Approximately 20% to 40% of patients with type 1 or type 2 diabetes mellitus develop diabetic kidney disease. This is a clinical syndrome characterized by persistent albuminuria (> 300 mg/24 h, or > ...300 mg/g creatinine), a relentless decline in glomerular filtration rate (GFR), raised arterial blood pressure, and enhanced cardiovascular morbidity and mortality. There is a characteristic histopathology. In classical diabetic nephropathy, the first clinical sign is moderately increased urine albumin excretion (microalbuminuria: 30–300 mg/24 h, or 30–300 mg/g creatinine; albuminuria grade A2). Untreated microalbuminuria will gradually worsen, reaching clinical proteinuria or severely increased albuminuria (albuminuria grade A3) over 5 to 15 years. The GFR then begins to decline, and without treatment, end-stage renal failure is likely to result in 5 to 7 years. Although albuminuria is the first sign of diabetic nephropathy, the first symptom is usually peripheral edema, which occurs at a very late stage. Regular, systematic screening for diabetic kidney disease is needed in order to identify patients at risk of or with presymptomatic diabetic kidney disease. Annual monitoring of urinary albumin-to-creatinine ratio, estimated GFR, and blood pressure is recommended. Several new biomarkers or profiles of biomarkers have been investigated to improve prognostic and diagnostic precision, but none have yet been implemented in routine clinical care. In the future such techniques may pave the way for personalized treatment.
End-stage renal disease is characterized by widespread inflammation and an increased cardiovascular mortality rate. Biomarkers are frequently examined to diversify risk prediction in addition to the ...usual clinical variables and also to explore potential pathological mechanisms that may be targets for future intervention. YKL-40 is an inflammatory biomarker that has been examined in a range of diseases and clinical conditions, and now in a dialysis population. The question is whether this marker will provide clues for future interventions.
Diabetic nephropathy (DN) is a progressive kidney disease, a well-known complication of long-standing diabetes. DN is the most frequent reason for dialysis in many Western countries. Early detection ...may enable development of specific drugs and early initiation of therapy, thereby postponing/preventing the need for renal replacement therapy. We evaluated urinary proteome analysis as a tool for prediction of DN. Capillary electrophoresis-coupled mass spectrometry was used to profile the low-molecular weight proteome in urine. We examined urine samples from a longitudinal cohort of type 1 and 2 diabetic patients (n = 35) using a previously generated chronic kidney disease (CKD) biomarker classifier to assess peptides of collected urines for signs of DN. The application of this classifier to samples of normoalbuminuric subjects up to 5 years prior to development of macroalbuminuria enabled early detection of subsequent progression to macroalbuminuria (area under the curve AUC 0.93) compared with urinary albumin routinely used to determine the diagnosis (AUC 0.67). Statistical analysis of each urinary CKD biomarker depicted its regulation with respect to diagnosis of DN over time. Collagen fragments were prominent biomarkers 3-5 years before onset of macroalbuminuria. Before albumin excretion starts to increase, there is a decrease in collagen fragments. Urinary proteomics enables noninvasive assessment of DN risk at an early stage via determination of specific collagen fragments.
Two biomarkers, growth differentiation factor 15 (GDF-15) and fibroblast growth factor 23 (FGF-23)), reflecting different aspects of renal pathophysiology, were evaluated as determinants of decline ...in estimated glomerular filtration rate (eGFR), incident cardiovascular disease (CVD) and all-cause mortality in patients with type 2 diabetes (T2D) and microalbuminuria, but without clinical cardiac disease.
Prospective study including 200 T2D patients. The predefined endpoint of chronic kidney disease (CKD) progression: A decline in eGFR of >30% at any time point during follow-up. Hazard ratios (HR) are provided per 1 SD increment of log2-transformed values.
Mean (± SD) age was 59 ± 9 years, eGFR 91.1 ± 18.3 ml/min/1.73m2 and median (IQR) UAER 103 (39-230) mg/24-h. During a median 6.1 years follow-up, 40 incident CVD events, 26 deaths and 42 patients reached the CKD endpoint after median 4.9 years. Higher GDF-15 was a determinant of decline in eGFR >30% and all-cause mortality in adjusted models (HR 1.7 (1.1-2.5); p = 0.018 and HR 1.9 (1.2-2.9); p = 0.003, respectively). Adding GDF-15 to traditional risk factors improved risk prediction of decline in renal function (relative integrated discrimination improvement (rIDI) = 30%; p = 0.037). Higher FGF-23 was associated with all-cause mortality in adjusted models (HR 1.6 (1.1-2.2); p = 0.011) with a rIDI of 30% (p = 0.024).
