Diabetes as a Genetic Disease

Heredity plays a significant, but variable, role in the etiology of DM—both type 1 and type 2 diabetes show a familial predisposition, indicating the involvement of genetic factors in determining individual susceptibility to the disease. The etiology and pathophysiology of each type of DM, however, is very different, suggesting that different genes are likely to be involved in this predisposition. The genetic basis of type 1 DM is complex and likely to be due to genes of both large and small effect. Population-based twin studies have confirmed an increased concordance in monozygotic (MZ) pairs, with a concordance of 30% to 40% compared with a concordance rate in dizygotic (DZ) pairs of 5% to 10% (6,7). Based on the results of these twin studies, it is clear that susceptibility to type 1 DM is determined, in part, by genetic risk factors but that probably <50% of the total risk can be attributed to the effects of shared genes. Similarly, in type 2 DM, twin studies have shown higher concordance rates in MZ than DZ twins, but there is a substantial amount of variability in concordance rates between different populations (6,8,9). It appears that the genetic model for type 2 DM is more complex, with multiple genes located on different chromosomes being associated with this condition (10). These findings are similar to those obtained for other common human disorders that exhibit familial aggregation but not simple Mendelian patterns of transmission of risk and is further complicated by numerous environmental factors that also contribute to the clinical manifestation of the disorder.

In type 2 DM there is evidence for a genetically programmed b-cell dysfunction that is unmasked by the failure to compensate for increasing insulin resistance (11). The work of Morris et al. (12) illustrates the synergism between genetic predisposition and the environmental pressure represented by obesity. Furthermore, in the case of maturity-onset diabetes of the young (MODY), the genetic cause of diabetes is an important determinant of the response to oral hypoglycemic drugs. This has implications for the wider management of diabetes in the future. The hope is that identification of the genes involved in b-cell dysfunction in MODY will lead to the uncovering of genes for the more common non-MODY forms of type 2 DM.

Diabetes largely exerts its effects on morbidity and mortality via its long-term macrovascular and microvascular complications (summarized in Table 1). There is now increasing evidence to show that genetic factors, together with elevated blood glucose, play an important role in the susceptibility to these complications. Polymorphisms of

Table 1 The Complications of Diabetes

Organ system/disease

Clinical manifestations

Eye disease

Retinopathy

Cataracts

Neuropathy

Autonomic

Diffuse symmetrical polyneuropathy

Mononeuropathies

Nephropathy

Hypertension

Dyslipidemia

Macrovascular disease

Cerebrovascular disease

(atherosclerosis)

Coronary artery disease (angina, acute coronary

syndromes, heart failure)

Peripheral vascular disease

Diabetic foot disease

Foot ulceration

Miscellaneous

Charcot's arthropathy

Cheiroarthropathy

Necrobiosis lipoidica diabeticorum

Dermopathy

Osteopenia

different genes, mainly from the renin-angiotensin system, have been studied extensively, and some of them have been suggested to contribute to the development of complications, especially nephropathy. This clearly has potential implications in management. However, very little is understood about the specific interaction between drugs and genes in this area, and therefore this review will focus on the role of pharmacogenetics in the management of type 2 DM per se. This is the field that has attracted the most research attention thus far.

Antidiabetic Drugs and Genetic Polymorphisms of CYP450 Enzymes

Cytochrome P450 (CYP) 2C9 hydroxylates a wide array of drugs in a diverse range of therapeutic categories—about 16% of the drugs in current clinical use, including drugs used for DM. The sulfonylureas, tolbutamide, glibenclamide, glimepiride, and glipizide are all CYP2C9 substrates (13-15). Nateglinide, an amino acid (¿-phenylalanine) derivative that improves early-phase insulin secretion and reduces mealtime glucose excursions, is also predominantly metabolized by CYP2C9 (and to a lesser extent by CYP3A4) (16-21).

Polymorphisms in CYP2C9 (especially *2 and *3 variants) are known to reduce enzyme activity to 5% to 12% of the wild-type (CYP2C9*1) activity. Thus, polymorphisms in CYP2C9, especially in the rare individuals who are homozygous for the CYP2C9*3 alleles, are likely to lead to a reduced dosage requirement and predisposition to severe toxicity—specifically the risk of life-threatening hypoglycemia.

The archetypal antidiabetic drug most widely studied with respect to CYP2C9 polymorphisms is tolbutamide (22). It is metabolized almost exclusively by methylhydro-xylation process that accounts for 85% of the tolbutamide clearance; this is the initial and rate-limiting step in metabolism (23,24). In vitro and in vivo evidence suggests that CYP2C9 solely mediates the hydroxylation of tolbutamide. This drug is therefore widely accepted as a prototypic substrate for the assessment of hepatic CYP2C9 activity and indeed has been used a probe substrate in many pharmacokinetic studies (25,26). An early study of tolbutamide metabolism suggested that approximately 30% of the subjects were poor metabolizers (PMs) (27). The pharmacokinetics of tolbutamide in 50 non-diabetic subjects, including twins, showed an almost ninefold variation in the elimination rate constant, with half-lives varying from 2.9 hours to 25.0 hours. However, at the time of those studies, the genetic basis of interindividual variability had not been defined. Although many subsequent studies failed to find a single individual who could be classified as a PM (28), later studies incorporating genotyping have shown that prolonged halflife is a consequence of the possession of allelic variants of the CYP2C9 isoform (29-31). In accordance with this, expressed recombinant CYP2C9*3 has been shown to exhibit lower intrinsic clearance (Vmax/Km) for tolbutamide methylhydroxylation than the wild type, caused by a higher Km value without a change of the Vmax values. In a further study, the relationship between CYP2C9 genotype and tolbutamide plasma clearance (CL/F) in 23 healthy subjects expressing all six CYP2C9 allele combinations has been evaluated and is summarized in Table 2 (32). According to this study, intermediate and slow metabolizers may be predicted to comprise approximately 12% and 1% of the population, respectively. These results are consistent with other work in this field (33,34). Most of these studies have been performed in Caucasians, and it is therefore important to remember that interethnic differences in the frequencies of the allelic variants may lead to varying prevalences of adverse effects associated with sulfonylureas.

