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2. Depression symptoms, wellbeing, health-related quality of life, and diabetes-related distress in novel subtypes of recent-onset diabetes in Germany: a 5-year observational follow-up study

Author

Al-Hasani, Hadi, Belgardt, Bengt-Frederik, Bönhof, Gidon, Geerling, Gerd, Herder, Christian, Icks, Andrea, Jandeleit-Dahm, Karin, Kotzka, Jörg, Kuss, Oliver, Lammert, Eckhard, Rathmann, Wolfgang, Roden, Michael, Schlesinger, Sabrina, Schrauwen-Hinderling, Vera, Szendroedi, Julia, Trenkamp, Sandra, Wagner, Robert, Sommer, Jana, Borgmann, Sandra Olivia, Gontscharuk, Veronika, Zaharia, Oana Patricia, Maalmi, Haifa, Strassburger, Klaus, Schön, Martin, Burkart, Volker, Pfeiffer, Andreas F H, Bornstein, Stefan, Blüher, Matthias, Seissler, Jochen, Birkenfeld, Andreas L, and Meyhöfer, Svenja

Published
2024
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3. Analysis of type 2 diabetes heterogeneity with a tree-like representation: insights from the prospective German Diabetes Study and the LURIC cohort

Author

Al-Hasani, Hadi, Belgardt, Bengt-Frederik, Bönhof, Gidon J., Geerling, Gerd, Herder, Christian, Icks, Andrea, Jandeleit-Dahm, Karin, Kotzka, Jörg, Kuss, Oliver, Lammert, Eckhard, Rathmann, Wolfgang, Roden, Michael, Schlesinger, Sabrina, Schrauwen-Hinderling, Vera, Szendroedi, Julia, Trenkamp, Sandra, Wagner, Robert, Schön, Martin, Prystupa, Katsiaryna, Mori, Tim, Zaharia, Oana P, Bódis, Kálmán, Bombrich, Maria, Möser, Clara, Yurchenko, Iryna, Kupriyanova, Yuliya, Strassburger, Klaus, Bobrov, Pavel, Nair, Anand T N, Bönhof, Gidon J, Strom, Alexander, Delgado, Graciela E, Kaya, Sema, Guthoff, Rainer, Stefan, Norbert, Birkenfeld, Andreas L, Hauner, Hans, Seissler, Jochen, Pfeiffer, Andreas, Blüher, Matthias, Bornstein, Stefan, Meyhöfer, Svenja, Burkart, Volker, Schrauwen-Hinderling, Vera B, Kleber, Marcus E, Niessner, Alexander, März, Winfried, and Pearson, Ewan R

Published
2024
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4. Sphingolipid subtypes differentially control proinsulin processing and systemic glucose homeostasis

Author

Griess, Kerstin, Rieck, Michael, Müller, Nadine, Karsai, Gergely, Hartwig, Sonja, Pelligra, Angela, Hardt, Robert, Schlegel, Caroline, Kuboth, Jennifer, Uhlemeyer, Celina, Trenkamp, Sandra, Jeruschke, Kay, Weiss, Jürgen, Peifer-Weiss, Leon, Xu, Weiwei, Cames, Sandra, Yi, Xiaoyan, Cnop, Miriam, Beller, Mathias, Stark, Holger, Kondadi, Arun Kumar, Reichert, Andreas S., Markgraf, Daniel, Wammers, Marianne, Häussinger, Dieter, Kuss, Oliver, Lehr, Stefan, Eizirik, Decio, Lickert, Heiko, Lammert, Eckhard, Roden, Michael, Winter, Dominic, Al-Hasani, Hadi, Höglinger, Doris, Hornemann, Thorsten, Brüning, Jens C., and Belgardt, Bengt-Frederik

Published
2023
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5. Pancreatic islet protection at the expense of secretory function involves serine-linked mitochondrial one-carbon metabolism

Author

Pelligra, Angela, Mrugala, Jessica, Griess, Kerstin, Kirschner, Philip, Nortmann, Oliver, Bartosinska, Barbara, Köster, Andrea, Krupenko, Natalia I., Gebel, Dominik, Westhoff, Philipp, Steckel, Bodo, Eberhard, Daniel, Herebian, Diran, Belgardt, Bengt-Frederik, Schrader, Jürgen, Weber, Andreas P.M., Krupenko, Sergey A., and Lammert, Eckhard

Published
2023
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7. Post mortem analysis of hepatic volume and lipid content by magnetic resonance imaging and spectroscopy in fixed murine neonates.

