Pharmacogenomics in type 2 diabetes: oral antidiabetic drugs.

Type 2 diabetes mellitus (T2DM) is a fast progressing disease reaching pandemic proportions. T2DM is specifically harmful because of its severe secondary complications. In the course of the disease, most patients require treatment with oral antidiabetic drugs (OADs), for which a relatively large number of different options are available. The growing number of individuals affected by T2DM as well as marked interindividual differences in the response to treatment call for individualized therapeutic regimens that can maximize treatment efficacy and thus reduce side effects and costs. A large number of genetic polymorphisms have been described affecting the response to treatment with OADs; in this review, we summarize the most recent advances in this area of research. Extensive evidence exists for polymorphisms affecting pharmacokinetics and pharmacodynamics of biguanides and sulfonylureas. Data on incretin-based medications as well as the new class of sodium/glucose cotransporter 2 (SGLT2) inhibitors are just starting to emerge. With diabetes being a known comorbidity of several psychiatric disorders, we also review genetic polymorphisms possibly responsible for a common treatment response in both conditions. For all drug classes reviewed here, large prospective trials are necessary in order to consolidate the existing evidence and derive treatment schemes based on individual genetic traits.

Effect of thiazolidinedione treatment on proteinuria and renal hemodynamic in type 2 diabetic patients with overt nephropathy.

Proteinuria in diabetic nephropathy predicts the progressive loss of glomerular filtration rate (GFR) and serves as independent predictor for mortality. We performed the present study (ClinicalTrials.gov identifier: NCT 00324675) to clarify whether the activation of PPARγ receptor by thiazolidinediones was able to improve proteinuria and preserve renal function in advanced diabetic nephropathy. A total of 28 type 2 diabetic patients (4 women and 24 men, mean age 66.1±9.1 years) with urinary albumin excretion >300 mg/24 h and an estimated GFR <60 ml/min were included into this prospective double blind trial to receive either rosiglitazone (RSG) 4 mg b.i.d or matching placebo (PLC) for 52 weeks in addition to their concomitant antidiabetic background therapy. At baseline and after 26 and 52 weeks, renal plasma flow (RPF) and GFR were determined before and after blockade of nitric oxide (NO) by intravenous administration of N-monomethyl-L-arginine acetate. RSG treatment resulted in a significant reduction of proteinuria (2.4±1.1; 1.2±0.6; 1.5±0.7 g/d at baseline, 26 weeks and 52 weeks; respectively, p<0.05) whereas PLC did not influence proteinuria (1.6±0.6; 1.6±0.8; 1.7±0.8 g/d). GFR and RPF did not change significantly during the study, however, RSG improved the intrarenal NO bioavailability. RSG treatment was generally well tolerated and the major adverse event - development of edema - could be controlled by dose adjustment of the study drug and diuretic agents. In conclusion, we demonstrated a possible renoprotective effect of RSG in patients with advanced diabetic nephropathy.

Effects of the alpha glucosidase inhibitor acarbose on endothelial function after a mixed meal in newly diagnosed type 2 diabetes.

Endothelial dysfunction (ED) has been suggested as a possible causal link between postprandial hyperglycemia and cardiovascular events in patients with type 2 diabetes. Recent trials demonstrated a reduction of cardiovascular events by treatment with alpha-glucosidase inhibitor acarbose - a drug which mainly reduces postprandial glucose excursions. We were interested to know whether patients with newly diagnosed type 2 diabetes showed postprandial ED and if so whether acarbose was able to improve this condition. Forearm blood flow (FBF) measurements for assessment of ED were performed in the fasting and postprandial state in 20 newly diagnosed type 2 diabetic patients and 10 healthy control subjects. After baseline examination, patients were randomly assigned to a 20-week treatment of acarbose 100 mg t.i.d or matching placebo, thereafter FBF measurements were repeated. FBF of patients in the fasting state was significantly impaired compared to healthy control subjects (max. FBF 5.3+/-0.7 vs. 8.0+/-0.9 ml/100 ml, p<0.02) and did not change in the postprandial state (max. FBF 5.6+/-0.7 ml/100 ml). In contrast, healthy controls showed a significant improvement of FBF in the postprandial state (11.5+/-1.2 ml/100 ml), which is compatible with postprandial ED in the group of patients. Twenty weeks of acarbose treatment did not affect either fasting or postprandial FBF in patients. Early type 2 diabetes is a state of both fasting and postprandial ED, which is not sensitive to acarbose treatment. Protective cardiovascular effects of acarbose might involve other mechanisms.

Search for mitochondrial DNA mutation at position 3243 in German patients with a positive family history of maternal diabetes mellitus.

