You are here
- Home
- This website is now closed
Pharmacogenetics of diabetes
Day 4
June 13, 2005: In this session at the American Diabetes Association’s annual meeting in San Diego, CA, USA, presenters discussed recent developments in the field of pharmacogenetics that promise to change the landscape of diabetes research and management.
The emergence of pharmacogenetics in diabetes research
Professor Scott Taylor, University of Waterloo, Ontario, Canada
In this presentation, Dr. Taylor provided an overview of the emergence of pharmacogenetics study of how genetic inheritance or genomic variation influences response to pharmacotherapy in diabetes.
Specifically, Dr. Taylor focused on recent evidence regarding heterogeneity in the genetic causes of hyperglycemia, insulin resistance, and response to treatment in patients with Type 2 diabetes.
A meta-analysis of 27 trials conducted in 2003 highlighted the association between Type 2 diabetes and the Gly972Arg variant in the insulin receptor substrate-1 (IRS-1) gene. [1]
Encompassing 3408 cases and 5419 control patients, the study showed that carriers of the 972Arg variant of the IRS-1 gene are at a 25% increased risk of having Type 2 diabetes compared with non-carriers.
Another study demonstrated that diabetic patients carrying the Arg(972) IRS-1 variant were at increased risk for secondary failure to sulfonylureas. [2]
This analysis of 477 patients with Type 2 diabetes showed that 53 patients (11.1%) were heterozygous for the Arg(972) IRS-1 variant, one patient (0.2%) was homozygous for the variant, and 423 patients (88.7%) were homozygous for the wild-type allele.
The frequency of the Arg(972) IRS-1 variant was 8.7% among diabetic patients who were well controlled with oral therapy, compared with 16.7% among patients with secondary failure to sulfonylureas (odds ratio 2.1; p=0.01).
Conversely, some patients with diabetes caused by mutations in the hepatocyte nuclear factor 1alpha (HNF-1alpha) gene are particularly sensitive to the hypoglycemic effects of sulfonylureas.
A randomized crossover trial of 36 patients, evaluated whether the glycemic responses to gliclazide and metformin differed in patients with HNF-1alpha diabetes and Type 2 diabetes. [3] The possible mechanisms for sulfonylurea sensitivity through insulin sensitivity, insulin secretory response to glucose and tolbutamide, and tolbutamide clearance, were also explored.
Patients with HNF-1alpha diabetes had a 5.2-fold greater response to gliclazide than to metformin (p=0.0007), and a 3.9-fold greater response to gliclazide than those with Type 2 diabetes (p=0.002).
Although sulfonylurea metabolism was similar in both patient groups, patients with HNF-1alpha diabetes had a strong insulin secretory response to intravenous tolbutamide, despite a small response to intravenous glucose.
Patients with HNF-1alpha diabetes were also more insulin-sensitive than those with Type 2 diabetes. This suggests that HNF-1alpha diabetes is associated with marked sulfonylurea sensitivity. Moreover, this finding is consistent with models of HNF-1alpha deficiency, which show that the beta-cell defect is upstream of the sulfonylurea receptor.
Recently, the effects of rosiglitazone on adiponectin and plasma glucose levels in relation to common adiponectin gene (ACDC) polymorphisms, specifically the single nucleotide polymorphism (SNP)45 and SNP276 of ACDC, were studied. [4] In this trial, 166 patients with Type 2 diabetes were treated with rosiglitazone (4 mg, once daily) for 12 weeks without changing any of their previous medications.
Compared with carriers of other genotypes, carriers of the GG genotype of SNP45 experienced a smaller reduction in the fasting plasma glucose (FPG) level and the HbA1c value (p=0.031 and p=0.013, respectively).
Patients with the GG genotype also underwent a smaller increase in the serum adiponectin concentration compared with those with other genotypes (p=0.003).
Carriers of the GG genotype of SNP276 also had a more modest reduction in the FPG level compared with patients with other genotypes (p=0.001). Overall, these findings suggest that genetic variations in the adiponectin gene in Type 2 diabetic patients can affect the response to rosiglitazone treatment, particularly with respect to circulating adiponectin levels and blood glucose control.
Dr. Taylor concluded his presentation with a discussion of an attractive target for diabetes treatment: protein tyrosine phosphatase 1B (PTP1B). A variety of potent and selective small-molecule PTP1B inhibitors have been identified and are currently under preclinical evaluation for the treatment of diabetes.
