Type 2 diabetes mellitus (T2DM) can be multifactorial where both genetics and environmental factors play a role. We aimed to investigate the use of polygenic risk scores (PRS) in the prediction of ...pre-transplant T2DM and post-transplant diabetes mellitus (PTDM) among solid organ transplant (SOT) patients. Using non-genetic risk scores alone; and the combination with PRS, separate logistic regression models were built and compared using receiver operator curves. Patients were assessed pre-transplant and in three post-transplant periods: 0-45, 46-365 and >365 days. A higher PRS was significantly associated with increased odds of pre-transplant T2DM. However, no improvement was observed for pre-transplant T2DM prediction when comparing PRS combined with non-genetic risk scores to using non-genetic risk scores alone. This was also true for predictions of PTDM in all three post-transplant periods. This study demonstrated that polygenic risk was only associated with the risk of T2DM among SOT recipients prior to transplant and not for PTDM. Combining PRS with a clinical model of non-genetic risk scores did not significantly improve the predictive ability, indicating its limited clinical utility in identifying patients at high risk for T2DM before transplantation, suggesting that non-genetic or different genetic factors may contribute to PTDM.
The pathogenesis of renal disease in obesity and metabolic syndrome (MS) is mostly unknown. This is in part because of the limited information about renal morphological changes in these conditions. ...We evaluated renal histology in subjects with MS and those without MS, who are participants in the European Nephrectomy Biobank (ENBiBA) project.
MS was defined with at least 3 of the following criteria: (i) body mass index (BMI) ≥27 kg/m2; (ii) prediabetes: fasting glucose of 100–125 mg/dl or HbA1c >5.7%; (iii) systolic or diastolic blood pressure >140/90 mm Hg or the use of medications; and (iv) triglycerides >150 mg/dl or high-density lipoprotein cholesterol <40 (in men) or 50 mg/dl (in women). The absence of these criteria defined patients without MS. Exclusion criteria were diabetes or known causes of renal disease.
A total of 157 cases were evaluated: 49 without and 108 with MS. Those with MS were older (54 ± 16 vs. 66 ± 11, P < 0.0001), had more prevalent chronic kidney disease (CKD, estimated glomerular filtration rate eGFR <60 ml/min): 24% (23%) versus 4% (8%) (P = 0.02), and had higher albumin-to-creatinine ratio (10 4–68 vs. 4.45 0–27, P = 0.05) than those without MS. Global sclerosis (3% 1–7 vs. 7% 3–13, P < 0.0001), nodular sclerosis, mesangial expansion, glomerulomegaly; moderate + severe hyalinosis, and arteriosclerosis were more frequent in those with MS than in those without (88 82 vs. 29 59; 83 77 vs. 30 61; P < 0.05). These vascular changes were independent of differences in age.
In MS, ischemic renal disease may play a role in renal disease. In addition, some patients may develop lesions compatible with diabetic nephropathy such as increased mesangial expansion and nodular sclerosis. Further analyses are needed to study the consequences of the pandemic of obesity on renal health.
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This study aimed to investigate the development of new-onset diabetes mellitus (NODM) in a prospective study of 97 nondiabetic uremic patients.
Included were 57 kidney recipients (Tx group, age 39 ...+/- 13 years) and 40 uremic patients remaining on the waiting list for kidney transplantation (uremic controls, age 47 +/- 11 years). All were examined at baseline before possible transplantation and after 12 months. The prevalence of diabetes, prediabetes, insulin sensitivity index (ISI), and insulin secretion index (Isecr) were estimated using an oral glucose tolerance test with measurements of plasma glucose and plasma insulin.
One year after transplantation NODM was present in 14% (8 of 57) compared with 5% (2 of 40) in the uremic control group (P = 0.01). ISI in the Tx group deteriorated from 6.8 +/- 3.9 before transplantation to 4.9 +/- 2.8 at 12 months after transplantation (P = 0.005), and a slight increase in Isecr from 37 +/- 19 to 46 +/- 22 (P = 0.02) was seen. No significant changes occurred in the uremic controls (ISI was 7.9 +/- 5 and 8.5 +/- 5, and Isecr was 31 +/- 17 and 28 +/- 15). Using multivariate ordinal logistic regression, pre-Tx ISI and age predicted NODM (odds ratios: 0.82, P = 0.01 and 1.06, P = 0.02, respectively).
