Publications by authors named "Louis H Philipson"

116 Publications

Monogenic Diabetes: From Genetic Insights to Population-Based Precision in Care. Reflections From a Editors' Expert Forum.

Diabetes Care 2020 12;43(12):3117-3128

Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K.

Individualization of therapy based on a person's specific type of diabetes is one key element of a "precision medicine" approach to diabetes care. However, applying such an approach remains difficult because of barriers such as disease heterogeneity, difficulties in accurately diagnosing different types of diabetes, multiple genetic influences, incomplete understanding of pathophysiology, limitations of current therapies, and environmental, social, and psychological factors. Monogenic diabetes, for which single gene mutations are causal, is the category most suited to a precision approach. The pathophysiological mechanisms of monogenic diabetes are understood better than those of any other form of diabetes. Thus, this category offers the advantage of accurate diagnosis of nonoverlapping etiological subgroups for which specific interventions can be applied. Although representing a small proportion of all diabetes cases, monogenic forms present an opportunity to demonstrate the feasibility of precision medicine strategies. In June 2019, the editors of convened a panel of experts to discuss this opportunity. This article summarizes the major themes that arose at that forum. It presents an overview of the common causes of monogenic diabetes, describes some challenges in identifying and treating these disorders, and reports experience with various approaches to screening, diagnosis, and management. This article complements a larger American Diabetes Association effort supporting implementation of precision medicine for monogenic diabetes, which could serve as a platform for a broader initiative to apply more precise tactics to treating the more common forms of diabetes.
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http://dx.doi.org/10.2337/dci20-0065DOI Listing
December 2020

The demise of islet allotransplantation in the United States: A call for an urgent regulatory update.

Am J Transplant 2021 04 10;21(4):1365-1375. Epub 2021 Feb 10.

Division of Kidney and Pancreas Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Islet allotransplantation in the United States (US) is facing an imminent demise. Despite nearly three decades of progress in the field, an archaic regulatory framework has stymied US clinical practice. Current regulations do not reflect the state-of-the-art in clinical or technical practices. In the US, islets are considered biologic drugs and "more than minimally manipulated" human cell and tissue products (HCT/Ps). In contrast, across the world, human islets are appropriately defined as "minimally manipulated tissue" and not regulated as a drug, which has led to islet allotransplantation (allo-ITx) becoming a standard-of-care procedure for selected patients with type 1 diabetes mellitus. This regulatory distinction impedes patient access to islets for transplantation in the US. As a result only 11 patients underwent allo-ITx in the US between 2016 and 2019, and all as investigational procedures in the settings of a clinical trials. Herein, we describe the current regulations pertaining to islet transplantation in the United States. We explore the progress which has been made in the field and demonstrate why the regulatory framework must be updated to both better reflect our current clinical practice and to deal with upcoming challenges. We propose specific updates to current regulations which are required for the renaissance of ethical, safe, effective, and affordable allo-ITx in the United States.
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http://dx.doi.org/10.1111/ajt.16397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016716PMC
April 2021

Approach to the Patient with MODY-Monogenic Diabetes.

J Clin Endocrinol Metab 2021 Jan;106(1):237-250

Kovler Diabetes Center, Departments of Medicine and Pediatrics, University of Chicago, Chicago, Illinois.

Maturity-onset diabetes of the young, or MODY-monogenic diabetes, is a not-so-rare collection of inherited disorders of non-autoimmune diabetes mellitus that remains insufficiently diagnosed despite increasing awareness. These cases are important to efficiently and accurately diagnose, given the clinical implications of syndromic features, cost-effective treatment regimen, and the potential impact on multiple family members. Proper recognition of the clinical manifestations, family history, and cost-effective lab and genetic testing provide the diagnosis. All patients must undergo a thorough history, physical examination, multigenerational family history, lab evaluation (glycated hemoglobin A1c [HbA1c], glutamic acid decarboxylase antibodies [GADA], islet antigen 2 antibodies [IA-2A], and zinc transporter 8 [ZnT8] antibodies). The presence of clinical features with 3 (or more) negative antibodies may be indicative of MODY-monogenic diabetes, and is followed by genetic testing. Molecular genetic testing should be performed before attempting specific treatments in most cases. Additional testing that is helpful in determining the risk of MODY-monogenic diabetes is the MODY clinical risk calculator (>25% post-test probability in patients not treated with insulin within 6 months of diagnosis should trigger genetic testing) and 2-hour postprandial (after largest meal of day) urinary C-peptide to creatinine ratio (with a ≥0.2 nmol/mmol to distinguish HNF1A- or 4A-MODY from type 1 diabetes). Treatment, as well as monitoring for microvascular and macrovascular complications, is determined by the specific variant that is identified. In addition to the diagnostic approach, this article will highlight recent therapeutic advancements when patients no longer respond to first-line therapy (historically sulfonylurea treatment in many variants).

Learning Objectives: Upon completion of this educational activity, participants should be able to.

Target Audience: This continuing medical education activity should be of substantial interest to endocrinologists and all health care professionals who care for people with diabetes mellitus.
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http://dx.doi.org/10.1210/clinem/dgaa710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765647PMC
January 2021

Exenatide extended release in patients with type 1 diabetes with and without residual insulin production.

Diabetes Obes Metab 2020 11 29;22(11):2045-2054. Epub 2020 Jul 29.

Department of Medicine (Endocrinology), SUNY Upstate Medical University, Syracuse, New York.

Aims: To test whether a long-acting GLP-1 receptor agonist would improve glucose control in patients with type 1 diabetes (T1D) and to determine whether the presence of residual beta cell function would affect the response. In addition, we sought to determine whether the drug would affect beta cell function.