Lessons in pharmacogenomics of cardiovascular disease and microvascular complications
Professor Donna K. Arnett, University of Alabama at Birmingham, AL, USA
In this presentation, Dr. Arnett discussed recent findings within the fields of cardiovascular (CV) and microvascular research that may be applicable to the pharmacogenomic study of diabetes.
Large-scale CV studies have shown that there is a considerable variation in response to pharmacologic treatment. For example, patients can have a range of responses to statin therapy.
Following treatment with statins, patients experience a reduction of low-density lipoprotein cholesterol (LDL-C) levels ranging from 18-56%, a reduction in triglyceride (TG) levels of 7-30%, and an increase in high-density lipoprotein cholesterol (HDL-C) levels ranging from 5-15%.
Despite these variations in response, statin studies have consistently shown a significant benefit in reducing major coronary events, invasive coronary procedures, stroke, and CV mortality.
Similar variations in response have been observed following treatment with fibric acids. Indeed, fibric acids have been shown to lower LDL-C by 5-20%, reduce TGs by 20-50%, and increase HDL-C by 10-20%.
The Diabetes Atherosclerosis Intervention Study (DAIS) identified genetic predictors of response to fenobribrate therapy in patients with Type 2 diabetes and at least one visible coronary lesion.
In DAIS, 207 patients were randomized to treatment with micronized fenofibrate (200 mg, once daily) and 211 patients were treated with placebo. After a minimum 3-year follow-up, patients treated with fenofibrate showed a significantly smaller increase in mean percentage diameter stenosis compared with patients in the placebo group (2.11% vs 3.65%, respectively; p=0.02).
Patients in the fenofibrate group also had a significantly smaller decrease in minimum lumen diameter compared with those in the placebo group (-0.06 mm vs -0.10 mm, respectively; p=0.029). Importantly, variations in response to fenofibrate therapy were shown to be driven by two peroxisome proliferator-activated receptor (PPAR)-alpha variants.
Large within- and between-person variations in response to antihypertensive medications have been demonstrated, although the mechanisms driving much of this variability remain unclear.
Upcoming results of the Genetics of Hypertension Associated Treatment (GenHAT) trial may shed important light on the variation in patient response to antihypertensive agents.
GenHAT is a prospective study ancillary to the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), where 42,515 patients with hypertension were randomized to one of four antihypertensive agents: lisinopril, chlorthalidone, amlodipine, or doxazosin.
GenHAT will characterize hypertension genetic variants and determine their interaction with antihypertensive treatments in relation to coronary heart disease. DNA from patients enrolled in ALLHAT will be used to genotype variants of hypertension genes:
Several other gene-treatment interactions will be evaluated in GenHAT, including all-cause mortality, stroke, heart failure, left ventricular hypertrophy, decreased renal function, peripheral arterial disease, and blood pressure lowering.
Because of the ethnic and gender diversity of ALLHAT, the effects of these genetic variants on outcomes in key subgroups such as patients aged >65 years, women, African Americans, and patients with Type 2 diabetes will also be evaluated.
References
1. Arnett DK, Boerwinkle E, Davis BR, et al . Pharmacogenetic approaches to hypertension therapy: design and rationale for the Genetics of Hypertension Associated Treatment (GenHAT) study. Pharmacogenomics J 2002; 2 :309-317.
2. Jellema A, Zeegers MP, Feskens EJ et al . Gly972Arg variant in the insulin receptor substrate-1 gene and association with Type 2 diabetes: a meta-analysis of 27 studies. Diabetologia 2003; 46 :990-995.
3. Kang ES, Park SY, Kim HJ et al . The influence of adiponectin gene polymorphism on the rosiglitazone response in patients with type 2 diabetes. Diabetes Care 2005;28 :1139-1144.
4. Pearson ER, Starkey BJ, Powell RJ et al . Genetic cause of hyperglycemia and response to treatment in diabetes. Lancet 2003; 362 :1275-1281.
5. Sesti G, Marini MA, Cardellini M et al . The Arg972 variant in insulin receptor substrate-1 is associated with an increased risk of secondary failure to sulfonylurea in patients with type 2 diabetes. Diabetes Care 2004; 27 :1394-1398
June 13, 2005: In this session at the American Diabetes Association’s annual meeting in San Diego, CA, USA, presenters discussed recent developments in the field of pharmacogenetics that promise to change the landscape of diabetes research and management.
