Skip to main content
Erschienen in: European Journal of Nutrition 3/2016

28.04.2015 | Original Contribution

Labrador tea (Rhododendron groenlandicum) attenuates insulin resistance in a diet-induced obesity mouse model

verfasst von: Meriem Ouchfoun, Hoda M. Eid, Lina Musallam, Antoine Brault, Shilin Li, Diane Vallerand, John T. Arnason, Pierre S. Haddad

Erschienen in: European Journal of Nutrition | Ausgabe 3/2016

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Using a diet-induced obesity (DIO) mouse model, we investigated the antidiabetic effect of Labrador tea [Rhododendron groenlandicum (Oeder) Kron and Judd], a beverage and medicinal tea used by the Cree Nations of northern Quebec.

Methods

C57BL6 mice were divided into five groups and given standard chow (~4 % of lipids) or high-fat diet (~35 % of lipids) for 8 weeks until they became obese and insulin resistant. Treatment began by adding the plant extract at three doses (125, 250 and 500 mg/kg) to the high-fat diet for another 8 weeks. At the end of the study, insulin-sensitive tissues (liver, skeletal muscle, adipose tissue) were collected to investigate the plant’s molecular mechanisms.

Results

Labrador tea significantly reduced blood glucose (13 %), the response to an oral glucose tolerance test (18.2 %) and plasma insulin (65 %) while preventing hepatic steatosis (42 % reduction in hepatic triglyceride levels) in DIO mice. It stimulated insulin-dependent Akt pathway (55 %) and increased the expression of GLUT4 (53 %) in skeletal muscle. In the liver, Labrador tea stimulated the insulin-dependent Akt and the insulin-independent AMP-activated protein kinase pathways. The improvement in hepatic steatosis observed in DIO-treated mice was associated with a reduction in inflammation (through the IKK α/β) and a decrease in the hepatic content of SREBP-1 (39 %).

