Louis H Philipson

University of Chicago, Chicago, Illinois, United States

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Publications (162)1049.42 Total impact

  • Endocrinology: Adult and Pediatric, 01/2016: pages 527-545.e6; , ISBN: 9780323189071
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    Fan Fan · Chen Ji · Yumei Wu · Shawn M Ferguson · Natalia Tamarina · Louis H Philipson · Xuelin Lou ·
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    ABSTRACT: Alterations in insulin granule exocytosis and endocytosis are paramount to pancreatic β cell dysfunction in diabetes mellitus. Here, using temporally controlled gene ablation specifically in β cells in mice, we identified an essential role of dynamin 2 GTPase in preserving normal biphasic insulin secretion and blood glucose homeostasis. Dynamin 2 deletion in β cells caused glucose intolerance and substantial reduction of the second phase of glucose-stimulated insulin secretion (GSIS); however, mutant β cells still maintained abundant insulin granules, with no signs of cell surface expansion. Compared with control β cells, real-time capacitance measurements demonstrated that exocytosis-endocytosis coupling was less efficient but not abolished; clathrin-mediated endocytosis (CME) was severely impaired at the step of membrane fission, which resulted in accumulation of clathrin-coated endocytic intermediates on the plasma membrane. Moreover, dynamin 2 ablation in β cells led to striking reorganization and enhancement of actin filaments, and insulin granule recruitment and mobilization were impaired at the later stage of GSIS. Together, our results demonstrate that dynamin 2 regulates insulin secretory capacity and dynamics in vivo through a mechanism depending on CME and F-actin remodeling. Moreover, this study indicates a potential pathophysiological link between endocytosis and diabetes mellitus.
    The Journal of clinical investigation 09/2015; DOI:10.1172/JCI80652 · 13.22 Impact Factor
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    ABSTRACT: The tumor suppressor Liver Kinase B1 (LKB1) is an important regulator of pancreatic β cell biology. LKB1-dependent phosphorylation of distinct AMPK family members determines proper β cell polarity and restricts β cell size, total β cell mass and glucose-stimulated insulin secretion (GSIS). However the full spectrum of LKB1 effects and the mechanisms involved in the secretory phenotype remains incompletely understood. We report here that in the absence of LKB1 in β cells, GSIS is dramatically and persistently improved. The enhancement is seen both in vivo and in vitro, and cannot be explained by altered cell polarity, increased β cell number or increased insulin content. Increased secretion does require membrane depolarization and calcium influx, but appears to rely mostly on a distal step in the secretion pathway. Surprisingly, enhanced GSIS is seen despite profound defects in mitochondrial structure and function in LKB1-deficient β cells, expected to greatly diminish insulin secretion via the classic triggering pathway. Thus LKB1 is essential for mitochondrial homeostasis in β cells, and in parallel is a powerful negative regulator of insulin secretion. This study shows that β cells can be manipulated to enhance GSIS to supra-normal levels even in the face of defective mitochondria, and without deterioration over months. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 07/2015; DOI:10.1074/jbc.M115.639237 · 4.57 Impact Factor
  • Marie E. Perrone · David Carmody · Louis H. Philipson · Siri Atma W. Greeley ·
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    ABSTRACT: Many online support groups are available for patients with rare disorders, but scant evidence is available on how effectively such groups provide useful information or valuable psychosocial support to their participants. It is also unclear to what extent physicians and researchers may learn more about these disorders by participating in such groups. To formally assess the utility of the Kovler Monogenic Diabetes Registry online discussion group for patients and families affected by KATP channel-related monogenic neonatal diabetes in providing psychosocial and informational support and in identifying concerns unique to patients with this rare form of diabetes. We qualitatively analyzed all 1,410 messages from the online group that consisted of 64 participants affected by KATP channel monogenic diabetes and 11 researchers. We utilized the Social Behavior Support Code to assign each message to a support category and deductive thematic analysis to identify discussion topics addressed by each message. 44% of messages provided/requested informational support, whereas 31.4% of the messages contained psychosocial/emotional support. The most popular topics of postings to the forums were diabetes treatment (503 messages) and neurodevelopmental concerns (472 messages). Participation in the discussion led researchers to modify survey instruments and design new studies focusing on specific topics of concern, such as sleep. We demonstrate that an online support group for a monogenic form of diabetes is an effective informational tool that also provides psychosocial support. Participation by researchers and care providers can inform future research directions and highlight issues of patient concern. Copyright © 2015 Elsevier Inc. All rights reserved.
