Islet amyloid accumulation is a hallmark of human type 2 diabetes (T2D). In contrast to human islet amyloid polypeptide (hIAPP), murine islet amyloid polypeptide (mIAPP) does not exhibit amyloidogenic propensity. Because autophagy is important in the clearance of amyloid-like proteins, we studied transgenic mice with β cell–specific expression of
Jinyoung Kim, Hwanju Cheon, Yeon Taek Jeong, Wenying Quan, Kook Hwan Kim, Jae Min Cho, Yu-Mi Lim, Seung Hoon Oh, Sang-Man Jin, Jae Hyeon Kim, Moon-Kyu Lee, Sunshin Kim, Masaaki Komatsu, Sang-Wook Kang, Myung-Shik Lee
Pancreatic islets in patients with type 2 diabetes mellitus (T2DM) are characterized by loss of β cells and formation of amyloid deposits derived from islet amyloid polypeptide (IAPP). Here we demonstrated that treatment of INS-1 cells with human IAPP (hIAPP) enhances cell death, inhibits cytoproliferation, and increases autophagosome formation. Furthermore, inhibition of autophagy increased the vulnerability of β cells to the cytotoxic effects of hIAPP. Based on these in vitro findings, we examined the pathogenic role of hIAPP and its relation to autophagy in hIAPP-knockin mice. In animals fed a standard diet, hIAPP had no toxic effects on β cell function; however, hIAPP-knockin mice did not exhibit a high-fat-diet–induced compensatory increase in β cell mass, which was due to limited β cell proliferation and enhanced β cell apoptosis. Importantly, expression of hIAPP in mice with a β cell–specific autophagy defect resulted in substantial deterioration of glucose tolerance and dispersed cytoplasmic expression of p62-associated toxic oligomers, which were otherwise sequestrated within p62-positive inclusions. Together, our results indicate that increased insulin resistance in combination with reduced autophagy may enhance the toxic potential of hIAPP and enhance β cell dysfunction and progression of T2DM.
Nayumi Shigihara, Ayako Fukunaka, Akemi Hara, Koji Komiya, Akira Honda, Toyoyoshi Uchida, Hiroko Abe, Yukiko Toyofuku, Motoyuki Tamaki, Takeshi Ogihara, Takeshi Miyatsuka, Henry J. Hiddinga, Setsuya Sakagashira, Masato Koike, Yasuo Uchiyama, Tamotsu Yoshimori, Norman L. Eberhardt, Yoshio Fujitani, Hirotaka Watada
During brain ischemia, an excessive release of glutamate triggers neuronal death through the overactivation of NMDA receptors (NMDARs); however, the underlying pathways that alter glutamate homeostasis and whether synaptic or extrasynaptic sites are responsible for excess glutamate remain controversial. Here, we monitored ischemia-gated currents in pyramidal cortical neurons in brain slices from rodents in response to oxygen and glucose deprivation (OGD) as a real-time glutamate sensor to identify the source of glutamate release and determined the extent of neuronal damage. Blockade of excitatory amino acid transporters or vesicular glutamate release did not inhibit ischemia-gated currents or neuronal damage after OGD. In contrast, pharmacological inhibition of the cystine/glutamate antiporter dramatically attenuated ischemia-gated currents and cell death after OGD. Compared with control animals, mice lacking a functional cystine/glutamate antiporter exhibited reduced anoxic depolarization and neuronal death in response to OGD. Furthermore, glutamate released by the cystine/glutamate antiporter activated extrasynaptic, but not synaptic, NMDARs, and blockade of extrasynaptic NMDARs reduced ischemia-gated currents and cell damage after OGD. Finally, PET imaging showed increased cystine/glutamate antiporter function in ischemic rats. Altogether, these data suggest that cystine/glutamate antiporter function is increased in ischemia, contributing to elevated extracellular glutamate concentration, overactivation of extrasynaptic NMDARs, and ischemic neuronal death.
