Circulating Free Fatty Acid and Phospholipid Signature Predicts Early Rapid Kidney Function Decline in Patients With Type 1 Diabetes

Objectives: Patients with type 1 diabetes (T1D) exhibit modest lipid abnormalities as measured by traditional metrics. This study aimed to identify lipidomic predictors of rapid decline of kidney function in T1D. Research Design and Methods: In a Case-Control study, 817 T1D patients from 3 large cohorts were randomly split into training and validation subsets. Case was defined as >3 mL/min/1.73 m2/year decline in estimated glomerular filtration rate (eGFR) while Control was defined as <1 mL/min/1.73 m2/year decline over a minimum 4-year follow up. Lipids were quantified in baseline serum samples using a targeted mass spectrometry lipidomic platform. Results: At individual lipids, free fatty-acid (FFA)20:2 was directly, and phosphatidylcholine (PC)16:0/22:6 was inversely and independently associated with rapid eGFR decline. When examined by lipid class, rapid eGFR decline was characterized by higher abundance of unsaturated FFAs, phosphatidylethanolamine (PE)-Ps and PCs with an unsaturated acyl chain at the sn1 carbon, and by lower abundance of saturated FFAs, longer triacylglycerols, and PCs, PEs, PE-Ps, and PE-Os with an unsaturated acyl chain at the sn1 carbon at eGFR ≥90 mL/min. A multi-lipid panel consisting of unsaturated FFAs and saturated PE-Ps predicted rapid eGFR decline better than individual lipids (C-statistic, 0.71) and improved C-statistic of clinical model from 0.816 to 0.841 (p=0.039). Observations were confirmed in the validation subset. Conclusion: Distinct from previously reported predictors of GFR decline in type 2 diabetes, these findings suggest differential incorporation of FFAs at sn1 carbon of the phospholipids’ glycerol backbone as independent predictor of rapid GFR decline in T1D.

Download Full-text

Circulating Free Fatty Acid and Phospholipid Signature Predicts Early Rapid Kidney Function Decline in Patients With Type 1 Diabetes

10.2337/figshare.14696676 ◽

2021 ◽

Author(s):

Farsad Afshinnia ◽

Thekkelnaycke M. Rajendiran ◽

Chenchen He ◽

Jaeman Byun ◽

Daniel Montemayor ◽

...

Keyword(s):

Type 1 Diabetes ◽

Fatty Acid ◽

Free Fatty Acid ◽

Kidney Function ◽

Acyl Chain ◽

C Statistic ◽

Unsaturated Acyl ◽

Gfr Decline ◽

Egfr Decline

Objectives: Patients with type 1 diabetes (T1D) exhibit modest lipid abnormalities as measured by traditional metrics. This study aimed to identify lipidomic predictors of rapid decline of kidney function in T1D. Research Design and Methods: In a Case-Control study, 817 T1D patients from 3 large cohorts were randomly split into training and validation subsets. Case was defined as >3 mL/min/1.73 m2/year decline in estimated glomerular filtration rate (eGFR) while Control was defined as <1 mL/min/1.73 m2/year decline over a minimum 4-year follow up. Lipids were quantified in baseline serum samples using a targeted mass spectrometry lipidomic platform. Results: At individual lipids, free fatty-acid (FFA)20:2 was directly, and phosphatidylcholine (PC)16:0/22:6 was inversely and independently associated with rapid eGFR decline. When examined by lipid class, rapid eGFR decline was characterized by higher abundance of unsaturated FFAs, phosphatidylethanolamine (PE)-Ps and PCs with an unsaturated acyl chain at the sn1 carbon, and by lower abundance of saturated FFAs, longer triacylglycerols, and PCs, PEs, PE-Ps, and PE-Os with an unsaturated acyl chain at the sn1 carbon at eGFR ≥90 mL/min. A multi-lipid panel consisting of unsaturated FFAs and saturated PE-Ps predicted rapid eGFR decline better than individual lipids (C-statistic, 0.71) and improved C-statistic of clinical model from 0.816 to 0.841 (p=0.039). Observations were confirmed in the validation subset. Conclusion: Distinct from previously reported predictors of GFR decline in type 2 diabetes, these findings suggest differential incorporation of FFAs at sn1 carbon of the phospholipids’ glycerol backbone as independent predictor of rapid GFR decline in T1D.

