<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04463849</url>
  </required_header>
  <id_info>
    <org_study_id>6/2020</org_study_id>
    <nct_id>NCT04463849</nct_id>
  </id_info>
  <brief_title>Effects of COVID-19 Infection on Beta-cell Function in Euglycemic Patients</brief_title>
  <acronym>COBETOX</acronym>
  <official_title>Effects of SARS-CoV-2 Infection on Beta-cell Function in Euglycemic Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Milan</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Luigi Sacco University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Milan</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      In recent months, a new coronavirus, SARS-CoV-2, has been identified as the cause of a&#xD;
      serious lung infection named COVID-19 by the World Health Organization. This virus has spread&#xD;
      rapidly among the nations of the world and it is the cause of a pandemic and a global health&#xD;
      emergency. There is still very little scientific evidence on the virus, however&#xD;
      epidemiological data suggest that one of the most frequent comorbidities is diabetes, along&#xD;
      with hypertension and heart disease. There is no scientific evidence on the possible effects&#xD;
      of this infection on the function of the β cell and on glycemic control. Clinical evidence&#xD;
      seems to suggest that COVID-19 infection mostly affects the respiratory system, and an acute&#xD;
      worsening of glycemic compensation is not described as generally observed in bacterial&#xD;
      pneumonia. However, previous work on acute respiratory syndromes (SARS) caused by similar&#xD;
      coronaviruses, had described that the infection has multi-organ involvement related to the&#xD;
      expression of the SARS coronavirus receptor, the angiotensin 2 converting enzyme, in&#xD;
      different organs, especially at the level of endocrine pancreatic tissue. In the population&#xD;
      of this previous work, glucose intolerance and fasting hyperglycaemia have been described and&#xD;
      in 37 of 39 diabetic patients examined, a remission of diabetes was observed three years&#xD;
      after the infection. It is possible that the coronaviruses responsible for SARS may enter the&#xD;
      pancreatic islets using the angiotensin 2 converting enzyme receptor, expressed at the level&#xD;
      of the endocrine pancreas, thus causing diabetes. Additionally, previous literature on&#xD;
      coronavirus infections (SARS and MERS or Middle-East Respiratory Syndrome) suggested that&#xD;
      diabetes could worsen the evolution of the disease. In particular, in case of Middle-East&#xD;
      Respiratory Syndrome-CoV infection, diabetic mice had a more prolonged serious illness and a&#xD;
      delay in recovery regardless of the viremic titer. This could probably be due to a&#xD;
      dysregulation of the immune response, which results in more serious and prolonged lung&#xD;
      disease.&#xD;
&#xD;
      There are currently no data on pancreatic beta cell function in patients with COVID-19.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The project is monocentric, interventional, non-pharmacological, non-profit. Patients will be&#xD;
      enrolled in hospital for confirmed COVID-19 infection (with reverse transcriptase-polymerase&#xD;
      chain reaction on the airway swab) but with normal basal blood glucose and no previous&#xD;
      history of diabetes or impaired fasting glucose or impaired glucose tolerance. Patients will&#xD;
      be compared to a control group of healthy volunteers, not affected by COVID-19 and with no&#xD;
      previous history of diabetes or impaired fasting glucose or impaired glucose tolerance.&#xD;
      Patients will be also compared with a group of patients with type 2 diabetes but without&#xD;
      COVID-19. Once the informed consent has been signed, the clinical parameters and biochemical&#xD;
      parameters will be collected according to the time points provided by the protocol in&#xD;
      positive COVID-19 patients, in healthy volunteers and in patients with type 2 diabetes.&#xD;
&#xD;
      COVID-19 positive patients and healthy controls as well as patients with type 2 diabetes,&#xD;
      will undergo a stimulation test of β-cell function (evaluation of the secretive response of&#xD;
      insulin to the stimulation test with arginine infusion) and the monitoring of glycemic values&#xD;
      through a professional retrospective continuous glucose monitoring. For the test, an infusion&#xD;
      solution containing 25% arginine hydrochloride will be used, arginine is an insulinogenic&#xD;
