Study to Investigate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK2330672 in Type 2 Diabetes Patients Taking Metformin

Metformin may have complex interactions in the gut and is generally first line therapy for type 2 diabetes mellitus (T2DM). It is important to understand whether there are significant pharmacokinetic or pharmacodynamic interactions when GSK2330672 is co-administered with metformin in subjects with T2DM. The purpose of this study is to investigate the safety and tolerability of GSK2330672 administered for 7 days to subjects with T2DM taking metformin. This will be a two-period crossover study; subjects will receive either GSK2330672 or placebo for 7 days in each period separated by a washout period of 13 to 15 days. All subjects will receive metformin throughout the study


Eligibility Criteria:
Inclusion Criteria:

* Males and females aged between 30 and 64 years of age inclusive, at the time of signing the informed consent.
* Subjects with documented T2DM diagnosis (diagnosed not less than 3 months prior to screening); AND one of the following: taking stable metformin 850 milligrams (mg) twice daily (BID) (or the equivalent of 1700 mg/day) for at least 4 weeks prior to screening and a glycosolated haemoglobin A1c (HbA1c) of \>=7.0% to \<=11% at screening; OR taking stable metformin of \>=1000 mg/day to \<1700 mg/day for at least 4 weeks prior to screening and a HbA1c of \>=7.5% to \<=11% at Screening; OR taking stable metformin of \>1700 to \<=2000 mg/day for at least 4 weeks prior to screening and a HbA1c of \>=7.0% to \<=10% at screening; not taking other anti-diabetic medications.
* All T2DM subjects must meet label recommendations for metformin, including: Adequate renal function, as evidenced by the Modification of Diet in Renal Disease estimate of glomerular filtration rate \>=60 milliliters (mL)/minute (min); No conditions which make hypoxia, dehydration, or sepsis likely; No clinical or laboratory evidence of hepatic disease (including history of cholecystitis or symptomatic gallstones) and cardiac disease (including a history of myocardial infarction or heart failure). Subjects with a history of cholelithiasis and uncomplicated cholecystectomy more than 3 months before screening may be eligible if approved by the GlaxoSmithKline (GSK) Medical Monitor; No excessive alcohol intake.
* C-peptide of \>0.8 nanogram (ng)/mL at screening visit.
* Urine albumin-to-creatinine ratio \<30 mg/gram (g).
* Fasting plasma glucose \<280 mg/decilitre (dL)
* Body mass index (BMI) of 24 to 40 kilograms (kg)/square meter (m\^2), inclusive
* In good general health with (in the opinion of the investigator) no clinically significant and relevant abnormalities of medical history or physical examination that would introduce additional risk factors or interfere with study procedures or objectives, based on a medical evaluation including medical history, physical examination, vital signs and laboratory tests.
* Female subjects of non-childbearing potential. Non-childbearing potential is defined as: Pre-menopausal females with a documented tubal ligation or hysterectomy \[for this definition, "documented" refers to the outcome of the investigator's/designee's review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records\]. Postmenopausal defined as 12 months of spontaneous amenorrhea. In questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 milli international units (MIU)/mL and estradiol \< 40 picograms (pg)/mL (\<147 picomole \[pmol\]/liter \[L\]) is confirmatory. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the acceptable contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2 to 4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.
* Male subjects with female partners of child-bearing potential must agree to use one of the acceptable contraception methods. This criterion must be followed from the time of the first dose of study medication until follow up visit.
* Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form

Exclusion Criteria:

* CRITERIA BASED UPON MEDICAL HISTORIES:
* Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome).
* History of chronic or acute pancreatitis. Approval from the GSK Medical Monitor must be obtained for subjects with a past history of pancreatitis more than 12 months from the start of the treatment period (subjects with a history of pancreatitis within 12 months prior to the start of the treatment period are excluded).
* History of gastrointestinal (GI) disease (e.g., irritable bowel disease, chronic or current diarrhea, inflamed bowel, steatorrhoea/fat malabsorption, celiac disease, symptomatic lactose intolerance). Subjects with gastroparesis requiring treatment are excluded.
* History of significant cardiovascular disease including acute myocardial infarction, stroke, hospitalization for acute coronary syndrome, heart failure within the previous 12 months.
* Uncontrolled hypertension, as evidenced by systolic pressure \>160 or diastolic pressure \>90. Subjects taking anti-hypertensive medications are permitted.
* Significant ECG abnormalities, defined as follows: Heart rate (resting) \<50 and \>100 beats per minute (bpm); PR Interval \<120 and \>220 milliseconds (msec); QRS duration \<70 and \>120 msec
* History of untreated pernicious anemia or who have laboratory parameters suggestive of subclinical megaloblastic anemia (e.g., increased mean corpuscular volume with low red blood cells count and/or haemoglobin level).
* Current or relevant previous significant medical disorder that may require treatment or make the subject unlikely to fully complete the study, or any condition that, in the opinion of the investigator, presents undue risk from the study medication or procedures.
* Thyroid Disease: Uncorrected Thyroid Dysfunction: Fasting plasma thyroid stimulating hormone (TSH) outside of the normal range, as determined at the screening visit; Subjects on stable thyroid replacement therapy and with TSH in the normal range are eligible if approved by the GSK Medical Monitor; Unevaluated thyroid nodule or goiter at Screening.
* History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of \>14 drinks for males or \>7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
* History of sensitivity to heparin or heparin-induced thrombocytopenia.
* History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation
* CRITERIA BASED UPON DIAGNOSTIC ASSESSMENTS:
* Alanine transaminase, alkaline phosphatase and bilirubin \> 1.5x upper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
* Based on averaged QTcF values of triplicate ECGs obtained at least 1 minute apart within approximately 15 minutes: QTcF \>=450 msec; or QTcF \>=480 msec in subjects with Bundle Branch Block (subjects with left bundle branch block are excluded)
* A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
* A positive test for human immunodeficiency virus antibody
* A positive pre-study drug/alcohol urine screen
* A subject with a positive urine cotinine test result will be excluded from the study unless in the judgment of the Investigator the subject will be able to abstain from using tobacco for the duration of the in-house periods of the study.
* OTHER CRITERIA
* Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
* The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
* Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
* A subject with a fasting plasma glucose at Day -1 that is more than 100 mg/dL lower than at screening must not be randomized, unless on a repeat test the value less than 100 mg/dL of the screening value.