Effect of LY2189265 on Insulin Secretion in Response to Intravenous Glucose
Condition: Diabetes Mellitus, Type 2
MeSH terms: Diabetes Mellitus, Type 2
Intervention: LY2189265; Placebo; Insulin; Glucose; Glucagon
Intervention description: Administered subcutaneously; Administered subcutaneously; Administered intravenously; Administered intravenously; Administered intravenously
Intervention MeSH terms: Dulaglutide; Glucagon; Glucagon-Like Peptide 1
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 32.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      The purpose of this study is to measure the effect of LY2189265 to increase insulin levels in
      response to glucose intake.
    

Eligibility criteria:

        Inclusion Criteria:

        All Participants

          -  Women must be surgically sterile (hysterectomy or bilateral oophorectomy or tubal
             ligation) or postmenopausal as defined by age >45 years without use of oral
             contraceptive agents for greater than 1 year and have either:

               -  spontaneous amenorrhea greater than 12 months, or

               -  spontaneous amenorrhea 6 to 12 months with documented follicle stimulating
                  hormone (FSH) >25 milli international units/milliliter (mIU/mL) and serum
                  estradiol <73 picomoles/liter (pmol/L) (20 picograms/milliliter [pg/mL])

          -  Are reliable and willing to make themselves available for the duration of the study
             and are willing to follow study procedures

          -  Have given written informed consent approved by Lilly and the ethical review board
             governing the site

          -  Have serum creatinine <150 micromoles/liter (µmol/L) (<1.3 milligrams/deciliter
             [mg/dl] in women, <170 µmol/L [<1.5 mg/dL] in men)

          -  Have normal hemoglobin result, as determined by the investigator

        Healthy Participants

          -  Overtly healthy men and women as determined by medical history, normal lab results and
             physical examination.

          -  Body mass index (BMI) between 19 and 25 kilograms/meter squared (kg/m^2), inclusive.

          -  Normal blood pressure and heart rate as determined by the investigator

          -  Have a normal response to an oral glucose tolerance test (OGTT) (glucose <7.8
             millimoles/liter [mmol/L] [<140 mg/dL] at 2 hours after 75 grams (g) oral glucose
             load)

        Participants with type 2 diabetes mellitus (T2DM)

          -  Participants will have a BMI between 22.0 and 40.0 kg/m^2

          -  Have T2DM controlled with diet and exercise alone or metformin for at least 4 weeks
             prior to admission

          -  Have a hemoglobin A1c (HbA1c) value at screening (or within 4 weeks prior to
             screening) of 6.0% to 9.5%

          -  Diagnosed with T2DM within the past 10 years

          -  Clinical laboratory test results within normal range or deemed clinically
             insignificant by the Investigator. Abnormalities of serum glucose, serum lipids,
             urinary glucose, and urinary protein consistent with T2DM are acceptable.

          -  Participants who are taking stable-dose prescription medications (for example,
             antihypertensive agents, aspirin, lipid-lowering agents) for treatment of concurrent
             medical conditions are permitted to participate providing the medication is not
             associated with development of torsade de pointes. However, use of beta-blockers and
             thiazide diuretics are not permitted during this study.

        Exclusion Criteria:

        All Participants

          -  Within 30 days of the initial dose of study drug, have received treatment with a drug
             that has not received regulatory approval for any indication

          -  Known allergies to Glucagon-Like Peptide 1 (GLP-1) related compounds

          -  Have previously completed or withdrawn from this study or any other study in the last
             year investigating glucagon-like peptides or incretin mimetics including exenatide
             (Byetta®)

          -  Regular use of known drugs of abuse and/or positive findings on urinary drug
             screening, other than findings consistent with medication prescribed by the
             participant's physician(s)

          -  History or presence of cardiovascular, respiratory, renal, endocrine (except T2DM),
             hematological, or neurological disorders capable of significantly altering the
             absorption, metabolism, or elimination of drugs or of constituting a risk when taking
             the study medication or interfering with the interpretation of data

          -  Have a history or presence of gastrointestinal disorder

          -  Poorly controlled hypertension (systolic greater than 160 millimeters of mercury
             [mmHg], diastolic greater than 95 mmHg) and/or evidence of labile blood pressure
             including symptomatic postural hypotension. Use of beta-blockers or thiazide diuretics
             is not permitted during the study

          -  Have a clinically significant history of cardiac disease or presence of active cardiac
             disease within 1 year of the screening period

          -  Evidence of hepatitis C and/or positive hepatitis C antibody

          -  Evidence of hepatitis B and/or positive hepatitis B surface antigen

          -  Evidence of human immunodeficiency virus (HIV) and/or positive for HIV antibodies

          -  Have an average weekly alcohol intake that exceeds 21 units per week (males) and 14
             units per week (females) or are unwilling to follow alcohol restrictions (1 unit = 12
             ounces [oz] or 360 milliliters[mL] of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of
             distilled spirits).

          -  Smoke more than 10 cigarettes or equivalent in nicotine use or nicotine substitutes
             per day

          -  Regular use of systemic corticosteroids by oral, intravenous, or intramuscular route,
             or potent, inhaled, or intranasal steroids known to have a high rate of systemic
             absorption

          -  Have a history or presence of significant active neuropsychiatric disease

          -  Blood donation of more than 500 mL in the last 3 months or any blood donation within
             the last month

          -  Any other condition, which in the opinion of the investigator would preclude
             participation in the study

          -  An abnormality in the 12-lead electrocardiogram (ECG) that in the opinion of the
             investigator increases the risk of participating in the study.

          -  Any clinically significant abnormal hematology, clinical chemistry, or urinary
             result(s) as determined by the investigator

          -  Evidence of significant active uncontrolled endocrine or autoimmune abnormalities (for
             example thyroid disease, or pernicious anemia) as judged by the screening physician

        Healthy Participants

          -  Intended use of over-the-counter or prescription medication 7 and 14 days,
             respectively, prior to dosing.

        Participants with T2DM

          -  Clinically significant peripheral vascular occlusive disease (PVOD).

          -  Known severe exudative diabetic retinopathy

          -  Known significant autonomic neuropathy as evidenced by urinary retention, diabetic
             diarrhea, or gastroparesis

          -  Have experienced a ketoacidotic episode (pH less than 7.3) requiring hospitalization
             in the last 6 months

          -  Outpatient use of insulin for control of diabetes within the past 2 years

          -  Use of antidiabetic agents other than metformin in the 4 weeks prior to study entry or
             use of thiazolidinediones within 12 weeks of study entry