Conclusions

Labrador tea exerts potential antidiabetic action by improving insulin sensitivity and mitigating high-fat diet-induced obesity and hyperglycemia. They validate the safety and efficacy of this plant, a promising candidate for culturally relevant complementary treatment in Cree diabetics.
Literatur
1.
Zurück zum Zitat Hegele RA (2001) Genes and environment in type 2 diabetes and atherosclerosis in aboriginal Canadians. Curr Atheroscler Rep 3:216–221CrossRef Hegele RA (2001) Genes and environment in type 2 diabetes and atherosclerosis in aboriginal Canadians. Curr Atheroscler Rep 3:216–221CrossRef
2.
Zurück zum Zitat Brassard P, Robinson E, Lavallee C (1993) Prevalence of diabetes mellitus among the James Bay Cree of northern Quebec. Can Med Assoc J 149:303–307 Brassard P, Robinson E, Lavallee C (1993) Prevalence of diabetes mellitus among the James Bay Cree of northern Quebec. Can Med Assoc J 149:303–307
3.
Zurück zum Zitat Leduc C, Coonishish J, Haddad P, Cuerrier A (2006) Plants used by the Cree Nation of Eeyou Istchee (Quebec, Canada) for the treatment of diabetes: a novel approach in quantitative ethnobotany. J Ethnopharmacol 105:55–63CrossRef Leduc C, Coonishish J, Haddad P, Cuerrier A (2006) Plants used by the Cree Nation of Eeyou Istchee (Quebec, Canada) for the treatment of diabetes: a novel approach in quantitative ethnobotany. J Ethnopharmacol 105:55–63CrossRef
4.
Zurück zum Zitat Hedrick UP (1972) Sturtevant’s edible plants of the world. Dover, New York Hedrick UP (1972) Sturtevant’s edible plants of the world. Dover, New York
5.
Zurück zum Zitat Saleem A, Harris CS, Asim M et al (2010) A RP-HPLC–DAD-APCI/MSD method for the characterisation of medicinal Ericaceae used by the Eeyou Istchee Cree First Nations. Phytochem Anal 21:328–339CrossRef Saleem A, Harris CS, Asim M et al (2010) A RP-HPLC–DAD-APCI/MSD method for the characterisation of medicinal Ericaceae used by the Eeyou Istchee Cree First Nations. Phytochem Anal 21:328–339CrossRef
6.
Zurück zum Zitat Rapinski M, Liu R, Saleem A, Arnason JT, Cuerrier A (2014) Environmental trends in the variation of biologically active phenolic compounds in Labrador tea, Rhododendron groenlandicum, from northern Quebec, Canada. Botany 92:783–794CrossRef Rapinski M, Liu R, Saleem A, Arnason JT, Cuerrier A (2014) Environmental trends in the variation of biologically active phenolic compounds in Labrador tea, Rhododendron groenlandicum, from northern Quebec, Canada. Botany 92:783–794CrossRef
7.
Zurück zum Zitat Spoor DC, Martineau LC, Leduc C et al (2006) Selected plant species from the Cree pharmacopoeia of northern Quebec possess anti-diabetic potential. Can J Physiol Pharmacol 84:847–858CrossRef Spoor DC, Martineau LC, Leduc C et al (2006) Selected plant species from the Cree pharmacopoeia of northern Quebec possess anti-diabetic potential. Can J Physiol Pharmacol 84:847–858CrossRef
8.
Zurück zum Zitat Martineau LC, Adeyiwola-Spoor DC, Vallerand D, Afshar A, Arnason JT, Haddad PS (2010) Enhancement of muscle cell glucose uptake by medicinal plant species of Canada’s native populations is mediated by a common, metformin-like mechanism. J Ethnopharmacol 127:396–406CrossRef Martineau LC, Adeyiwola-Spoor DC, Vallerand D, Afshar A, Arnason JT, Haddad PS (2010) Enhancement of muscle cell glucose uptake by medicinal plant species of Canada’s native populations is mediated by a common, metformin-like mechanism. J Ethnopharmacol 127:396–406CrossRef
9.
Zurück zum Zitat Jiang T, Wang Z, Proctor G et al (2005) Diet-induced obesity in C57BL/6J mice causes increased renal lipid accumulation and glomerulosclerosis via a sterol regulatory element-binding protein-1c-dependent pathway. J Biol Chem 280:32317–32325CrossRef Jiang T, Wang Z, Proctor G et al (2005) Diet-induced obesity in C57BL/6J mice causes increased renal lipid accumulation and glomerulosclerosis via a sterol regulatory element-binding protein-1c-dependent pathway. J Biol Chem 280:32317–32325CrossRef
10.
Zurück zum Zitat Bray GA, Lovejoy JC, Smith SR et al (2002) The influence of different fats and fatty acids on obesity, insulin resistance and inflammation. J Nutr 132:2488–2491 Bray GA, Lovejoy JC, Smith SR et al (2002) The influence of different fats and fatty acids on obesity, insulin resistance and inflammation. J Nutr 132:2488–2491
11.
Zurück zum Zitat Wallberg-Henriksson H, Zierath JR (2001) GLUT4: a key player regulating glucose homeostasis? Insights from transgenic and knockout mice (review). Mol Membr Biol 18:205–211CrossRef Wallberg-Henriksson H, Zierath JR (2001) GLUT4: a key player regulating glucose homeostasis? Insights from transgenic and knockout mice (review). Mol Membr Biol 18:205–211CrossRef