      amino acid, useful to verify the possible existence of damage to the cellular beta function&#xD;
      induced by COVID-19 infection, clinically observable with changes in insulin secretory&#xD;
      response. Given the usefulness of the test, performed for diagnostic purposes, this protocol&#xD;
      is identified as &quot;non-pharmacological&quot;. The test is contraindicated only in patients with&#xD;
      severe hepatic and renal insufficiency, in all other subjects the side effects are minimal&#xD;
      and spontaneous resolution before the end of the test (flushing 33%, oral paraesthesia 46%,&#xD;
      nausea 12%, dizziness 14%). For the stimulation test with arginine infusion, after the basal&#xD;
      sampling at (0 minutes), an intravenous injection of arginine 5 grams will be practiced in 60&#xD;
      seconds followed by serial withdrawals at +2, +5, +10 and +30 minutes. The following analytes&#xD;
      will be assayed on the basal sample: glycosylated hemoglobin, glycaemia, insulin,&#xD;
      pro-insulin, C-peptide, glucagon, serum inflammatory cytokines (Il1β, IL-2, IL-6, IL-7,&#xD;
      IL-10, TNF- α, IFN-γ, MIP-1β, MCP-1, GM-CSF, G-CSF Insulin, C-peptide and glucagon will be&#xD;
      dosed on all points of the curve.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 30, 2020</start_date>
  <completion_date type="Actual">December 31, 2021</completion_date>
  <primary_completion_date type="Actual">October 31, 2021</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Serum β - cellular function index insulin levels</measure>
    <time_frame>all data were collected at Visit 1, 12 months</time_frame>
    <description>Difference in insulin levels during and after COVID-19 infection and compared to patients in the control group</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Serum β - cellular function index C-peptide levels</measure>
    <time_frame>all data were collected at Visit 1, 12 months</time_frame>
    <description>Difference in C-peptide levels during and after COVID-19 infection and compared to patients in the control group</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Serum β - cellular function HOMA-β index</measure>
    <time_frame>all data were collected at Visit 1, 12 months</time_frame>
    <description>Difference in HOMA-β index during and after COVID-19 infection and compared to patients in the control group</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Serum β - cellular function pro-insulin/insulin ratio</measure>
    <time_frame>all data were collected at Visit 1, 12 months</time_frame>
    <description>Difference in pro-insulin/insulin ratio during and after COVID-19 infection and compared to patients in the control group</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Evaluation of the secretory response of insulin to the arginine stimulation test</measure>
    <time_frame>all data were collected at Visit 1, 12 months</time_frame>
    <description>Check for the existence of damage to the beta cell function induced by COVID-19 infection, clinically observable with changes in the secretory response of insulin</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percentage of patients with preserved β cells function</measure>
    <time_frame>all data were collected at Visit 1, 12 months</time_frame>
    <description>Evidence of impairment of β cell function in the serum of COVID-19 patients</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Glucose values</measure>
    <time_frame>all data were collected at Visit 1, 12 months</time_frame>
    <description>Changes in glucose values in COVID-19 patients and healthy volunteers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Values of continuous glucose monitoring</measure>
    <time_frame>all data were collected at Visit 1 and after 7 days, 12 months</time_frame>
    <description>Changes in the values of continuous glucose monitoring in both COVID-19 patients and healthy volunteers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in the inflammatory marker interleukin 1-β</measure>
    <time_frame>all data were collected at Visit 1, 12 months</time_frame>
    <description>Comparison of interleukin 1-β levels in COVID-19 patients compared with healthy subjects</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in the inflammatory marker interleukin IL-2</measure>
    <time_frame>all data were collected at Visit 1, 12 months</time_frame>
    <description>Comparison of interleukin IL-2 levels in COVID-19 patients compared with healthy subjects</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in the inflammatory marker interleukin IL-6</measure>