Methods: We performed a randomized placebo-controlled trial of exenatide extended release (ER) in participants with T1D with and without detectable levels of C-peptide. Seventy-nine participants were randomized to exenatide ER 2 mcg weekly, or placebo, stratified by the presence or absence of detectable C-peptide levels. The primary outcome was the difference in glycated haemoglobin (HbA1c) levels at 24 weeks. Participants were followed for another 6 months off study drug.

Results: At week 24, the time of the primary outcome, the least squares (LS) mean HbA1c level was 7.76% (95% confidence interval [CI] 7.42, 8.10) in the exenatide ER group versus 8.0% (95% CI 7.64, 8.35) in the placebo group (P = 0.08). At week 12 the LS mean HbA1c levels were 7.71% (95% CI 7.37, 8.05) in the exenatide ER group versus 8.05% (95% CI 7.7, 8.4) in the placebo group (P = 0.01). The improvement at week 12 was driven mainly by those with detectable levels of C-peptide. Those treated with exenatide ER lost weight at 12 and 24 weeks compared to those treated with placebo (P <0.001 and P = 0.007). The total insulin dose was lower, but not when corrected for body weight, and was not affected by residual insulin production. Adverse events were more frequent with exenatide ER, but hypoglycaemia was not increased.

Conclusion: Treatment with exenatide ER may have short-term benefits in some individuals with T1D who are overweight or who have detectable levels of C-peptide, but short-term improvements were not sustained.
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http://dx.doi.org/10.1111/dom.14121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009602PMC
November 2020

Integrated Pancreatic Blood Flow: Bidirectional Microcirculation Between Endocrine and Exocrine Pancreas.

Diabetes 2020 07 20;69(7):1439-1450. Epub 2020 Mar 20.

Department of Medicine, The University of Chicago, Chicago, IL

The pancreatic islet is a highly vascularized endocrine micro-organ. The unique architecture of rodent islets, a so-called core-mantle arrangement seen in two-dimensional images, led researchers to seek functional implications for islet hormone secretion. Three models of islet blood flow were previously proposed, all based on the assumption that islet microcirculation occurs in an enclosed structure. Recent electrophysiological and molecular biological studies using isolated islets also presumed unidirectional flow. Using intravital analysis of the islet microcirculation in mice, we found that islet capillaries were continuously integrated to those in the exocrine pancreas, which made the islet circulation rather open, not self-contained. Similarly in human islets, the capillary structure was integrated with pancreatic microvasculature in its entirety. Thus, islet microcirculation has no relation to islet cytoarchitecture, which explains its well-known variability throughout species. Furthermore, tracking fluorescent-labeled red blood cells at the endocrine-exocrine interface revealed bidirectional blood flow, with similar variability in blood flow speed in both the intra- and extra-islet vasculature. To date, the endocrine and exocrine pancreas have been studied separately by different fields of investigators. We propose that the open circulation model physically links both endocrine and exocrine parts of the pancreas as a single organ through the integrated vascular network.
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http://dx.doi.org/10.2337/db19-1034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306124PMC
July 2020

Harnessing heterogeneity in type 2 diabetes mellitus.

Nat Rev Endocrinol 2020 02;16(2):79-80

Departments of Medicine, University of Chicago, Chicago, IL, USA.

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http://dx.doi.org/10.1038/s41574-019-0308-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035709PMC
February 2020

Iatrogenic Hyperinsulinemia, Not Hyperglycemia, Drives Insulin Resistance in Type 1 Diabetes as Revealed by Comparison With GCK-MODY (MODY2).

Diabetes 2019 08 15;68(8):1565-1576. Epub 2019 May 15.

Ian Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University School of Medicine, Nashville, TN.

Although insulin resistance consistently occurs with type 1 diabetes, its predominant driver is uncertain. We therefore determined the relative contributions of hyperglycemia and iatrogenic hyperinsulinemia to insulin resistance using hyperinsulinemic-euglycemic clamps in three participant groups ( = 10/group) with differing insulinemia and glycemia: healthy control subjects (euinsulinemia and euglycemia), glucokinase-maturity-onset diabetes of the young (GCK-MODY; euinsulinemia and hyperglycemia), and type 1 diabetes (hyperinsulinemia and hyperglycemia matching GCK-MODY). We assessed the contribution of hyperglycemia by comparing insulin sensitivity in control and GCK-MODY and the contribution of hyperinsulinemia by comparing GCK-MODY and type 1 diabetes. Hemoglobin A was normal in control subjects and similarly elevated for type 1 diabetes and GCK-MODY. Basal insulin levels in control subjects and GCK-MODY were nearly equal but were 2.5-fold higher in type 1 diabetes. Low-dose insulin infusion suppressed endogenous glucose production similarly in all groups and suppressed nonesterified fatty acids similarly between control subjects and GCK-MODY, but to a lesser extent for type 1 diabetes. High-dose insulin infusion stimulated glucose disposal similarly in control subjects and GCK-MODY but was 29% and 22% less effective in type 1 diabetes, respectively. Multivariable linear regression showed that insulinemia-but not glycemia-was significantly associated with muscle insulin sensitivity. These data suggest that iatrogenic hyperinsulinemia predominates in driving insulin resistance in type 1 diabetes.
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http://dx.doi.org/10.2337/db19-0324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692813PMC
August 2019

GCK-MODY in the US Monogenic Diabetes Registry: Description of 27 unpublished variants.

Diabetes Res Clin Pract 2019 May 4;151:231-236. Epub 2019 May 4.

Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago, 5841 S. Maryland Ave., MC 1027, Chicago, IL 60637, USA.

