in overweight girls with hypothyroidism |
|
| Sahar Mohammadi Sefat,Ramin Shabani,Marzieh Nazari | | Hormone Molecular Biology and Clinical Investigation. 2019; 0(0) | | [Pubmed] | [DOI] | | | 17 |
Mathematical model of diabetes and lipid metabolism linked to diet, leptin sensitivity, insulin sensitivity and VLDLTG clearance predicts paths to health and Type II diabetes |
|
| Catherine Z.W. Hassell Sweatman | | Journal of Theoretical Biology. 2019; : 110037 | | [Pubmed] | [DOI] | | | 18 |
Effect of Methanolic Extract of Phyllanthus niruri on Leptin Level in Animal Model of Diabetes Mellitus |
|
| Anuj Kumar,Akhilesh Kumar Rana,Amit Singh,Alok Singh | | Biomedical and Pharmacology Journal. 2019; 12(1): 57 | | [Pubmed] | [DOI] | | | 19 |
The depressed heart |
|
| SethW Perry,Julio Licinio,Ma-Li Wong | | Heart and Mind. 2019; 3(2): 35 | | [Pubmed] | [DOI] | | | 20 |
Developmental exposure to Pb2+ induces transgenerational changes to zebrafish brain transcriptome |
|
| Danielle N. Meyer,Emily J. Crofts,Camille Akemann,Katherine Gurdziel,Rebecca Farr,Bridget B. Baker,Daniel Weber,Tracie R. Baker | | Chemosphere. 2019; : 125527 | | [Pubmed] | [DOI] | | | 21 |
Vitamin D3 potentiates the renoprotective effects of vildagliptin in a rat model of fructose/salt-induced insulin resistance |
|
| Nehal S. Wahba,Rasha H. Abdel-Ghany,Salah A. Ghareib,Mohamed Abdel-Aal,Amira E. El Semeh | | European Journal of Pharmaceutical Sciences. 2019; : 105196 | | [Pubmed] | [DOI] | | | 22 |
Insulin Signaling Impairment in the Brain as a Risk Factor in Alzheimer’s Disease |
|
| Christian Hölscher | | Frontiers in Aging Neuroscience. 2019; 11 | | [Pubmed] | [DOI] | | | 23 |
The Role of Energy Balance on Colorectal Cancer Survival |
|
| Sarah A. Purcell,Jingjie Xiao,Katherine L. Ford,Carla M. Prado | | Current Colorectal Cancer Reports. 2018; | | [Pubmed] | [DOI] | | | 24 |
The leptin receptor mutation of the obese Zucker rat causes sciatic nerve demyelination with a centripetal pattern defect |
|
| Jacques Gilloteaux,Kritika Subramanian,Nadia Solomon,Charles Nicaise | | Ultrastructural Pathology. 2018; 42(5): 377 | | [Pubmed] | [DOI] | | | 25 |
Odor Sensitivity After Intranasal Insulin Application Is Modulated by Gender |
|
| Rea Rodriguez-Raecke,Yvonne F. Brünner,Anja Kofoet,Smiljana Mutic,Christian Benedict,Jessica Freiherr | | Frontiers in Endocrinology. 2018; 9 | | [Pubmed] | [DOI] | | | 26 |
Circulating Leptin and Branched Chain Amino Acids—Correlation with Intraductal Papillary Mucinous Neoplasm Dysplastic Grade |
|
| Michele T. Yip-Schneider,Rachel Simpson,Rosalie A. Carr,Huangbing Wu,Hao Fan,Ziyue Liu,Murray Korc,Jianjun Zhang,C. Max Schmidt | | Journal of Gastrointestinal Surgery. 2018; | | [Pubmed] | [DOI] | | | 27 |
Gastrointestinal factors regulating lipid droplet formation in the intestine |
|
| N. Auclair,L. Melbouci,D. St-Pierre,E. Levy | | Experimental Cell Research. 2018; | | [Pubmed] | [DOI] | | | 28 |
A Mathematical Model of Type 1 Diabetes Involving Leptin Effects on Glucose Metabolism |
|