12.
Zurück zum Zitat Saltiel AR, Kahn CR (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414:799–806CrossRef Saltiel AR, Kahn CR (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414:799–806CrossRef
13.
Zurück zum Zitat Gibbs EM, Stock JL, McCoid SC et al (1995) Glycemic improvement in diabetic db/db mice by overexpression of the human insulin-regulatable glucose transporter (GLUT4). J Clin Investig 95:1512–1518CrossRef Gibbs EM, Stock JL, McCoid SC et al (1995) Glycemic improvement in diabetic db/db mice by overexpression of the human insulin-regulatable glucose transporter (GLUT4). J Clin Investig 95:1512–1518CrossRef
14.
Zurück zum Zitat Kurth-Kraczek EJ, Hirshman MF, Goodyear LJ, Winder WW (1999) 5′ AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle. Diabetes 48:1667–1671CrossRef Kurth-Kraczek EJ, Hirshman MF, Goodyear LJ, Winder WW (1999) 5′ AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle. Diabetes 48:1667–1671CrossRef
15.
Zurück zum Zitat Farmer SR (2005) Regulation of PPARgamma activity during adipogenesis. Int J Obes 29(Suppl 1):S13–S16CrossRef Farmer SR (2005) Regulation of PPARgamma activity during adipogenesis. Int J Obes 29(Suppl 1):S13–S16CrossRef
16.
Zurück zum Zitat Rasouli N, Kern PA (2008) Adipocytokines and the metabolic complications of obesity. J Clin Endocrinol Metab 93:S64–S73CrossRef Rasouli N, Kern PA (2008) Adipocytokines and the metabolic complications of obesity. J Clin Endocrinol Metab 93:S64–S73CrossRef
17.
Zurück zum Zitat Diez JJ, Iglesias P (2003) The role of the novel adipocyte-derived hormone adiponectin in human disease. Eur J Endocrinol 148:293–300CrossRef Diez JJ, Iglesias P (2003) The role of the novel adipocyte-derived hormone adiponectin in human disease. Eur J Endocrinol 148:293–300CrossRef
18.
Zurück zum Zitat Ukkola O, Santaniemi M (2002) Adiponectin: a link between excess adiposity and associated comorbidities? J Mol Med 80:696–702CrossRef Ukkola O, Santaniemi M (2002) Adiponectin: a link between excess adiposity and associated comorbidities? J Mol Med 80:696–702CrossRef
19.
Zurück zum Zitat Considine RV, Sinha MK, Heiman ML et al (1996) Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334:292–295CrossRef Considine RV, Sinha MK, Heiman ML et al (1996) Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334:292–295CrossRef
20.
Zurück zum Zitat Shimano H (2001) Sterol regulatory element-binding proteins (SREBPs): transcriptional regulators of lipid synthetic genes. Prog Lipid Res 40:439–452CrossRef Shimano H (2001) Sterol regulatory element-binding proteins (SREBPs): transcriptional regulators of lipid synthetic genes. Prog Lipid Res 40:439–452CrossRef
21.
Zurück zum Zitat Tobe K, Suzuki R, Aoyama M et al (2001) Increased expression of the sterol regulatory element-binding protein-1 gene in insulin receptor substrate-2(−/−) mouse liver. J Biol Chem 276:38337–38340CrossRef Tobe K, Suzuki R, Aoyama M et al (2001) Increased expression of the sterol regulatory element-binding protein-1 gene in insulin receptor substrate-2(−/−) mouse liver. J Biol Chem 276:38337–38340CrossRef
22.
Zurück zum Zitat Postic C, Dentin R, Girard J (2004) Role of the liver in the control of carbohydrate and lipid homeostasis. Diabetes Metab 30:398–408CrossRef Postic C, Dentin R, Girard J (2004) Role of the liver in the control of carbohydrate and lipid homeostasis. Diabetes Metab 30:398–408CrossRef
23.
Zurück zum Zitat Marchesini G, Brizi M, Bianchi G et al (2001) Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 50:1844–1850CrossRef Marchesini G, Brizi M, Bianchi G et al (2001) Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 50:1844–1850CrossRef
24.
Zurück zum Zitat Arkan MC, Hevener AL, Greten FR et al (2005) IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 11:191–198CrossRef Arkan MC, Hevener AL, Greten FR et al (2005) IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 11:191–198CrossRef
25.
Zurück zum Zitat Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22:659–661 Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22:659–661
26.
Zurück zum Zitat Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419CrossRef Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419CrossRef
27.
Zurück zum Zitat Folch J, Lees M, Sloane Stanley GH (1957) A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 226:497–509 Folch J, Lees M, Sloane Stanley GH (1957) A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 226:497–509
28.