    <time_frame>all data were collected at Visit 1, 12 months</time_frame>
    <description>Comparison of interleukin IL-6 levels in COVID-19 patients compared with healthy subjects</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in the inflammatory marker interleukin IL-7</measure>
    <time_frame>all data were collected at Visit 1, 12 months</time_frame>
    <description>Comparison of interleukin IL-7 levels in COVID-19 patients compared with healthy subjects</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in the inflammatory marker interleukin IL-10</measure>
    <time_frame>all data were collected at Visit 1, 12 months</time_frame>
    <description>Comparison of interleukin IL-10 levels in COVID-19 patients compared with healthy subjects</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in the inflammatory marker tumor necrosis factor-α</measure>
    <time_frame>all data were collected at Visit 1, 12 months</time_frame>
    <description>Comparison of interleukin tumor necrosis factor-α levels in COVID-19 patients compared with healthy subjects</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in the inflammatory marker interferon gamma</measure>
    <time_frame>all data were collected at Visit 1, 12 months</time_frame>
    <description>Comparison of interferon gamma levels in COVID-19 patients compared with healthy subjects</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in the inflammatory marker macrophage inflammatory protein-1β</measure>
    <time_frame>all data were collected at Visit 1, 12 months</time_frame>
    <description>Comparison of macrophage inflammatory protein-1β levels in COVID-19 patients compared with healthy subjects</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in the inflammatory marker monocyte chemoattractant protein-1</measure>
    <time_frame>all data were collected at Visit 1, 12 months</time_frame>
    <description>Comparison of macrophage inflammatory monocyte chemoattractant protein-1 in COVID-19 patients compared with healthy subjects</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in the inflammatory marker granulocyte-macrophage colony-stimulating factor</measure>
    <time_frame>all data were collected at Visit 1, 12 months</time_frame>
    <description>Comparison of macrophage inflammatory granulocyte-macrophage colony-stimulating factor in COVID-19 patients compared with healthy subjects</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in the inflammatory marker granulocyte colony-stimulating factor</measure>
    <time_frame>all data were collected at Visit 1, 12 months</time_frame>
    <description>Comparison of macrophage inflammatory granulocyte colony-stimulating factor in COVID-19 patients compared with healthy subjects</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">90</enrollment>
  <condition>COVID19</condition>
  <condition>BETA-CELL FUNCTION</condition>
  <arm_group>
    <arm_group_label>COVID-19 positive patients</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will be enrolled in hospital for confirmed COVID-19 infection (with reverse transcriptase-polymerase chain reaction on the airway swab) but with normal basal glucose and no previous history of diabetes or impaired fasting glucose or impaired tolerance glucose. Patients will be placed with a professional retrospective glucose monitoring device and will be tested for stimulation with arginine infusion. The device will be placed on the day of the test and will be removed after seven days of recording the glycemic data. During the entire recording period, parameters such as mean glucose, estimated glycosylated hemoglobin, peak glucose and nadir, blood sugar levels above the limit of 140 mg / dL, average glucose values at 60 and 120 minutes after meals, standard deviation and variability coefficient.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy volunteers</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Healthy volunteers, not affected by COVID-19 and with no previous history of diabetes or impaired fasting glucose or impaired glucose tolerance will be enrolled. Healthy volunteers will be placed with a professional retrospective glucose monitoring device and will be tested for stimulation with arginine infusion. The device will be placed on the day of the test and will be removed after seven days of recording the glycemic data. During the entire recording period, parameters such as mean glucose, estimated glycosylated hemoglobin, peak glucose and nadir, blood sugar levels above the limit of 140 mg / dL, average glucose values at 60 and 120 minutes after meals, standard deviation and variability coefficient.