Mitochondrial diabetes is one of the most common monogenetic forms of diabetes mellitus. However, variable prevalences have been reported by different investigators. Therefore, the aim of our study was to investigate the prevalence of the most prevalent mitochondrial DNA mutation at position 3243 (A --> G) in german patients with a positive family history of maternally inherited diabetes mellitus and/or hearing loss. We screened 1460 patients with diabetes mellitus by a questionnaire and identified 122 patients with a positive family history of maternal diabetes mellitus. Seven of the 122 patients suffered from hearing loss in addition. An EDTA blood sample of each patient was examined by polymerase chain reaction followed by a digestion with Bsp120I. In addition all samples were further examined by denaturing gradient gel electrophoresis to increase the detection limit for heteroplasmy. Only one mt DNA mutation at position 3243 could be detected in the 122 patients. The detection limit of denaturing gradient gel electrophoresis (DGGE) for heteroplasmy was 3%. We detected one new polymorphism at position 3333 (C --> T) of the mitochondrial genome (0.8% of the patients), and a known polymorphism at position 3197 (T --> C) in 10.6% of the patients. We therefore conclude that the frequency of the A3243G mutation is much lower in the investigated study population, mostly originating from Saxonia, than in asian populations.

Effects of insulin glargine versus metformin on glycemic variability, microvascular and beta-cell function in early type 2 diabetes.

We investigated whether basal insulin as first-line treatment in recently diagnosed type 2 diabetes (T2D) can improve glucose control, microvascular function and preserve insulin secretion in comparison with metformin (MET). In this open-label, randomized, prospective 36-week study, 75 patients (44 m, 31 f, mean age 60.7 ± 9.2 year) were allocated to treatment with either MET 1,000 mg b.i.d. (n = 36) or insulin glargine (GLA) at bedtime (n = 39). At baseline and study end, we performed a continuous glucose monitoring for assessment of interstitial glucose (IG) and measured microvascular function using Laser-Doppler fluxmetry. GLA versus MET treatment resulted in a more pronounced reduction in FPG (Δ: 3.1 ± 2.5 vs. 1.4 ± 1.5 mmol/l; p < 0.001) and overall IG (Δ AUC. 671 ± 507 vs. 416 ± 537 mmol/l min; p = 0.04). Postprandial PG and IG differences after a standardized test meal did not reach significance. Proinsulin/C-peptide and HOMA B as marker of endogenous insulin secretion were significantly more improved by GLA. Microvascular blood flow improved only in MET-treated patients. Early basal insulin treatment with GLA in T2D patients provided a better control of FPG, overall IG load and biomarker of beta-cell function compared to the standard treatment with MET. MET treatment resulted in an improvement of microvascular function. Studies of longer duration are needed to evaluate the durability of glucose control and ß cell protection with early GLA treatment.

Role of rho-kinase in the regulation of vascular tone in hypertensive renal transplant recipients.

Activation of rho-kinase (ROK) is involved in the development of hypertension as it is a potent regulator of vascular smooth muscle cell (VSMC) contractility. Here we evaluated whether activation of ROK is present in hypertensive kidney transplant recipients (NTX). We tested the effect of the ROK-inhibitor fasudil on the regulation of forearm blood flow (FBF) in NTX and in healthy control subjects (CTL). In addition potential modulating effects of ROK-inhibition on local vascular nitric oxide (NO) release were studied. The effect of intra-arterial infusion of fasudil on FBF was studied by venous-occlusion plethysmography in NTX and CTL. To unmask the role of NO fasudil was infused with/without clamping of vascular NO in NTX and CTL. To unravel the basal NO-mediated tone the NO-synthase inhibitor l-NMMA was infused. Fasudil markedly but comparably increased FBF in NTX and CTL. The vascular response to fasudil was blunted during NO-clamp in CTL (104+/-18% vs. 244+/-48% for NO-clamp+fasudil vs. fasudil alone; baseline=0%, P<0.05) but not in NTX. The l-NMMA-induced vasoconstriction was impaired in NTX compared to CTL. In NTX and CTL basal vascular tone equally depends on ROK. Fasudil-induced vasodilatation is partly mediated by vascular NO in CTL but not in NTX. The greater NO-insensitive fasudil-induced increase in FBF in NTX suggests an increased ROK-mediated VSMC constrictor tone in these patients. Basal NO-mediated tone is attenuated in hypertensive NTX.

Relationship between diurnal glucose levels and HbA1c in type 2 diabetes.

AIMS AND METHODS: Study results still conflict on the contribution of diurnal blood glucose (BG) values to Hb (A1c) in type 2 diabetes. We investigated the relationship between Hb (A1c) and diurnal BG obtained under standardized conditions - before breakfast, two hours after breakfast, before lunch, two hours after lunch, before dinner, two hours after dinner, and at 10 PM, 12 midnight and 3 AM in 68 type 2 diabetic patients before and after optimizing glycemic control. The areas under the curve above fasting BG (AUC1) and above 5.6 mmol/l (AUC2) were calculated for further evaluation. Hb (A1c) was measured at baseline and after a mean of 89 (74 to 108) days. RESULTS: Each BG value at baseline and after treatment optimization significantly correlated with baseline and follow-up Hb (A1c), respectively. The pre-breakfast BG showed the closest correlation with Hb (A1c). The relative contribution of postprandial BG concentrations (AUC1) to overall hyperglycemia (AUC2) decreased with poorer glycemic control. However, treatment optimization mainly resulted in improved blood glucose values in patients with the poorest glycemic control at baseline. Multiple regression analysis demonstrated that fasting (AUC2-AUC1) and postprandial (AUC1) hyperglycemia independently determined Hb (A1c) or the change in Hb (A1c) after treatment optimization. CONCLUSIONS: Our findings indicate that intensive blood glucose monitoring during fasting and postprandial states is important for glycemic control, and is therefore an essential part of good clinical practice.