Author

Jonuscheit, Marc, Uhlemeyer, Celina, Korzekwa, Benedict, Schouwink, Marten, Öner‐Sieben, Soner, Ensenauer, Regina, Roden, Michael, Belgardt, Bengt‐Frederik, and Schrauwen‐Hinderling, Vera B.

Subjects
NUCLEAR magnetic resonance spectroscopy, MAGNETIC resonance imaging, NEWBORN infants, ADULT children
Abstract

Maternal obesity and hyperglycemia are linked to an elevated risk for obesity, diabetes, and steatotic liver disease in the adult offspring. To establish and validate a noninvasive workflow for perinatal metabolic phenotyping, fixed neonates of common mouse strains were analyzed postmortem via magnetic resonance imaging (MRI)/magnetic resonance spectroscopy (MRS) to assess liver volume and hepatic lipid (HL) content. The key advantage of nondestructive MRI/MRS analysis is the possibility of further tissue analyses, such as immunohistochemistry, RNA extraction, and even proteomics, maximizing the data that can be gained per individual and therefore facilitating comprehensive correlation analyses. This study employed an MRI and 1H‐MRS workflow to measure liver volume and HL content in 65 paraformaldehyde‐fixed murine neonates at 11.7 T. Liver volume was obtained using semiautomatic segmentation of MRI acquired by a RARE sequence with 0.5‐mm slice thickness. HL content was measured by a STEAM sequence, applied with and without water suppression. T1 and T2 relaxation times of lipids and water were measured for respective correction of signal intensity. The HL content, given as CH2/(CH2 + H2O), was calculated, and the intrasession repeatability of the method was tested. The established workflow yielded robust results with a variation of ~3% in repeated measurements for HL content determination. HL content measurements were further validated by correlation analysis with biochemically assessed triglyceride contents (R2 = 0.795) that were measured in littermates. In addition, image quality also allowed quantification of subcutaneous adipose tissue and stomach diameter. The highest HL content was measured in C57Bl/6N (4.2%) and the largest liver volume and stomach diameter in CBA (53.1 mm3 and 6.73 mm) and NMRI (51.4 mm3 and 5.96 mm) neonates, which also had the most subcutaneous adipose tissue. The observed effects were independent of sex and litter size. In conclusion, we have successfully tested and validated a robust MRI/MRS workflow that allows assessment of morphology and HL content and further enables paraformaldehyde‐fixed tissue‐compatible subsequent analyses in murine neonates. [ABSTRACT FROM AUTHOR]

Published
2024
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8. Risk of diabetes-associated diseases in subgroups of patients with recent-onset diabetes: a 5-year follow-up study

Author

Belgardt, Bengt-Frederik, Buyken, Anette, Eckel, Jürgen, Geerling, Gerd, Al-Hasani, Hadi, Herder, Christian, Hwang, Jong-Hee, Icks, Andrea, Kotzka, Jörg, Kuss, Oliver, Lammert, Eckart, Markgraf, Daniel, Müssig, Karsten, Rathmann, Wolfgang, Roden, Michael, Szendroedi, Julia, Ziegler, Dan, Zaharia, Oana P, Strassburger, Klaus, Strom, Alexander, Bönhof, Gidon J, Karusheva, Yanislava, Antoniou, Sofia, Bódis, Kálmán, Markgraf, Daniel F, Burkart, Volker, Asplund, Olof, Groop, Leif, Ahlqvist, Emma, Seissler, Jochen, Nawroth, Peter, Kopf, Stefan, Schmid, Sebastian M, Stumvoll, Michael, Pfeiffer, Andreas F H, Kabisch, Stefan, Tselmin, Sergey, and Häring, Hans U

Published
2019
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9. Analysis of type 2 diabetes heterogeneity with a tree-like representation: insights from the prospective German Diabetes Study and the LURIC cohort