    06/2015; 166(5). DOI:10.1016/j.trsl.2015.06.013
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    ABSTRACT: Diabetes in neonates usually has a monogenic aetiology; however, the cause remains unknown in 20-30%. Heterozygous INS mutations represent one of the most common gene causes of neonatal diabetes mellitus. Clinical and functional characterisation of a novel homozygous intronic mutation (c.187+241G>A) in the insulin gene in a child identified through the Monogenic Diabetes Registry (http://monogenicdiabetes.uchicago.edu). The proband had insulin-requiring diabetes from birth. Ultrasonography revealed a structurally normal pancreas and C-peptide was undetectable despite readily detectable amylin, suggesting the presence of dysfunctional β cells. Whole-exome sequencing revealed the novel mutation. In silico analysis predicted a mutant mRNA product resulting from preferential recognition of a newly created splice site. Wild-type and mutant human insulin gene constructs were derived and transiently expressed in INS-1 cells. We confirmed the predicted transcript and found an additional transcript created via an ectopic splice acceptor site. Dominant INS mutations cause diabetes via a mutated translational product causing endoplasmic reticulum stress. We describe a novel mechanism of diabetes, without β cell death, due to creation of two unstable mutant transcripts predicted to undergo nonsense and non-stop-mediated decay, respectively. Our discovery may have broader implications for those with insulin deficiency later in life. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Journal of Medical Genetics 06/2015; 52(9). DOI:10.1136/jmedgenet-2015-103220 · 6.34 Impact Factor
  • David Carmody · Rochelle N Naylor · Louis H Philipson ·
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    ABSTRACT: IMPORTANCE: The standard recommended dose (0.1 U/kg per hour) of insulin in diabetic ketoacidosis (DKA) guidelines is not backed by strong clinical evidence. Physiologic dose-effect studies have found that even lower doses could adequately normalize ketonemia and acidosis. Lowering the insulin dose may be advantageous in the initial hours of therapy when a gradual decrease in glucose, electrolytes, and resultant osmolality is desired. OBJECTIVE: To compare the efficacy and safety of low-dose insulin against the standard dose in children with DKA. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective, open-label randomized clinical trial conducted in the pediatric emergency department and intensive care unit of a tertiary care teaching hospital in northern India from November 1, 2011, through December 31, 2012. A total of 50 consecutive children 12 years or younger with a diagnosis of DKA were randomized to low-dose(n = 25) and standard-dose (n = 25) groups. INTERVENTIONS: Low-dose (0.05 U/kg per hour) vs standard-dose (0.1 U/kg per hour) insulin infusion. MAINOUTCOMES ANDMEASURES: The primary outcome was the rate of decrease in blood glucose until a level of 250 mg/dL or less is reached (to convert to millimoles per liter, multiply by 0.0555). The secondary outcomes included time to resolution of acidosis, episodes of treatment failures, and incidences of hypokalemia and hypoglycemia. RESULTS: The mean (SD) rate of blood glucose decrease until a level of 250 mg/dL or less is reached (45.1 [17.6] vs 52.2 [23.4] mg/dL/h) and the mean (SD) time taken to achieve this target (6.0 [3.3] vs 6.2 [2.2] hours) were similar in the low- and standard-dose groups, respectively. Mean (SD) length of time to achieve resolution of acidosis (low vs standard dose: 16.5 [7.2] vs 17.2 [7.7] hours; P = .73) and rate of resolution of acidosis were also similar in the groups. Hypokalemia was seen in 12 children (48%) receiving the standard dose vs 5 (20%) of those receiving the low dose (P = .07); the tendency was more pronounced in malnourished children (7 [88%] vs 2 [28%]). Five children (20%) and 1 child (4%) receiving standard- and low-dose infusion (P = .17), respectively, developed hypoglycemia. Treatment failure was rare and comparable. One child in the standard-dose group developed cerebral edema, and no deaths occurred during the study period. CONCLUSIONS AND RELEVANCE: Low dose is noninferior to standard dose with respect to rate of blood glucose decrease and resolution of acidosis. We advocate a superiority trial with a larger sample size before 0.05 U/kg per hour replaces 0.1 U/kg per hour in the practice recommendations.