Endothelial dysfunction in patients with rheumatoid arthritis is associated with a reduced number and impaired function of endothelial progenitor cells.

BACKGROUND: Rheumatoid arthritis (RA) is associated with increased morbidity and mortality attributable to accelerated atherosclerosis and cardiovascular events. OBJECTIVE: To determine the role played by endothelial progenitor cells (EPC) in the defence system against arteriosclerosis. METHODS: The number and function of EPC in 13 young patients with RA with low disease activity (DAS28 3.5 (0.3)) and 13 healthy control subjects was studied. Endothelial function was investigated by agonist-induced, endothelium dependent vasodilatation measured by the forearm blood flow technique. Migratory activity and adhesion of EPC to tumour necrosis factor alpha (TNFalpha) activated mature endothelial cells and components of the extracellular matrix were tested in vitro. Putative precursor populations (CD34(+), CD34(+)/CD133(+), and CD34(+)/KDR(+) haematopoietic stem cells) were measured by flow cytometric analysis. RESULTS: Acetylcholine-induced, endothelium dependent vasodilatation was reduced by about 50% in patients with RA, indicating endothelial dysfunction, whereas endothelium-independent vasodilatation in response to glyceryl trinitrate was at control level. Significantly reduced numbers of EPC were found in the patients compared with controls. Migratory activity of EPC was decreased in patients with RA. Adhesion to mature endothelial cells after activation with TNFalpha was enhanced only in controls. The adhesion to matrix proteins and the number of putative precursor cell lineages was comparable in both groups. CONCLUSION: Endothelial dysfunction in patients with RA with low grade inflammation is associated with a reduced number and partial dysfunction of EPC. Further studies are needed to explore whether interventions that potentially ameliorate the number and function of EPC also improve endothelial function in these patients.

Kidney transplantation substantially improves endothelial progenitor cell dysfunction in patients with end-stage renal disease.

Endothelial progenitor cells (EPC) are involved in endothelial repair and maintenance. Dysfunction of EPC may contribute to accelerated arteriosclerosis in chronic kidney disease. Kidney transplantation (KTx) improves both survival and endothelial function of dialysis patients. In a prospective study, we tested to which extent KTx changes EPC biology. We studied number and function (migratory activity, adhesion to extracellular matrix proteins and to mature endothelial cells [EC]) of EPC in 20 patients during dialysis and 3, 6, 9 and 12 months after KTx. Twenty-two healthy volunteers served as matched controls. Circulating precursor populations were measured by flow cytometric analysis. Cytokines relevant for EPC mobilization were monitored. Compared to the dialysis state, KTx increased the migration of EPC to approximately 2-fold. Adhesion to fibronectin and to collagen type IV was significantly increased after KTx. An improved adhesion rate of EPC to mature EC was observed. The number of EPC decreased. The amount of precursor populations showed no difference compared to the pretransplant state. Our study shows an improved function of EPC after KTx. This finding indicates an improved potential for endothelial repair which in turn may contribute to enhanced endothelial function and reduced cardiovascular morbidity after KTx.

Insulin resistance and metabolic parameters in type 2 diabetic patients.

Background: The importance of insulin resistance in type 2 diabetes mellitus has been generally accepted. Only very few data about the degree of insulin resistance in a representative group of type 2 diabetic patients are available. The aim of this study was to ascertain the degree of insulin resistance and its relation to metabolic parameters in type 2 diabetic patients. Methods: We studied 96 type 2 diabetic patients. The inclusion criteria were type 2 diabetes according to WHO criteria and HbA(1c) between 6.8% and 10.5%. Insulin resistance was estimated in a euglycemic hyperinsulinemic clamp. Blood parameters like lipids, insulin, glucose, fatty acids, and leukocytes were also studied. Results: The insulin sensitivity of 71 of the type 2 diabetic patients was markedly lower than that of the controls. Twenty-five diabetic patients had an M(c) value within the range of the controls. The M(c) values, as a measure of insulin resistance, of the diabetic patients were between 0.3 and 5.2 mg/(kg min insulin), whereas the M(c) range of the controls was from 2.6 to 10.8 mg/(kg min insulin). Conclusions: Approximately 75% of the type 2 diabetic patients were insulin-resistant. Hence, type 2 diabetes mellitus was not equivalent to insulin resistance in every case.