Author

Schön, Martin, primary, Prystupa, Katsiaryna, additional, Mori, Tim, additional, Zaharia, Oana P, additional, Bódis, Kálmán, additional, Bombrich, Maria, additional, Möser, Clara, additional, Yurchenko, Iryna, additional, Kupriyanova, Yuliya, additional, Strassburger, Klaus, additional, Bobrov, Pavel, additional, Nair, Anand T N, additional, Bönhof, Gidon J, additional, Strom, Alexander, additional, Delgado, Graciela E, additional, Kaya, Sema, additional, Guthoff, Rainer, additional, Stefan, Norbert, additional, Birkenfeld, Andreas L, additional, Hauner, Hans, additional, Seissler, Jochen, additional, Pfeiffer, Andreas, additional, Blüher, Matthias, additional, Bornstein, Stefan, additional, Szendroedi, Julia, additional, Meyhöfer, Svenja, additional, Trenkamp, Sandra, additional, Burkart, Volker, additional, Schrauwen-Hinderling, Vera B, additional, Kleber, Marcus E, additional, Niessner, Alexander, additional, Herder, Christian, additional, Kuss, Oliver, additional, März, Winfried, additional, Pearson, Ewan R, additional, Roden, Michael, additional, Wagner, Robert, additional, Al-Hasani, Hadi, additional, Belgardt, Bengt-Frederik, additional, Bönhof, Gidon J., additional, Geerling, Gerd, additional, Icks, Andrea, additional, Jandeleit-Dahm, Karin, additional, Kotzka, Jörg, additional, Lammert, Eckhard, additional, Rathmann, Wolfgang, additional, Schlesinger, Sabrina, additional, and Schrauwen-Hinderling, Vera, additional

Published
2023
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10. Pancreatic islet protection at the expense of secretory function associates with serine-linked one-carbon metabolism

Author

Pelligra, Angela, additional, Mrugala, Jessica, additional, Griess, Kerstin, additional, Nortmann, Oliver, additional, Bartosinska, Barbara, additional, Köster, Andrea, additional, Krupenko, Natalia, additional, Gebel, Dominik, additional, Westhoff, Philipp, additional, Steckel, Bodo, additional, Eberhard, Daniel, additional, Belgardt, Bengt-Frederik, additional, Schrader, Jürgen, additional, Weber, Andreas P.M., additional, Krupenko, Sergey A., additional, and Lammert, Eckhard, additional

Published
2023
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11. Selective ablation of P53 in pancreatic beta cells fails to ameliorate glucose metabolism in genetic, dietary and pharmacological models of diabetes mellitus

Author

Uhlemeyer, Celina, additional, Müller, Nadine, additional, Rieck, Michael, additional, Kuboth, Jennifer, additional, Schlegel, Caroline, additional, Griess, Kerstin, additional, Dorweiler, Tim Florian, additional, Heiduschka, Sonja, additional, Eckel, Jürgen, additional, Roden, Michael, additional, Lammert, Eckhard, additional, Stoffel, Markus, additional, and Belgardt, Bengt-Frederik, additional

Published
2023
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12. Analysis of type 2 diabetes heterogeneity with a tree-like representation: insights from the prospective German Diabetes Study and the LURIC cohort

Author

Schön, Martin, Prystupa, Katsiaryna, Mori, Tim, Zaharia, Oana P, Bódis, Kálmán, Bombrich, Maria, Möser, Clara, Yurchenko, Iryna, Kupriyanova, Yuliya, Strassburger, Klaus, Bobrov, Pavel, Nair, Anand T N, Bönhof, Gidon J, Strom, Alexander, Delgado, Graciela E, Kaya, Sema, Guthoff, Rainer, Stefan, Norbert, Birkenfeld, Andreas L, Hauner, Hans, Seissler, Jochen, Pfeiffer, Andreas, Blüher, Matthias, Bornstein, Stefan, Szendroedi, Julia, Meyhöfer, Svenja, Trenkamp, Sandra, Burkart, Volker, Schrauwen-Hinderling, Vera B, Kleber, Marcus E, Niessner, Alexander, Herder, Christian, Kuss, Oliver, März, Winfried, Pearson, Ewan R, Roden, Michael, Wagner, Robert, Al-Hasani, Hadi, Belgardt, Bengt-Frederik, Bönhof, Gidon J., Geerling, Gerd, Herder, Christian, Icks, Andrea, Jandeleit-Dahm, Karin, Kotzka, Jörg, Kuss, Oliver, Lammert, Eckhard, Rathmann, Wolfgang, Roden, Michael, Schlesinger, Sabrina, Schrauwen-Hinderling, Vera, Szendroedi, Julia, Trenkamp, Sandra, and Wagner, Robert

Abstract

Heterogeneity in type 2 diabetes can be represented by a tree-like graph structure by use of reversed graph-embedded dimensionality reduction. We aimed to examine whether this approach can be used to stratify key pathophysiological components and diabetes-related complications during longitudinal follow-up of individuals with recent-onset type 2 diabetes.