The emergence of pharmacogenetics in diabetes research
Professor Scott Taylor, University of Waterloo, Ontario, Canada
In this presentation, Dr. Taylor provided an overview of the emergence of pharmacogenetics study of how genetic inheritance or genomic variation influences response to pharmacotherapy in diabetes.
Specifically, Dr. Taylor focused on recent evidence regarding heterogeneity in the genetic causes of hyperglycemia, insulin resistance, and response to treatment in patients with Type 2 diabetes.
A meta-analysis of 27 trials conducted in 2003 highlighted the association between Type 2 diabetes and the Gly972Arg variant in the insulin receptor substrate-1 (IRS-1) gene. [1]
Encompassing 3408 cases and 5419 control patients, the study showed that carriers of the 972Arg variant of the IRS-1 gene are at a 25% increased risk of having Type 2 diabetes compared with non-carriers.
Another study demonstrated that diabetic patients carrying the Arg(972) IRS-1 variant were at increased risk for secondary failure to sulfonylureas. [2]
This analysis of 477 patients with Type 2 diabetes showed that 53 patients (11.1%) were heterozygous for the Arg(972) IRS-1 variant, one patient (0.2%) was homozygous for the variant, and 423 patients (88.7%) were homozygous for the wild-type allele.
The frequency of the Arg(972) IRS-1 variant was 8.7% among diabetic patients who were well controlled with oral therapy, compared with 16.7% among patients with secondary failure to sulfonylureas (odds ratio 2.1; p=0.01).
Conversely, some patients with diabetes caused by mutations in the hepatocyte nuclear factor 1alpha (HNF-1alpha) gene are particularly sensitive to the hypoglycemic effects of sulfonylureas.
A randomized crossover trial of 36 patients, evaluated whether the glycemic responses to gliclazide and metformin differed in patients with HNF-1alpha diabetes and Type 2 diabetes. [3] The possible mechanisms for sulfonylurea sensitivity through insulin sensitivity, insulin secretory response to glucose and tolbutamide, and tolbutamide clearance, were also explored.
Patients with HNF-1alpha diabetes had a 5.2-fold greater response to gliclazide than to metformin (p=0.0007), and a 3.9-fold greater response to gliclazide than those with Type 2 diabetes (p=0.002).
Although sulfonylurea metabolism was similar in both patient groups, patients with HNF-1alpha diabetes had a strong insulin secretory response to intravenous tolbutamide, despite a small response to intravenous glucose.
Patients with HNF-1alpha diabetes were also more insulin-sensitive than those with Type 2 diabetes. This suggests that HNF-1alpha diabetes is associated with marked sulfonylurea sensitivity. Moreover, this finding is consistent with models of HNF-1alpha deficiency, which show that the beta-cell defect is upstream of the sulfonylurea receptor.
Recently, the effects of rosiglitazone on adiponectin and plasma glucose levels in relation to common adiponectin gene (ACDC) polymorphisms, specifically the single nucleotide polymorphism (SNP)45 and SNP276 of ACDC, were studied. [4] In this trial, 166 patients with Type 2 diabetes were treated with rosiglitazone (4 mg, once daily) for 12 weeks without changing any of their previous medications.
Compared with carriers of other genotypes, carriers of the GG genotype of SNP45 experienced a smaller reduction in the fasting plasma glucose (FPG) level and the HbA1c value (p=0.031 and p=0.013, respectively).
Patients with the GG genotype also underwent a smaller increase in the serum adiponectin concentration compared with those with other genotypes (p=0.003).
Carriers of the GG genotype of SNP276 also had a more modest reduction in the FPG level compared with patients with other genotypes (p=0.001). Overall, these findings suggest that genetic variations in the adiponectin gene in Type 2 diabetic patients can affect the response to rosiglitazone treatment, particularly with respect to circulating adiponectin levels and blood glucose control.
Dr. Taylor concluded his presentation with a discussion of an attractive target for diabetes treatment: protein tyrosine phosphatase 1B (PTP1B). A variety of potent and selective small-molecule PTP1B inhibitors have been identified and are currently under preclinical evaluation for the treatment of diabetes.
Lessons in pharmacogenomics of cardiovascular disease and microvascular complications
Professor Donna K. Arnett, University of Alabama at Birmingham, AL, USA
In this presentation, Dr. Arnett discussed recent findings within the fields of cardiovascular (CV) and microvascular research that may be applicable to the pharmacogenomic study of diabetes.
