Louis H Philipson

University of Illinois at Chicago, Chicago, Illinois, United States

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Publications (134)823.73 Total impact

  • Lee Ducat, Louis H Philipson, Barbara J Anderson
    JAMA The Journal of the American Medical Association 07/2014; · 29.98 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;
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    ABSTRACT: Ferrets are an important emerging model of cystic fibrosis related diabetes. However, there is little documented experience in the use of advanced techniques to quantify aspects of diabetes pathophysiology in the ferret. Glycemic clamps are the gold standard technique to assess both insulin sensitivity and insulin secretion in humans and animal models of diabetes. We therefore sought to develop techniques for glycemic clamps in ferrets. To assess insulin sensitivity, we performed euglycemic hyperinsulinemic clamps in 5-6 week old ferrets in the anesthetized and conscious states. To assess insulin secretion, we performed hyperglycemic clamps in conscious ferrets. To evaluate responsiveness of ferret islet and entero-insular hormones to low glucose, a portion of the hyperglycemic clamps were followed by a hypoglycemic clamp. The euglycemic hyperinsulinemic clamps demonstrated insulin responsiveness in ferrets similar to that previously observed in humans and rats. The anesthetic isoflurane induced marked insulin resistance, whereas lipid emulsion induced mild insulin resistance. In conscious ferrets, glucose appearance was largely suppressed at 4 mU/kg/min insulin infusion, whereas glucose disposal was progressively increased at 4 and 20 mU/kg/min insulin. Hyperglycemic clamp induced first phase insulin secretion. Hypoglycemia induced a rapid diminishment of insulin, as well as a rise in glucagon and pancreatic polypeptide levels. The incretins GLP-1 and GIP were affected minimally by hyperglycemic and hypoglycemic clamp. These techniques will prove useful in better defining the pathophysiology in ferrets with cystic fibrosis related diabetes.
    PLoS ONE 01/2014; 9(3):e90519. · 3.73 Impact Factor
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    ABSTRACT: β cell failure in type 2 diabetes (T2D) is associated with hyperglycemia, but the mechanisms are not fully understood. Congenital hyperinsulinism caused by glucokinase mutations (GCK-CHI) is associated with β cell replication and apoptosis. Here, we show that genetic activation of β cell glucokinase, initially triggering replication, causes apoptosis associated with DNA double-strand breaks and activation of the tumor suppressor p53. ATP-sensitive potassium channels (KATP channels) and calcineurin mediate this toxic effect. Toxicity of long-term glucokinase overactivity was confirmed by finding late-onset diabetes in older members of a GCK-CHI family. Glucagon-like peptide-1 (GLP-1) mimetic treatment or p53 deletion rescues β cells from glucokinase-induced death, but only GLP-1 analog rescues β cell function. DNA damage and p53 activity in T2D suggest shared mechanisms of β cell failure in hyperglycemia and CHI. Our results reveal membrane depolarization via KATP channels, calcineurin signaling, DNA breaks, and p53 as determinants of β cell glucotoxicity and suggest pharmacological approaches to enhance β cell survival in diabetes.
    Cell metabolism 12/2013; · 17.35 Impact Factor
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    ABSTRACT: Drosophila melanogaster has been widely used as models of human Mendelian disease, but its value in modeling complex disease has received little attention. Fly models of complex disease would enable high-resolution mapping of disease-modifying loci and the identification of novel targets for therapeutic intervention. Here, we describe a fly model of permanent neonatal diabetes mellitus and explore the complexity of this model. The approach involves the transgenic expression of a misfolded mutant of human preproinsulin, hINS(C96Y), which is a cause of permanent neonatal diabetes. When expressed in fly imaginal discs, hINS(C96Y) causes a reduction of adult structures, including the eye, wing and notum. Eye imaginal discs exhibit defects in both the structure and arrangement of ommatidia. In the wing, expression of hINS(C96Y) leads to ectopic expression of veins and mechano-sensory organs, indicating disruption of wild type signaling processes regulating cell fates. These readily measurable "disease" phenotypes are sensitive to temperature, gene dose and sex. Mutant (but not wild type) proinsulin expression in the eye imaginal disc induces IRE1-mediated XBP1 alternative splicing, a signal for endoplasmic reticulum (ER) stress response activation, and produces global change in gene expression. Mutant hINS transgene tester strains, when crossed to stocks from the Drosophila Genetic Reference Panel (DGRP) produce F1 adults with a continuous range of disease phenotypes and large broad-sense heritability. Surprisingly, the severity of mutant hINS-induced disease in the eye is not correlated with that in the notum in these crosses, nor with eye reduction phenotypes caused by the expression of two dominant eye mutants acting in two different eye development pathways, Drop (Dr) or Lobe (L) when crossed into the same genetic backgrounds. The tissue specificity of genetic variability for mutant hINS-induced disease has, therefore, its own distinct signature. The genetic dominance of disease-specific phenotypic variability in our model of misfolded human proinsulin makes this approach amenable to genome-wide association study (GWAS) in a simple F1 screen of natural variation.
