Effects and Response of LY2605541 in Patients With Type 1 Diabetes Mellitus (BIDO)

The primary objective is to assess the effect of daily subcutaneous injections of LY2605541
on sleep respiratory quotient, measured during the post-absorptive period (0000 to 0600
hours), compared to daily subcutaneous injections of insulin glargine, in patients with Type
1 diabetes mellitus.

Inclusion Criteria:

- Healthy subjects and patients with T1DM are eligible for enrollment in the study only
if they meet all of the following criteria:

- Cohort A: are male or female patients with T1DM of duration >1 year, as determined by
medical history and physical examination, and are receiving a basal insulin. The
following insulins are permitted if the patient is prepared to transition to once
daily injection of insulin glargine in the evening combined with prandial insulin
use:

- Glargine (once or split dosing),

- Detemir (once or split dosing),

- Neutral Protamine Hagedorn (once or split dosing),

- regular (once or split dosing),

- Insulin pump with rapid acting insulins.

- Cohort B: are overtly healthy males or females, as determined by medical history and
physical examination. male patients: agree to use a reliable method of birth control
during the study and for 3 months following the last dose of the investigational
product. Cohort B subjects are not required to use birth control as they will not
receive any study drugs during this study. female patients: are women of
child-bearing potential (women not surgically sterilized and between menarche and 2
years postmenopause) who test negative for pregnancy at the time of screening based
on a urine pregnancy test and agree to use a reliable method of birth control (for
example, use of oral contraceptives, Norplant®, or contraceptive transdermal patch; a
reliable barrier method of birth control [diaphragms with contraceptive jelly;
cervical caps with contraceptive jelly; condoms with contraceptive foam];
intrauterine device; sexual abstinence, or partner with vasectomy) during the study
and until the time they complete the follow up visit. Cohort B subjects are not
required to take contraceptive medication as they will not receive any study drugs
during this study. or women not of child-bearing potential due to surgical
sterilization (at least 6 weeks after surgical bilateral oophorectomy with or without
hysterectomy or at least 6 weeks after tubal ligation) confirmed by medical history,
or menopause.

Menopausal women include women with either:

1. spontaneous amenorrhea for at least 12 months, not induced by a medical condition
such as anorexia nervosa and not taking medications during the amenorrhea that
induced the amenorrhea (for example oral contraceptives, hormones, gonadotropin
releasing hormone, anti-estrogens, selective estrogen receptor modulators, or
chemotherapy) or

2. spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating hormone level
greater than 40 million international units/mL.

- are between the ages of 18 and 60 years of age, inclusive, at screening.

- have a body mass index of 19 to 30 kg/m2, inclusive.

- have clinical laboratory test results within normal reference range for the
population or investigator site, or results with acceptable deviations that are
judged to be not clinically significant by the investigator.

- have venous access sufficient to allow for blood sampling and IV administration
as per the protocol.

- 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 (ERB) governing the site.

- Cohort A (patients with T1DM) are required to have a glycated hemoglobin (HbA1c)
of ≤9.5%.

Exclusion Criteria:

Cohort A - Patients with T1DM and Cohort B - Healthy Subjects Healthy subjects and
patients with T1DM will be excluded from study enrollment if they meet any of the
following criteria:

- are investigator site personnel directly affiliated with this study and their
immediate families. Immediate family is defined as a spouse, parent, child or
sibling, whether biological or legally adopted.

- are Lilly, Translational Research Institute, University of Wisconsin (UW) Office of
Clinical Trials, UW Nutritional Sciences, UW Health West Endocrinology Clinic, or
Covance employees

- are currently enrolled in a clinical trial involving an investigational product or
off-label use of a drug or device, or are concurrently enrolled in any other type of
medical research judged not to be scientifically or medically compatible with this
study.

- have participated, within the last 30 days, in a clinical trial involving an
investigational product. If the previous investigational product has a long t1/2, 3
months or 5 half-lives (whichever is longer) should have passed.

- are persons who have previously completed or withdrawn from this study or any other
study investigating LY2605541, and have previously received the investigational
product.