Large-scale CV studies have shown that there is a considerable variation in response to pharmacologic treatment. For example, patients can have a range of responses to statin therapy.
Following treatment with statins, patients experience a reduction of low-density lipoprotein cholesterol (LDL-C) levels ranging from 18-56%, a reduction in triglyceride (TG) levels of 7-30%, and an increase in high-density lipoprotein cholesterol (HDL-C) levels ranging from 5-15%.
Despite these variations in response, statin studies have consistently shown a significant benefit in reducing major coronary events, invasive coronary procedures, stroke, and CV mortality.
Similar variations in response have been observed following treatment with fibric acids. Indeed, fibric acids have been shown to lower LDL-C by 5-20%, reduce TGs by 20-50%, and increase HDL-C by 10-20%.
The Diabetes Atherosclerosis Intervention Study (DAIS) identified genetic predictors of response to fenobribrate therapy in patients with Type 2 diabetes and at least one visible coronary lesion.
In DAIS, 207 patients were randomized to treatment with micronized fenofibrate (200 mg, once daily) and 211 patients were treated with placebo. After a minimum 3-year follow-up, patients treated with fenofibrate showed a significantly smaller increase in mean percentage diameter stenosis compared with patients in the placebo group (2.11% vs 3.65%, respectively; p=0.02).
Patients in the fenofibrate group also had a significantly smaller decrease in minimum lumen diameter compared with those in the placebo group (-0.06 mm vs -0.10 mm, respectively; p=0.029). Importantly, variations in response to fenofibrate therapy were shown to be driven by two peroxisome proliferator-activated receptor (PPAR)-alpha variants.
Large within- and between-person variations in response to antihypertensive medications have been demonstrated, although the mechanisms driving much of this variability remain unclear.
Upcoming results of the Genetics of Hypertension Associated Treatment (GenHAT) trial may shed important light on the variation in patient response to antihypertensive agents.
GenHAT is a prospective study ancillary to the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), where 42,515 patients with hypertension were randomized to one of four antihypertensive agents: lisinopril, chlorthalidone, amlodipine, or doxazosin.
GenHAT will characterize hypertension genetic variants and determine their interaction with antihypertensive treatments in relation to coronary heart disease. DNA from patients enrolled in ALLHAT will be used to genotype variants of hypertension genes:
- Angiotensinogen-6
- Angiotensin converting enzyme insertion/deletion
- Angiotensin type-1 receptor
- Alpha-adducin
- Beta-2 adrenergic receptor
- Lipoprotein lipase
- 10 new hypertension variants expected to be discovered during the course of the study
Several other gene-treatment interactions will be evaluated in GenHAT, including all-cause mortality, stroke, heart failure, left ventricular hypertrophy, decreased renal function, peripheral arterial disease, and blood pressure lowering.
Because of the ethnic and gender diversity of ALLHAT, the effects of these genetic variants on outcomes in key subgroups such as patients aged >65 years, women, African Americans, and patients with Type 2 diabetes will also be evaluated.
References
1. Arnett DK, Boerwinkle E, Davis BR, et al . Pharmacogenetic approaches to hypertension therapy: design and rationale for the Genetics of Hypertension Associated Treatment (GenHAT) study. Pharmacogenomics J 2002; 2 :309-317.
2. Jellema A, Zeegers MP, Feskens EJ et al . Gly972Arg variant in the insulin receptor substrate-1 gene and association with Type 2 diabetes: a meta-analysis of 27 studies. Diabetologia 2003; 46 :990-995.
3. Kang ES, Park SY, Kim HJ et al . The influence of adiponectin gene polymorphism on the rosiglitazone response in patients with type 2 diabetes. Diabetes Care 2005;28 :1139-1144.
4. Pearson ER, Starkey BJ, Powell RJ et al . Genetic cause of hyperglycemia and response to treatment in diabetes. Lancet 2003; 362 :1275-1281.
5. Sesti G, Marini MA, Cardellini M et al . The Arg972 variant in insulin receptor substrate-1 is associated with an increased risk of secondary failure to sulfonylurea in patients with type 2 diabetes. Diabetes Care 2004; 27 :1394-1398
Page tools
Contact us
Information for
This is an AstraZeneca International website for healthcare professionals and is not intended for the following audiences who should use the links below:
