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A Key Role in Insulin Secretion View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector ARTICLE Nicotinamide nucleotide transhydrogenase: A key role in insulin secretion Helen Freeman,1,2 Kenju Shimomura,2 Emma Horner,1 Roger D. Cox,1,3,* and Frances M. Ashcroft2,3,* 1 Medical Research Council, Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, United Kingdom 2 University Laboratory of Physiology, Parks Road, Oxford, OX1 3PT, United Kingdom 3 These authors contributed equally to this work. *Correspondence: [email protected] (R.D.C.); [email protected] (F.M.A.) Summary The C57BL/6J mouse displays glucose intolerance and reduced insulin secretion. QTL mapping identified Nicotinamide Nu- cleotide Transhydrogenase (Nnt), a nuclear-encoded mitochondrial protein thought to be involved in free radical detoxifica- tion, as a candidate gene. To investigate its functional role, we used siRNA to knock down Nnt in insulin-secreting MIN6 cells. 2+ This produced a dramatic reduction in insulin secretion and the rise in [Ca ]i evoked by glucose, but not tolbutamide. We identified two ENU-induced point mutations in Nnt (N68K, G745D). Nnt mutant mice were glucose intolerant and secreted less insulin during a glucose tolerance test. Isolated islets showed impaired insulin secretion in response to glucose, but not to tolbutamide, and glucose failed to enhance ATP levels. Glucose utilization and production of reactive oxygen species were increased in Nnt b cells. We hypothesize that Nnt mutations/deletion uncouple b cell mitochondrial metabolism leading to less ATP production, enhanced KATP channel activity, and consequently impaired insulin secretion. Introduction 2001). Changes in b cell metabolism are coupled to changes in insulin release via metabolic regulation of the activity of the Type 2 diabetes mellitus is a serious metabolic disease that is ATP-sensitive potassium (KATP) channel (Ashcroft and Rorsman reaching epidemic proportions in Western societies and is pre- 1989, 2004)(Figure 1). At low blood glucose levels, KATP chan- dicted to affect 300 million people worldwide by 2025 (King nels are open, hyperpolarizing the b cell membrane and prevent- et al., 1998). Impaired glucose tolerance, which precedes diabe- ing Ca2+ influx and insulin secretion. When glucose levels rise, tes and is a risk factor for the disease, currently affects a further increased b cell metabolism produces elevation of cellular 200 million worldwide. Type 2 diabetes is characterized by ele- ATP levels. This causes closure of KATP channels, which leads vation of the blood glucose concentration, usually presents in to membrane depolarization, activation of voltage-gated Ca2+ 2+ 2+ middle age, and is exacerbated by age and obesity. It is associ- channels, Ca entry, and a rise in [Ca ]i that triggers insulin ated with both impaired insulin secretion and insulin action, but it secretion. is now recognized that b cell dysfunction is a key element in the Earlier studies have shown that the reduced insulin secretion development of the disease (Bell and Polonsky, 2001; Kahn, of C57BL/6J mice derives from the failure of glucose to close 2003; Ashcroft and Rorsman, 2004). pancreatic b cell KATP channels (Toye et al., 2005). Conse- Mouse models of diabetes and glucose intolerance may pro- quently, the membrane potential is not depolarized and Ca2+ en- vide useful insights into insulin secretory mechanisms and the try is prevented. However, the sensitivity of KATP channels in etiology of human type 2 diabetes. One such example is the C57BL/6J mice to inhibition by ATP (IC50 =10mM; Toye et al., C57BL/6J mouse strain, which shows impaired glucose toler- 2005) is similar to that observed for NMRI mice (Ashcroft and ance under free-fed and postprandial conditions: using an intra- Kakei, 1989) and for cloned b cell KATP channels expressed in peritoneal glucose tolerance test (IPGTT), the blood glucose heterologous systems (Tucker et al., 1997). This suggests that level of nonobese C57BL/6J mice rises higher and takes longer the defect in C57BL/6J mice lies prior to KATP channel closure, to regain the resting level than that of other mouse strains (Kaku probably at the level of b cell metabolism (Toye et al., 2005). et al., 1988; Rossmeisl et al., 2003; Kulkarni et al., 2003; Toye By intercrossing nonobese C57BL/6J and C3H/HeH mice and et al., 2005). This is associated with reduced plasma insulin lev- employing QTL mapping, we identified three main genetic loci els, resulting from impaired first and second phase insulin re- that influence the difference in glucose homeostasis (Toye lease (Kaku et al., 1988; Rossmeisl et al., 2003; Kooptiwut et al., 2005). These were located on chromosomes 9, 11, and et al., 2002; KayoRETRACTED et al., 2000). These effects are magnified in 13. Within the chromosome 13 locus lay the gene encoding Nic- mice that possess a genetic defect in insulin resistance (Kulkarni otinamide Nucleotide Transhydrogenase (Nnt), and sequencing et al., 2003). In addition, C57BL/6J mice develop