Pharmacodynamic monitoring remains the rational option for monitoring tolbutamide treatment (35). To evaluate the pharmacokinetic-pharmacodynamic relationship, nondia-betic healthy subjects were monitored for blood/serum glucose (and plasma insulin)

Table 2 The Relationship Between CYP2C9 Genotype and Phenotype

Tolbutamide

Metabolizer

clearance (Lhr_1)

Genotype

phenotype

0.97

*1/*1

Extensive

0.88

*1/*2

Extensive

0.75

*2/*2

Extensive

0.56

*1/*3

Intermediate

0.45

*2/*3

Intermediate

0.16

*3/*3

Slow

Abbreviations: *1, Wild-type allele; *2, Arg144Cys; *3, Ile359Leu. Source: From Ref. 14.

Abbreviations: *1, Wild-type allele; *2, Arg144Cys; *3, Ile359Leu. Source: From Ref. 14.

following tolbutamide administration (500 mg administered orally) with or without a glucose/dextrose challenge in three prospective studies (32-34). No relationship between glucose or insulin concentrations and CYP2C9 genotype was reported by Lee et al. (34) and Kirchheiner et al (32). Furthermore, hypoglycemia was not observed, even without additional carbohydrate administration after tolbutamide. In contrast, in another study, evaluating Korean subjects, the enhancement in serum glucose increase relative to baseline was significantly lower in CYP2C9* 1/*3 heterozygotes, compared with homozygotes for the wild-type allele (33). The reason for such a difference is not entirely clear, but CYP2C19 may also contribute to the metabolism of tolbutamide, and there is a relatively high CYP2C19 PM genotype frequency in Korean and East Asian populations (compared with the Caucasians).

Genetic polymorphisms of CYP2C9 have also been shown to affect the pharmacokinetics of glibenclamide and glimepiride in healthy volunteers (14,15). Glibenclamide AUC (area under concentration curve) was 280% higher in individuals heterozygous for the CYP2C9 *3 allele (15). In CYP2C9*3 homozygotes, the oral clearance was reduced by more than 50% in comparison with the individuals with CYP2C9*1/*1 genotype

(14). Similar results have also been shown for glimepiride, with the AUC in CYP2C9*3 heterozygotes being increased by 267%, compared with individuals with the *1/*1 genotype

(15). In both studies, however, blood glucose responses to glibenclamide and glimepiride were not significantly affected, whereas the insulin secretion after glibenclamide ingestion was higher in subjects with the *3/*3 genotype, compared with the other genotypes (14).

The effect of genetic polymorphisms in another CYP2C gene product, CYP2C8, on the pharmacokinetics and pharmacodynamics of the new meglitinide analog, repaglinide, has been studied in 28 healthy volunteers (36). There were 19 subjects (68%) with the CYP2C8* 1 /* 1 genotype (wild-type), six subjects (21%) with the CYP2C8*1/*3 genotype, and three subjects (11%) with the CYP2C8*1/*4 genotype. Unexpectedly, the CYP2C8*3 variant allele was associated with reduced plasma concentrations of repaglinide. The mean AUC of repaglinide was 45% lower, and the peak concentration in plasma was 39% lower in subjects with the CYP2C8*1/*3 genotype, compared with those with the CYP2C8*1/*1 genotype. However, no statistically significant differences were found in the blood glucose response to repaglinide between the genotypes.

The clinical consequences of CYP2C9 polymorphisms for the treatment with oral hypoglycemic agents are largely unclear because the relevant patient studies have not been undertaken. Further data are necessary to evaluate whether dosage adjustment on the basis of genotype is needed in diabetic patients. There appears to be discordance between the pharmacokinetic and pharmacodynamic responses elicted. This is likely to be multifactorial—a reflection of study design, the fact that the studies have been carried out in healthy volunteers rather than diabetic patients, but most importantly this may be attributable to the complex counterregulatory mechanisms that exist in glucose homeostasis. Blood glucose levels in nondiabetics are regulated by several factors, the most important being the counteracting hormones, insulin and glucagon. Decreases in blood glucose caused by oral hypoglycemic-triggered insulin secretion may have been concealed by a counteracting glucagon secretion that keeps the blood glucose levels constant. In diabetic patients, however, the regulation of blood glucose levels and insulin secretion is of course impaired, and thus a greater risk for hypoglycemia cannot be excluded in diabetic people with reduced CYP2C9 activity and higher concentrations of antidiabetic drug. Given the relative ease of pharmacodynamic monitoring and the lack of correlation between the kinetics and dynamics of antidiabetic compounds, it can be argued that monitoring of blood sugar, rather that genotyping, may be more clinical and cost-effective. Whether this is true or false awaits further study. Nevertheless, a clearer understanding of the pharmacokinetic-pharmacodynamic relationship in diabetic patients in the presence of CYP2C9 polymorphisms is required.

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The term vaginitis is one that is applied to any inflammation or infection of the vagina, and there are many different conditions that are categorized together under this ‘broad’ heading, including bacterial vaginosis, trichomoniasis and non-infectious vaginitis.

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