We report on 134 unique GCK variants in 217 families, including 27 unpublished variants, identified in the US Monogenic Diabetes Registry in the last decade. Using ACMG guidelines, 26% were pathogenic, 56% likely pathogenic and 18% were of uncertain significance. Those with pathogenic variants had clinical features consistent with GCK-MODY.
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http://dx.doi.org/10.1016/j.diabres.2019.04.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544496PMC
May 2019

Management and pregnancy outcomes of women with GCK-MODY enrolled in the US Monogenic Diabetes Registry.

Acta Diabetol 2019 Apr 11;56(4):405-411. Epub 2018 Dec 11.

Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, Kovler Diabetes Center, University of Chicago, 5841 South Maryland Ave., MC 1027, Chicago, IL, 60637, USA.

Aims: GCK-MODY is characterized by mild hyperglycemia. Treatment is not required outside of pregnancy. During pregnancy, insulin treatment is recommended if second trimester fetal ultrasound monitoring shows macrosomia, suggesting the fetus has not inherited the GCK gene. There are limited data about GCK-MODY management in pregnancy. The aim of this study was to examine clinical management and pregnancy outcomes amongst women with a known diagnosis of GCK-MODY.

Methods: In this observational, cross-sectional study, a survey was distributed via Redcap to women ≥ 18 years enrolled in the University of Chicago Monogenic Diabetes Registry (n = 94). All or part of the survey was completed by 54 women (128 pregnancies).

Results: There were 78 term births (61%), 15 pre-term births (12%), and 24 miscarriages (19%). Of the 39 pregnancies where insulin was given, 22 (56%) had occasional or frequent hypoglycemia including 9 with severe hypoglycemia. Average birth weight for full-term GCK-affected infants was significantly less in cases of maternal insulin treatment versus no treatment (2967 and 3725 g, p = 0.005). For GCK-unaffected infants, conclusions are limited by small sample size but large for gestational age (LGA) was common with maternal insulin treatment (56%) and no treatment (33%), p = 0.590.

Conclusions: The observed miscarriage rate was comparable to the background US population rate (15-20%). Patients treated with insulin experienced a 23% incidence of severe hypoglycemia and lower birth weights were observed in the insulin-treated, GCK-affected neonates. These data support published guidelines of no treatment if the fetus is suspected to have inherited GCK-MODY and highlight the importance of additional studies to determine optimal pregnancy management for GCK-MODY, particularly among unaffected fetuses.
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http://dx.doi.org/10.1007/s00592-018-1267-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468988PMC
April 2019

Human islets expressing HNF1A variant have defective β cell transcriptional regulatory networks.

J Clin Invest 2019 01 3;129(1):246-251. Epub 2018 Dec 3.

Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA.

Using an integrated approach to characterize the pancreatic tissue and isolated islets from a 33-year-old with 17 years of type 1 diabetes (T1D), we found that donor islets contained β cells without insulitis and lacked glucose-stimulated insulin secretion despite a normal insulin response to cAMP-evoked stimulation. With these unexpected findings for T1D, we sequenced the donor DNA and found a pathogenic heterozygous variant in the gene encoding hepatocyte nuclear factor-1α (HNF1A). In one of the first studies of human pancreatic islets with a disease-causing HNF1A variant associated with the most common form of monogenic diabetes, we found that HNF1A dysfunction leads to insulin-insufficient diabetes reminiscent of T1D by impacting the regulatory processes critical for glucose-stimulated insulin secretion and suggest a rationale for a therapeutic alternative to current treatment.
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http://dx.doi.org/10.1172/JCI121994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307934PMC
January 2019

Multi-level Supervision and Modification of Artificial Pancreas Control System.

Comput Chem Eng 2018 Apr 10;112:57-69. Epub 2018 Feb 10.

Department of Chemical and Biological Engineering, Illinois Institute of Technology, Chicago, IL, USA.

Artificial pancreas (AP) systems provide automated regulation of blood glucose concentration (BGC) for people with type 1 diabetes (T1D). An AP includes three components: a continuous glucose monitoring (CGM) sensor, a controller calculating insulin infusion rate based on the CGM signal, and a pump delivering the insulin amount calculated by the controller to the patient. The performance of the AP system depends on successful operation of these three components. Many APs use model predictive controllers that rely on models to predict BGC and to calculate the optimal insulin infusion rate. The performance of model-based controllers depends on the accuracy of the models that is affected by large dynamic changes in glucose-insulin metabolism or equipment performance that may move the operating conditions away from those used in developing the models and designing the control system. Sensor errors and missing signals will cause calculation of erroneous insulin infusion rates. And the performance of the controller may vary at each sampling step and each period (meal, exercise, and sleep), and from day to day. Here we describe a multi-level supervision and controller modification (ML-SCM) module is developed to supervise the performance of the AP system and retune the controller. It supervises AP performance in 3 time windows: sample level, period level, and day level. At sample level, an online controller performance assessment sub-module will generate controller performance indexes to evaluate various components of the AP system and conservatively modify the controller. A sensor error detection and signal reconciliation module will detect sensor error and reconcile the CGM sensor signal at each sample. At period level, the controller performance is evaluated with information collected during a certain time period and the controller is tuned more aggressively. At the day level, the daily CGM ranges are further analyzed to determine the adjustable range of controller parameters used for sample level and period level. Thirty subjects in the UVa/Padova metabolic simulator were used to evaluate the performance of the ML-SCM module and one clinical experiment is used to illustrate its performance in a clinical environment. The results indicate that the AP system with an ML-SCM module has a safer range of glucose concentration distribution and more appropriate insulin infusion rate suggestions than an AP system without the ML-SCM module.
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http://dx.doi.org/10.1016/j.compchemeng.2018.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166877PMC
April 2018

Monogenic Diabetes in Children and Adolescents: Recognition and Treatment Options.