- have an abnormal blood pressure that is clinically relevant to this study as
determined by the investigator. Patients who are on antihypertensive medication are
eligible for inclusion in the study, but the doses of the antihypertensive medication
must have been stable for1 month and must not change during the study.

- have a history or presence of cardiovascular, respiratory, hepatic, gastrointestinal,
endocrine (except T1DM, Cohort A), hematological, or neurological disorders capable
of significantly altering the absorption, metabolism, or elimination of drugs; of
constituting a risk when taking the study medication; or of interfering with the
interpretation of data.

- intend to start new concomitant medication during the study, including
over-the-counter and herbal medication (vitamin/mineral supplements, and occasional
acetaminophen are permitted). The use of topical medication may also be permitted if
no evidence of a risk of systemic absorption exists with chronic dosing.

- intend to make dietary changes during the study, that may in the opinion of the
investigator impact on body weight or the results of the study.

- have a previous history of heart disease including atrial fibrillation, QT
prolongation, or angina.

- regularly use known drugs of abuse and/or show positive findings on urinary drug
screening.

- show evidence of human immunodeficiency virus infection and/or positive human
immunodeficiency virus antibodies.

- show evidence of hepatitis C and/or positive hepatitis C antibody.

- show evidence of hepatitis B and/or positive hepatitis B surface antigen.

- are women with a positive pregnancy test or women who are lactating.

- have an average weekly alcohol intake that exceeds 21 units per week (males) and 14
units per week (females), or are unwilling to stop alcohol consumption for the
duration of the study (1 unit = 12 oz or 360 mL of beer; 5 oz or 150 mL of wine; 1.5
oz or 45 mL of distilled spirits).

- have triglyceride levels >400 mg/dL (>4.5 mmol/L); if triglyceride is >400 mg/dL, one
retest is allowed, per investigator discretion. Retest value must be <400mg/dL.

- suffer from insomnia, are shift workers, or have abnormal sleep patterns.

- are smokers.

- are excessive consumers of xanthines (more than 10 cups of tea, coffee, cola, or hot
chocolate per day).

- in the opinion of the investigator or sponsor, are unsuitable for inclusion in the
study.

Cohort A - Patients with T1DM

- have known allergies to LY2605541, related compounds or any components of the
formulation, or history of significant atopy.

- have a previous history or family history of deep vein thrombosis.

- have a previous history of proliferative retinopathy.

- require treatment with any drug other than insulin to treat diabetes.

- have poorly controlled diabetes or are known to have poor awareness of hypoglycemia.

- have had more than 1 episode of severe hypoglycemia (defined as requiring assistance
due to neurologically disabling hypoglycemia) within the last 6 months.

- have had 2 or more emergency room visits or hospitalizations due to poor glucose
control (hyperglycemias or diabetic ketoacidosis) within the last 6 months.

- have a level of insulin resistance, insulin sensitivity, or responsiveness to insulin
(based on insulin doses) that, in the opinion of the investigator, would impact on
the study results.

- use ß-blockers or medications that have been reported to impact on hypoglycemia
awareness within 4 weeks before dosing, or during the study.

- require the use of diuretics within 4 weeks of dosing, or during the study.

- regularly use or intend to use any nutritional supplements, systemic corticosteroids,
or any over-the-counter or prescription medications that affect blood glucose or the
body's sensitivity to insulin or that promote weight loss within the 4 weeks before
dosing, or during the study. Patients who agree to stop taking supplements prior to
or at screening are permitted at the discretion of the investigator. Thyroxine
replacement therapy, and hormone replacement therapy are permitted, however patients
must have been on a stable dose for at least 6 weeks prior to dosing.

- are unwilling to transition to a single daily injection of insulin glargine in the
evening prior to enrollment.

- have suffered significant blood loss or donated blood of more than 500 mL within the
last month.

Cohort- B Healthy Subjects

-have used, or intend to use over-the-counter medication within 7 days or prescription
medication within 14 days of the start of their respiratory quotient measurements (apart
from contraceptive medication, vitamin/mineral supplements, and occasional acetaminophen).