Federico N. Soria, Alberto Pérez-Samartín, Abraham Martin, Kiran Babu Gona, Jordi Llop, Boguslaw Szczupak, Juan Carlos Chara, Carlos Matute, María Domercq
Type 2 diabetes (T2D) is characterized by a deficiency in β cell mass, increased β cell apoptosis, and extracellular accumulation of islet amyloid derived from islet amyloid polypeptide (IAPP), which β cells coexpress with insulin. IAPP expression is increased in the context of insulin resistance, the major risk factor for developing T2D. Human IAPP is potentially toxic, especially as membrane-permeant oligomers, which have been observed to accumulate within β cells of patients with T2D and rodents expressing human IAPP. Here, we determined that β cell IAPP content is regulated by autophagy through p62-dependent lysosomal degradation. Induction of high levels of human IAPP in mouse β cells resulted in accumulation of this amyloidogenic protein as relatively inert fibrils within cytosolic p62-positive inclusions, which temporarily averts formation of toxic oligomers. Mice hemizygous for transgenic expression of human IAPP did not develop diabetes; however, loss of β cell–specific autophagy in these animals induced diabetes, which was attributable to accumulation of toxic human IAPP oligomers and loss of β cell mass. In human IAPP–expressing mice that lack β cell autophagy, increased oxidative damage and loss of an antioxidant-protective pathway appeared to contribute to increased β cell apoptosis. These findings indicate that autophagy/lysosomal degradation defends β cells against proteotoxicity induced by oligomerization-prone human IAPP.
Jacqueline F. Rivera, Safia Costes, Tatyana Gurlo, Charles G. Glabe, Peter C. Butler
The past decade has witnessed an explosion in studies — both clinical and basic science — examining the relationship between the microbiota and human health, and it is now clear that the effects of commensal organisms are much broader than previously believed. Among the microbiota’s major contributions to host physiology is regulation of the development and maintenance of the immune system. There are now a handful of examples of intestinal commensal bacteria with defined immunomodulatory properties, but our mechanistic understanding of how microbes influence the immune system is still in its infancy. Nevertheless, several themes have emerged that provide a framework for appreciating microbe-induced immunoregulation. In this Review, we discuss the current state of knowledge regarding the role of the intestinal microbiota in immunologic development, highlighting mechanistic principles that can guide future work.
Neeraj K. Surana, Dennis L. Kasper
Anna M. Seekatz, Vincent B. Young
Cells isolated from patients with ataxia telangiectasia are exquisitely sensitive to ionizing radiation. Kinase inhibitors of ATM, the gene mutated in ataxia telangiectasia, can sensitize tumor cells to radiation therapy, but concern that inhibiting ATM in normal tissues will also increase normal tissue toxicity from radiation has limited their clinical application. Endothelial cell damage can contribute to the development of long-term side effects after radiation therapy, but the role of endothelial cell death in tumor response to radiation therapy remains controversial. Here, we developed dual recombinase technology using both FlpO and Cre recombinases to generate primary sarcomas in mice with endothelial cell–specific deletion of
Everett J. Moding, Chang-Lung Lee, Katherine D. Castle, Patrick Oh, Lan Mao, Shan Zha, Hooney D. Min, Yan Ma, Shiva Das, David G. Kirsch
Stem cell–based regenerative therapy is a promising treatment for head and neck cancer patients that suffer from chronic dry mouth (xerostomia) due to salivary gland injury from radiation therapy. Current xerostomia therapies only provide temporary symptom relief, while permanent restoration of salivary function is not currently feasible. Here, we identified and characterized a stem cell population from adult murine submandibular glands. Of the different cells isolated from the submandibular gland, this specific population, Lin–CD24+c-Kit+Sca1+, possessed the highest capacity for proliferation, self renewal, and differentiation during serial passage in vitro. Serial transplantations of this stem cell population into the submandibular gland of irradiated mice successfully restored saliva secretion and increased the number of functional acini. Gene-expression analysis revealed that glial cell line–derived neurotrophic factor (
Nan Xiao, Yuan Lin, Hongbin Cao, Davud Sirjani, Amato J. Giaccia, Albert C. Koong, Christina S. Kong, Maximilian Diehn, Quynh-Thu Le
Patient responses to placebo and sham effects are a major obstacle to the development of therapies for brain disorders, including Parkinson’s disease (PD). Here, we used functional brain imaging and network analysis to study the circuitry underlying placebo effects in PD subjects randomized to sham surgery as part of a double-blind gene therapy trial. Metabolic imaging was performed prior to randomization, then again at 6 and 12 months after sham surgery. In this cohort, the sham response was associated with the expression of a distinct cerebello-limbic circuit. The expression of this network increased consistently in patients blinded to treatment and correlated with independent clinical ratings. Once patients were unblinded, network expression declined toward baseline levels. Analogous network alterations were not seen with open-label levodopa treatment or during disease progression. Furthermore, sham outcomes in blinded patients correlated with baseline network expression, suggesting the potential use of this quantitative measure to identify “sham-susceptible” subjects before randomization. Indeed, Monte Carlo simulations revealed that a priori exclusion of such individuals substantially lowers the number of randomized participants needed to demonstrate treatment efficacy. Individualized subject selection based on a predetermined network criterion may therefore limit the need for sham interventions in future clinical trials.