| Rei Kadota,Kazuma Sugita,Kenko Uchida,Hitoshi Yamada,Masashi Yamashita,Hidenori Kimura | | Journal of Theoretical Biology. 2018; | | [Pubmed] | [DOI] | | | 29 |
Correlation between PAI-1, leptin and ferritin with HOMA in HIV/AIDS patients |
|
| Gordana Dragovic,Mirjana Sumarac-Dumanovic,Al Musalhi Khawla,Ivan Soldatovic,Mladen Andjic,Djordje Jevtovic,Devaki Nair | | Experimental and Molecular Pathology. 2018; | | [Pubmed] | [DOI] | | | 30 |
Rebelling against the (Insulin) Resistance: A Review of the Proposed Insulin-Sensitizing Actions of Soybeans, Chickpeas, and Their Bioactive Compounds |
|
| Jaime Clark,Carla Taylor,Peter Zahradka | | Nutrients. 2018; 10(4): 434 | | [Pubmed] | [DOI] | | | 31 |
Pharmacogenetics of Risperidone-Induced Insulin Resistance in Children and Adolescents with Autism Spectrum Disorder |
|
| Chonlaphat Sukasem,Natchaya Vanwong,Pornpen Srisawasdi,Nattawat Ngamsamut,Nopphadol Nuntamool,Yaowaluck Hongkaew,Apichaya Puangpetch,Bhunnada Chamkrachangpada,Penkhae Limsila | | Basic & Clinical Pharmacology & Toxicology. 2018; | | [Pubmed] | [DOI] | | | 32 |
Leptin contributes to the beneficial effects of insulin treatment in streptozotocin-diabetic male mice |
|
| Ursula H. Neumann,Michelle M. Kwon,Robert K. Baker,Timothy J. Kieffer | | American Journal of Physiology-Endocrinology and Metabolism. 2018; 315(6): E1264 | | [Pubmed] | [DOI] | | | 33 |
Glycated proteins in nutrition: Friend or foe? |
|
| Katarína Šebeková,Katarína Brouder Šebeková | | Experimental Gerontology. 2018; | | [Pubmed] | [DOI] | | | 34 |
Broken Energy Homeostasis and Obesity Pathogenesis: The Surrounding Concepts |
|
| Abdelaziz Ghanemi,Mayumi Yoshioka,Jonny St-Amand | | Journal of Clinical Medicine. 2018; 7(11): 453 | | [Pubmed] | [DOI] | | | 35 |
Ironing out the Details: Untangling Dietary Iron and Genetic Background in Diabetes |
|
| Mario Miranda,Heather Lawson | | Nutrients. 2018; 10(10): 1437 | | [Pubmed] | [DOI] | | | 36 |
miR-876-3p regulates glucose homeostasis and insulin sensitivity by targeting adiponectin |
|
| Sujith Rajan,Ganesh Panzade,Ankita Srivastava,Kripa Shankar,Rajesh Pandey,Durgesh Kumar,Sanchita Gupta,Abhishek Gupta,Salil Varshney,Muheeb Beg,Raj Kumar Mishra,Ravi Shankar,Anil Gaikwad | | Journal of Endocrinology. 2018; 239(1): 1 | | [Pubmed] | [DOI] | | | 37 |
Association between Leptin, Adiponectin, and Leptin/Adiponectin Ratio with Clustered Metabolic Risk Factors in Portuguese Adolescents: The LabMed Physical Activity Study |
|
| César A. Agostinis-Sobrinho,Edmar Lacerda Mendes,Carla Moreira,Sandra Abreu,Luís Lopes,José Oliveira-Santos,Albertas Skurvydas,Jorge Mota,Rute Santos | | Annals of Nutrition and Metabolism. 2017; : 321 | | [Pubmed] | [DOI] | | | 38 |
Serum apelin levels and metabolic risk markers in obese women |
|
| Moushira Zaki,Sanaa Kamal,Wafaa Ezzat,Naglaa Hassan,Walaa Yousef,Hanaa Ryad,Ramy Mohamed,Eman Youness,Walaa Basha,Yasser Elhosary | | Journal of Genetic Engineering and Biotechnology. 2017; | | [Pubmed] | [DOI] | | | 39 |
Effects of maternal and fetal LEP common variants on maternal glycemic traits in pregnancy |
|