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Type 2 diabetes patients</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Patients with established Type 2 diabetes, not affects by COVID-19. Patients will be placed with a professional retrospective glucose monitoring device and will be tested for stimulation with arginine infusion. The device will be placed on the day of the test and will be removed after seven days of recording the glycemic data. During the entire recording period, parameters such as mean glucose, estimated glycosylated hemoglobin, peak glucose and nadir, blood sugar levels above the limit of 140 mg / dL, average glucose values at 60 and 120 minutes after meals, standard deviation and variability coefficient.</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Stimulation test with arginine infusion in order to verify the possible existence of damage to the beta cell function induced by COVID-19 infection</intervention_name>
    <description>All participants will be subjected to the collection of glycemic data through continuous professional retrospective monitoring of blood glucose for seven days, positioned on the day the test will be performed. During the entire recording period, parameters such as mean glucose, estimated glycosylated hemoglobin, peak glucose and nadir, blood sugar levels above the limit of 140 mg / dL, average glucose values at 60 and 120 minutes after meals, standard deviation and variability coefficient.&#xD;
The evaluation of insulin secretion will be evaluated by performing the stimulus test with arginine infusion according to validated protocols.</description>
    <arm_group_label>COVID-19 positive patients</arm_group_label>
    <arm_group_label>Healthy volunteers</arm_group_label>
    <arm_group_label>Type 2 diabetes patients</arm_group_label>
    <other_name>Positioning of the device for glycemic monitoring</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria for COVID-19 positive patients&#xD;
&#xD;
          -  Male and female patients with COVID19 and normal basal blood sugar, unprecedented in&#xD;
             diabetes or impaired fasting glucose or impaired glucose tolerance&#xD;
&#xD;
          -  Age&gt; 18 years and &lt;80 years&#xD;
&#xD;
          -  Availability to informed consent and corporate privacy&#xD;
&#xD;
        Inclusion criteria for healthy subjects&#xD;
&#xD;
          -  Male and female patients not affected by COVID19, unprecedented in diabetes or&#xD;
             impaired fasting glucose or impaired glucose tolerance&#xD;
&#xD;
          -  Age&gt; 18 years and &lt;80 years&#xD;
&#xD;
          -  Availability to informed consent and corporate privacy&#xD;
&#xD;
        Exclusion criteria for COVID-19 positive patients&#xD;
&#xD;
          -  Age &lt;18 years&#xD;
&#xD;
          -  Previous history of diabetes or impaired fasting glucose or impaired glucose tolerance&#xD;
&#xD;
          -  Severe liver failure&#xD;
&#xD;
          -  Severe kidney failure&#xD;
&#xD;
        Exclusion criteria for healthy subjects&#xD;
&#xD;
          -  Age &lt;18 years&#xD;
&#xD;
          -  Previous history of diabetes or impaired fasting glucose or impaired glucose tolerance&#xD;
&#xD;
          -  Positivity to the nasopharyngeal swab for SARS-CoV-2&#xD;
&#xD;
          -  Severe liver failure&#xD;
&#xD;
          -  Severe kidney failure&#xD;
&#xD;
        Inclusion criteria for T2D patients&#xD;
&#xD;
          -  Male and female patients not affected by COVID19 with a diagnosis of type 2 diabetes&#xD;
&#xD;
          -  Age&gt; 18 years and &lt;80 years&#xD;
&#xD;
          -  Availability to informed consent and corporate privacy&#xD;
&#xD;
        Exclusion criteria for T2D patients&#xD;
&#xD;
          -  Age &lt;18 years&#xD;
&#xD;
          -  Positivity to the nasopharyngeal swab for SARS-CoV-2&#xD;
&#xD;
          -  Severe liver failure&#xD;
&#xD;
          -  Severe kidney failure&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Sacco University Hospital</name>
      <address>
        <city>Milan</city>
        <state>MI</state>
        <zip>20157</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>Deng SQ, Peng HJ. Characteristics of and Public Health Responses to the Coronavirus Disease 2019 Outbreak in China. J Clin Med. 2020 Feb 20;9(2):575. doi: 10.3390/jcm9020575.</citation>
    <PMID>32093211</PMID>
  </reference>
  <reference>