Curr Diab Rep 2018 06 22;18(8):58. Epub 2018 Jun 22.

Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago, 5841 S. Maryland Ave., MC 1027, Chicago, IL, 60637, USA.

Purpose Of Review: We provide a review of monogenic diabetes in young children and adolescents with a focus on recognition, management, and pharmacological treatment.

Recent Findings: Monogenic forms of diabetes account for approximately 1-2% of diabetes in children and adolescents, and its incidence has increased in recent years due to greater awareness and wider availability of genetic testing. Monogenic diabetes is due to single gene defects that primarily affect beta cell function with more than 30 different genes reported. Children with antibody-negative, C-peptide-positive diabetes should be evaluated and genetically tested for monogenic diabetes. Accurate genetic diagnosis impacts treatment in the most common types of monogenic diabetes, including the use of sulfonylureas in place of insulin or other glucose-lowering agents or discontinuing pharmacologic treatment altogether. Diagnosis of monogenic diabetes can significantly improve patient care by enabling prediction of the disease course and guiding appropriate management and treatment.
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http://dx.doi.org/10.1007/s11892-018-1024-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312113PMC
June 2018

Precision medicine in KCNJ11 permanent neonatal diabetes.

Lancet Diabetes Endocrinol 2018 08 4;6(8):594-595. Epub 2018 Jun 4.

Departments of Medicine and Pediatrics, University of Chicago, Chicago, IL, USA; Kovler Diabetes Center, University of Chicago, Chicago, IL 60637, USA. Electronic address:

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http://dx.doi.org/10.1016/S2213-8587(18)30138-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345272PMC
August 2018

α Cell Function and Gene Expression Are Compromised in Type 1 Diabetes.

Cell Rep 2018 03;22(10):2667-2676

Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA; Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA. Electronic address:

Many patients with type 1 diabetes (T1D) have residual β cells producing small amounts of C-peptide long after disease onset but develop an inadequate glucagon response to hypoglycemia following T1D diagnosis. The features of these residual β cells and α cells in the islet endocrine compartment are largely unknown, due to the difficulty of comprehensive investigation. By studying the T1D pancreas and isolated islets, we show that remnant β cells appeared to maintain several aspects of regulated insulin secretion. However, the function of T1D α cells was markedly reduced, and these cells had alterations in transcription factors constituting α and β cell identity. In the native pancreas and after placing the T1D islets into a non-autoimmune, normoglycemic in vivo environment, there was no evidence of α-to-β cell conversion. These results suggest an explanation for the disordered T1D counterregulatory glucagon response to hypoglycemia.
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http://dx.doi.org/10.1016/j.celrep.2018.02.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368357PMC
March 2018

Early Intensive Insulin Use May Preserve -Cell Function in Neonatal Diabetes Due to Mutations in the Proinsulin Gene.

J Endocr Soc 2018 Jan 24;2(1):1-8. Epub 2017 Nov 24.

Department of Medicine, Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, University of Chicago, Chicago, Illinois, 60637.

Although mutations in the proinsulin gene () are the second most common cause of neonatal diabetes mellitus, the natural history of -cell death and the most appropriate treatments remains unknown. We describe the management and outcome of two sisters with -mediated diabetes (S1 and S2) and suggest that more intensive insulin treatment of S2 may have resulted in better clinical outcomes. S1 was diagnosed with diabetes after presenting with serum glucose of 404 mg/dL (22.4 mmol/L) and started multiple daily insulin injections at age 4 months, followed by continuous subcutaneous insulin infusion (CSII) at age 42 months. S1 had positive genetic testing at age 4 months for the GlyB8Ser or Gly32Ser mutation in proinsulin. S2 had positive research-based genetic testing, age 1 month, before she had consistently elevated blood glucose levels. Continuous glucose monitoring revealed abnormal excursions to 200 mg/dL. Low-dose insulin therapy was initiated at age 2.5 months via CSII. At age-matched time points, S2 had higher C-peptide levels, lower hemoglobin A1c values, and lower estimated doses of insulin as compared with S1. Earlier, more intensive insulin treatment was associated with higher C-peptide levels, decreased insulin dosing, and improved glycemic control. Initiating exogenous insulin before overt hyperglycemia and maintaining intensive insulin management may reduce the demand for endogenous insulin production and may preserve -cell function. Studies accumulating data on greater numbers of participants will be essential to determine whether these associations are consistent for all gene mutations.
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http://dx.doi.org/10.1210/js.2017-00356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738118PMC
January 2018

FOXP3 mutations causing early-onset insulin-requiring diabetes but without other features of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.

Pediatr Diabetes 2018 05 29;19(3):388-392. Epub 2017 Nov 29.

Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism and Kovler Diabetes Center, The University of Chicago, Chicago, Illinois.

Diabetes occurs in 1/90 000 to 1/160 000 births and when diagnosed under 6 months of age is very likely to have a primary genetic cause. FOXP3 encodes a transcription factor critical for T regulatory cell function and mutations are known to cause "immune dysregulation, polyendocrinopathy (including insulin-requiring diabetes), enteropathy, X-linked" (IPEX) syndrome. This condition is often fatal unless patients receive a bone-marrow transplant. Here we describe the phenotype of male neonates and infants who had insulin-requiring diabetes without other features of IPEX syndrome and were found to have mutations in FOXP3. Whole-exome or next generation sequencing of genes of interest was carried out in subjects with isolated neonatal diabetes without a known genetic cause. RT-PCR was carried out to investigate the effects on RNA splicing of a novel intronic splice-site variant. Four male subjects were found to have FOXP3 variants in the hemizygous state: p.Arg114Trp, p.Arg347His, p.Lys393Met, and c.1044+5G>A which was detected in 2 unrelated probands and in a brother diagnosed with diabetes at 2.1 years of age. Of these, p.Arg114Trp is likely a benign rare variant found in individuals of Ashkenazi Jewish ancestry and p.Arg347His has been previously described in patients with classic IPEX syndrome. The p.Lys393Met and c.1044+5G>A variants are novel to this study. RT-PCR studies of the c.1044+5G>A splice variant confirmed it affected RNA splicing by generating both a wild type and truncated transcript. We conclude that FOXP3 mutations can cause early-onset insulin-requiring diabetes with or without other features of IPEX syndrome.
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http://dx.doi.org/10.1111/pedi.12612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5918222PMC
May 2018

Simultaneous Real-Time Measurement of the β-Cell Membrane Potential and Ca Influx to Assess the Role of Potassium Channels on β-Cell Function.