| Rong Lin,Hongfang Ju,Ziyu Yuan,Caicai Zhang,Liangliang Zeng,Yuantian Sun,Zhenyu Su,Li Jin | | Scientific Reports. 2017; 7(1) | | [Pubmed] | [DOI] | | | 40 |
Endocrine Disruptors Leading to Obesity and Related Diseases |
|
| Demetrios Petrakis,Loukia Vassilopoulou,Charalampos Mamoulakis,Christos Psycharakis,Aliki Anifantaki,Stavros Sifakis,Anca Docea,John Tsiaoussis,Antonios Makrigiannakis,Aristides Tsatsakis | | International Journal of Environmental Research and Public Health. 2017; 14(11): 1282 | | [Pubmed] | [DOI] | | | 41 |
Chronic Hyperinsulinaemic Hypoglycaemia in Rats Is Accompanied by Increased Body Weight, Hyperleptinaemia, and Decreased Neuronal Glucose Transporter Levels in the Brain |
|
| Vivi F. H. Jensen,Anne-Marie Mølck,Melissa Chapman,Lene Alifrangis,Lene Andersen,Jens Lykkesfeldt,Ingrid B. Bøgh | | International Journal of Endocrinology. 2017; 2017: 1 | | [Pubmed] | [DOI] | | | 42 |
Metabolic syndrome in children and teenagers: worth assessing it, but how? |
|
| Gilberto J. Paz Filho | | Archives of Endocrinology and Metabolism. 2017; 61(1): 1 | | [Pubmed] | [DOI] | | | 43 |
Exogenous leptin protects rat models of sodium taurocholate-induced severe acute pancreatitis through endocrinal and immunological pathways |
|
| Haiyu Qi,Qin Lu,Chenghong Yin,Hongli Xiao,Yan Wen,Shuwen Zhang,Qu Cui,Wei Yang | | Molecular Medicine Reports. 2017; 16(5): 6306 | | [Pubmed] | [DOI] | | | 44 |
Leptin Receptor Gene Variant rs11804091 Is Associated with BMI and Insulin Resistance in Spanish Female Obese Children: A Case-Control Study |
|
| Josune Olza,Azahara Rupérez,Mercedes Gil-Campos,Rosaura Leis,Ramón Cañete,Rafael Tojo,Ángel Gil,Concepción Aguilera | | International Journal of Molecular Sciences. 2017; 18(8): 1690 | | [Pubmed] | [DOI] | | | 45 |
Evaluation of fish oil-rich in MUFAs for anti-diabetic and anti-inflammation potential in experimental type 2 diabetic rats |
|
| Waranya Keapai,Sopida Apichai,Doungporn Amornlerdpison,Narissara Lailerd | | The Korean Journal of Physiology & Pharmacology. 2016; 20(6): 581 | | [Pubmed] | [DOI] | | | 46 |
Energy homeostasis and appetite regulating hormones as predictors of weight loss in men and women |
|
| Rebecca L. Williams,Lisa G. Wood,Clare E. Collins,Philip J. Morgan,Robin Callister | | Appetite. 2016; 101: 1 | | [Pubmed] | [DOI] | | | 47 |
Noncoding RNAs: Possible Players in the Development of Fluorosis |
|
| Atul P. Daiwile,Saravanadevi Sivanesan,Alberto Izzotti,Amit Bafana,Pravin K. Naoghare,Patrizio Arrigo,Hemant J. Purohit,Devendra Parmar,Krishnamurthi Kannan | | BioMed Research International. 2015; 2015: 1 | | [Pubmed] | [DOI] | | | 48 |
Thiazolidinedione compounds: a patent review (2010 – present) |
|
| Nisheeth C Desai,Unnat P Pandit,Amit Dodiya | | Expert Opinion on Therapeutic Patents. 2015; : 1 | | [Pubmed] | [DOI] | | | 49 |
FTO contributes to hepatic metabolism regulation through regulation of leptin action and STAT3 signalling in liver |
|
| Amélie Bravard,Guillaume Vial,Marie-Agnès Chauvin,Yves Rouillé,Bernard Bailleul,Hubert Vidal,Jennifer Rieusset | | Cell Communication and Signaling. 2014; 12(1): 4 | | [Pubmed] | [DOI] | |
|
 |
|
|
|