In patients with T2D and microalbuminuria, higher GDF-15 and FGF-23 were independently associated with all-cause mortality and higher GDF-15 improved risk prediction of decline in kidney function and higher FGF-23 of all-cause mortality, beyond traditional risk factors, but not independently of GDF-15.
Sodium glucose cotransporter 2 inhibition with dapagliflozin decreases hemoglobin A1c (HbA1c), body weight, BP, and albuminuria (urinary albumin-to-creatinine ratio). Dapagliflozin also modestly ...increases hematocrit, likely related to osmotic diuresis/natriuresis. Prior studies suggest that the HbA1c-lowering effects of dapagliflozin attenuate at lower eGFR. However, effects on other cardiovascular risk factors at different eGFR levels are incompletely understood.
This pooled analysis of 11 phase 3 clinical trials assessed changes in HbA1c, body weight, BP, hematocrit, and urinary albumin-to-creatinine ratio with placebo (
=2178) or dapagliflozin 10 mg (
=2226) over 24 weeks in patients with type 2 diabetes according to baseline eGFR (eGFR≥45 to <60 ml/min per 1.73 m
, eGFR≥60 to <90 ml/min per 1.73 m
, and eGFR≥90 ml/min per 1.73 m
).
Compared with placebo, reductions in HbA1c with dapagliflozin were 0.6%, 0.5%, and 0.3%, respectively, for each consecutive lower eGFR subgroup (
value interaction <0.001). Effects of dapagliflozin on hematocrit, body weight, and BP were similar regardless of baseline eGFR, suggesting that effects potentially related to volume and natriuresis are eGFR independent. Moreover, among individuals with baseline urinary albumin-to-creatinine ratio ≥30 mg/g, placebo-adjusted reductions in urinary albumin-to-creatinine ratio were larger in the lowest eGFR subgroup (
value interaction <0.001). Adverse events occurred more frequently in the lowest eGFR subgroup; this was true for both dapagliflozin- and placebo
treated patients.
The HbA1c-lowering effects of dapagliflozin decrease as renal function declines. However, dapagliflozin consistently decreases body weight, BP, and urinary albumin-to-creatinine ratio regardless of eGFR. These effects in conjunction with the finding of similar effects on hematocrit, a proxy for volume contraction, suggest that the effects of dapagliflozin are partly mediated
nonglucosuric-dependent mechanisms.
Aims
Among patients with type 2 diabetes and albuminuria, cardiorenal morbidity and mortality are high despite multifactorial treatment. Short‐term reduction in albuminuria is considered suggestive ...of long‐term renoprotective effects. We evaluated the renal effects of the glucagon‐like peptide‐1 (GLP‐1) receptor agonist liraglutide on top of multifactorial care, including renin‐angiotensin‐system (RAS)‐inhibition.
Materials and methods
Randomized, double‐blind, placebo‐controlled, cross‐over trial including patients with type 2 diabetes and persistent albuminuria (urinary albumin‐to‐creatinine ratio >30 mg/g) and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2. Patients received liraglutide (1.8 mg/d) and matched placebo for 12 weeks in a random order. The primary endpoint was change in 24‐h urinary albumin excretion rate (UAER).
Results
A total of 32 patients were randomized and 27 completed the study. After placebo treatment, geometric mean (IQR) UAER was 199 (81‐531) mg/24‐h, mean (SD) measured GFR (mGFR) 75 (36) mL/min/1.73 m2, 24‐h blood pressure 145/80 (15/8) mm Hg and HbA1c 61 (11) mmol/mol. Liraglutide reduced HbA1c by 8 (95% CI: 5; 11) mmol/mol (P
< .001) and weight by 1.8 (95% CI: 0.2; 3.4) kg (P
= .032) compared to placebo. Furthermore, liraglutide reduced UAER by 32 (95% CI: 7; 50)% (
P
= .017) compared with placebo. The change in mGFR was −5 (95% CI: −11; 2) mL/min/1.73 m2 (
P
= .15), and change in 24‐h systolic blood pressure was −5 (95% CI: −10; 0) mm Hg (
P
= .07). In multivariate regression models, change in UAER was associated with change in 24‐h systolic blood pressure (
P
= .025) but not with change in HbA1c, weight or mGFR (
P
≥ .14), overall model
R
2
= .39.