Methods Mol Biol 2018 ;1684:73-84

Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA.

Stimulus-secretion coupling in pancreatic β-cells requires Ca influx through voltage-dependent Ca channels, whose activity is controlled by the plasma membrane potential (V ). Here, we present a method of measuring fluctuations in the β-cell V and Ca influx simultaneously, which provides valuable information about the ionic signaling mechanisms that underlie insulin secretion. This chapter describes the use of perforated patch clamp electrophysiology on cells loaded with a fluorescent intracellular Ca indicator, which permits the stable recording conditions needed to monitor the V and Ca influx in β-cells. Moreover, this chapter describes the protocols necessary for the preparation of mouse and human islet cells for the simultaneous recording of V and Ca as well as determining the specific islet cell type assessed in each experiment.
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http://dx.doi.org/10.1007/978-1-4939-7362-0_7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927608PMC
July 2018

Deletion of Protein Kinase D1 in Pancreatic β-Cells Impairs Insulin Secretion in High-Fat Diet-Fed Mice.

Diabetes 2018 01 16;67(1):71-77. Epub 2017 Oct 16.

Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada

Ββ-Cell adaptation to insulin resistance is necessary to maintain glucose homeostasis in obesity. Failure of this mechanism is a hallmark of type 2 diabetes (T2D). Hence, factors controlling functional β-cell compensation are potentially important targets for the treatment of T2D. Protein kinase D1 (PKD1) integrates diverse signals in the β-cell and plays a critical role in the control of insulin secretion. However, the role of β-cell PKD1 in glucose homeostasis in vivo is essentially unknown. Using β-cell-specific, inducible PKD1 knockout mice (βPKD1KO), we examined the role of β-cell PKD1 under basal conditions and during high-fat feeding. βPKD1KO mice under a chow diet presented no significant difference in glucose tolerance or insulin secretion compared with mice expressing the Cre transgene alone; however, when compared with wild-type mice, both groups developed glucose intolerance. Under a high-fat diet, deletion of PKD1 in β-cells worsened hyperglycemia, hyperinsulinemia, and glucose intolerance. This was accompanied by impaired glucose-induced insulin secretion both in vivo in hyperglycemic clamps and ex vivo in isolated islets from high-fat diet-fed βPKD1KO mice without changes in islet mass. This study demonstrates an essential role for PKD1 in the β-cell adaptive secretory response to high-fat feeding in mice.
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http://dx.doi.org/10.2337/db17-0982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741145PMC
January 2018

Pancreatic Histopathology of Human Monogenic Diabetes Due to Causal Variants in KCNJ11, HNF1A, GATA6, and LMNA.

J Clin Endocrinol Metab 2018 01;103(1):35-45

Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago, Chicago, Illinois.

Context: Monogenic diabetes is thought to account for 2% of all diabetes cases, but most patients receive misdiagnoses of type 1 or type 2 diabetes. To date, little is known about the histopathological features of pancreata from patients with monogenic diabetes.

Objective: Retrospective study of the JDRF Network for Pancreatic Organ Donors with Diabetes biorepository to identify possible cases of monogenic diabetes and to compare effects of genetic variants on pancreas histology.

Methods: We selected cases of diabetes for genetic testing on the basis of criteria that included young age at diagnosis, low body mass index, negative autoantibody status, and/or detectable C-peptide level. Samples underwent next-generation-targeted sequencing of 140 diabetes/diabetes-related genes. Pancreas weight and histopathology were reviewed.

Results: Forty-one of 140 cases of diabetes met the clinical inclusion criteria, with 38 DNA samples available. Genetic variants of probable clinical significance were found in four cases: one each in KCNJ11, HNF1A, GATA6, and LMNA. The KCNJ11 and HNF1A samples had significantly decreased pancreas weight and insulin mass similar to that of type 1 diabetes but had no insulitis. The GATA6 sample had severe pancreatic atrophy but with abundant β cells and severe amyloidosis similar to type 2 diabetes. The LMNA sample had preserved pancreas weight and insulin mass but abnormal islet architecture and exocrine fatty infiltrates.

Conclusions: Four cases of diabetes had putative causal variants in monogenic diabetes genes. This study provides further insight into the heterogeneous nature of monogenic diabetes cases that exhibited clinical and pathophysiological features that overlap with type 1/type 2 diabetes.
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http://dx.doi.org/10.1210/jc.2017-01159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761488PMC
January 2018

Diabetes Presentation in Infancy: High Risk of Diabetic Ketoacidosis.

Diabetes Care 2017 10 4;40(10):e147-e148. Epub 2017 Aug 4.

Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Chicago, Chicago, IL

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http://dx.doi.org/10.2337/dc17-1145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606305PMC
October 2017

Correlative imaging across microscopy platforms using the fast and accurate relocation of microscopic experimental regions (FARMER) method.

Rev Sci Instrum 2017 May;88(5):053702

Department of Chemistry, University of Chicago, Chicago, Illinois 60637, USA.