    Genetics 11/2013; · 4.39 Impact Factor
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    ABSTRACT: Analyses of random walks traditionally use the mean square displacement (MSD) as an order parameter characterizing dynamics. We show that the distribution of relative angles of motion between successive time intervals of random walks in two or more dimensions provides information about stochastic processes beyond the MSD. We illustrate the behavior of this measure for common models and apply it to experimental particle tracking data. For a colloidal system, the distribution of relative angles reports sensitively on caging as the density varies. For transport mediated by molecular motors on filament networks in vitro and in vivo, we discover self-similar properties that cannot be described by existing models and discuss possible scenarios that can lead to the elucidated statistical features.
    Proceedings of the National Academy of Sciences 11/2013; · 9.74 Impact Factor
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    David Carmody, Louis Philipson
    The lancet. Diabetes & endocrinology. 11/2013; 1(3):167-8.
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    ABSTRACT: Neonatal diabetes mellitus is known to have over 20 different monogenic causes. A syndrome of permanent neonatal diabetes along with primary microcephaly with simplified gyral pattern associated with severe infantile epileptic encephalopathy was recently described in two independent reports in which disease-causing homozygous mutations were identified in the immediate early response-3 interacting protein-1 (IER3IP1) gene. We report here an affected male born to a non-consanguineous couple who was noted to have insulin-requiring permanent neonatal diabetes, microcephaly, and generalized seizures. He was also found to have cortical blindness, severe developmental delay and numerous dysmorphic features. He experienced a slow improvement but not abrogation of seizure frequency and severity on numerous anti-epileptic agents. His clinical course was further complicated by recurrent respiratory tract infections and he died at 8 years of age. Whole exome sequencing was performed on DNA from the proband and parents. He was found to be a compound heterozygote with two different mutations in IER3IP1: p.Val21Gly (V21G) and a novel frameshift mutation p.Phe27fsSer*25. IER3IP1 is a highly conserved protein with marked expression in the cerebral cortex and in beta cells. This is the first reported case of compound heterozygous mutations within IER3IP1 resulting in neonatal diabetes. The triad of microcephaly, generalized seizures, and permanent neonatal diabetes should prompt screening for mutations in IER3IP1. As mutations in genes such as NEUROD1 and PTF1A could cause a similar phenotype, next-generation sequencing approaches-such as exome sequencing reported here-may be an efficient means of uncovering a diagnosis in future cases.
    Pediatric Diabetes 10/2013; · 2.08 Impact Factor
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    ABSTRACT: Objective To evaluate the cost-effectiveness of a genetic testing policy for HNF1A, HNF4A and GCK-MODY in a hypothetical cohort of type 2 diabetes patients 25-40 years old with a MODY prevalence of 2%.Research Design and Methods We used a simulation model of type 2 diabetes complications based on UKPDS data, modified to account for the natural history of disease by genetic subtype, to compare a policy of genetic testing at diabetes diagnosis versus a policy of no testing. Under the screening policy, successful sulfonylurea treatment of HNF1A-MODY and HNF4A-MODY was modeled to produce a glycosylated hemoglobin reduction of -1.5%, compared to usual care. GCK-MODY received no therapy. Main outcome measures were costs and quality-adjusted life years (QALYs), based on lifetime risk of complications and treatments, expressed as the incremental cost-effectiveness ratio (ICER, $/QALY).ResultsThe testing policy yielded an average gain of 0.012 QALYs and resulted in an ICER of $205,000. Sensitivity analysis showed that if the MODY prevalence was 6%, the ICER would be ∼$50,000. If MODY prevalence was >30%, the testing policy was cost-saving. Reducing genetic testing costs to $700 also resulted in an ICER of ∼$50,000.Conclusions Our simulated model suggests a policy of testing for MODY in selected populations is cost-effective for the United States based on contemporary ICER thresholds. Higher prevalence of MODY in the tested population or decreased testing costs would enhance cost-effectiveness. Our results make a compelling argument for routine coverage of genetic testing in patients with high clinical suspicion of MODY.