    <citation>Kulcsar KA, Coleman CM, Beck SE, Frieman MB. Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infection. JCI Insight. 2019 Oct 17;4(20):e131774. doi: 10.1172/jci.insight.131774.</citation>
    <PMID>31550243</PMID>
  </reference>
  <reference>
    <citation>Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24. Erratum In: Lancet. 2020 Jan 30;:</citation>
    <PMID>31986264</PMID>
  </reference>
  <reference>
    <citation>Yang JK, Lin SS, Ji XJ, Guo LM. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta Diabetol. 2010 Sep;47(3):193-9. doi: 10.1007/s00592-009-0109-4. Epub 2009 Mar 31.</citation>
    <PMID>19333547</PMID>
  </reference>
  <reference>
    <citation>Shankar SS, Vella A, Raymond RH, Staten MA, Calle RA, Bergman RN, Cao C, Chen D, Cobelli C, Dalla Man C, Deeg M, Dong JQ, Lee DS, Polidori D, Robertson RP, Ruetten H, Stefanovski D, Vassileva MT, Weir GC, Fryburg DA; Foundation for the National Institutes of Health beta-Cell Project Team. Standardized Mixed-Meal Tolerance and Arginine Stimulation Tests Provide Reproducible and Complementary Measures of beta-Cell Function: Results From the Foundation for the National Institutes of Health Biomarkers Consortium Investigative Series. Diabetes Care. 2016 Sep;39(9):1602-13. doi: 10.2337/dc15-0931. Epub 2016 Jul 12.</citation>
    <PMID>27407117</PMID>
  </reference>
  <reference>
    <citation>Brandle M, Lehmann R, Maly FE, Schmid C, Spinas GA. Diminished insulin secretory response to glucose but normal insulin and glucagon secretory responses to arginine in a family with maternally inherited diabetes and deafness caused by mitochondrial tRNA(LEU(UUR)) gene mutation. Diabetes Care. 2001 Jul;24(7):1253-8. doi: 10.2337/diacare.24.7.1253.</citation>
    <PMID>11423511</PMID>
  </reference>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>July 2, 2020</study_first_submitted>
  <study_first_submitted_qc>July 8, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 9, 2020</study_first_posted>
  <last_update_submitted>May 9, 2023</last_update_submitted>
  <last_update_submitted_qc>May 9, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 10, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Milan</investigator_affiliation>
    <investigator_full_name>Paolo Fiorina, MD</investigator_full_name>
    <investigator_title>Clinical Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04463849
org study id: 6/2020
nct id: NCT04463849
lead sponsor: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
In recent months, a new coronavirus, SARS-CoV-2, has been identified as the cause of a
      serious lung infection named COVID-19 by the World Health Organization. This virus has spread
      rapidly among the nations of the world and it is the cause of a pandemic and a global health
      emergency. There is still very little scientific evidence on the virus, however
      epidemiological data suggest that one of the most frequent comorbidities is diabetes, along
      with hypertension and heart disease. There is no scientific evidence on the possible effects
      of this infection on the function of the β cell and on glycemic control. Clinical evidence
      seems to suggest that COVID-19 infection mostly affects the respiratory system, and an acute
      worsening of glycemic compensation is not described as generally observed in bacterial
      pneumonia. However, previous work on acute respiratory syndromes (SARS) caused by similar
      coronaviruses, had described that the infection has multi-organ involvement related to the
      expression of the SARS coronavirus receptor, the angiotensin 2 converting enzyme, in
      different organs, especially at the level of endocrine pancreatic tissue. In the population
      of this previous work, glucose intolerance and fasting hyperglycaemia have been described and
      in 37 of 39 diabetic patients examined, a remission of diabetes was observed three years
      after the infection. It is possible that the coronaviruses responsible for SARS may enter the
      pancreatic islets using the angiotensin 2 converting enzyme receptor, expressed at the level
      of the endocrine pancreas, thus causing diabetes. Additionally, previous literature on
      coronavirus infections (SARS and MERS or Middle-East Respiratory Syndrome) suggested that
      diabetes could worsen the evolution of the disease. In particular, in case of Middle-East
      Respiratory Syndrome-CoV infection, diabetic mice had a more prolonged serious illness and a
      delay in recovery regardless of the viremic titer. This could probably be due to a
      dysregulation of the immune response, which results in more serious and prolonged lung
      disease.

