Metabolic inflexibility and protein lysine acetylation in heart mitochondria of a chronic model of Type 1 diabetes

Diabetic cardiomyopathy refers to the changes in contractility that occur to the diabetic heart that can arise in the absence of vascular disease. Mitochondrial bioenergetic deficits and increased free radical production are pathological hallmarks of diabetic cardiomyopathy, but the mechanisms and causal relationships between mitochondrial deficits and the progression of disease are not understood. We evaluated cardiac mitochondrial function in a rodent model of chronic Type 1 diabetes (OVE26 mice) before the onset of contractility deficits. We found that the most pronounced change in OVE26 heart mitochondria is severe metabolic inflexibility. This inflexibility is characterized by large deficits in mitochondrial respiration measured in the presence of non-fatty acid substrates. Metabolic inflexibility occurred concomitantly with decreased activities of PDH (pyruvate dehydrogenase) and complex II. Hyper-acetylation of protein lysine was also observed. Treatment of control heart mitochondria with acetic anhydride (Ac2O), an acetylating agent, preferentially inhibited respiration by non-fatty acid substrates and increased superoxide production. We have concluded that metabolic inflexibility, induced by discrete enzymatic and molecular changes, including hyper-acetylation of protein lysine residues, precedes mitochondrial defects in a chronic rodent model of Type 1 diabetes.

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1666-P: Increased Levels of Autophagy in a Rodent Model of Type 1 Diabetes

Diabetes ◽

10.2337/db20-1666-p ◽

2020 ◽

Vol 69 (Supplement 1) ◽

pp. 1666-P

Author(s):

CEREN KARACAY ◽

PETRA KOTZBECK ◽

BARBARA PRIETL ◽

CLEMENS HARER ◽

THOMAS PIEBER

Keyword(s):

Type 1 Diabetes ◽

Rodent Model

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Omega-3 polyunsaturated fatty acid supplementation versus placebo on vascular health, glycaemic control, and metabolic parameters in people with type 1 diabetes: a randomised controlled preliminary trial

Cardiovascular Diabetology ◽

10.1186/s12933-020-01094-5 ◽

2020 ◽

Vol 19 (1) ◽

Author(s):

Lauren L. O’Mahoney ◽

Gareth Dunseath ◽

Rachel Churm ◽

Mel Holmes ◽

Christine Boesch ◽

...

Keyword(s):

Type 1 Diabetes ◽

Fatty Acid ◽

Glycaemic Control ◽

Polyunsaturated Fatty Acid ◽

Vascular Health ◽

Omega 3 ◽

Fatty Acid Supplementation ◽

Acid Supplementation ◽

Randomised Controlled

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PP210-MON EFFECTS OF STARVATION ON PLASMA ADIPOCYTE FATTY ACID BINDING PROTEIN CONCENTRATION IN OBESE PATIENTS WITH TYPE 1 DIABETES MELLITUS

Clinical Nutrition Supplements ◽

10.1016/s1744-1161(12)70549-5 ◽

2012 ◽

Vol 7 (1) ◽

pp. 221

Author(s):

F. Musil ◽

A. Smahelova ◽

A. Ticha ◽

R. Hyspler ◽

M. Haluzik ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Fatty Acid ◽

Type 1 Diabetes Mellitus ◽

Protein Concentration ◽

Fatty Acid Binding Protein ◽

Obese Patients ◽

Fatty Acid Binding ◽

Acid Binding Protein

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GH replacement causing acute hyperglycaemia and ketonuria in a type 1 diabetic patient

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-13-0047 ◽

2013 ◽

Vol 2013 ◽

Cited By ~ 1

Author(s):

Dominic Cavlan ◽

Shanti Vijayaraghavan ◽

Susan Gelding ◽

William Drake

Keyword(s):