    Journal of the American Medical Association 06/2015; 313(22):2274-2275. DOI:10.1001/jama.2015.135.
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    Diabetes care 06/2015; 38(6):e86-7. DOI:10.2337/dc14-3056 · 8.42 Impact Factor
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    ABSTRACT: Individuals with heterozygous activating mutations of the KCNJ11 gene encoding a subunit of the ATP-sensitive potassium channel (KATP) can usually be treated with oral sulfonylurea (SU) pills in lieu of insulin injections. The aim of this study was to test our hypothesis that younger age at the time of initiation of SU therapy is correlated with lower required doses of SU therapy, shorter transition time and decreased likelihood of requiring additional diabetes medications. We performed a retrospective cohort study using data on 58 individuals with neonatal diabetes due to KCNJ11 mutations identified through the University of Chicago Monogenic Diabetes Registry ( http://monogenicdiabetes.uchicago.edu/registry ). We assessed the influence of age at initiation of SU therapy on treatment outcomes. HbA1c fell from an average of 8.5% (69 mmol/mol) before transition to 6.2% (44 mmol/mol) after SU therapy (p < 0.001). Age of initiation of SU correlated with the dose (mg kg(-1) day(-1)) of SU required at follow-up (r = 0.80, p < 0.001). Similar associations were observed across mutation subtypes. Ten participants required additional glucose-lowering medications and all had initiated SU at age 13 years or older. No serious adverse events were reported. Earlier age at initiation of SU treatment is associated with improved response to SU therapy. Declining sensitivity to SU may be due to loss of beta cell mass over time in those treated with insulin. Our data support the need for early genetic diagnosis and appropriate personalised treatment in all cases of neonatal diabetes.
    Diabetologia 04/2015; 58(7). DOI:10.1007/s00125-015-3593-9 · 6.67 Impact Factor
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    ABSTRACT: Glucagon-like peptide 1 (GLP-1) enhances insulin secretion and protects β-cell mass. Diabetes therapies targeting the GLP-1 receptor (GLP-1R), expressed in numerous tissues, have diminished dose-response in patients with type 2 diabetes compared with healthy human controls. The aim of this study was to determine the mechanistic causes underlying the reduced efficacy of GLP-1R ligands. Using primary mouse islets and the β-cell line MIN6, outcomes downstream of the GLP-1R were analyzed: Insulin secretion; phosphorylation of the cAMP-response element binding protein (CREB); cAMP responses. Signaling systems were studied by immunoblotting and qRT-PCR, and PKA activity was assayed. Cell surface localization of the GLP-1R was studied by confocal microscopy using a fluorescein-tagged exendin-4 and GFP-tagged GLP-1R. Rodent β-cells chronically exposed to high glucose had diminished responses to GLP-1R agonists including: diminished insulin secretory response; reduced phosphorylation of (CREB); impaired cAMP response, attributable to chronically increased cAMP levels. GLP-1R signaling systems were affected by hyperglycemia with increased expression of mRNAs encoding the inducible cAMP early repressor (ICER) and adenylyl cyclase 8, reduced PKA activity due to increased expression of the PKA-RIα subunit, reduced GLP-1R mRNA expression and loss of GLP-1R from the cell surface. To specifically examine the loss of GLP-1R from the plasma membrane a GLP-1R-GFP fusion protein was employed to visualize subcellular localization. Under low glucose conditions or when PKA activity was inhibited, GLP-1R-GFP was found at the plasma membrane. Conversely high glucose, expression of a constitutively active PKA subunit, or exposure to exendin-4 or forskolin led to GLP-1R-GFP internalization. Mutation of serine residue 301 of the GLP-1R abolished the glucose-dependent loss of the receptor from the plasma membrane. This was associated with a loss of an interaction between the receptor and the small ubiquitin-related modifier (SUMO), an interaction that was found to be necessary for internalization of the receptor. These data show that glucose acting, at least in part, via PKA leads to the loss of the GLP-1R from the cell surface and an impairment of GLP-1R signaling, which may underlie the reduced clinical efficacy of GLP-1R based therapies in individuals with poorly controlled hyperglycemia.
