Effect of LY2189265 on Insulin Secretion in Response to Intravenous Glucose

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