obesity, hyper- of the coding region of Nnt in C57BL/6J mice identified two mu- glycemia, and insulin resistance when fed a high-fat diet (Ross- tations (Toye et al., 2005). The first is a missense mutation meisl et al., 2003). (M35T) in the mitochondrial leader sequence of the Nnt precur- Insulin secretion from the b cells of the pancreatic islets is crit- sor protein. The second is an in-frame 5-exon deletion that re- ically dependent on cellular ATP levels generated by glucose- moves four predicted transmembrane helices and their con- stimulated mitochondrial metabolism (Maechler and Wollheim, necting linkers. CELL METABOLISM 3, 35–45, JANUARY 2006 ª2006 ELSEVIER INC. DOI 10.1016/j.cmet.2005.10.008 35 ARTICLE compared to wild-type b cells. Our data are consistent with the idea that impaired Nnt function reduces b cell metabolism, thereby preventing closure of KATP channels in response to glu- cose, calcium influx, and insulin secretion. Results siRNA knockdown of Nnt in MIN6 cells To determine the functional role of Nnt in b cells, we used siRNA to silence Nnt in the insulin-secreting b cell line MIN6. MIN6 cells were mock-transfected or transfected with one of four different siRNA duplexes: nonsense, glucokinase (Gck), or two different Nnt-specific siRNAs. Gck was used as positive control, as it is a key glycolytic enzyme, and in its absence, insulin secretion is abolished (Terauchi et al., 1995). A scrambled (nonsense) Figure 1. Mechanism of insulin secretion from pancreatic b cells siRNA was used as a negative control. We used two separate Under resting conditions, KATP channels are open, producing hyperpolarization of the b cell plasma membrane and so preventing insulin secretion. Glucose uptake Nnt siRNAs targeted to different regions of the gene. All siRNAs (via the GLUT2 transporter) and its subsequent metabolism elevates ATP and re- were tagged with a fluorescent probe to enable transfected cells duces MgADP levels, causing KATP channels to close. This produces a membrane to be easily detected. depolarization that activates voltage-gated Ca2+ channels, causing Ca2+ influx and 2+ Quantitative real-time PCR and Western blotting were used to a rise in cytosolic Ca that triggers release of insulin granules. ATP also stimulates verify mRNA and protein knockdown. Expression of Gck and the secretory machinery directly. Nnt mRNAs was abolished by siRNAs targeted against these genes, but neither was affected in cells transfected with non- Nnt is a nuclear-encoded mitochondrial protein that is located sense siRNA (Figure 2A). Similar results were found for protein in the inner mitochondrial membrane of eukaryotes and in the expression. Figure 2B shows Western blots of MIN6 cells plasma membrane of some bacteria (for review, see Hoek and probed with antibodies to Gck and Nnt following transfection Rydstrom, 1988). It functions as a redox-driven proton pump, with one of the three different siRNA. Islets isolated from C3H/ catalyzing the reversible reduction of NADP+ by NADH and con- HeH and C57BL/6J mice are also included as positive and neg- version of NADH to NAD+. This is linked to proton translocation ative controls, respectively. The Nnt protein is not found in across the membrane according to the reaction: C57BL/6J mice, although as previously reported, the RNA is present (Toye et al., 2005). It is also clear that Nnt is present in + + MIN6 cells transfected with nonsense (upper panels) or Gck NADH + NADP + Hcytosolic4NAD + NADPH + Hmatrix siRNA (lower panels) but not in cells transfected with Nnt siRNA Under physiological conditions, a marked proton gradient is present (middle panels). Transfection with Gck siRNA abolished expres- across the inner mitochondrial membrane so that the reaction is sion of Gck without altering Nnt expression (Figure 2B, lower driven strongly to the right. This makes Nnt a very efficient generator panels). A second Nnt siRNA also abolished protein and RNA of NADPH. Moreover, it couples the production of NADPH to the expression (data not shown). Thus, we achieved target-specific rate of mitochondrial metabolism, and hence to the production of knockdown of Nnt with both siRNAs. reactive oxygen species (ROS) generated by the electron transport chain. Thus, Nnt is postulated to play an important role in the detox- Insulin secretion in MIN6 cells ification of ROS (Hoek and Rydstrom, 1988; Arkblad et al., 2005). We next compared insulin secretion from MIN6 cells transfected Nnt is a homodimer and the individual subunits (Mr w110 kDa) with nonsense siRNA or Nnt siRNA. Figure 2C shows that basal are composed of three domains (Hoek and Rydstrom, 1988). insulin secretion in glucose-free solution was almost identical for The N-terminal hydrophilic domain (I) binds NAD(H), the central both nonsense and Nnt siRNA-transfected cells but that glucose hydrophobic domain (II) intercalates into the membrane (it con- failed to stimulate insulin secretion from cells in which Nnt had sists of 14 transmembrane domains and forms the proton chan- been knocked down.
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