The objective of this study is to demonstrate the different effects of two DPP-4 inhibitors(Sitagliptin, Saxagliptin)and the insulin secretagogue: glimepiride on first and second phase insulin secretion by using a Biphase-Hyperglycemic Clamp and to explore the different effects of the study drugs on the GLP-1 response, and the glucagon concentration which indicates alpha cell function in healthy subjects.

After enrollment and two weeks screening period eligible subjects will be counseled to follow a dietary program for approximately 2 wk and recorded of personal history, full clinical examination and screening blood samples.

Subjects will be randomized using a computer-generated allocation schedule to one of 12 sequences during which each subjects will be assigned to take 4 times of bi-phase hyperglycaemic clamp experiments at a randomized sequence separated by a washout period of 7-14d.

At each experimental day, the subject will take the given dose of Sitagliptin, Saxagliptin, Glimepiride and nothing for blank control two hours before the clamp experiment starts.

The hyperglycaemic clamp will be performed after an overnight fast. Subjects will be placed in a recumbent position and cannula will be inserted in a dorsal hand vein. The hand will be placed in a heating box (42C) throughout the experiment to allow frequent sampling of arterialized blood. A second cannula will be inserted in a contralateral cubital vein for glucose infusion.

At time zero (0 min), a 50% glucose bolus will be injected during 1 min to increase PG to 12mM. The glucose bolus will be calculated as:(12mM-FPG)×35 mg glucose × body weight (kg). PG will be measured bedside every 5 min and maintained at 12mM by an adjustable continuous 20% glucose infusion. After 90min, PG will be lowered down below 6mM for the islet cells to rest, then the subject will be instructed to consume 75g glucose solution orally in 5min, PG will be measured bedside every 5 min and maintained below 6mM for 40min then restart the 90min-hyperglycaemic clamp experiment. The oral period of hyperglycaemic clamp process is the same as what's done in fasting period. Blood samples will be collected in -2h, 0min, 10min, 90min in both hyperglycaemic clamp experimental process for the measurement of insulin, C-peptide, glucagon, active GLP-1, total GLP-1 and DPP-4 activity.

Thus we could evaluate the beta cell function represented by the first phase and the second phase of insulin secretion(C-peptide secretion) and alpha cell function represented by the change of glucagon concentration during the fasting period and oral period of hyperglycaemic clamp experiment and the change of active GLP-1, total GLP-1 and DPP-4 activity as well.

Inclusion Criteria:

1. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted;
2. Having good study compliance;
3. Healthy Male subjects between 20-30 years of age (inclusive), and in good health as determined by past medical history, physical examination, vital signs, and clinical laboratory test;
4. Must have a body mass index (BMI) between 19-25kg/m2 (inclusive);
5. No weight fluctuation greater than 5% in late 3 months。

Exclusion Criteria:

1. With impaired glucose tolerance, T2DM or any significant medical condition (within 3 years), laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study;
2. Used any prescribed systemic or topical medication within 30 days of the first dose administration;
3. Any medical or surgical conditions possibly affecting study drug absorption, distribution, metabolism and excretion;
4. Participated in a clinical study involving administration of an investigational drug within 90 days preceding the first dose administration or within five half-lives of the first dose administration (whichever is longer);
5. Donated blood or plasma or had any other significant blood loss within 2 months preceding the first dose administration;
6. History of multiple drug allergies;
7. Any clinically significant allergic disease;
8. Recently drug or alcohol abuse (>35 unit/week, 1 unit=8g alcohol @ 1 standard drink @ 250ml beer @ 140ml wine @ 25ml strong alcohol drink like whiskey);
9. Smokers or users of other tobacco products in the 3 months prior to screening.