Ji Hyun Ko, Andrew Feigin, Paul J. Mattis, Chris C. Tang, Yilong Ma, Vijay Dhawan, Matthew J. During, Michael G. Kaplitt, David Eidelberg
Channa N. Jayasena, Ali Abbara, Alexander N. Comninos, Gurjinder M.K. Nijher, Georgios Christopoulos, Shakunthala Narayanaswamy, Chioma Izzi-Engbeaya, Mathini Sridharan, Alexina J. Mason, Jane Warwick, Deborah Ashby, Mohammad A. Ghatei, Stephen R. Bloom, Anna Carby, Geoffrey H. Trew, Waljit S. Dhillo
Glutamate excitotoxicity represents a major cellular component of ischemic brain injury. In this issue of the
Kathryn J. Reissner
Evaluation of potential therapies for neurological disease has been challenging due to beneficial responses in patients receiving the sham/placebo treatment. Placebo effects are especially prominent in Parkinson’s disease (PD), which has become a useful model for studying the neurobiology of placebo responses. In this issue of the
Mariya V. Cherkasova, A. Jon Stoessl
Xerostomia, or dry mouth, is a common side effect of head and neck radiotherapy, Sjögren syndrome, diabetes, old age, and numerous medications. In this issue of the
Adam Swick, Randall J. Kimple
Numerous in vitro studies have shown that human cell lines lacking functional ATM are extremely radiosensitive. In this issue, Moding et al. demonstrate using a murine model of sarcoma that deletion of the
Ester M. Hammond, Ruth J. Muschel
A 30-year-old primigravid (G1P000) female with infertility secondary to her partner’s oligospermia and her chronic anovulation presented 13 days after an oocyte retrieval for in vitro fertilization (IVF) with a positive home pregnancy test, abdominal distention, a 5-pound weight gain, nausea, shortness of breath, and reduced urinary frequency. Her IVF cycle included the usual cocktail for gonadotropin stimulation and was uncomplicated, except for excessively stimulated ovaries that led to a peak estradiol level of 6,000 pg/ml and the retrieval of 30 oocytes. Her past history was relevant only for anovulation due to polycystic ovarian syndrome (PCOS), though her preprocedure body mass index was normal at 21 kg/m2. Pelvic ultrasound revealed abundant ascites and enlarged ovaries, at 8 cm average diameter. Serum human chorionic gonadotropin (hCG) concentration was 200 mIU/ml; she was hemoconcentrated (hemoglobin 16 g/dl), with normal liver function and coagulation testing. An ultrasound guided, transvaginal paracentesis removed 4 liters of straw-colored fluid, resulting in significant short-term symptom relief.
Steven L. Young
A hallmark of type 2 diabetes is the reduction of pancreatic islet β cell mass through induction of apoptosis and lack of regeneration. In most patients, β cell dysfunction is associated with the presence of extracellular amyloid plaques adjacent to β cells and intracellular toxic oligomers that are comprised of islet amyloid polypeptide (IAPP). In this issue of the
Dhananjay Gupta, Jack L. Leahy
JCI Impact is a digest of the research, reviews, and other features published in each month's issue of the Journal of Clinical Investigation.
The image shows sympathetic neurons (immunostained for tyrosine hydroxylase, red) extending axonal bundles along an artery (PECAM staining, blue), with sympathetic fibers surrounding and innervating arterial smooth muscle cells (smooth muscle actin staining, green). On page 3230, Brunet et al. uncover a critical role for the axon guidance cue netrin-1 in sympathetic arterial innervation and blood flow.
JCI Impact is a digest of the research, reviews, and other features published in each month's issue of the Journal of Clinical Investigation.
Nephrology encompasses the study of normal kidney function, kidney disease, and kidney replacement therapy, including kidney transplantation and dialysis. Kidney diseases are a serious public health problem, with nearly 12% of American adults suffering from chronic kidney disease (CKD). Importantly, kidney dysfunction is associated with the increasingly common conditions of obesity, diabetes, and hypertension. Recent technological advances, including genetic and epigenetic screens, metabolic profiling, new model systems, and the use of kidney biopsies for diagnosis and treatment, have created new avenues for the study of kidney pathology. Reviews in this series provide a survey of kidney pathogenesis, including hypertension, diabetic kidney disease, IgA nephropathy, idiopathic membranous nephropathy, acute kidney injury, fibrosis, and mechanisms mediating graft failure after transplantation.