      There are currently no data on pancreatic beta cell function in patients with COVID-19.
The project is monocentric, interventional, non-pharmacological, non-profit. Patients will be
      enrolled in hospital for confirmed COVID-19 infection (with reverse transcriptase-polymerase
      chain reaction on the airway swab) but with normal basal blood glucose and no previous
      history of diabetes or impaired fasting glucose or impaired glucose tolerance. Patients will
      be compared to a control group of healthy volunteers, not affected by COVID-19 and with no
      previous history of diabetes or impaired fasting glucose or impaired glucose tolerance.
      Patients will be also compared with a group of patients with type 2 diabetes but without
      COVID-19. Once the informed consent has been signed, the clinical parameters and biochemical
      parameters will be collected according to the time points provided by the protocol in
      positive COVID-19 patients, in healthy volunteers and in patients with type 2 diabetes.

      COVID-19 positive patients and healthy controls as well as patients with type 2 diabetes,
      will undergo a stimulation test of β-cell function (evaluation of the secretive response of
      insulin to the stimulation test with arginine infusion) and the monitoring of glycemic values
      through a professional retrospective continuous glucose monitoring. For the test, an infusion
      solution containing 25% arginine hydrochloride will be used, arginine is an insulinogenic
      amino acid, useful to verify the possible existence of damage to the cellular beta function
      induced by COVID-19 infection, clinically observable with changes in insulin secretory
      response. Given the usefulness of the test, performed for diagnostic purposes, this protocol
      is identified as "non-pharmacological". The test is contraindicated only in patients with
      severe hepatic and renal insufficiency, in all other subjects the side effects are minimal
      and spontaneous resolution before the end of the test (flushing 33%, oral paraesthesia 46%,
      nausea 12%, dizziness 14%). For the stimulation test with arginine infusion, after the basal
      sampling at (0 minutes), an intravenous injection of arginine 5 grams will be practiced in 60
      seconds followed by serial withdrawals at +2, +5, +10 and +30 minutes. The following analytes
      will be assayed on the basal sample: glycosylated hemoglobin, glycaemia, insulin,
      pro-insulin, C-peptide, glucagon, serum inflammatory cytokines (Il1β, IL-2, IL-6, IL-7,
      IL-10, TNF- α, IFN-γ, MIP-1β, MCP-1, GM-CSF, G-CSF Insulin, C-peptide and glucagon will be
      dosed on all points of the curve.
allocation: Non-Randomized
intervention model: Crossover Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: Serum β - cellular function index insulin levels
time frame: all data were collected at Visit 1, 12 months
description: Difference in insulin levels during and after COVID-19 infection and compared to patients in the control group
measure: Serum β - cellular function index C-peptide levels
time frame: all data were collected at Visit 1, 12 months
description: Difference in C-peptide levels during and after COVID-19 infection and compared to patients in the control group
measure: Serum β - cellular function HOMA-β index
time frame: all data were collected at Visit 1, 12 months
description: Difference in HOMA-β index during and after COVID-19 infection and compared to patients in the control group
measure: Serum β - cellular function pro-insulin/insulin ratio
time frame: all data were collected at Visit 1, 12 months
description: Difference in pro-insulin/insulin ratio during and after COVID-19 infection and compared to patients in the control group
measure: Evaluation of the secretory response of insulin to the arginine stimulation test
time frame: all data were collected at Visit 1, 12 months
description: Check for the existence of damage to the beta cell function induced by COVID-19 infection, clinically observable with changes in the secretory response of insulin
measure: Percentage of patients with preserved β cells function
time frame: all data were collected at Visit 1, 12 months
description: Evidence of impairment of β cell function in the serum of COVID-19 patients
measure: Glucose values
time frame: all data were collected at Visit 1, 12 months
description: Changes in glucose values in COVID-19 patients and healthy volunteers
measure: Values of continuous glucose monitoring
