Skip to main content
Erschienen in: Diabetologia 5/2016

10.03.2016 | Mini-Review

Pleotropic effects of leptin to reverse insulin resistance and diabetic ketoacidosis

verfasst von: Rachel J. Perry, Kitt Falk Petersen, Gerald I. Shulman

Erschienen in: Diabetologia | Ausgabe 5/2016

Einloggen, um Zugang zu erhalten

Abstract

In this review we discuss the mechanisms for the pleotropic effects of leptin replacement therapy to reverse liver and muscle insulin resistance in lipodystrophic individuals, as well as insulin-independent effects of leptin replacement therapy to suppress white adipose tissue lipolysis, hepatic gluconeogenesis and fasting hyperglycaemia in rodent models of poorly controlled diabetes. On the basis of these studies we conclude with a view of the potential therapeutic applications of leptin replacement therapy in humans. This review summarises a presentation given at the ‘Is leptin coming back?’ symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Thomas Meek and Gregory Morton, DOI: 10.​1007/​s00125-016-3898-3, and by Christoffer Clemmensen and colleagues, DOI: 10.​1007/​s00125-016-3906-7) and an overview by the Session Chair, Ulf Smith (DOI: 10.​1007/​s00125-016-3894-7).
Literatur
1.
Zurück zum Zitat Petersen KF, Oral EA, Dufour S et al (2002) Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 109:1345–1350CrossRefPubMedPubMedCentral Petersen KF, Oral EA, Dufour S et al (2002) Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 109:1345–1350CrossRefPubMedPubMedCentral
3.
Zurück zum Zitat Shulman GI (2014) Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Engl J Med 371:1131–1141CrossRefPubMed Shulman GI (2014) Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Engl J Med 371:1131–1141CrossRefPubMed
4.
Zurück zum Zitat Kim JK, Gavrilova O, Chen Y, Reitman ML, Shulman GI (2000) Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J Biol Chem 275:8456–8460CrossRefPubMed Kim JK, Gavrilova O, Chen Y, Reitman ML, Shulman GI (2000) Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J Biol Chem 275:8456–8460CrossRefPubMed
5.
Zurück zum Zitat Fujikawa T, Berglund ED, Patel VR et al (2013) Leptin engages a hypothalamic neurocircuitry to permit survival in the absence of insulin. Cell Metab 18:431–444CrossRefPubMedPubMedCentral Fujikawa T, Berglund ED, Patel VR et al (2013) Leptin engages a hypothalamic neurocircuitry to permit survival in the absence of insulin. Cell Metab 18:431–444CrossRefPubMedPubMedCentral
6.
Zurück zum Zitat Meek TH, Matsen ME, Dorfman MD et al (2013) Leptin action in the ventromedial hypothalamic nucleus is sufficient, but not necessary, to normalize diabetic hyperglycemia. Endocrinology 154:3067–3076CrossRefPubMedPubMedCentral Meek TH, Matsen ME, Dorfman MD et al (2013) Leptin action in the ventromedial hypothalamic nucleus is sufficient, but not necessary, to normalize diabetic hyperglycemia. Endocrinology 154:3067–3076CrossRefPubMedPubMedCentral
7.
Zurück zum Zitat Fujikawa T, Chuang JC, Sakata I, Ramadori G, Coppari R (2010) Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice. Proc Natl Acad Sci U S A 107:17391–17396CrossRefPubMedPubMedCentral Fujikawa T, Chuang JC, Sakata I, Ramadori G, Coppari R (2010) Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice. Proc Natl Acad Sci U S A 107:17391–17396CrossRefPubMedPubMedCentral
8.
Zurück zum Zitat Chinookoswong N, Wang JL, Shi ZQ (1999) Leptin restores euglycemia and normalizes glucose turnover in insulin-deficient diabetes in the rat. Diabetes 48:1487–1492CrossRefPubMed Chinookoswong N, Wang JL, Shi ZQ (1999) Leptin restores euglycemia and normalizes glucose turnover in insulin-deficient diabetes in the rat. Diabetes 48:1487–1492CrossRefPubMed
10.
Zurück zum Zitat Yu X, Park BH, Wang MY, Wang ZV, Unger RH (2008) Making insulin-deficient type 1 diabetic rodents thrive without insulin. Proc Natl Acad Sci U S A 105:14070–14075CrossRefPubMedPubMedCentral Yu X, Park BH, Wang MY, Wang ZV, Unger RH (2008) Making insulin-deficient type 1 diabetic rodents thrive without insulin. Proc Natl Acad Sci U S A 105:14070–14075CrossRefPubMedPubMedCentral
11.
Zurück zum Zitat Chen L, Philippe J, Unger RH (2011) Glucagon responses of isolated alpha cells to glucose, insulin, somatostatin, and leptin. Endocr Pract: Off J Am Coll Endocrinol Am Assoc Clin Endocrinologists 17:819–825CrossRef Chen L, Philippe J, Unger RH (2011) Glucagon responses of isolated alpha cells to glucose, insulin, somatostatin, and leptin. Endocr Pract: Off J Am Coll Endocrinol Am Assoc Clin Endocrinologists 17:819–825CrossRef
12.
Zurück zum Zitat Kim GH, Szabo A, King EM, Ayala J, Ayala JE, Altarejos JY (2015) Leptin recruits Creb-regulated transcriptional coactivator 1 to improve hyperglycemia in insulin-deficient diabetes. Mol Metab 4:227–236CrossRefPubMedPubMedCentral Kim GH, Szabo A, King EM, Ayala J, Ayala JE, Altarejos JY (2015) Leptin recruits Creb-regulated transcriptional coactivator 1 to improve hyperglycemia in insulin-deficient diabetes. Mol Metab 4:227–236CrossRefPubMedPubMedCentral