    Diabetes care 09/2013; · 7.74 Impact Factor
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    ABSTRACT: Here we use Drosophila melanogaster to create a genetic model of human permanent neonatal diabetes mellitus and present experimental results describing dimensions of this complexity. The approach involves the transgenic expression of a misfolded mutant of human preproinsulin, hINSC96Y, which is a cause of the disease. When expressed in fly imaginal discs, hINSC96Y causes a reduction of adult structures, including the eye, wing and notum. Eye imaginal discs exhibit defects in both the structure and arrangement of ommatidia. In the wing, expression of hINSC96Y leads to ectopic expression of veins and mechano-sensory organs, indicating disruption of wild type signaling processes regulating cell fates. These readily measurable disease phenotypes are sensitive to temperature, gene dose and sex. Mutant (but not wild type) proinsulin expression in the eye imaginal disc induces IRE1-mediated Xbp1 alternative splicing, a signal for endoplasmic reticulum stress response activation, and produces global change in gene expression. Mutant hINS transgene tester strains, when crossed to stocks from the Drosophila Genetic Reference Panel produces F1 adults with a continuous range of disease phenotypes and large broad-sense heritability. Surprisingly, the severity of mutant hINS-induced disease in the eye is not correlated with that in the notum in these crosses, nor with eye reduction phenotypes caused by the expression of two dominant eye mutants acting in two different eye development pathways, Drop (Dr) or Lobe (L) when crossed into the same genetic backgrounds. The tissue specificity of genetic variability for mutant hINS-induced disease thus has its own distinct signature. The genetic dominance of disease-specific phenotypic variability makes this approach amenable to genome-wide association study (GWAS) in a simple F1 screen of natural variation.
    05/2013;
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    ABSTRACT: The human insulin gene/preproinsulin protein mutation C43G disrupts disulfide bond formation and causes diabetes in humans. Previous in vitro studies showed that these mutant proteins are retained in the endoplasmic reticulum (ER), are not secreted and are associated with decreased secretion of wild-type insulin. The current study extends this work to an in vivo zebrafish model. We hypothesized that C43G-green fluorescent protein (GFP) would be retained in the ER, disrupt β-cell function and lead to impaired glucose homeostasis.
    Journal of diabetes investigation. 03/2013; 4(2):157-67.
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    ABSTRACT: We quantitatively analyzed particle tracking data on insulin granules expressing fluorescent fusion proteins in MIN6 cells to better understand the motions contributing to intracellular transport and, more generally, the means for characterizing systems far from equilibrium. Care was taken to ensure that the statistics reflected intrinsic features of the individual granules rather than details of the measurement and overall cell state. We find anomalous diffusion. Interpreting such data conventionally requires assuming that a process is either ergodic with particles working against fluctuating obstacles (fractional Brownian motion) or nonergodic with a broad distribution of dwell times for traps (continuous-time random walk). However, we find that statistical tests based on these two models give conflicting results. We resolve this issue by introducing a subordinated scheme in which particles in cages with random dwell times undergo correlated motions owing to interactions with a fluctuating environment. We relate this picture to the underlying microtubule structure by imaging in the presence of vinblastine. Our results provide a simple physical picture for how diverse pools of insulin granules and, in turn, biphasic secretion could arise.
    Proceedings of the National Academy of Sciences 03/2013; · 9.74 Impact Factor
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    ABSTRACT: Acute insulin secretion determines the efficiency of glucose clearance. Moreover, impaired acute insulin release is characteristic of reduced glucose control in the prediabetic state. Incretin hormones, which increase β-cell cAMP, restore acute phase insulin secretion and improve glucose control. To determine the physiological role of the cAMP-dependent protein kinase (PKA), a mouse model was developed to increase PKA activity specifically in the pancreatic β-cells. In response to sustained hyperglycemia, PKA activity potentiated both acute and sustained insulin release. In contrast, a glucose bolus enhanced acute phase insulin secretion alone. Acute phase insulin secretion was increased 3.5-fold, reducing circulating glucose to 58% of levels in controls. Exendin-4 increased acute phase insulin release to a similar degree as PKA activation. However, incretins did not augment the effects of PKA on acute phase insulin secretion, consistent with incretins acting primarily via PKA to potentiate acute phase insulin secretion. Intracellular calcium signaling was unaffected by PKA activation, suggesting that the effects of PKA on acute phase insulin secretion are mediated by the phosphorylation of proteins involved in β-cell exocytosis. Thus, β-cell PKA activity transduces the cAMP signal to dramatically increase acute phase insulin secretion, thereby enhancing the efficiency of insulin to control circulating glucose.