Published
2024
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13. E96V Mutation in the Kdelr3 Gene Is Associated with Type 2 Diabetes Susceptibility in Obese NZO Mice

Author

Altenhofen, Delsi, primary, Khuong, Jenny Minh-An, additional, Kuhn, Tanja, additional, Lebek, Sandra, additional, Görigk, Sarah, additional, Kaiser, Katharina, additional, Binsch, Christian, additional, Griess, Kerstin, additional, Knebel, Birgit, additional, Belgardt, Bengt-Frederik, additional, Cames, Sandra, additional, Eickelschulte, Samaneh, additional, Stermann, Torben, additional, Rasche, Axel, additional, Herwig, Ralf, additional, Weiss, Jürgen, additional, Vogel, Heike, additional, Schürmann, Annette, additional, Chadt, Alexandra, additional, and Al-Hasani, Hadi, additional

Published
2023
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14. Selective ablation of P53 in pancreatic beta cells fails to ameliorate glucose metabolism in genetic, dietary and pharmacological models of diabetes mellitus

Author

Uhlemeyer, Celina, primary, Müller, Nadine, additional, Rieck, Michael, additional, Kuboth, Jennifer, additional, Schlegel, Caroline, additional, Grieß, Kerstin, additional, Dorweiler, Tim Florian, additional, Heiduschka, Sonja, additional, Eckel, Jürgen, additional, Roden, Michael, additional, Lammert, Eckhard, additional, Stoffel, Markus, additional, and Belgardt, Bengt-Frederik, additional

Published
2023
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15. Sphingolipid subtypes differentially control proinsulin processing and systemic glucose homeostasis

Author

Griess, Kerstin, primary, Rieck, Michael, additional, Müller, Nadine, additional, Karsai, Gergely, additional, Hartwig, Sonja, additional, Pelligra, Angela, additional, Hardt, Robert, additional, Schlegel, Caroline, additional, Kuboth, Jennifer, additional, Uhlemeyer, Celina, additional, Trenkamp, Sandra, additional, Jeruschke, Kay, additional, Weiss, Jürgen, additional, Peifer-Weiss, Leon, additional, Xu, Weiwei, additional, Cames, Sandra, additional, Yi, Xiaoyan, additional, Cnop, Miriam, additional, Beller, Mathias, additional, Stark, Holger, additional, Kondadi, Arun Kumar, additional, Reichert, Andreas S., additional, Markgraf, Daniel, additional, Wammers, Marianne, additional, Häussinger, Dieter, additional, Kuss, Oliver, additional, Lehr, Stefan, additional, Eizirik, Decio, additional, Lickert, Heiko, additional, Lammert, Eckhard, additional, Roden, Michael, additional, Winter, Dominic, additional, Al-Hasani, Hadi, additional, Höglinger, Doris, additional, Hornemann, Thorsten, additional, Brüning, Jens C., additional, and Belgardt, Bengt-Frederik, additional

Published
2022
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16. The microRNA-200 family regulates pancreatic beta cell survival in type 2 diabetes

Author

Belgardt, Bengt-Frederik, Ahmed, Kashan, Spranger, Martina, Latreille, Mathieu, Denzler, Remy, Kondratiuk, Nadiia, von Meyenn, Ferdinand, Villena, Felipe Nunez, Herrmanns, Karolin, Bosco, Domenico, Kerr-Conte, Julie, Pattou, Francois, Rulicke, Thomas, and Stoffel, Markus

Subjects
Pancreatic beta cells -- Physiological aspects -- Genetic aspects -- Research, MicroRNA -- Physiological aspects -- Research, Type 2 diabetes -- Development and progression -- Genetic aspects -- Research, Biological sciences, Health
Abstract