Zurück zum Zitat Benhaddou-Andaloussi A, Martineau LC, Vallerand D et al (2010) Multiple molecular targets underlie the antidiabetic effect of Nigella sativa seed extract in skeletal muscle, adipocyte and liver cells. Diabetes Obes Metab 12:148–157CrossRef Benhaddou-Andaloussi A, Martineau LC, Vallerand D et al (2010) Multiple molecular targets underlie the antidiabetic effect of Nigella sativa seed extract in skeletal muscle, adipocyte and liver cells. Diabetes Obes Metab 12:148–157CrossRef
29.
Zurück zum Zitat Surwit RS, Kuhn CM, Cochrane C, McCubbin JA, Feinglos MN (1988) Diet-induced type II diabetes in C57BL/6J mice. Diabetes 37:1163–1167CrossRef Surwit RS, Kuhn CM, Cochrane C, McCubbin JA, Feinglos MN (1988) Diet-induced type II diabetes in C57BL/6J mice. Diabetes 37:1163–1167CrossRef
30.
Zurück zum Zitat Unnikrishnan MK, Veerapur V, Nayak Y, Mudgal PP, Mathew G (2013) Antidiabetic antihyperlipidemic and antioxidant effects of the flavonoids. In: Watson VRP, Zibadi S, Ronald R (eds) Polyphenols in human health and disease, 1st edn. Elsevier Inc., USA, pp 143–161 Unnikrishnan MK, Veerapur V, Nayak Y, Mudgal PP, Mathew G (2013) Antidiabetic antihyperlipidemic and antioxidant effects of the flavonoids. In: Watson VRP, Zibadi S, Ronald R (eds) Polyphenols in human health and disease, 1st edn. Elsevier Inc., USA, pp 143–161
31.
Zurück zum Zitat Takahashi M, Miyashita M, Suzuki K et al (2014) Acute ingestion of catechin-rich green tea improves postprandial glucose status and increases serum thioredoxin concentrations in postmenopausal women. Br J Nutr 112:1542–1550CrossRef Takahashi M, Miyashita M, Suzuki K et al (2014) Acute ingestion of catechin-rich green tea improves postprandial glucose status and increases serum thioredoxin concentrations in postmenopausal women. Br J Nutr 112:1542–1550CrossRef
32.
Zurück zum Zitat Curtis PJ, Sampson M, Potter J, Dhatariya K, Kroon PA, Cassidy A (2012) Chronic ingestion of flavan-3-ols and isoflavones improves insulin sensitivity and lipoprotein status and attenuates estimated 10-year CVD risk in medicated postmenopausal women with type 2 diabetes: a 1-year, double-blind, randomized, controlled trial. Diabetes Care 35:226–232CrossRef Curtis PJ, Sampson M, Potter J, Dhatariya K, Kroon PA, Cassidy A (2012) Chronic ingestion of flavan-3-ols and isoflavones improves insulin sensitivity and lipoprotein status and attenuates estimated 10-year CVD risk in medicated postmenopausal women with type 2 diabetes: a 1-year, double-blind, randomized, controlled trial. Diabetes Care 35:226–232CrossRef
33.
Zurück zum Zitat Xie Y, Xie Z (2015) Experimental models of high fat obesity and leucine supplementation. In: Rajendram R, Preedy VR, Patel VB, Chain Branched (eds) Amino Acids in Clinical Nutrition. Springer, New York, pp 219–227 Xie Y, Xie Z (2015) Experimental models of high fat obesity and leucine supplementation. In: Rajendram R, Preedy VR, Patel VB, Chain Branched (eds) Amino Acids in Clinical Nutrition. Springer, New York, pp 219–227
34.
Zurück zum Zitat Karlsson HK, Zierath JR, Kane S, Krook A, Lienhard GE, Wallberg-Henriksson H (2005) Insulin-stimulated phosphorylation of the Akt substrate AS160 is impaired in skeletal muscle of type 2 diabetic subjects. Diabetes 54:1692–1697CrossRef Karlsson HK, Zierath JR, Kane S, Krook A, Lienhard GE, Wallberg-Henriksson H (2005) Insulin-stimulated phosphorylation of the Akt substrate AS160 is impaired in skeletal muscle of type 2 diabetic subjects. Diabetes 54:1692–1697CrossRef
35.
Zurück zum Zitat Sanz P (2008) AMP-activated protein kinase: structure and regulation. Curr Protein Pept Sci 9:478–492CrossRef Sanz P (2008) AMP-activated protein kinase: structure and regulation. Curr Protein Pept Sci 9:478–492CrossRef
36.
Zurück zum Zitat Haber BA, Chin S, Chuang E, Buikhuisen W, Naji A, Taub R (1995) High levels of glucose-6-phosphatase gene and protein expression reflect an adaptive response in proliferating liver and diabetes. J Clin Investig 95:832–841CrossRef Haber BA, Chin S, Chuang E, Buikhuisen W, Naji A, Taub R (1995) High levels of glucose-6-phosphatase gene and protein expression reflect an adaptive response in proliferating liver and diabetes. J Clin Investig 95:832–841CrossRef
37.
Zurück zum Zitat Clore JN, Stillman J, Sugerman H (2000) Glucose-6-phosphatase flux in vitro is increased in type 2 diabetes. Diabetes 49:969–974CrossRef Clore JN, Stillman J, Sugerman H (2000) Glucose-6-phosphatase flux in vitro is increased in type 2 diabetes. Diabetes 49:969–974CrossRef
38.
Zurück zum Zitat Nachar A, Vallerand D, Musallam L et al (2013) The action of antidiabetic plants of the Canadian James bay Cree traditional pharmacopeia on key enzymes of hepatic glucose homeostasis. Evidence-based Complement Altern Med 2013:189819CrossRef Nachar A, Vallerand D, Musallam L et al (2013) The action of antidiabetic plants of the Canadian James bay Cree traditional pharmacopeia on key enzymes of hepatic glucose homeostasis. Evidence-based Complement Altern Med 2013:189819CrossRef