    Diabetes 01/2013; · 7.90 Impact Factor
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    ABSTRACT: In mammals an increase in glucose leads to block of ATP dependent potassium channels in pancreatic β cells leading to membrane depolarization. This leads to the repetitive firing of action potentials that increases calcium influx and triggers insulin granule exocytosis. Several important differences between species in this process suggest that a dedicated human-oriented approach is advantageous as extrapolating from rodent data may be misleading in several respects. We examined depolarization-induced spike activity in pancreatic human islet-attached β-cells employing whole-cell patch-clamp methods. We also reviewed the literature concerning regulation of insulin secretion by channel activity and constructed a data-based computer model of human β cell function. The model couples the Hodgkin-Huxley-type ionic equations to the equations describing intracellular Ca ( 2+) homeostasis and insulin release. On the basis of this model we employed computational simulations to better understand the behavior of action potentials, calcium handling and insulin secretion in human β cells under a wide range of experimental conditions. This computational system approach provides a framework to analyze the mechanisms of human β cell insulin secretion.
    Islets 01/2013; 5(1):1-15. · 1.55 Impact Factor
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    Leonid E Fridlyand, Louis H Philipson
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    ABSTRACT: Glucagon, a peptide hormone secreted from the α-cells of the pancreatic islets, is critical for blood glucose homeostasis. We reviewed the literature and employed a computational systems analysis of intracellular metabolic and electrical regulation of glucagon secretion to better understand these processes. The mathematical model of α-cell metabolic parameters is based on our previous model for pancreatic β-cells. We also formulated an ionic model for action potentials that incorporates Ca ( 2+) , K (+) , Na (+) and Cl (-) currents. Metabolic and ionic models are coupled to the equations describing Ca ( 2+) homeostasis and glucagon secretion that depends on activation of specific voltage-gated Ca ( 2+) channels. Paracrine and endocrine regulations were analyzed with an emphasis on their effects on a hyperpolarization of membrane potential. This general model simulates and gives insight into the mechanisms of regulation of glucagon secretion under a wide range of experimental conditions. We also reviewed and analyzed dysfunctional mechanisms in α-cells to determine key pharmacological targets for modulating glucagon secretion in type 1 and 2 diabetes.
    Islets 07/2012; 4(4). · 1.55 Impact Factor
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    ABSTRACT: Glucagon-like peptide-1 (GLP-1)-based incretin therapy is becoming central to the treatment of type 2 diabetes. Activation of incretin hormone receptors results in rapid elevation of cAMP followed by enhanced insulin secretion. However, the incretin effect may be significantly impaired in diabetes. The objective of this study is to investigate downregulation of GLP-1 signaling by small ubiquitin-related modifier protein (SUMO). Mouse islets exposed to high glucose showed increased expression of endogenous SUMO transcripts and its conjugating enzyme Ubc-9. Overexpression of SUMO-1 in mouse insulinoma 6 (MIN6) cells and primary mouse β-cells resulted in reduced static and real-time estimates of intracellular cAMP upon receptor stimulation with exendin-4, a GLP-1 receptor (GLP-1R) agonist. GLP1-R was covalently modified by SUMO. Overexpression of SUMO-1 attenuated cell surface trafficking of GLP-1R, which resulted in significantly reduced insulin secretion when stimulated by exendin-4. Partial knock down of SUMO-conjugating enzyme Ubc-9 resulted in enhanced exendin-4-stimulated insulin secretion in mouse islets exposed to high glucose. Thus, SUMO modification of the GLP-1R could be a contributing factor to reduced incretin responsiveness. Elucidating mechanisms of GLP-1R regulation by sumoylation will help improve our understanding of incretin biology and of GLP-1-based treatment of type 2 diabetes.
    AJP Endocrinology and Metabolism 01/2012; 302(6):E714-23. · 4.51 Impact Factor
  • Biophysical Journal 01/2012; 102(3):378-. · 3.67 Impact Factor
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    ABSTRACT: There has been major progress in recent years uncovering the genetic causes of diabetes presenting in the first year of life. Twenty genes have been identified to date. The most common causes accounting for the majority of cases are mutations in the genes encoding the two subunits of the ATP-sensitive potassium channel (K(ATP)), KCNJ11 and ABCC8, and the insulin gene (INS), as well as abnormalities in chromosome 6q24. Patients with activating mutations in KCNJ11 and ABCC8 can be treated with oral sulfonylureas in lieu of insulin injections. This compelling example of personalized genetic medicine leading to improved glucose regulation and quality of life may-with continued research-be repeated for other forms of neonatal diabetes in the future.
