Khajavi Lab

Head of lab

Prof. Dr. rer. medic. Khajavi Noushafarin

Type 2 diabetes (T2D) arises from the inability of β-cells to adequately compensate for increased metabolic demands by releasing sufficient insulin. Currently, two billion adults and forty million children are dealing with obesity, a condition that affects 350 million individuals who are also burdened by T2D. The majority of individuals with excess body weight have exhibited significant resistance to prevailing weight loss methods. Consequently, the urgent need to develop safe and efficacious drug therapies, complementing a healthy lifestyle, has become a global priority. A pivotal objective in diabetes research and drug development involves the identification of factors governing β‐cell function and impacting insulin secretion. Recent studies have unveiled the presence of several TRP channels in pancreatic β-cells, implying their crucial role in insulin secretion regulation. However, the precise functions of various TRPs, such as TRPM7, in insulin secretion, glucose homeostasis, and T2D development remain elusive.

In our recent study, we highlighted the disruptive impact on insulin secretion and progressive glucose intolerance resulting from the selective deletion of Trpm7 in β-cells. TRPM7, being the primary Mg2+ channel highly expressed in pancreatic β-cells, initially led us to associate this effect with a decrease in Mg2+ concentration within the cells of this mouse model. However, our comprehensive investigations unveiled that the diminished insulinotropic response in β-cell–specific Trpm7-knockout mice stems from a reduction in insulin production due to impaired enzymatic activity of this protein. Although our research emphasizes the pivotal role of TRPM7 kinase in insulin synthesis, β-cell dynamics, and glucose homeostasis, the precise molecular mechanism governing these functions remains elusive. Our next phase in this project will be to delve into understanding the intricate molecular mechanisms and downstream signaling pathways that contribute to gene transcription via TRPM7 kinase. This exciting journey aims to unravel the complexities and unlock key insights that could potentially revolutionize diabetes research and therapeutic approaches.

Publications

1. Khajavi N, Riçku K, Schreier PCF, Gentz T, Beyerle P, Cruz E, Breit A, Reinach PS, Gudermann T. Chronic Mg2+ Deficiency Does Not Impair Insulin Secretion in Mice. Cells. 2023 Jul 5;12(13):1790.

2. Liskiewicz D, Zhang Q, Barthem CS, Jastroch M, Liskiewicz A, Khajavi N, Grandl G, Coupland C, Kleinert M, Garcia-Caceres C, Novikoff A, Maity G, Boehm U, Tschöp MH, Müller TD. Neuronal loss of TRPM8 leads to obesity and glucose intolerance in male mice. Mol Metab. 2023 Jun;72:101714.

3. Khajavi N, Beck A, Riçku K, Beyerle P, Jacob K, Syamsul SF, Belkacemi A, Reinach PS, Schreier PC, Salah H, Popp T, Novikoff A, Breit A, Chubanov V, Müller TD, Zierler S, Gudermann T. TRPM7 kinase is required for insulin production and compensatory islet responses during obesity. JCI Insight. 2023 Feb 8;8(3):e163397.

4. Jacobi S, Khajavi N, Kleinau G, Teumer A, Scheerer P, Homuth G, Völzke H, Wiegand S, Kühnen P, Krude H, Gong M, Raile K, Biebermann H. Evaluation of a rare glucose-dependent insulinotropic polypeptide receptor variant in a patient with disturbed glucose homeostasis. Diabetes, Obesity and Metabolism. 2019 May;21(5):1168-1176.

5. Türker E, Garreis F, Khajavi N, Reinach PS, Joshi P, Brockmann T, Lucius A, Ljubojevic N, Turan E, Pleyer U, Köhrle J and Mergler S. Vascular endothelial growth factor (VEGF) induced downstream responses to transient receptor potential vanilloid 1 (TRPV1) and 3-Iodothyronamine (3-T1AM) in human corneal keratocytes. Front Endocrinol (Lausanne). 2018 Nov 22;9:670.

6. Bräunig J, Mergler S, Jyrch S, Hoefig CS, Rosowski M, Mittag J, Biebermann H, Khajavi N. 3- Iodothyronamine Activates a Set of Membrane Proteins in Murine Hypothalamic Cell Lines. Front Endocrinol (Lausanne). 2018 Sep 11;9:523.

7. Khajavi N, Finan B, Kluth O, Müller TD, Mergler S, Schulz A, Kleinau G, Scheerer P, Schürmann A, Gudermann T, Tschöp MH, Krude H, DiMarchi RD, Biebermann H. An incretin-based tri-agonist promotes superior insulin secretion from murine pancreatic islets via PLC activation. Cell Signal. 2018 Nov; 51:13-22.

8. Fischer J, Kleinau G, Rutz C, Zwanziger D, Khajavi N, Müller A, Rehders M, Brix K, Worth C, Führer D, Krude H, Wiesner B, Schülein R, Biebermann H. Evidence of G-protein-coupled receptor and substrate transporter heteromerization at a single molecule level. Cell Mol Life Sci. 2018 Jun;75(12):2227-2239.

9. Khajavi N, Biebermann H, Tschöp M, DiMarchi R. Treatment of diabetes and obesity by rationally designed peptide agonists functioning at multiple metabolic receptors. Developmental Biology of Gastrointestinal Hormones. Endocr Dev. 2017;32:165-182.

10. Khajavi N, Mergler S, Biebermann H. 3-iodothyronamine, a novel endogenous modulator of transient receptor potential melastatin 8? Front Endocrinol. 2017 Aug 16;8:198.