Pancreatic beta cell death is a hallmark of type 1 (T1D) and type 2 (T2D) diabetes, but the molecular mechanisms underlying this aspect of diabetic pathology are poorly understood. Here we report that expression of the microRNA (miR)-200 family is strongly induced in islets of diabetic mice and that beta cell-specific overexpression of miR-200 in mice is sufficient to induce beta cell apoptosis and lethal T2D. Conversely, mir-200 ablation in mice reduces beta cell apoptosis and ameliorates T2D. We show that miR-200 negatively regulates a conserved anti-apoptotic and stress-resistance network that includes the essential beta cell chaperone Dnajc3 (also known as p58IPK) and the caspase inhibitor Xiap. We also observed that mir-200 dosage positively controls activation of the tumor suppressor Trp53 and thereby creates a pro-apoptotic gene-expression signature found in islets of diabetic mice. Consequently, miR-200-induced T2D is suppressed by interfering with the signaling of Trp53 and Bax, a proapoptotic member of the B cell lymphoma 2 protein family. Our results reveal a crucial role for the miR-200 family in beta cell survival and the pathophysiology of diabetes., Adequate insulin secretion from pancreatic beta cells is necessary to maintain blood glucose levels within a physiological range. During the development of T2D, insulin secretion becomes insufficient to normalize blood [...]

Published
2015
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17. MIC26 and MIC27 are bona fide subunits of the MICOS complex in mitochondria and do not exist as glycosylated apolipoproteins.

Author

Lubeck, Melissa, Derkum, Nick H., Naha, Ritam, Strohm, Rebecca, Driessen, Marc D., Belgardt, Bengt-Frederik, Roden, Michael, Stühler, Kai, Anand, Ruchika, Reichert, Andreas S., and Kondadi, Arun Kumar

Subjects
APOLIPOPROTEINS, MEMBRANE proteins, MITOCHONDRIA, MITOCHONDRIAL membranes, MASS spectrometry
Abstract

Impairments of mitochondrial functions are linked to human ageing and pathologies such as cancer, cardiomyopathy, neurodegeneration and diabetes. Specifically, aberrations in ultrastructure of mitochondrial inner membrane (IM) and factors regulating them are linked to diabetes. The development of diabetes is connected to the 'Mitochondrial Contact Site and Cristae Organising System' (MICOS) complex which is a large membrane protein complex defining the IM architecture. MIC26 and MIC27 are homologous apolipoproteins of the MICOS complex. MIC26 has been reported as a 22 kDa mitochondrial and a 55 kDa glycosylated and secreted protein. The molecular and functional relationship between these MIC26 isoforms has not been investigated. In order to understand their molecular roles, we depleted MIC26 using siRNA and further generated MIC26 and MIC27 knockouts (KOs) in four different human cell lines. In these KOs, we used four anti-MIC26 antibodies and consistently detected the loss of mitochondrial MIC26 (22 kDa) and MIC27 (30 kDa) but not the loss of intracellular or secreted 55 kDa protein. Thus, the protein assigned earlier as 55 kDa MIC26 is nonspecific. We further excluded the presence of a glycosylated, high-molecular weight MIC27 protein. Next, we probed GFP- and myc-tagged variants of MIC26 with antibodies against GFP and myc respectively. Again, only the mitochondrial versions of these tagged proteins were detected but not the corresponding high-molecular weight MIC26, suggesting that MIC26 is indeed not post-translationally modified. Mutagenesis of predicted glycosylation sites in MIC26 also did not affect the detection of the 55 kDa protein band. Mass spectrometry of a band excised from an SDS gel around 55 kDa could not confirm the presence of any peptides derived from MIC26. Taken together, we conclude that both MIC26 and MIC27 are exclusively localized in mitochondria and that the observed phenotypes reported previously are exclusively due to their mitochondrial function. [ABSTRACT FROM AUTHOR]

Published
2023
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24. Risk of diabetes-associated diseases in subgroups of patients with recent-onset diabetes: a 5-year follow-up study