time frame: all data were collected at Visit 1 and after 7 days, 12 months
description: Changes in the values of continuous glucose monitoring in both COVID-19 patients and healthy volunteers
measure: Changes in the inflammatory marker interleukin 1-β
time frame: all data were collected at Visit 1, 12 months
description: Comparison of interleukin 1-β levels in COVID-19 patients compared with healthy subjects
measure: Changes in the inflammatory marker interleukin IL-2
time frame: all data were collected at Visit 1, 12 months
description: Comparison of interleukin IL-2 levels in COVID-19 patients compared with healthy subjects
measure: Changes in the inflammatory marker interleukin IL-6
time frame: all data were collected at Visit 1, 12 months
description: Comparison of interleukin IL-6 levels in COVID-19 patients compared with healthy subjects
measure: Changes in the inflammatory marker interleukin IL-7
time frame: all data were collected at Visit 1, 12 months
description: Comparison of interleukin IL-7 levels in COVID-19 patients compared with healthy subjects
measure: Changes in the inflammatory marker interleukin IL-10
time frame: all data were collected at Visit 1, 12 months
description: Comparison of interleukin IL-10 levels in COVID-19 patients compared with healthy subjects
measure: Changes in the inflammatory marker tumor necrosis factor-α
time frame: all data were collected at Visit 1, 12 months
description: Comparison of interleukin tumor necrosis factor-α levels in COVID-19 patients compared with healthy subjects
measure: Changes in the inflammatory marker interferon gamma
time frame: all data were collected at Visit 1, 12 months
description: Comparison of interferon gamma levels in COVID-19 patients compared with healthy subjects
measure: Changes in the inflammatory marker macrophage inflammatory protein-1β
time frame: all data were collected at Visit 1, 12 months
description: Comparison of macrophage inflammatory protein-1β levels in COVID-19 patients compared with healthy subjects
measure: Changes in the inflammatory marker monocyte chemoattractant protein-1
time frame: all data were collected at Visit 1, 12 months
description: Comparison of macrophage inflammatory monocyte chemoattractant protein-1 in COVID-19 patients compared with healthy subjects
measure: Changes in the inflammatory marker granulocyte-macrophage colony-stimulating factor
time frame: all data were collected at Visit 1, 12 months
description: Comparison of macrophage inflammatory granulocyte-macrophage colony-stimulating factor in COVID-19 patients compared with healthy subjects
measure: Changes in the inflammatory marker granulocyte colony-stimulating factor
time frame: all data were collected at Visit 1, 12 months
description: Comparison of macrophage inflammatory granulocyte colony-stimulating factor in COVID-19 patients compared with healthy subjects
arm group label: COVID-19 positive patients
arm group type: Experimental
description: Patients will be enrolled in hospital for confirmed COVID-19 infection (with reverse transcriptase-polymerase chain reaction on the airway swab) but with normal basal glucose and no previous history of diabetes or impaired fasting glucose or impaired tolerance glucose. Patients will be placed with a professional retrospective glucose monitoring device and will be tested for stimulation with arginine infusion. The device will be placed on the day of the test and will be removed after seven days of recording the glycemic data. During the entire recording period, parameters such as mean glucose, estimated glycosylated hemoglobin, peak glucose and nadir, blood sugar levels above the limit of 140 mg / dL, average glucose values at 60 and 120 minutes after meals, standard deviation and variability coefficient.
arm group label: Healthy volunteers
arm group type: Other
description: Healthy volunteers, not affected by COVID-19 and with no previous history of diabetes or impaired fasting glucose or impaired glucose tolerance will be enrolled. Healthy volunteers will be placed with a professional retrospective glucose monitoring device and will be tested for stimulation with arginine infusion. The device will be placed on the day of the test and will be removed after seven days of recording the glycemic data. During the entire recording period, parameters such as mean glucose, estimated glycosylated hemoglobin, peak glucose and nadir, blood sugar levels above the limit of 140 mg / dL, average glucose values at 60 and 120 minutes after meals, standard deviation and variability coefficient.