Insulin Resistance ◽

Fatty Acids ◽

Type 1 Diabetes ◽

Fatty Acid ◽

Diabetic Patient ◽

Acid Cycle ◽

Gh Replacement ◽

Glucose Fatty Acid Cycle ◽

Gh Excess

Summary A state of insulin resistance is common to the clinical conditions of both chronic growth hormone (GH) deficiency and GH excess (acromegaly). GH has a physiological role in glucose metabolism in the acute settings of fast and exercise and is the only anabolic hormone secreted in the fasting state. We report the case of a patient in whom knowledge of this aspect of GH physiology was vital to her care. A woman with well-controlled type 1 diabetes mellitus who developed hypopituitarism following the birth of her first child required GH replacement therapy. Hours after the first dose, she developed a rapid metabolic deterioration and awoke with hyperglycaemia and ketonuria. She adjusted her insulin dose accordingly, but the pattern was repeated with each subsequent increase in her dose. Acute GH-induced lipolysis results in an abundance of free fatty acids (FFA); these directly inhibit glucose uptake into muscle, and this can lead to hyperglycaemia. This glucose–fatty acid cycle was first described by Randle et al. in 1963; it is a nutrient-mediated fine control that allows oxidative muscle to switch between glucose and fatty acids as fuel, depending on their availability. We describe the mechanism in detail. Learning points There is a complex interplay between GH and insulin resistance: chronically, both GH excess and deficiency lead to insulin resistance, but there is also an acute mechanism that is less well appreciated by clinicians. GH activates hormone-sensitive lipase to release FFA into the circulation; these may inhibit the uptake of glucose leading to hyperglycaemia and ketosis in the type 1 diabetic patient. The Randle cycle, or glucose–fatty acid cycle, outlines the mechanism for this acute relationship. Monitoring the adequacy of GH replacement in patients with type 1 diabetes is difficult, with IGF1 an unreliable marker.

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Abstract 26: Fibroblast Growth Factor 21 Prevents Diabetic Cardiomyopathy by Attenuating Cardiac Lipotoxicity via Erk1/2-dependent Signaling Pathway in Mice

Circulation Research ◽

10.1161/res.117.suppl_1.26 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Yi Tan ◽

Chi Zhang ◽

Xiaoqing Yan ◽

Zhifeng Huang ◽

Junlian Gu ◽

...

Keyword(s):

Cell Death ◽

Type 1 Diabetes ◽

Signaling Pathway ◽

P38 Mapk ◽

Diabetic Cardiomyopathy ◽

Cardiac Cell ◽

Diabetic Mice ◽

Ampk Signaling

The role of FGF21 plays in the development and progression of diabetic cardiomyopathy (DCM) has not been addressed. Here we demonstrated that type 1 diabetes decreased FGF21 levels in the blood, but up-regulated cardiac fgf21 expression about 40 fold at 2 months and 3-1.5 fold at 4 and 6 months after diabetes, which indicated a cardiac specific FGF21 adaptive up-regulation. To define the critical role of FGF21 in DCM, type 1 diabetes was induced in FGF21 knock out (FGF21KO) mice. At 1, 2 and 4 months after diabetes onset, no significant differences between FGF21KO and wild type (WT) diabetic mice in blood glucose and triglyceride levels were observed. But FGF21KO diabetic mice showed earlier and more severe cardiac dysfunction, remodeling and oxidative stress, as well as greater increase in cardiac lipid accumulation than WT diabetic mice. Mechanistically, FGF21 reduced palmitate-induced cardiac cell death, which was accompanied by up-regulation of cardiac Erk1/2, p38 MAPK and AMPK phosphorylation. Inhibition of each kinase with its inhibitor and/ or siRNA revealed that FGF21 prevents palmitate-induced cardiac cell death via up-regulating the Erk1/2-dependent p38 MAPK/AMPK signaling pathway. In vivo administration of FGF21, but not FGF21 plus ERK1/2 inhibitor, to diabetic mice significantly prevented cardiac cell death and reduced inactivation of Erk1/2, p38 MAPK and AMPK, and prevented cardiac remodeling and dysfunction at late-stage. Our results demonstrate that cardiac FGF21 decompensation may contribute to the development of DCM and FGF21 may be a therapeutic target for the treatment of diabetic cardiac damage via activation of Erk1/2-P38 MAPK-AMPK signaling.

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

Diabetes Care ◽

10.2337/dc21-0737 ◽

2021 ◽

pp. dc210737

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 ◽

Kidney Function Decline

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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.

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