    Current Diabetes Reports 12/2011; 11(6):519-32. · 3.17 Impact Factor
  • Leonid E Fridlyand, Louis H Philipson
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    ABSTRACT: Insulin secretory responses to nutrient stimuli and hormonal modulators in pancreatic beta-cells are controlled by a variety of secondary messengers. We have analyzed numerous mechanisms responsible for regulated exocytosis in these cells and present an integrated mathematical model of cytosolic Ca²⁺, cAMP and granule dynamics. The insulin-containing granules in the beta-cell were divided into four classes: a large "reserve" granule pool, a smaller pool of the morphologically docked granules that is chemically 'primed' for release or the "readily releasable pool", and a pool of "restless newcomer granules" that undergoes preferential exocytosis. The model incorporates glucose and other aspects of metabolism, the cAMP amplifying pathway, insulin granule dynamics and the exocyst concept for granule binding. The values of most of the model parameters were inferred from available experimental data. The model can generate both the fast first phase and slow biphasic insulin secretion found experimentally in response to a step increase of membrane potential or of glucose. The numerical simulations have also reproduced a variety of experimental conditions, such as periodic stimulation by high K⁺ and the potentiation induced in islets by pre-incubation with cAMP pathway activators. The explicit incorporation of Ca²⁺ channels, Ca²⁺ and cAMP dynamics allows the model to be further connected to current models for calcium and metabolic dynamics and provides an interpretation of the roles of the triggering and amplifying pathways of glucose-stimulated insulin secretion. The model may be important in the identification of pharmacological targets for improving insulin secretion in type 2 diabetes.
    Progress in Biophysics and Molecular Biology 09/2011; 107(2):293-303. · 2.91 Impact Factor
  • Rochelle Naylor, Louis H Philipson
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    ABSTRACT: Maturity-onset diabetes of the young (MODY) is a clinically heterogeneous group of monogenic disorders characterized by autosomal dominant inheritance of young-onset, non-insulin-dependent diabetes. The genes involved are important in beta cell development, function and regulation and lead to disorders in glucose sensing and insulin secretion. Heterozygous GCK mutations cause impaired glucokinase activity resulting in stable, mild hyperglycaemia that rarely requires treatment. HNF1A mutations cause a progressive insulin secretory defect that is sensitive to sulphonylureas, most often resulting in improved glycaemic control compared with other diabetes treatment. MODY owing to mutations in the HNF4A gene results in a similar phenotype, including sensitivity to sulphonylurea treatment. HNF1B mutations most frequently cause developmental renal disease (particularly renal cysts) but may also cause MODY in isolation or may cause the renal cysts and diabetes syndrome (RCAD syndrome). Mutations in NEUROD1, PDX1 (IPF1), CEL and INS are rare causes of MODY. MODY is often misdiagnosed as type 1 or type 2 diabetes. However, a correct genetic diagnosis impacts treatment and identifies at-risk family members. Thus, it is important to consider a diagnosis of MODY in appropriate individuals and to pursue genetic testing to establish a molecular diagnosis.
    Clinical Endocrinology 03/2011; 75(4):422-6. · 3.40 Impact Factor

Publication Stats

3k Citations
823.73 Total Impact Points

Institutions

  • 1993–2014
    • University of Illinois at Chicago
      • • Department of Medicine (Chicago)
      • • Department of Neurology and Rehabilitation (Chicago)
      Chicago, Illinois, United States
  • 1991–2014
    • University of Chicago
      • • Department of Medicine
      • • Department of Pediatrics
      • • Committee on Neurobiology
      Chicago, Illinois, United States
  • 2013
    • The University of Chicago Medical Center
      • Section of Pediatric Endocrinology
      Chicago, Illinois, United States
  • 2010–2011
    • Aarhus University Hospital
      • Department of Endocrinology and Internal Medicine
      Århus, Central Jutland, Denmark
    • Vanderbilt University
      • Department of Molecular Physiology and Biophysics
      Nashville, MI, United States
  • 2001
    • Leidos Biomedical Research
      Maryland, United States
  • 1991–2001
    • Howard Hughes Medical Institute
      Maryland, United States