arm group label: Type 2 diabetes patients
arm group type: Other
description: Patients with established Type 2 diabetes, not affects by COVID-19. Patients will be placed with a professional retrospective glucose monitoring device and will be tested for stimulation with arginine infusion. The device will be placed on the day of the test and will be removed after seven days of recording the glycemic data. During the entire recording period, parameters such as mean glucose, estimated glycosylated hemoglobin, peak glucose and nadir, blood sugar levels above the limit of 140 mg / dL, average glucose values at 60 and 120 minutes after meals, standard deviation and variability coefficient.
intervention type: Diagnostic Test
intervention name: Stimulation test with arginine infusion in order to verify the possible existence of damage to the beta cell function induced by COVID-19 infection
description: All participants will be subjected to the collection of glycemic data through continuous professional retrospective monitoring of blood glucose for seven days, positioned on the day the test will be performed. During the entire recording period, parameters such as mean glucose, estimated glycosylated hemoglobin, peak glucose and nadir, blood sugar levels above the limit of 140 mg / dL, average glucose values at 60 and 120 minutes after meals, standard deviation and variability coefficient.
The evaluation of insulin secretion will be evaluated by performing the stimulus test with arginine infusion according to validated protocols.
arm group label: COVID-19 positive patients
arm group label: Healthy volunteers
arm group label: Type 2 diabetes patients
other name: Positioning of the device for glycemic monitoring
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: Italy
citation: Deng SQ, Peng HJ. Characteristics of and Public Health Responses to the Coronavirus Disease 2019 Outbreak in China. J Clin Med. 2020 Feb 20;9(2):575. doi: 10.3390/jcm9020575.
PMID: 32093211
citation: Kulcsar KA, Coleman CM, Beck SE, Frieman MB. Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infection. JCI Insight. 2019 Oct 17;4(20):e131774. doi: 10.1172/jci.insight.131774.
PMID: 31550243
citation: Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24. Erratum In: Lancet. 2020 Jan 30;:
PMID: 31986264
citation: Yang JK, Lin SS, Ji XJ, Guo LM. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta Diabetol. 2010 Sep;47(3):193-9. doi: 10.1007/s00592-009-0109-4. Epub 2009 Mar 31.
PMID: 19333547
citation: Shankar SS, Vella A, Raymond RH, Staten MA, Calle RA, Bergman RN, Cao C, Chen D, Cobelli C, Dalla Man C, Deeg M, Dong JQ, Lee DS, Polidori D, Robertson RP, Ruetten H, Stefanovski D, Vassileva MT, Weir GC, Fryburg DA; Foundation for the National Institutes of Health beta-Cell Project Team. Standardized Mixed-Meal Tolerance and Arginine Stimulation Tests Provide Reproducible and Complementary Measures of beta-Cell Function: Results From the Foundation for the National Institutes of Health Biomarkers Consortium Investigative Series. Diabetes Care. 2016 Sep;39(9):1602-13. doi: 10.2337/dc15-0931. Epub 2016 Jul 12.
PMID: 27407117
citation: Brandle M, Lehmann R, Maly FE, Schmid C, Spinas GA. Diminished insulin secretory response to glucose but normal insulin and glucagon secretory responses to arginine in a family with maternally inherited diabetes and deafness caused by mitochondrial tRNA(LEU(UUR)) gene mutation. Diabetes Care. 2001 Jul;24(7):1253-8. doi: 10.2337/diacare.24.7.1253.
PMID: 11423511
responsible party type: Principal Investigator
investigator affiliation: University of Milan
investigator full name: Paolo Fiorina, MD
investigator title: Clinical Professor
mesh term: COVID-19
sharing ipd: No