Incretin-based therapy is currently one of the most popular diabetes treatment approaches. However, differences of response ware found in previous studies. We hypothesis that SNPs of DPP-4, GLP-1 and GLP-1R genes may play crucial roles in the response differences. Therefore, this study aims to investigate the correlation of incretin-related gene polymorphism and individual differences in the response of DPP-4 inhibators (take Sitagliptin as an example). In addition, The distribution differences of the SNPs in diabetics and non-diabetics are evaluated to study the relationships between the SNPs and diabetes onsets.

Single Nucleotide Polymorphism (SNP) plays an important role in the differences of clinical manifestations and drug responses of diseases. The vast majority of SNP sites are located in the non-coding region of the gene (about 95%), which is called SNP(non-coding SNP (ncSNP), while the other part of SNP is located in the coding region of the gene, which is called coding SNP (cSNP). Furthermore, cSNP can be divided into two categories: SNP that does not change the encoded amino acid sequence is called synonymous SNP(synonymous SNP, SSNP); SNP that changes amino acid sequence is called SNP(non-synonymous SNP (NSNP). Although not involved in coding amino acid, some ncSNPs may also affect the regulation of protein expression. Therefore, it is of great significance to study the effects of NC SNP and cSNP on the occurrence and development of diseases and drugs.

DPP-4 enzyme inhibitor is combined with DPP-4 enzyme in human body to reduce hydrolysis of active GLP-1, thus increasing the level of endogenous active GLP-1. Active GLP-1 combines with its receptor GLP-1R to promote insulin release and inhibit glucagon release in hyperglycemia state, and produces opposite effect in hypoglycemia state.

Based on the above principles, we speculate that SNP of genes that may affect the hypoglycemic effect of DPP-4 enzyme inhibitor are:

1. SNP of DPP-4 enzyme gene. SNP of DPP-4 enzyme gene may affect the enzyme activity and/or protein expression level of DPP-4. Assuming that the effect of DPP-4 enzyme inhibitor is sufficient, patients with higher DPP-4 enzyme activity are more sensitive to DPP-4 enzyme inhibitor drugs; However, for patients with low DPP-4 enzyme activity, DPP-4 enzyme inhibitor drugs cannot play a stronger role in lowering blood sugar.
2. SNP of GLP-1 gene. SNP of GLP-1 gene may affect activity or expression level of GLP-1. Patients with high GLP-1 level are more sensitive to DPP-4 enzyme inhibitor drugs.
3. SNP of GLP-1R gene. SNP of GLP-1R gene may affect activity or expression level of GLP-1R. Patients with high GLP-1R level are also more susceptible to DPP-4 enzyme inhibitor drugs.

However, studies on the hypoglycemic effect of DPP-4, GLP-1 and their receptors on DPP-4 enzyme inhibitors in the treatment of T2DM are rare, which is not conducive to the evaluation of individualized treatment of such drugs. Therefore, this chapter intends to select SNP sites with high mutation frequencies of DPP-4, GLP-1 and GLP-1R genes to study the mutation frequencies of these SNPs in diabetic patients and non-diabetic patients and their effects on DPP-4 enzyme inhibitor sitagliptin's hypoglycemic effect on T2DM patients.

For Sitagliptin group--

Inclusion Criteria:

1. According to diagnostic criteria from Chinese type 2 diabetes prevention and treatment guidelines in diabetes, that published in the Chinese Medical Association Diabetes credits in 2010: Symptoms of diabetes (polydipsia, polyphagia, polyuria, weight loss, itchy skin, blurred vision and other acute metabolic disorders performance caused by hyperglycemia) and RBG≥11.1mmol/L, or fasting plasma glucose (FPG)≥7.0mmol/L, or plasma glucose of 2 hours post glucose-load≥11.1 and patients diagnosed with type 2 diabetes; HbA1c in the range of 7%-10%;
2. Age 40-70 years;
3. Body Mass Index(BMI) 18-40;
4. Did not accepted any antihyperglycemic therapies during the past 4 weeks, or did not change their antihyperglycemic treatment plan in the past 3 months;
5. Did not participate in clinical trials within three months;
6. No serious heart, brain, liver and kidney disease;
7. Signed informed consent.

Exclusion Criteria:

1. Have taken any incretin drugs within recent 1 month;
2. Patients with a weakened immune system;
3. C-peptide < 0.3ng/ml;
4. GLP-1 and DPP4-i drugs allergies;
5. Pregnancy and breast-feeding patients;
6. Patients taking drugs that may affect the metabolism of GLP-1 and DPP4;
7. Patients have serious heart, liver, kidney and respiratory dysfunction; Patients have medullary thyroid carcinoma (MTC) with past history or family history, as well as multiple endocrine neoplasia type 2 syndrome (MEN2);
8. Drug abusing and alcoholism within a year.

For non-T2D group--

No major diseases such as tumors, no dyslipidemia, chronic diseases such as hypertension, and non-diabetic patients whose blood sugar and glycated hemoglobin values cannot meet the criteria for diagnosis of T2DM, and the age is over 50 years old.

3 months

All-Cause Mortality, Serious, or Other (non-serious) Adverse Events were monitored/assessed, but no All-Cause Mortality or Serious Adverse Events observed during the study period.The dosage and administration of the drugs were not adjusted, and all adverse reactions improved after 3 days.