Author

Zaharia, Oana P, primary, Strassburger, Klaus, additional, Strom, Alexander, additional, Bönhof, Gidon J, additional, Karusheva, Yanislava, additional, Antoniou, Sofia, additional, Bódis, Kálmán, additional, Markgraf, Daniel F, additional, Burkart, Volker, additional, Müssig, Karsten, additional, Hwang, Jong-Hee, additional, Asplund, Olof, additional, Groop, Leif, additional, Ahlqvist, Emma, additional, Seissler, Jochen, additional, Nawroth, Peter, additional, Kopf, Stefan, additional, Schmid, Sebastian M, additional, Stumvoll, Michael, additional, Pfeiffer, Andreas F H, additional, Kabisch, Stefan, additional, Tselmin, Sergey, additional, Häring, Hans U, additional, Ziegler, Dan, additional, Kuss, Oliver, additional, Szendroedi, Julia, additional, Roden, Michael, additional, Belgardt, Bengt-Frederik, additional, Buyken, Anette, additional, Eckel, Jürgen, additional, Geerling, Gerd, additional, Al-Hasani, Hadi, additional, Herder, Christian, additional, Icks, Andrea, additional, Kotzka, Jörg, additional, Lammert, Eckart, additional, Markgraf, Daniel, additional, and Rathmann, Wolfgang, additional

Published
2019
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25. Depression symptoms, wellbeing, health-related quality of life, and diabetes-related distress in novel subtypes of recent-onset diabetes in Germany: a 5-year observational follow-up study

Author

Sommer, Jana, Borgmann, Sandra Olivia, Gontscharuk, Veronika, Zaharia, Oana Patricia, Maalmi, Haifa, Herder, Christian, Wagner, Robert, Strassburger, Klaus, Schön, Martin, Burkart, Volker, Szendroedi, Julia, Pfeiffer, Andreas F H, Bornstein, Stefan, Blüher, Matthias, Seissler, Jochen, Birkenfeld, Andreas L, Meyhöfer, Svenja, Roden, Michael, Icks, Andrea, Al-Hasani, Hadi, Belgardt, Bengt-Frederik, Bönhof, Gidon, Geerling, Gerd, Herder, Christian, Icks, Andrea, Jandeleit-Dahm, Karin, Kotzka, Jörg, Kuss, Oliver, Lammert, Eckhard, Rathmann, Wolfgang, Roden, Michael, Schlesinger, Sabrina, Schrauwen-Hinderling, Vera, Szendroedi, Julia, Trenkamp, Sandra, and Wagner, Robert

Abstract

The subjective experiences of individuals living with diabetes is commonly assessed with patient-reported outcomes (PROs; eg, depression symptoms, wellbeing, health-related quality of life [HRQOL], and diabetes-related distress). Cluster analyses have identified novel diabetes subtypes differing in phenotypic and metabolic characteristics. We aimed to investigate associations between these subtypes and PROs and whether subtype predicted PROs 5 years later.

Published
2024
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27. Obesity-linked dysfunction of hypothalamic and pituitary circuits in regulation of energy homeostasis

Author

Belgardt, Bengt-Frederik

Subjects
endocrine system, ddc:570, digestive, oral, and skin physiology, hormones, hormone substitutes, and hormone antagonists
Abstract

Insulin and leptin action in the central nervous system (CNS) controls food intake, energy expenditure and glucose metabolism, partially by regulating the activity of hypothalamic proopiomelanocortin (POMC) neurons. Moreover, insulin- and leptinstimulated phosphatidylinositol-3 kinase (PI3K) activation has been demonstrated to play a critical role in the control of energy homeostasis. To delinearize the importance of pathways downstream of PI3K specifically in POMC cell regulation, mice with selective inactivation of 3-phosphoinositide-dependent protein kinase-1 (PDK1) in POMC-expressing cells were generated. These mice initially display hyperphagia, increased body weight and impaired glucose metabolism caused by reduced hypothalamic POMC expression. In contrast, older mice exhibit normalized food intake and body weight as well as enhanced insulin and glucose sensitivity, due to a progressive loss of POMC-expressing corticotrophs in the pituitary and subsequent severe hypocortisolism. Expression of a dominant negative mutant of FOXO1 specifically in POMC cells is sufficient to prevent initial hyperphagia, transiently increased body weight and reduced hypothalamic POMC expression in these knockout mice, but cannot restore regular pituitary function. These results reveal important but differential roles for PDK1 signaling in hypothalamic and pituitary POMC cell function and survival in control of energy homeostasis and stress response. To understand potential pathomechanisms involved in neuronal insulin and leptin resistance, the effect of obesity on hypothalamic expression of inflammatory mediators was examined. High-fat feeding was found to induce hypothalamic expression of several of cytokines , which was not readily reversible by switching to low-fat diet. Since cytokines and lipids are known to activate c-Jun N-terminal kinases (JNKs), mice with JNK1 deficiency in Nestin-expressing cells (which include neurons and pituitary stem cells) were generated. These mice demonstrated increased hypothalamic insulin sensitivity, as well as reduced activation of the somatotrophic axis and elevated activation of the thyrotrophic axis, resulting in improved improved glucose tolerance, elevated systemic insulin sensitivity, and were protected against obesity-induced hepatosteatosis and adipose tissue dysfunction. Taken together, obesity-induced JNK1 activation in the hypothalamus and pituitary is a crucial event in the induction of CNS insulin resistance and systemic glucose intolerance caused by obesity.