One year after kidney transplantation, NODM was present in 14% of patients. This was mainly caused by an increase in insulin resistance and was observed despite improvement in insulin secretion.
Glucagon-like peptide-2 (GLP-2) is known to increase mesenteric blood flow. The aim of the study was to evaluate the effect of GLP-2 on blood flow in different vascular sites, and dynamic changes in ...cardiac parameters.
10 healthy volunteers were given 450
nmol subcutaneous (SC) GLP-2 or isotonic saline (5 subjects) in a single blinded manner. During the following 90
min, blood flow in the superior mesenteric artery (SMA), celiac artery (CA), renal artery (RA), common carotid artery (CCA) was measured using Doppler ultrasound (US), and cardiovascular variables were measured by impedance cardiography and finger plethysmography. Plasma GLP-2 was measured at times 0, 30 and 60
min.
Compared to the placebo group, GLP-2 elicited a 27% decrease in the resistance index (RI) and a 269.4% increase in Time Averaged Maximal Velocity (TAMV) in the SMA (
P
<
0.01). CA, RA and CCA: There were no significant changes in RI or TAMV in the GLP-2 or placebo group, and no change in CA diameter.
Cardiac parameters: GLP-2 increased cardiac output (CO), stroke volume (SV) and heart rate (HR) compared to baseline (respectively: 15.3, 4.81 and 8.2% (
P
<
0.001,
P
<
0.01 and
P
<
0.01)). The CO, SV and HR changes were not significantly different from the placebo group.
Mean plasma GLP-2 serum levels in the placebo group at times 0, 30 and 60
min were 22.8, 23.4 and 23.2
pmol/l. In the GLP-2 group 20.3, 1273 and 1725
pmol/l.
SC GLP-2 increased SMA blood flow, as previously shown, but elicited no changes in other vascular sites. CO and HR increased significantly, presumably due to the increased mesenteric blood flow.
The T allele of TCF7L2 rs7903146 is a common genetic variant associated with type 2 diabetes (T2D), possibly by modulation of incretin action. In this study, we evaluated the effect of the TCF7L2 ...rs7903146 T allele on the incretin effect and other glucometabolic parameters in normal glucose tolerant individuals (NGT) and participants with T2D. The rs7903146 variant was genotyped in cohorts of 61 NGT individuals (23 were heterozygous (CT) or homozygous (TT) T allele carriers) and 43 participants with T2D (20 with CT/TT). Participants were previously examined by an oral glucose tolerance test (OGTT) and a subsequent isoglycemic intravenous glucose infusion (IIGI). The incretin effect was assessed by quantification of the difference in integrated beta cell secretory responses during the OGTT and IIGI. Glucose and hormonal levels were measured during experimental days, and from these, indices of beta cell function and insulin sensitivity were calculated. No genotype-specific differences in the incretin effect were observed in the NGT group (P = 0.70) or the T2D group (P = 0.68). NGT T allele carriers displayed diminished glucose-dependent insulinotropic polypeptide response during OGTT (P = 0.01) while T allele carriers with T2D were characterized by lower C-peptide AUC after OGTT (P = 0.04) and elevated glucose AUC after OGTT (P = 0.04). In conclusion, our findings do not exclude that this specific TCF7L2 variant increases the risk of developing T2D via diminished incretin effect, but genotype-related defects were not detectable in these cohorts.
Drug dosing in accordance with the renal function is a long-standing challenge to clinicians. For many years it has been evident that in many clinical situations there is no easy way to correctly ...dose any drug that is mainly cleared by the kidneys. Despite the development of many formulas for estimating the glomerular filtration rate, they all have serious shortcomings. Much effort has been put in to develop estimation formulas to evaluate the renal function as an alternative to direct methods with the aim of safely dosing drugs that are mainly cleared by the kidneys. Both creatinine- and cystatin C-based formulas with additional clinical and biochemical parameters deduced from association studies with methods to measure the glomerular filtration rate (mGFR) have been developed. None of them have been good enough to perform safely in the wide range of situations in daily clinical praxis. Despite serious limitations, there has also been a tendency to use estimated GFR (eGFR) as a "hard" clinical endpoint in clinical studies. This has increased the risk of misinterpretation and has led to conclusions that are not necessarily supported by data. Finally, new methods of testing drug toxicity and the use of pharmacological support in order to fix the right doses are mentioned in this short overview of studies; possible problems that are encountered using eGFR instead of mGFR in the clinic and in research are also mentioned in this report.
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