Imaging specific regions of interest (ROIs) of nanomaterials or biological samples with different imaging modalities (e.g., light and electron microscopy) or at subsequent time points (e.g., before and after off-microscope procedures) requires relocating the ROIs. Unfortunately, relocation is typically difficult and very time consuming to achieve. Previously developed techniques involve the fabrication of arrays of features, the procedures for which are complex, and the added features can interfere with imaging the ROIs. We report the Fast and Accurate Relocation of Microscopic Experimental Regions (FARMER) method, which only requires determining the coordinates of 3 (or more) conspicuous reference points (REFs) and employs an algorithm based on geometric operators to relocate ROIs in subsequent imaging sessions. The 3 REFs can be quickly added to various regions of a sample using simple tools (e.g., permanent markers or conductive pens) and do not interfere with the ROIs. The coordinates of the REFs and the ROIs are obtained in the first imaging session (on a particular microscope platform) using an accurate and precise encoded motorized stage. In subsequent imaging sessions, the FARMER algorithm finds the new coordinates of the ROIs (on the same or different platforms), using the coordinates of the manually located REFs and the previously recorded coordinates. FARMER is convenient, fast (3-15 min/session, at least 10-fold faster than manual searches), accurate (4.4 μm average error on a microscope with a 100x objective), and precise (almost all errors are <8 μm), even with deliberate rotating and tilting of the sample well beyond normal repositioning accuracy. We demonstrate this versatility by imaging and re-imaging a diverse set of samples and imaging methods: live mammalian cells at different time points; fixed bacterial cells on two microscopes with different imaging modalities; and nanostructures on optical and electron microscopes. FARMER can be readily adapted to any imaging system with an encoded motorized stage and can facilitate multi-session and multi-platform imaging experiments in biology, materials science, photonics, and nanoscience.
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http://dx.doi.org/10.1063/1.4982818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910601PMC
May 2017

Preservation of Reduced Numbers of Insulin-Positive Cells in Sulfonylurea-Unresponsive KCNJ11-Related Diabetes.

J Clin Endocrinol Metab 2017 01;102(1):1-5

Section of Adult and Pediatric Endocrinology, University of Chicago, Chicago, Illinois 60637.

Context: The most common genetic cause of permanent neonatal diabetes mellitus is activating mutations in KCNJ11, which can usually be treated using oral sulfonylureas (SUs) instead of insulin injections, although some mutations are SU unresponsive. In this work, we provide a report of the pancreatic islet endocrine cell composition and area in a patient with an SU-unresponsive KCNJ11 mutation (p.G334D), in comparison with age-matched controls.

Case Description: Pancreatic autopsy tissue sections from a 2-year-old female child diagnosed with KCNJ11-related diabetes at 4 days of age and 13 age-matched controls were stained with insulin, glucagon, somatostatin, pancreatic polypeptide, and Ki67 antibodies to determine islet endocrine cell composition and area. β-cell ultrastructure was assessed by electron microscopic (EM) analysis. The patient's pancreas (sampling from head to tail) revealed insulin-positive cells in all regions. The pancreatic β-cell (insulin) area was significantly reduced compared with controls: 0.50% ± 0.04% versus 1.67% ± 0.20%, respectively (P < 0.00001). There were no significant differences in α-cell (glucagon) or δ-cell (somatostatin) area. EM analysis revealed secretory granules with a dense core typical of mature β-cells as well as granules with a lighter core characteristic of immature granules.

Conclusions: Our results suggest that mechanisms exist that allow preservation of β-cells in the absence of insulin secretion. It remains to be determined to what extent this reduction in β-cells may be reversible.
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http://dx.doi.org/10.1210/jc.2016-2826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413092PMC
January 2017

Outcomes of Pancreatic Islet Allotransplantation Using the Edmonton Protocol at the University of Chicago.

Transplant Direct 2016 Oct 13;2(10):e105. Epub 2016 Sep 13.

Department of Surgery, Transplant Center, The University of Chicago, Chicago, IL.

Objective: The aim of this study was to assess short-term and long-term results of the pancreatic islet transplantation using the Edmonton protocol at the University of Chicago.

Materials And Methods: Nine patients underwent pancreatic islet cell transplantation using the Edmonton Protocol; they were followed up for 10 years after initial islet transplant with up to 3 separate islet infusions. They were given induction treatment using an IL-2R antibody and their maintenance immunosuppression regimen consisted of sirolimus and tacrolimus.

Results: Nine patients received a total of 18 islet infusions. Five patients dropped out in the early phase of the study. Greater than 50% drop-out and noncompliance rate resulted from both poor islet function and recurrent side effects of immunosuppression. The remaining 4 (44%) patients stayed insulin free with intervals for at least over 5 years (cumulative time) after the first transplant. Each of them received 3 infusions, on average 445 000 islet equivalent per transplant. Immunosuppression regimen required multiple adjustments in all patients due to recurrent side effects. In the long-term follow up, kidney function remained stable, and diabetic retinopathy and polyneuropathy did not progress in any of the patients. Patients' panel reactive antibodies remained zero and anti-glutamic acid decarboxylase 65 antibody did not rise after the transplant. Results of metabolic tests including hemoglobin A1c, arginine stimulation, and mixed meal tolerance test were correlated with clinical islet function.

Conclusions: Pancreatic islet transplantation initiated according to Edmonton protocol offered durable long-term insulin-free glycemic control in only highly selected brittle diabetics providing stable control of diabetic neuropathy and retinopathy and without increased sensitization or impaired renal function. Immunosuppression adjustments and close follow-up were critical for patient retention and ultimate success.
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http://dx.doi.org/10.1097/TXD.0000000000000609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5068201PMC
October 2016

Growth Hormone-Releasing Hormone in Diabetes.

