Higher circulating levels of non-esterified fatty acids are associated with faster kidney function decline in post-menopausal women with type 2 diabetes: a pilot prospective study.

AIMS: Currently, there is little and inconsistent evidence regarding the possible adverse effects of circulating levels of non-esterified fatty acids (NEFA) on kidney function decline in patients with type 2 diabetes mellitus (T2DM). METHODS: We followed for a median of 4.6 years 85 post-menopausal women with non-insulin-treated T2DM and preserved kidney function at baseline. Serum NEFA concentrations were measured using an enzymatic colorimetric method. Glomerular filtration rate (eGFR) was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. RESULTS: Enrolled patients had a baseline mean eGFRCKD-EPI of 83 ± 12 mL/min/1.73 m2 and a median serum NEFA concentration of 662 uEq/L (interquartile range 524-842 uEq/L). During the follow-up period, 13 patients developed kidney function decline at follow-up (defined as an eGFRCKD-EPI decline ≥ 30% from baseline). In Cox proportional hazards regression analyses, higher serum NEFA levels were significantly associated with an increased risk of developing kidney function decline (adjusted-hazard ratio 3.67, 95% CI 1.64-8.22, p < 0.001; for each 1-SD increment, i.e., 262 uEq/L), even after adjustment for waist circumference, hemoglobin A1c, C-reactive protein, HOMA-estimated insulin resistance, hypertension, dyslipidemia, microalbuminuria, baseline eGFRCKD-EPI, as well as temporal changes in HbA1c levels or the use of renin-angiotensin system inhibitors over the follow-up. CONCLUSIONS: The findings of this exploratory prospective study show that in post-menopausal women with T2DM and preserved kidney function at baseline, higher circulating levels of NEFA were strongly associated with a faster kidney function decline, even after adjustment for established renal risk factors and potential confounders.

Association between PNPLA3 rs738409 variant and 5-year estimated glomerular filtration rate decline in post-menopausal women with type 2 diabetes: A panel-data analysis.

BACKGROUND AND AIMS: Little is known about the relationship between patatin-like phospholipase domain-containing protein-3 (PNPLA3) rs738409 variant and decline in estimated glomerular filtration rate (eGFR) over time in individuals with type 2 diabetes (T2DM). METHODS AND RESULTS: We enrolled an outpatient sample of 46 post-menopausal women with T2DM and preserved kidney function at baseline (in 2017), who were followed through 2022. eGFR and albuminuria were measured annually. Genotyping of PNPLA3 rs738409 was performed by TaqMan-based RT-PCR system. Overall, 25 (54.3%) patients had PNPLA3 rs738409 CC (homozygous wild-type) genotype and 21 had CG or GG genotypes. During the 5-year follow-up, the presence of rs738409 CG/GG genotypes was associated with faster eGFR decline (coefficient: -6.55; 95% CI -11.0 to -2.08; p = 0.004 by random-effects panel data analysis). This association remained significant even after adjustment for 5-year changes in age, hemoglobin A1c, hypertension status, albuminuria and use of sodium-glucose co-transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists. CONCLUSIONS: This pilot study suggests that in post-menopausal T2DM women with preserved kidney function at baseline, the risk allele (G) of PNPLA3 rs738409 is associated with a faster eGFR decline during a 5-year follow-up, independent of annual changes in common renal risk factors and use of certain glucose-lowering medications.

Association between metabolic dysfunction-associated fatty liver disease and supraventricular and ventricular tachyarrhythmias in patients with type 2 diabetes.

BACKGROUND: Currently, it remains uncertain whether metabolic dysfunction-associated fatty liver disease (MAFLD) is associated with increased risk of supraventricular and ventricular tachyarrhythmias in people with type 2 diabetes mellitus (T2DM). METHODS: We retrospectively examined the data of 367 ambulatory patients with T2DM who underwent 24-hour Holter monitoring between 2015 and 2022 for clinical indications, and who did not have pre-existing permanent atrial fibrillation (AF), kidney failure or known liver diseases. Paroxysmal supraventricular tachycardia (PSVT), paroxysmal AF and episodes of ventricular tachyarrhythmias (i.e., presence of ventricular tachycardia, >30 premature ventricular complexes per hour, or both) were recorded. The presence and severity of MAFLD was diagnosed by ultrasonography and fibrosis-4 (FIB-4) index. RESULTS: Patients with T2DM who had MAFLD (n = 238) had a significantly greater prevalence of PSVT (51.7% vs. 38.8%), paroxysmal AF (6.3% vs. 1.3%) and combined ventricular tachyarrhythmias (31.9% vs. 20.2%) compared to their counterparts without MAFLD (n = 129). MAFLD was significantly associated with a greater than two-fold risk of having PSVT (adjusted-odds ratio [OR] 2.04, 95% confidence interval 1.04-4.00) or ventricular tachyarrhythmias (adjusted-OR 2.44, 95%CI 1.16-5.11), after adjusting for age, sex, smoking, alcohol intake, diabetes-related factors, comorbidities, medication use and left ventricular ejection fraction on echocardiography. The risk of supraventricular and ventricular tachyarrhythmias was even greater amongst patients with MAFLD and FIB-4 ≥ 1.3. CONCLUSIONS: In ambulatory patients with T2DM, the presence and severity of MAFLD was strongly associated with an increased risk of supraventricular and ventricular arrhythmias on 24-hour Holter monitoring.

Long-Term Adverse Effect of Liver Stiffness on Glycaemic Control in Type 2 Diabetic Patients with Nonalcoholic Fatty Liver Disease: A Pilot Study.

Currently, there are limited data regarding the long-term effect of liver stiffness on glycaemic control in patients with type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD). We prospectively followed an outpatient sample of 61 consecutive postmenopausal women with T2DM and NAFLD who had baseline data on liver ultrasonography and Fibroscan®-assessed liver stiffness measurement (LSM) in 2017 and who underwent follow-up in 2022. Haemoglobin A1c (HbA1c) was measured both at baseline and follow-up. At baseline, 52 patients had NAFLD (hepatic steatosis) alone, and 9 had NAFLD with coexisting clinically significant fibrosis (defined as LSM ≥ 7 kPa on Fibroscan®). At follow-up, 16 patients had a worsening of glycaemic control (arbitrarily defined as HbA1c increase ≥ 0.5% from baseline). The prevalence of NAFLD and coexisting clinically significant fibrosis at baseline was at least three times greater among patients who developed worse glycaemic control at follow-up, compared with those who did not (31.3% vs. 8.9%; p = 0.030). In logistic regression analysis, the presence of NAFLD and clinically significant fibrosis was associated with an approximately 4.5-fold increased likelihood of developing worse glycaemic control at follow-up (odds ratio 4.66, 95% confidence interval 1.07-20.3; p = 0.041), even after adjustment for baseline confounding factors, such as age, body mass index, haemoglobin A1c (or HOMA-estimated insulin resistance) and use of some glucose-lowering agents that may positively affect NAFLD and liver fibrosis. In conclusion, our results suggest that the presence of Fibroscan®-assessed significant fibrosis was associated with a higher risk of developing worse glycaemic control in postmenopausal women with T2DM and NAFLD.