39.
Zurück zum Zitat Samuel VT, Liu ZX, Qu X et al (2004) Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem 279:32345–32353CrossRef Samuel VT, Liu ZX, Qu X et al (2004) Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem 279:32345–32353CrossRef
40.
Zurück zum Zitat Foretz M, Taleux N, Guigas B et al (2006) Regulation of energy metabolism by AMPK: a novel therapeutic approach for the treatment of metabolic and cardiovascular diseases. Med Sci M/S 22:381–388 Foretz M, Taleux N, Guigas B et al (2006) Regulation of energy metabolism by AMPK: a novel therapeutic approach for the treatment of metabolic and cardiovascular diseases. Med Sci M/S 22:381–388
41.
Zurück zum Zitat Hardie DG, Scott JW, Pan DA, Hudson ER (2003) Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett 546:113–120CrossRef Hardie DG, Scott JW, Pan DA, Hudson ER (2003) Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett 546:113–120CrossRef
42.
Zurück zum Zitat Winder WW, Hardie DG (1999) AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am J Physiol 277:E1–E10 Winder WW, Hardie DG (1999) AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am J Physiol 277:E1–E10
43.
Zurück zum Zitat Fatehi-Hassanabad Z, Chan CB (2005) Transcriptional regulation of lipid metabolism by fatty acids: a key determinant of pancreatic beta-cell function. Nutr Metab 2:1CrossRef Fatehi-Hassanabad Z, Chan CB (2005) Transcriptional regulation of lipid metabolism by fatty acids: a key determinant of pancreatic beta-cell function. Nutr Metab 2:1CrossRef
44.
Zurück zum Zitat Poynter ME, Daynes RA (1998) Peroxisome proliferator-activated receptor alpha activation modulates cellular redox status, represses nuclear factor-kappaB signaling, and reduces inflammatory cytokine production in aging. J Biol Chem 273:32833–32841CrossRef Poynter ME, Daynes RA (1998) Peroxisome proliferator-activated receptor alpha activation modulates cellular redox status, represses nuclear factor-kappaB signaling, and reduces inflammatory cytokine production in aging. J Biol Chem 273:32833–32841CrossRef
45.
Zurück zum Zitat Kohjima M, Higuchi N, Kato M et al (2008) SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease. Int J Mol Med 21:507–511 Kohjima M, Higuchi N, Kato M et al (2008) SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease. Int J Mol Med 21:507–511
46.
Zurück zum Zitat Yahagi N, Shimano H, Hasty AH et al (2002) Absence of sterol regulatory element-binding protein-1 (SREBP-1) ameliorates fatty livers but not obesity or insulin resistance in Lep(ob)/Lep(ob) mice. J Biol Chem 277:19353–19357CrossRef Yahagi N, Shimano H, Hasty AH et al (2002) Absence of sterol regulatory element-binding protein-1 (SREBP-1) ameliorates fatty livers but not obesity or insulin resistance in Lep(ob)/Lep(ob) mice. J Biol Chem 277:19353–19357CrossRef
47.
Zurück zum Zitat Lowell BB (1999) PPARgamma: an essential regulator of adipogenesis and modulator of fat cell function. Cell 99:239–242CrossRef Lowell BB (1999) PPARgamma: an essential regulator of adipogenesis and modulator of fat cell function. Cell 99:239–242CrossRef
48.
Zurück zum Zitat de Souza CJ, Eckhardt M, Gagen K et al (2001) Effects of pioglitazone on adipose tissue remodeling within the setting of obesity and insulin resistance. Diabetes 50:1863–1871CrossRef de Souza CJ, Eckhardt M, Gagen K et al (2001) Effects of pioglitazone on adipose tissue remodeling within the setting of obesity and insulin resistance. Diabetes 50:1863–1871CrossRef
49.
Zurück zum Zitat Schilling TM, Kolsch M, Larra MF et al (2013) For whom the bell (curve) tolls: cortisol rapidly affects memory retrieval by an inverted U-shaped dose–response relationship. Psychoneuroendocrinology 38:1565–1572CrossRef Schilling TM, Kolsch M, Larra MF et al (2013) For whom the bell (curve) tolls: cortisol rapidly affects memory retrieval by an inverted U-shaped dose–response relationship. Psychoneuroendocrinology 38:1565–1572CrossRef
Metadaten
Titel
Labrador tea (Rhododendron groenlandicum) attenuates insulin resistance in a diet-induced obesity mouse model
verfasst von
Meriem Ouchfoun
Hoda M. Eid
Lina Musallam
Antoine Brault
Shilin Li
Diane Vallerand
John T. Arnason
Pierre S. Haddad
Publikationsdatum
28.04.2015
Verlag
Springer Berlin Heidelberg
Erschienen in
European Journal of Nutrition / Ausgabe 3/2016
Print ISSN: 1436-6207
Elektronische ISSN: 1436-6215
DOI
https://doi.org/10.1007/s00394-015-0908-z

Weitere Artikel der Ausgabe 3/2016

European Journal of Nutrition 3/2016 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.