Front Endocrinol (Lausanne) 2016 10;7:129. Epub 2016 Oct 10.

Department of Medicine, Kovler Diabetes Center, The University of Chicago, Chicago, IL, USA; Department of Pediatrics, The University of Chicago, Chicago, IL, USA.

Growth hormone-releasing hormone (GHRH) is produced by the hypothalamus and stimulates growth hormone synthesis and release in the anterior pituitary gland. In addition, GHRH is an important regulator of cellular functions in many cells and organs. Expression of GHRH G-Protein Coupled Receptor (GHRHR) has been demonstrated in different peripheral tissues and cell types, including pancreatic islets. Among the peripheral activities, recent studies demonstrate a novel ability of GHRH analogs to increase and preserve insulin secretion by beta-cells in isolated pancreatic islets, which makes them potentially useful for diabetes treatment. This review considers the role of GHRHR in the beta-cell and addresses the unique engineered GHRH agonists and antagonists for treatment of type 2 diabetes mellitus. We discuss the similarity of signaling pathways activated by GHRHR in pituitary somatotrophs and in pancreatic beta-cells and possible ways as to how the GHRHR pathway can interact with glucose and other secretagogues to stimulate insulin secretion. We also consider the hypothesis that novel GHRHR agonists can improve glucose metabolism in Type 2 diabetes by preserving the function and survival of pancreatic beta-cells. Wound healing and cardioprotective action with new GHRH agonists suggest that they may prove useful in ameliorating certain diabetic complications. These findings highlight the future potential therapeutic effectiveness of modulators of GHRHR activity for the development of new therapeutic approaches in diabetes and its complications.
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http://dx.doi.org/10.3389/fendo.2016.00129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5056186PMC
October 2016

The Brain-to-Pancreatic Islet Neuronal Map Reveals Differential Glucose Regulation From Distinct Hypothalamic Regions.

Diabetes 2016 09 12;65(9):2711-23. Epub 2016 Apr 12.

Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Chicago, Chicago, IL

The brain influences glucose homeostasis, partly by supplemental control over insulin and glucagon secretion. Without this central regulation, diabetes and its complications can ensue. Yet, the neuronal network linking to pancreatic islets has never been fully mapped. Here, we refine this map using pseudorabies virus (PRV) retrograde tracing, indicating that the pancreatic islets are innervated by efferent circuits that emanate from the hypothalamus. We found that the hypothalamic arcuate nucleus (ARC), ventromedial nucleus (VMN), and lateral hypothalamic area (LHA) significantly overlap PRV and the physiological glucose-sensing enzyme glucokinase. Then, experimentally lowering glucose sensing, specifically in the ARC, resulted in glucose intolerance due to deficient insulin secretion and no significant effect in the VMN, but in the LHA it resulted in a lowering of the glucose threshold that improved glucose tolerance and/or improved insulin sensitivity, with an exaggerated counter-regulatory response for glucagon secretion. No significant effect on insulin sensitivity or metabolic homeostasis was noted. Thus, these data reveal novel direct neuronal effects on pancreatic islets and also render a functional validation of the brain-to-islet neuronal map. They also demonstrate that distinct regions of the hypothalamus differentially control insulin and glucagon secretion, potentially in partnership to help maintain glucose homeostasis and guard against hypoglycemia.
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http://dx.doi.org/10.2337/db15-0629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5001176PMC
September 2016

Pancreatic Beta Cell G-Protein Coupled Receptors and Second Messenger Interactions: A Systems Biology Computational Analysis.

PLoS One 2016 3;11(5):e0152869. Epub 2016 May 3.

Departments of Medicine and Pediatrics, the Kovler Diabetes Center, The University of Chicago, Chicago, IL, 60637, United States of America.

Insulin secretory in pancreatic beta-cells responses to nutrient stimuli and hormonal modulators include multiple messengers and signaling pathways with complex interdependencies. Here we present a computational model that incorporates recent data on glucose metabolism, plasma membrane potential, G-protein-coupled-receptors (GPCR), cytoplasmic and endoplasmic reticulum calcium dynamics, cAMP and phospholipase C pathways that regulate interactions between second messengers in pancreatic beta-cells. The values of key model parameters were inferred from published experimental data. The model gives a reasonable fit to important aspects of experimentally measured metabolic and second messenger concentrations and provides a framework for analyzing the role of metabolic, hormones and neurotransmitters changes on insulin secretion. Our analysis of the dynamic data provides support for the hypothesis that activation of Ca2+-dependent adenylyl cyclases play a critical role in modulating the effects of glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and catecholamines. The regulatory properties of adenylyl cyclase isoforms determine fluctuations in cytoplasmic cAMP concentration and reveal a synergistic action of glucose, GLP-1 and GIP on insulin secretion. On the other hand, the regulatory properties of phospholipase C isoforms determine the interaction of glucose, acetylcholine and free fatty acids (FFA) (that act through the FFA receptors) on insulin secretion. We found that a combination of GPCR agonists activating different messenger pathways can stimulate insulin secretion more effectively than a combination of GPCR agonists for a single pathway. This analysis also suggests that the activators of GLP-1, GIP and FFA receptors may have a relatively low risk of hypoglycemia in fasting conditions whereas an activator of muscarinic receptors can increase this risk. This computational analysis demonstrates that study of second messenger pathway interactions will improve understanding of critical regulatory sites, how different GPCRs interact and pharmacological targets for modulating insulin secretion in type 2 diabetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0152869PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854486PMC
April 2017

GCK-MODY in the US National Monogenic Diabetes Registry: frequently misdiagnosed and unnecessarily treated.

Acta Diabetol 2016 Oct 22;53(5):703-8. Epub 2016 Apr 22.