13.
Zurück zum Zitat Meek TH, Matsen ME, Damian V, Cubelo A, Chua SC Jr, Morton GJ (2014) Role of melanocortin signaling in neuroendocrine and metabolic actions of leptin in male rats with uncontrolled diabetes. Endocrinology 155:4157–4167CrossRefPubMedPubMedCentral Meek TH, Matsen ME, Damian V, Cubelo A, Chua SC Jr, Morton GJ (2014) Role of melanocortin signaling in neuroendocrine and metabolic actions of leptin in male rats with uncontrolled diabetes. Endocrinology 155:4157–4167CrossRefPubMedPubMedCentral
14.
Zurück zum Zitat Perry RJ, Lee S, Ma L, Zhang D, Schlessinger J, Shulman GI (2015) FGF1 and FGF19 reverse diabetes by suppression of the hypothalamic–pituitary–adrenal axis. Nat Commun 6:6980CrossRefPubMedPubMedCentral Perry RJ, Lee S, Ma L, Zhang D, Schlessinger J, Shulman GI (2015) FGF1 and FGF19 reverse diabetes by suppression of the hypothalamic–pituitary–adrenal axis. Nat Commun 6:6980CrossRefPubMedPubMedCentral
15.
Zurück zum Zitat Perry RJ, Zhang XM, Zhang D et al (2014) Leptin reverses diabetes by suppression of the hypothalamic–pituitary–adrenal axis. Nat Med 20:759–763CrossRefPubMedPubMedCentral Perry RJ, Zhang XM, Zhang D et al (2014) Leptin reverses diabetes by suppression of the hypothalamic–pituitary–adrenal axis. Nat Med 20:759–763CrossRefPubMedPubMedCentral
16.
Zurück zum Zitat Minokoshi Y, Toda C, Okamoto S (2012) Regulatory role of leptin in glucose and lipid metabolism in skeletal muscle. Indian J Endocrinol Metab 16:S562–S568CrossRefPubMedPubMedCentral Minokoshi Y, Toda C, Okamoto S (2012) Regulatory role of leptin in glucose and lipid metabolism in skeletal muscle. Indian J Endocrinol Metab 16:S562–S568CrossRefPubMedPubMedCentral
17.
Zurück zum Zitat Toda C, Shiuchi T, Kageyama H et al (2013) Extracellular signal-regulated kinase in the ventromedial hypothalamus mediates leptin-induced glucose uptake in red-type skeletal muscle. Diabetes 62:2295–2307CrossRefPubMedPubMedCentral Toda C, Shiuchi T, Kageyama H et al (2013) Extracellular signal-regulated kinase in the ventromedial hypothalamus mediates leptin-induced glucose uptake in red-type skeletal muscle. Diabetes 62:2295–2307CrossRefPubMedPubMedCentral
18.
Zurück zum Zitat Laker RC, Henry BA, Wadley GD, Clarke IJ, Canny BJ, McConell GK (2011) Central infusion of leptin does not increase AMPK signaling in skeletal muscle of sheep. Am J Physiol Regul Integr Comp Physiol 300:R511–R518CrossRefPubMed Laker RC, Henry BA, Wadley GD, Clarke IJ, Canny BJ, McConell GK (2011) Central infusion of leptin does not increase AMPK signaling in skeletal muscle of sheep. Am J Physiol Regul Integr Comp Physiol 300:R511–R518CrossRefPubMed
19.
Zurück zum Zitat Oral EA, Simha V, Ruiz E et al (2002) Leptin-replacement therapy for lipodystrophy. N Engl J Med 346:570–578CrossRefPubMed Oral EA, Simha V, Ruiz E et al (2002) Leptin-replacement therapy for lipodystrophy. N Engl J Med 346:570–578CrossRefPubMed
20.
Zurück zum Zitat Farooqi IS, Matarese G, Lord GM et al (2002) Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest 110:1093–1103CrossRefPubMedPubMedCentral Farooqi IS, Matarese G, Lord GM et al (2002) Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest 110:1093–1103CrossRefPubMedPubMedCentral
21.
Zurück zum Zitat Morton GJ, Meek TH, Matsen ME, Schwartz MW (2015) Evidence against hypothalamic-pituitary-adrenal axis suppression in the antidiabetic action of leptin. J Clin Invest 125:4587–4591CrossRefPubMed Morton GJ, Meek TH, Matsen ME, Schwartz MW (2015) Evidence against hypothalamic-pituitary-adrenal axis suppression in the antidiabetic action of leptin. J Clin Invest 125:4587–4591CrossRefPubMed
22.
Zurück zum Zitat Rossetti L, Smith D, Shulman GI, Papachristou D, DeFronzo RA (1987) Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J Clin Invest 79:1510–1515CrossRefPubMedPubMedCentral Rossetti L, Smith D, Shulman GI, Papachristou D, DeFronzo RA (1987) Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J Clin Invest 79:1510–1515CrossRefPubMedPubMedCentral
23.
Zurück zum Zitat Perry RJ, Camporez JP, Kursawe R et al (2015) Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes. Cell 160:745–758CrossRefPubMedPubMedCentral Perry RJ, Camporez JP, Kursawe R et al (2015) Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes. Cell 160:745–758CrossRefPubMedPubMedCentral
Metadaten
Titel
Pleotropic effects of leptin to reverse insulin resistance and diabetic ketoacidosis
verfasst von
Rachel J. Perry
Kitt Falk Petersen
Gerald I. Shulman
Publikationsdatum
10.03.2016
Verlag
Springer Berlin Heidelberg
Erschienen in
Diabetologia / Ausgabe 5/2016
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-016-3909-4

Weitere Artikel der Ausgabe 5/2016

Diabetologia 5/2016 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.