Conclusions
Our placebo‐controlled randomized trial suggests that liraglutide has renoprotective effects on top of multifactorial treatment, including RAS‐inhibition, in patients with type 2 diabetes and albuminuria.
Gastrointestinal dysbiosis is common among persons with type 1 diabetes (T1D), but its potential impact on diabetic nephropathy (DN) remains obscure. We examined whether faecal biomarkers, previously ...associated with low-grade gastrointestinal inflammation, differ between healthy controls and T1D subjects with and without DN. Faecal samples were analyzed for levels of calprotectin, intestinal alkaline phosphatase (IAP), short-chain fatty acids (SCFA) and immunoglobulins in subjects with T1D (n = 159) and healthy controls (NDC; n = 50). The subjects with T1D were stratified based on albuminuria: normoalbuminuria (< 30 mg/g; n = 49), microalbuminuria (30-299 mg/g; n = 50) and macroalbuminuria (≥ 300 mg/g; n = 60). aecal calprotectin, IAP and immunoglobulin levels did not differ between the T1D albuminuria groups. However, when subjects were stratified based on faecal calprotectin cut-off level (50 µg/g), macroalbuminuric T1D subjects exceeded the threshold more frequently than NDC (p = 0.02). Concentrations of faecal propionate and butyrate were lower in T1D subjects compared with NDC (p = 0.04 and p = 0.03, respectively). Among T1D subjects, levels of branched SCFA (BCFA) correlated positively with current albuminuria level (isobutyrate, p = 0.03; isovalerate, p = 0.005). In our study cohort, fatty acid metabolism seemed to be altered among T1D subjects and those with albuminuria compared to NDC. This may reflect gastrointestinal imbalances associated with T1D and renal complications.
Up to 25% of people with type 2 diabetes (T2D) may binge eat which is almost 10 times as many as in the general population. Binge eating is associated with depression, anxiety, and social isolation. ...Moreover, binge eating may increase the risk of obesity and high blood glucose levels, both of which can accelerate the onset of complications to diabetes and death in people with T2D. Still, little is known about the experiences, needs, and preferences of people with T2D and binge eating that can inform and develop current and future treatment efforts. The aim of the study was therefore to gain in-depth insights into the experiences and biopsychosocial support needs of women and men with T2D and binge eating. Twenty semi-structured individual interviews (65% with females) were conducted and analyzed according to the methodology of Interpretive Description. Four themes were identified: (a) T2D and binge eating: Feeling trapped in a vicious circle; (b) Unwanted outcasts: Responding to continuous criticism; (c) Biomedical relief: Blaming and adjusting the body; and, (d) Silent struggles: Wanting to cease the secrecy. Pertinent to all themes were the guilt, shame, and worries about developing complications that the participants experienced when binge eating despite having T2D. Although binge eating triggered emotional distress, binge eating was at the same time a way of coping with such distress. Implications for treatment and future research are discussed, including the need to systematically assess and address binge eating in routine T2D care.
Time-restricted eating (TRE) has been shown to improve body weight and glucose metabolism in people at high risk of type 2 diabetes. However, the safety of TRE in the treatment of type 2 diabetes is ...unclear. We investigated the safety of TRE interventions in people with type 2 diabetes by identifying published and ongoing studies. Moreover, we identified the commonly used antidiabetic drugs and discussed the safety of TRE in people with type 2 diabetes considering the use of these drugs. In addition, we addressed the research needed before TRE can be recommended in the treatment of type 2 diabetes. A literature search was conducted to identify published (MEDLINE PubMed) and ongoing studies (ClinicalTrials.gov) on TRE in people with type 2 diabetes. To assess the usage of antidiabetic drugs and to discuss pharmacodynamics and pharmacokinetics in a TRE context, the most used antidiabetic drugs were identified and analysed. Statistics regarding sale of pharmaceuticals were obtained from MEDSTAT.DK which are based on data from the national Register of Medicinal Product Statistics, and from published studies on medication use in different countries. Four published studies investigating TRE in people with type 2 diabetes were identified as well as 14 ongoing studies. The completed studies suggested that TRE is safe among people with type 2 diabetes. Common antidiabetic drugs between 2010 and 2019 were metformin, insulin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, sulfonylureas, and sodium-glucose cotransporter-2 inhibitors. Existing studies suggest that TRE is not associated with major safety issues in people with type 2 diabetes as long as medication is monitored and adjusted. However, because of low generalisability of the few studies available, more studies are needed to make concrete recommendations regarding efficacy and safety of TRE in people with type 2 diabetes.
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