Published
2010

29. Sphingolipid subtypes differentially control proinsulin processing and systemic glucose homeostasis

Author

Griess, Kerstin, Rieck, Michael, Muller, Nadine, Karsai, Gergely, Hartwig, Sonja, Pelligra, Angela, Hardt, Robert, Schlegel, Caroline, Kuboth, Jennifer, Uhlemeyer, Celina, Trenkamp, Sandra, Jeruschke, Kay, Weiss, Jurgen, Peifer-Weiss, Leon, Xu, Weiwei, Cames, Sandra, Yi, Xiaoyan, Cnop, Miriam, Beller, Mathias, Stark, Holger, Kondadi, Arun Kumar, Reichert, Andreas S., Markgraf, Daniel, Wammers, Marianne, Haeussinger, Dieter, Kuss, Oliver, Lehr, Stefan, Eizirik, Decio, Lickert, Heiko, Lammert, Eckhard, Roden, Michael, Winter, Dominic, Al-Hasani, Hadi, Hoeglinger, Doris, Hornemann, Thorsten, Bruning, Jens C., Belgardt, Bengt-Frederik, Griess, Kerstin, Rieck, Michael, Muller, Nadine, Karsai, Gergely, Hartwig, Sonja, Pelligra, Angela, Hardt, Robert, Schlegel, Caroline, Kuboth, Jennifer, Uhlemeyer, Celina, Trenkamp, Sandra, Jeruschke, Kay, Weiss, Jurgen, Peifer-Weiss, Leon, Xu, Weiwei, Cames, Sandra, Yi, Xiaoyan, Cnop, Miriam, Beller, Mathias, Stark, Holger, Kondadi, Arun Kumar, Reichert, Andreas S., Markgraf, Daniel, Wammers, Marianne, Haeussinger, Dieter, Kuss, Oliver, Lehr, Stefan, Eizirik, Decio, Lickert, Heiko, Lammert, Eckhard, Roden, Michael, Winter, Dominic, Al-Hasani, Hadi, Hoeglinger, Doris, Hornemann, Thorsten, Bruning, Jens C., and Belgardt, Bengt-Frederik

Abstract

Impaired proinsulin-to-insulin processing in pancreatic beta-cells is a key defective step in both type 1 diabetes and type 2 diabetes (T2D) (refs. (1)(,)(2)), but the mechanisms involved remain to be defined. Altered metabolism of sphingolipids (SLs) has been linked to development of obesity, type 1 diabetes and T2D (refs. (3-8)); nonetheless, the role of specific SL species in beta-cell function and demise is unclear. Here we define the lipid signature of T2D-associated beta-cell failure, including an imbalance of specific very-long-chain SLs and long-chain SLs. beta-cell-specific ablation of CerS2, the enzyme necessary for generation of very-long-chain SLs, selectively reduces insulin content, impairs insulin secretion and disturbs systemic glucose tolerance in multiple complementary models. In contrast, ablation of long-chain-SL-synthesizing enzymes has no effect on insulin content. By quantitatively defining the SL-protein interactome, we reveal that CerS2 ablation affects SL binding to several endoplasmic reticulum-Golgi transport proteins, including Tmed2, which we define as an endogenous regulator of the essential proinsulin processing enzyme Pcsk1. Our study uncovers roles for specific SL subtypes and SL-binding proteins in beta-cell function and T2D-associated beta-cell failure.

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