Departments of Pediatrics and Medicine, Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, The University of Chicago, Chicago, IL, 60637, USA.

Aims: GCK-MODY leads to mildly elevated blood glucose typically not requiring therapy. It has been described in all ethnicities, but mainly in Caucasian Europeans. Here we describe our US cohort of GCK-MODY.

Methods: We examined the rates of detection of heterozygous mutations in the GCK gene in individuals referred to the US Monogenic Diabetes Registry with a phenotype consistent with GCK-MODY. We also assessed referral patterns, treatment and demography, including ethnicity, of the cohort.

Results: Deleterious heterozygous GCK mutations were found in 54.7 % of Registry probands selected for GCK sequencing for this study. Forty-nine percent were previously unnecessarily treated with glucose-lowering agents, causing hypoglycemia and other adverse effects in some of the subjects. The proportion of probands found to have a GCK mutation through research-based testing was similar across each ethnic group. However, together African-American, Latino and Asian subjects represented only 20.5 % of screened probands and 17.2 % of those with GCK-MODY, despite higher overall diabetes prevalence in these groups.

Conclusions: Our data show that a high detection rate of GCK-MODY is possible based on clinical phenotype and that prior to genetic diagnosis, a large percentage are inappropriately treated with glucose-lowering therapies. We also find low minority representation in our Registry, which may be due to disparities in diagnostic diabetes genetic testing and is an area needing further investigation.
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http://dx.doi.org/10.1007/s00592-016-0859-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5016218PMC
October 2016

A Transient Metabolic Recovery from Early Life Glucose Intolerance in Cystic Fibrosis Ferrets Occurs During Pancreatic Remodeling.

Endocrinology 2016 05 10;157(5):1852-65. Epub 2016 Feb 10.

Anatomy and Cell Biology (Y.Y., X.S., W.X., B.L., N.H., S.R.T., J.F.E.), Departments of Pathology (K.G.-C.) and Pediatrics (A.U., K.L.O., A.W.N.), Fraternal Order of Eagles Diabetes Research Center (A.W.N., J.F.E.), and Department of Biostatistics (K.W.), College of Public Health, University of Iowa, Iowa City, Iowa 52242; and Department of Medicine (L.H.P., M.H.), University of Chicago, Chicago, Illinois 60637.

Cystic fibrosis (CF)-related diabetes in humans is intimately related to exocrine pancreatic insufficiency, yet little is known about how these 2 disease processes simultaneously evolve in CF. In this context, we examined CF ferrets during the evolution of exocrine pancreatic disease. At 1 month of age, CF ferrets experienced a glycemic crisis with spontaneous diabetic-level hyperglycemia. This occurred during a spike in pancreatic inflammation that was preceded by pancreatic fibrosis and loss of β-cell mass. Surprisingly, there was spontaneous normalization of glucose levels at 2-3 months, with intermediate hyperglycemia thereafter. Mixed meal tolerance was impaired at all ages, but glucose intolerance was not detected until 4 months. Insulin secretion in response to hyperglycemic clamp and to arginine was impaired. Insulin sensitivity, measured by euglycemic hyperinsulinemic clamp, was normal. Pancreatic inflammation rapidly diminished after 2 months of age during a period where β-cell mass rose and gene expression of islet hormones, peroxisome proliferator-activated receptor-γ, and adiponectin increased. We conclude that active CF exocrine pancreatic inflammation adversely affects β-cells but is followed by islet resurgence. We predict that very young humans with CF may experience a transient glycemic crisis and postulate that pancreatic inflammatory to adipogenic remodeling may facilitate islet adaptation in CF.
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http://dx.doi.org/10.1210/en.2015-1935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4870869PMC
May 2016

TCF1 links GIPR signaling to the control of beta cell function and survival.

Nat Med 2016 Jan 7;22(1):84-90. Epub 2015 Dec 7.

Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada.

The glucagon-like peptide-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor transduce nutrient-stimulated signals to control beta cell function. Although the GLP-1 receptor (GLP-1R) is a validated drug target for diabetes, the importance of the GIP receptor (GIPR) for the function of beta cells remains uncertain. We demonstrate that mice with selective ablation of GIPR in beta cells (MIP-Cre:Gipr(Flox/Flox); Gipr(-/-βCell)) exhibit lower levels of meal-stimulated insulin secretion, decreased expansion of adipose tissue mass and preservation of insulin sensitivity when compared to MIP-Cre controls. Beta cells from Gipr(-/-βCell) mice display greater sensitivity to apoptosis and markedly lower islet expression of T cell-specific transcription factor-1 (TCF1, encoded by Tcf7), a protein not previously characterized in beta cells. GIP, but not GLP-1, promotes beta cell Tcf7 expression via a cyclic adenosine monophosphate (cAMP)-independent and extracellular signal-regulated kinase (ERK)-dependent pathway. Tcf7 (in mice) or TCF7 (in humans) levels are lower in islets taken from diabetic mice and in humans with type 2 diabetes; knockdown of TCF7 in human and mouse islets impairs the cytoprotective responsiveness to GIP and enhances the magnitude of apoptotic injury, whereas restoring TCF1 levels in beta cells from Gipr(-/-βCell) mice lowers the number of apoptotic cells compared to that seen in MIP-Cre controls. Tcf7(-/-) mice show impaired insulin secretion, deterioration of glucose tolerance with either aging and/or high-fat feeding and increased sensitivity to beta cell injury relative to wild-type (WT) controls. Hence the GIPR-TCF1 axis represents a potential therapeutic target for preserving both the function and survival of vulnerable, diabetic beta cells.
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http://dx.doi.org/10.1038/nm.3997DOI Listing
January 2016