Download Full-text

Abstract P005: Evaluation of the Association between the Free Fatty Acid to serum Albumin Ratio with the Time to Cardiac Repolarization

Circulation ◽

10.1161/circ.129.suppl_1.p005 ◽

2014 ◽

Vol 129 (suppl_1) ◽

Author(s):

Baqiyyah N Conway ◽

Rhobert W Evans ◽

Orchard Trevor

Keyword(s):

Type 1 Diabetes ◽

Fatty Acid ◽

Free Fatty Acid ◽

Serum Albumin ◽

Colorimetric Method ◽

Albumin Excretion Rate ◽

Cardiac Autonomic Neuropathy ◽

Cardiac Repolarization ◽

Dead In Bed Syndrome

Background: Elevated free fatty acid (FFA) levels have been shown to increase cardiac repolarization time and are a hypothesized mediator of arrhythmic death. However, as albumin binds and transports FFA, it has been argued that it is the ratio of serum FFA to serum albumin (SA) that is critical. As FFA are chronically elevated in type 1 diabetes and form a major part of the counterregulatory response to hypoglycemia, we investigated the association of the FFA-to-SA ratio with the corrected Q-T (Q-Tc) interval in 87 men and 96 women with type 1 diabetes from the Pittsburgh Epidemiology of Diabetes Complications Study. We also investigated whether this relationship varied by cardiac autonomic neuropathy (CAN: R-R interval<1.1) status. Methods: FFAs were measured using a colorimetric method in participants with a mean age and diabetes duration of 44 and 33 years, respectively. The corrected Q-T interval was calculated using Hogdes formula and the FFA-SA ratio determined as FFA (mmol/L) ÷ SA (mg/dL). Because of the sexual dimorphism in FFA metabolism and the Q-T interval, analyses were also conducted sex-specifically. Results: Mean (std) FFA levels were 0.95 (o.48) mmol/l and did not vary by sex (men vs women: 0.93 (0.46) vs 0.96 (0.49) mmol/L, p=0.76). The FFA-SA ratio demonstrated a modest association with Q-Tc interval in men (r=0.23, p=0.03), but no association in women (r=-0.07, p=0.48). Overall, in multivariable analyses controlling for sex, visceral adipose tissue, blood glucose levels and albumin excretion rate, FFA-SA, and CAN, a significant interaction was observed between the FFA-SA ratio and CAN in the association of the Q-Tc interval (p=0.03). FFA remained significantly associated with the Q-Tc interval in those without CAN (p<0.05), but not in those with CAN (p=0.30). Sex-specific analyses revealed that although no significant FFA-SA ratio and CAN interaction was observed in men (p=0.42), a relationship between the FFA-SA ratio and Q-Tc interval existed in men free of CAN (p=0.04). No association was observed in women with or without CAN. Conculsion: We conclude that a higher FFA-SA ratio is associated with an increased time to cardiac repolarization in those without CAN, particularly in men, helping to explain why the "dead in bed" syndrome is predominantly seen in men.

Download Full-text

Insulin Sensitivity, Glucose Effectiveness, and Free Fatty Acid Dynamics after Human Islet Transplantation for Type 1 Diabetes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2005-2519 ◽

2006 ◽

Vol 91 (6) ◽

pp. 2138-2144 ◽

Cited By ~ 32

Author(s):

Michael R. Rickels ◽

Ali Naji ◽

Karen L. Teff

Keyword(s):

Type 1 Diabetes ◽

Fatty Acid ◽

Insulin Sensitivity ◽

Free Fatty Acid ◽

Islet Transplantation ◽

Human Islet ◽

Glucose Effectiveness ◽

Human Islet Transplantation

Download Full-text

Free fatty acid receptor 2, a candidate target for type 1 diabetes, induces cell apoptosis through ERK signaling

Journal of Molecular Endocrinology ◽

10.1530/jme-14-0065 ◽

2014 ◽

Vol 53 (3) ◽

pp. 367-380 ◽

Cited By ~ 19

Author(s):

Guojun Shi ◽

Chen Sun ◽

Weiqiong Gu ◽

Minglan Yang ◽

Xiaofang Zhang ◽

...

Keyword(s):

Type 1 Diabetes ◽

Fatty Acid ◽

Free Fatty Acid ◽

Glucose Homeostasis ◽

Cell Apoptosis ◽

Erk Signaling ◽

Diabetic Mice ◽

Acid Receptor ◽

Free Fatty Acid Receptor

Recent reports have highlighted the roles of free fatty acid receptor 2 (FFAR2) in the regulation of metabolic and inflammatory processes. However, the potential function of FFAR2 in type 1 diabetes (T1D) remains unexplored. Our results indicated that the mRNA level of FFAR2 was upregulated in peripheral blood mononuclear cells of T1D patients. The human FFAR2 promoter regions were cloned, and luciferase reporter assays revealed that NFκB activation induced FFAR2 expression. Furthermore, we showed that FFAR2 activation by overexpression induced cell apoptosis through ERK signaling. Finally, treatment with the FFAR2 agonists acetate or phenylacetamide 1 attenuated the inflammatory response in multiple-low-dose streptozocin-induced diabetic mice, and improved the impaired glucose tolerance. These results indicate that FFAR2 may play a protective role by inducing apoptosis of infiltrated macrophage in the pancreas through its feedback upregulation and activation, thus, in turn, improving glucose homeostasis in diabetic mice. These findings highlight FFAR2 as a potential therapeutic target of T1D, representing a link between immune response and glucose homeostasis.

Download Full-text