    Molecular Metabolism 02/2015; 4(4). DOI:10.1016/j.molmet.2015.01.010
  • Lee Ducat · Arthur Rubenstein · Louis H Philipson · Barbara J Anderson ·
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    ABSTRACT: Individuals with type 1 diabetes are at increased risk for depression, anxiety disorder, and eating disorder diagnoses. People with type 1 diabetes are also at risk for subclinical levels of diabetes distress and anxiety. These mental/behavioral health comorbidities of diabetes are associated with poor adherence to treatment and poor glycemic control, thus increasing the risk for serious short- and long-term physical complications, which can result in blindness, amputations, stroke, cognitive decline, decreased quality of life, as well as premature death. When mental health comorbidities of diabetes are not diagnosed and treated, the financial cost to society and health care systems is catastrophic, and the human suffering that results is profound. This review summarizes state-of-the-art presentations and working group scholarly reports from the Mental Health Issues of Diabetes Conference (7-8 October 2013, Philadelphia, PA), which included stakeholders from the National Institutes of Health, people living with type 1 diabetes and their families, diabetes consumer advocacy groups, the insurance industry, as well as psychologists, psychiatrists, endocrinologists, and nurse practitioners who are all nationally and internationally recognized experts in type 1 diabetes research and care. At this landmark conference current evidence for the incidence and the consequences of mental health problems in type 1 diabetes was presented, supporting the integration of mental health screening and mental health care into routine diabetes medical care. Future research directions were recommended to establish the efficacy and cost-effectiveness of paradigms of diabetes care in which physical and mental health care are both priorities. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes Care 02/2015; 38(2):333-338. DOI:10.2337/dc14-1383 · 8.42 Impact Factor
  • Leonid E. Fridlyand · Louis H. Philipson ·

    Biophysical Journal 01/2015; 108(2):104a. DOI:10.1016/j.bpj.2014.11.593 · 3.97 Impact Factor
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    Louis H Philipson · Graeme Bell · Kenneth S Polonsky ·

    Proceedings of the National Academy of Sciences 01/2015; 112(4). DOI:10.1073/pnas.1423774112 · 9.67 Impact Factor
  • Colin A. Leech · Richard F. Kopp · Louis H. Philipson · Michael W. Roe ·
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    ABSTRACT: Signaling molecules produced in the pancreatic β-cell following mitochondrial oxidation of glycolytic intermediate metabolites and oxidative phosphorylation trigger Ca2+-dependent signaling pathways that regulate insulin exocytosis. Much is known about ATP-sensitive K+ and voltage-gated Ca2+ currents that contribute to Ca2+-dependent signal transduction in β-cells and insulin secretion, but relatively little is known about other Ca2+ channels that regulate β-cell Ca2+ signaling dynamics and insulin secretion. In a wide range of eukaryotic cells, store-operated Ca2+ entry (SOCE) plays a critical role regulating spatial and temporal changes in cytoplasmic Ca2+ concentration, endoplasmic reticulum (ER) Ca2+ homeostasis, gene expression, protein biosynthesis, and cell viability. Although SOCE has been proposed to play important roles in β-cell Ca2+ signaling and insulin secretion, the underlying molecular mechanisms remain undefined. In this chapter, we provide both an overview of our current understanding of ionic currents regulated by ER Ca2+ stores in insulin-secreting cells and a review of studies in other cell systems that have identified the molecular basis and regulation of SOCE.