11. Buonocore F, Kühnen P, Suntharalingham JP, Del Valle I, Digweed M, Stachelscheid H, Khajavi N, Didi M, Brady AF, Blankenstein O, Procter AM, Dimitri P, Wales JKH, Ghirri P, Knöbl D, Strahm B, Erlacher M, Wlodarski MW, Chen W, Kokai GK, Anderson G, Morrogh D, Moulding DA, McKee SA, Niemeyer CM, Grüters A, Achermann JC. Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans. J Clin Invest. 2017 May 1;127(5):1700-1713.

12. Skrzypski M, Billert M, Mergler S, Khajavi N, Nowak KW, Strowski MZ. Role of TRPV channels in regulating various pancreatic β-cell functions: Lessons from in vitro studies. Biosci Trends. 2017 Mar 22;11(1):9-15.

13. Skrzypski M, Khajavi N, Mergler S, Billert M, Szczepankiewicz D, Wojciechowicz T, Nowak KW, Strowski MZ. Orexin A modulates INS-1E cell proliferation and insulin secretion via extracellular signal-regulated kinase and transient receptor potential channels. J Physiol Pharmacol. 2016 Oct;67(5):643-652.

14. Schanze N, Jacobi S, Rijntjes E, Mergler S, del Olmo M, Hoefig C, Khajavi N, Lehmphul I, Biebermann H, Mittag J, Köhrle J. 3-iodothyronamine decreases expression of genes involved in iodide metabolism in mouse thyroids and inhibits iodide uptake in PCCL3 thyrocytes. Thyroid. 2017 Jan;27(1):11-22.

15. Kleinau G, Khajavi N, Köhrle J, Biebermann H. Differential Modulation of Adrenergic Receptor Signaling by Octopamine, Tyramine, Phenylethylamine, and 3-Iodothyronamine. Book chapter-Trace Amines and Neurological Disorders. 2016 Pages 63–81.

16. Skrzypski M, Kołodziejski PA, Mergler S, Khajavi N, Nowak KW, Strowski MZ. TRPV6 modulates proliferation of human pancreatic neuroendocrine BON-1 tumour cells. Biosci Rep. 2016 Aug 24;36(4).

17. Garreis F, Schröder A, Reinach PS, Zoll S, Khajavi N, Dhandapani P, Lucius A, Pleyer U, Paulsen F, Mergler S. Upregulation of transient receptor potential vanilloid type-1 Channel activity and Ca2+ influx dysfunction in human pterygial cells. Invest Ophthalmol Vis Sci., 2016 May 1;57(6):2564-77.

18. Lucius A, Khajavi N, Reinach PS, Köhrle J, Dhandapani P, Huimann P, Ljubojevic N, Grötzinger C, Mergler S. Cell Signal. 3-Iodothyronamine increases transient receptor potential melastatin channel 8 (TRPM8) activity in immortalized human corneal epithelial cells. Cell Signal, 2016 Mar;28(3):136-47.

19. Dinter J*, Khajavi N*, Mühlhaus J, Wienchol C, Coster M, Hermsdorf T, Staubert C, Köhrle J, Schöneberg T, Kleinau G, Mergler S, Biebermann H. The multi-target molecule 3-iodothyronamine is a modulator of β-adrenergic receptor 2 mediated signaling with impact on human conjunctival epithelial cells. European Thyroid Journal, 2015 Sep;4:21-9.

20. Skrzypski M, Khajavi N, Mergler S, Szczepankiewicz D, Kołodziejski PA, Metzke D, Wojciechowicz T, Billert M, Nowak KW, Strowski MZ. TRPV6 channel modulates proliferation of insulin secreting INS-1E beta cell line. Biochim Biophys Acta, 2015 Dec;1853(12):3202-10.

18. Khajavi N, Reinach PS, Slavi N, Skrzypski M, Lucius A, Strauß O, Köhrle J, Mergler S. Thyronamine induces TRPM8 channel activation in human conjunctival epithelial cells. Cell Signal, 2015 Feb;27 (2):315-25.

21. Khajavi N, Reinach PS, Skrzypski M, Lude A, Mergler S. L-Carnitine reduces in human conjunctival epithelial cells hypertonic-induced shrinkage through interacting with TRPV1 channels. Cell Physiol Biochem, 2014;34:790-803.

22. Khajavi N, Akbari M, Abolhassani F, Dehpour AR, Koruji M, Habibi Roudkenar M. Role of Somatic Testicular Cells during Mouse Spermatogenesis in Three-Dimensional Collagen Gel Culture System. Cell J. 2014 Feb 3;16(1):79-90.

23. Mergler S, Derckx R, Reinach PS, Garreis F, Böhm A, Schmelzer L, Khajavi N, Riechardt A. Calcium regulation by temperature-sensitive transient receptor potential channels in human uveal melanoma cells, Cell signaling Journal, 2013 Sep;26(1):56-69.

24. Skrzypski M, Kakkassery M, Mergler S, Grötzinger C, Khajavi N, Sassek M, Szczepankiewicz D, Wiedenmann B, Nowak KW, Strowski MZ. Activation of TRPV4 channel in pancreatic INS-1E beta cells enhances glucose-stimulated insulin secretion via calcium-dependent mechanisms. FEBS Lett, 2013 Oct;587(19):3281-7

AG Khajavi

The role of TRP channels in pancreatic beta-cell function and regulation of insulin release