Key pointsr Although the role of TBC1D1 within the heart remains unknown, expression of TBC1D1 increases in the left ventricle following an acute infarction, suggesting a biological importance within this tissue.r We investigated the mechanistic role of TBC1D1 within the heart, aiming to establish the consequences of attenuating TBC1D1 signalling in the development of diabetic cardiomyopathy, as well as to determine potential sex differences. r TBC1D1 ablation increased plasma membrane fatty acid binding protein content and myocardial palmitate oxidation. r Following high-fat feeding, TBC1D1 ablation dramatically increased fibrosis and induced end-diastolic dysfunction in both male and female rats in the absence of changes in mitochondrial bioenergetics.r Altogether, independent of sex, ablating TBC1D1 predisposes the left ventricle to pathological remodelling following high-fat feeding, and suggests TBC1D1 protects against diabetic cardiomyopathy.Abstract TBC1D1, a Rab-GTPase activating protein, is involved in the regulation of glucose handling and substrate metabolism within skeletal muscle, and is essential for maintaining pancreatic β-cell mass and insulin secretion. However, the function of TBC1D1 within the heart is largely unknown. Therefore, we examined the role of TBC1D1 in the left ventricle and the functional consequence of ablating TBC1D1 on the susceptibility to high-fat diet-induced abnormalities. Since mutations within TBC1D1 (R125W) display stronger associations with clinical parameters in women, we further examined possible sex differences in the predisposition to diabetic cardiomyopathy. In control-fed animals, TBC1D1 ablation did not alter Pierre-Andre Barbeau completed his undergraduate (2015) and Master's (2017) degrees at the University of Guelph, having been supervised by Dr Graham Holloway in the department of Human Health and Nutritional Sciences. His research focuses on the effects of adaptive (omega 3 fatty acids and exercise) and maladaptive (high-fat feeding) paradigms on various aspects of skeletal and cardiac muscle metabolism, with a particular emphasis on mitochondrial bioenergetics. Jacy Houad attended the University of Guelph to complete an undergraduate degree (2013) in Human Kinetics, and a Master's degree (2014) insulin-stimulated glucose uptake, or echocardiogram parameters, but increased accumulation of a plasma membrane fatty acid transporter and the capacity for palmitate oxidation. When challenged with an 8 week high-fat diet, TBC1D1 knockout rats displayed a four-fold increase in fibrosis compared to wild-type animals, and this was associated with diastolic dysfunction, suggesting a predisposition to diet-induced cardiomyopathy. Interestingly, high-fat feeding only induced cardiac hypertrophy in male TBC1D1 knockout animals, implicating a possible sex difference. Mitochondrial respiratory capacity and substrate sensitivity to pyruvate and ADP were not altered by diet or TBC1D1 ablation, nor were markers of oxidative stress, or indices of overt heart failure. Altogethe...

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Key points Although the role of TBC1D1 within the heart remains unknown, expression of TBC1D1 increases in the left ventricle following an acute infarction, suggesting a biological importance within this tissue. We investigated the mechanistic role of TBC1D1 within the heart, aiming to establish the consequences of attenuating TBC1D1 signalling in the development of diabetic cardiomyopathy, as well as to determine potential sex differences. TBC1D1 ablation increased plasma membrane fatty acid binding protein content and myocardial palmitate oxidation. Following high‐fat feeding, TBC1D1 ablation dramatically increased fibrosis and induced end‐diastolic dysfunction in both male and female rats in the absence of changes in mitochondrial bioenergetics. Altogether, independent of sex, ablating TBC1D1 predisposes the left ventricle to pathological remodelling following high‐fat feeding, and suggests TBC1D1 protects against diabetic cardiomyopathy. Abstract TBC1D1, a Rab‐GTPase activating protein, is involved in the regulation of glucose handling and substrate metabolism within skeletal muscle, and is essential for maintaining pancreatic β‐cell mass and insulin secretion. However, the function of TBC1D1 within the heart is largely unknown. Therefore, we examined the role of TBC1D1 in the left ventricle and the functional consequence of ablating TBC1D1 on the susceptibility to high‐fat diet‐induced abnormalities. Since mutations within TBC1D1 (R125W) display stronger associations with clinical parameters in women, we further examined possible sex differences in the predisposition to diabetic cardiomyopathy. In control‐fed animals, TBC1D1 ablation did not alter insulin‐stimulated glucose uptake, or echocardiogram parameters, but increased accumulation of a plasma membrane fatty acid transporter and the capacity for palmitate oxidation. When challenged with an 8 week high‐fat diet, TBC1D1 knockout rats displayed a four‐fold increase in fibrosis compared to wild‐type animals, and this was associated with diastolic dysfunction, suggesting a predisposition to diet‐induced cardiomyopathy. Interestingly, high‐fat feeding only induced cardiac hypertrophy in male TBC1D1 knockout animals, implicating a possible sex difference. Mitochondrial respiratory capacity and substrate sensitivity to pyruvate and ADP were not altered by diet or TBC1D1 ablation, nor were markers of oxidative stress, or indices of overt heart failure. Altogether, independent of sex, ablation of TBC1D1 not only increased the susceptibility to high‐fat diet‐induced diastolic dysfunction and left ventricular fibrosis, independent of sex, but also predisposed male animals to the development of cardiac hypertrophy. These data suggest that TBC1D1 may exert cardioprotective effects in the development of diabetic cardiomyopathy.

Understanding the mechanisms regulating islet function is crucial for establishing novel therapeutic modalities to combat diabetes. TBC1D1, a Rab‐GTPase activating protein involved in skeletal muscle GLUT4 trafficking events, was recently identified withinβ‐cells and implicated in cell proliferation. However, the in vivo function of TBC1D1 remains to be elucidated. Therefore, we addressed the role of TBC1D1 in the pancreas utilizing a rat knockout (KO) model. Wild‐type and TBC1D1 KO rats were maintained on a chow or high‐fat diet. We demonstrated that TBC1D1 KO rats were glucose intolerant and displayed reduced insulin levels during a glucose challenge, suggesting that their phenotype prominently manifests within the pancreas. Next, we examined islet function and β‐cell mass. While, glucose‐stimulated insulin secretion from harvested islets was increased in TBC1D1 KO rats, we observed an overall decrease in β‐cell mass by ~30%. In addition, consumption of a high‐fat diet did not influence these changes observed in the KO rats. Altogether, our data suggests that in vivo impaired glucose homeostasis observed in TBC1D1 KO rats is a consequence of altered islet mass, thereby establishing a fundamental in vivo role for TBC1D1 in maintaining β‐cell mass. Therefore, pancreatic TBC1D1 may represent an attractive target to improve β‐cell function and stability to treat and prevent diabetes.