    Islets of Langerhans, 01/2015: pages 337-368; , ISBN: 978-94-007-6685-3
  • Lee J Ducat · Louis H Philipson · Barbara J Anderson ·

    JAMA The Journal of the American Medical Association 12/2014; 312(22):2413. DOI:10.1001/jama.2014.14778 · 35.29 Impact Factor
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    ABSTRACT: The physiological role of serotonin in pancreatic β cell function was previously elucidated using a pregnant mouse model. During pregnancy, 5-HT (5-Hydroxytryptamine, serotonin) increases β cell proliferation and glucose-stimulated insulin secretion through the Gαq-coupled 5-HT2b receptor (Htr2b) and the 5-HT3 receptor (Htr3), a ligand-gated cation channel, respectively. However, the role of 5-HT in β cell function in an insulin-resistant state has yet to be elucidated. Here, we characterized the metabolic phenotypes of β cell-specific Htr2b(-/-) (Htr2b βKO), Htr3a(-/-) (Htr3a KO) and β cell-specific Tph1(-/-) (Tph1 βKO) mice on a high-fat diet (HFD). Htr2b βKO, Htr3a KO and Tph1 βKO mice exhibited normal glucose tolerance on a standard chow diet (SCD). After 6 weeks on an HFD, beginning at 4 weeks of age, both Htr3a KO and Tph1 βKO mice developed glucose intolerance, but Htr2b βKO mice remained normoglycemic. Pancreas perfusion assays revealed defective first phase insulin secretion in Htr3a KO mice. Glucose-stimulated insulin secretion (GSIS) was impaired in islets isolated from HFD-fed Htr3a KO and Tph1 βKO mice, and 5-HT treatment improved insulin secretion from Tph1 βKO islets but not from Htr3a KO islets. Tph1 and Htr3a gene expression in pancreatic islets was not affected by an HFD, and immunostaining could not detect 5-HT in pancreatic islets from mice fed an HFD. Taken together, these results demonstrate that basal 5-HT levels in β cells play a role in glucose-stimulated insulin secretion through Htr3, which becomes more evident in a diet-induced insulin-resistant state.
    Endocrinology 11/2014; 156(2):en20141687. DOI:10.1210/en.2014-1687 · 4.50 Impact Factor
  • Celeste C. Thomas · Louis H. Philipson ·
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    ABSTRACT: Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The goal in diagnosing diabetes mellitus is to identify those with significantly increased premature mortality and increased risk of microvascular and cardiovascular complications. This brief review shows the evolving nature of the classification of diabetes mellitus. No classification scheme is ideal, and all have some overlap and inconsistencies. Diabetes mellitus classification will continue to evolve as we work to fully understand the pathogenesis of the major forms. Copyright © 2015 Elsevier Inc. All rights reserved.
    Medical Clinics of North America 11/2014; 99(1). DOI:10.1016/j.mcna.2014.08.015 · 2.61 Impact Factor
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    ABSTRACT: Context: Diabetes in neonates nearly always has a monogenic etiology. Earlier sulfonylurea therapy can improve glycemic control and potentially neurodevelopmental outcomes in children with KCNJ11 or ABCC8 mutations, the most common gene causes. Objective: Assess the risks and benefits of initiating sulfonylurea therapy before genetic testing results become available. Design, Setting, and Patients: Observational retrospective study of subjects with neonatal diabetes within the University of Chicago Monogenic Diabetes Registry ( http://monogenicdiabetes.uchicago.edu/registry/ ). Main Outcome Measures: Response to sulfonylurea (determined by whether insulin could be discontinued) and treatment side effects in those treated empirically. Results: 154 subjects were diagnosed with diabetes before 6 months of age. A genetic diagnosis had been determined in 118 (77%), with 73 (47%) having a mutation in KCNJ11 or ABCC8. The median time from clinical diagnosis to genetic diagnosis was 10.4 weeks (range 1.6 to 58.2 weeks). In nine probands, an empiric sulfonylurea trial was initiated within 28 days of diabetes diagnosis. A genetic cause was subsequently found in eight cases and insulin was discontinued within 14 days of sulfonylurea initiation in all of these cases. Conclusions: Sulfonylurea therapy appears to be safe and often successful in neonatal diabetes patients before genetic testing results are available; however, larger numbers of cases must be studied. Given the potential beneficial effect on neurodevelopmental outcome, glycemic control and the current barriers to expeditious acquisition of genetic testing, an empiric inpatient trial of sulfonylurea can be considered. However, obtaining a genetic diagnosis remains imperative to inform long-term management and prognosis.
    Journal of Clinical Endocrinology &amp Metabolism 09/2014; 99(12):jc20142494. DOI:10.1210/jc.2014-2494 · 6.21 Impact Factor
  • Lee Ducat · Louis H Philipson · Barbara J Anderson ·

    JAMA The Journal of the American Medical Association 07/2014; 312(7). DOI:10.1001/jama.2014.8040 · 35.29 Impact Factor
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    ABSTRACT: Insulin resistance, hyperinsulinemia, and hyperproinsulinemia occur early in the pathogenesis of type 2 diabetes (T2D). Elevated levels of proinsulin and proinsulin intermediates are markers of β-cell dysfunction and are strongly associated with development of T2D in humans. However, the mechanism(s) underlying β-cell dysfunction leading to hyperproinsulinemia is poorly understood. Here, we show that disruption of insulin receptor (IR) expression in β cells has a direct impact on the expression of the convertase enzyme carboxypeptidase E (CPE) by inhibition of the eukaryotic translation initiation factor 4 gamma 1 translation initiation complex scaffolding protein that is mediated by the key transcription factors pancreatic and duodenal homeobox 1 and sterol regulatory element-binding protein 1, together leading to poor proinsulin processing. Reexpression of IR or restoring CPE expression each independently reverses the phenotype. Our results reveal the identity of key players that establish a previously unknown link between insulin signaling, translation initiation, and proinsulin processing, and provide previously unidentified mechanistic insight into the development of hyperproinsulinemia in insulin-resistant states.
    Proceedings of the National Academy of Sciences 06/2014; 111(22):E2319-28. DOI:10.1073/pnas.1323066111 · 9.67 Impact Factor
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    ABSTRACT: Glucagon-like peptide-1 (GLP-1), an insulinotropic gut peptide released after eating, is essential for normal glucose tolerance (GT). To determine whether this effect is mediated directly by GLP-1 receptors (GLP1R) on islet β cells, we developed mice with β cell-specific knockdown of Glp1r. β cell Glp1r knockdown mice had impaired GT after intraperitoneal (i.p.) glucose and did not secrete insulin in response to i.p. or intravenous GLP-1. However, they had normal GT after oral glucose, a response that was impaired by a GLP1R antagonist. β cell Glp1r knockdown mice had blunted responses to a GLP1R agonist but intact glucose lowering with a dipeptidylpeptidase 4 (DPP-4) inhibitor. Thus, in mice, β cell Glp1rs are required to respond to hyperglycemia and exogenous GLP-1, but other factors compensate for reduced GLP-1 action during meals. These results support a role for extraislet GLP1R in oral glucose tolerance and paracrine regulation of β cells by islet GLP-1.
    Cell metabolism 05/2014; 19(6). DOI:10.1016/j.cmet.2014.04.005 · 17.57 Impact Factor

Publication Stats

5k Citations
1,049.42 Total Impact Points


  • 1991-2015
    • University of Chicago
      • • Department of Medicine
      • • Section of Endocrinology, Diabetes and Metabolism
      • • Department of Surgery
      Chicago, Illinois, United States
  • 2006
    • University of Illinois at Chicago
      • Division of Transplantation
      Chicago, Illinois, United States