Insulin-stimulated endoproteolytic TUG cleavage links energy expenditure with glucose uptake.

TUG tethering proteins bind and sequester GLUT4 glucose transporters intracellularly, and insulin stimulates TUG cleavage to translocate GLUT4 to the cell surface and increase glucose uptake. This effect of insulin is independent of phosphatidylinositol 3-kinase, and its physiological relevance remains uncertain. Here we show that this TUG cleavage pathway regulates both insulin-stimulated glucose uptake in muscle and organism-level energy expenditure. Using mice with muscle-specific Tug (Aspscr1)-knockout and muscle-specific constitutive TUG cleavage, we show that, after GLUT4 release, the TUG C-terminal cleavage product enters the nucleus, binds peroxisome proliferator-activated receptor (PPAR)γ and its coactivator PGC-1α and regulates gene expression to promote lipid oxidation and thermogenesis. This pathway acts in muscle and adipose cells to upregulate sarcolipin and uncoupling protein 1 (UCP1), respectively. The PPARγ2 Pro12Ala polymorphism, which reduces diabetes risk, enhances TUG binding. The ATE1 arginyltransferase, which mediates a specific protein degradation pathway and controls thermogenesis, regulates the stability of the TUG product. We conclude that insulin-stimulated TUG cleavage coordinates whole-body energy expenditure with glucose uptake, that this mechanism might contribute to the thermic effect of food and that its attenuation could promote obesity.

Peroxisome proliferator-activated receptors gamma and alpha agonists stimulate cardiac glucose uptake via activation of AMP-activated protein kinase.

Myocardial energy and glucose homeostasis are crucial for normal cardiac structure and function. Peroxisome proliferator-activated receptors (PPARs) play an important role in controlling transcriptional expression of key enzymes that are involved in glucose metabolism, and they have been demonstrated to significantly reduce tissue injury in cardiovascular diseases. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a sensor that maintains intracellular energy homeostasis and mediates a number of physiological signals. It has been reported that AMPK promotes glucose uptake. We hypothesize that PPAR gamma and alpha agonists may play a role in the regulation of glucose metabolism through AMPK. We tested this hypothesis by using isolated papillary muscles of rat hearts treated with PPAR gamma and alpha agonists, troglitazone and GW7647, respectively. Our results demonstrated that both troglitazone and GW7647 significantly stimulated 2-deoxyglucose uptake of cardiac muscles. Interestingly, both agonists stimulated phosphorylation of AMPK and its downstream protein target acetyl-CoA carboxylase. Endothelial nitric oxide synthase (eNOS) was also activated by both agonists. In addition, AMPK activator 5-amino-4-imidazole-1-beta-D-carboxamide ribofuranoside increased glucose uptake, while AMPK inhibitor compound C and NOS inhibitor, N(omega)-nitro-L-arginine, significantly blocked troglitazone- and GW7647-stimulated glucose uptake in cardiac muscles. There was also a reduction of glucose uptake with a marked decrease in AMPK and eNOS phosphorylation. In conclusion, both PPAR gamma and alpha activation play a role in the regulation of glucose uptake in cardiac muscles and this regulation is mediated by the AMPK and eNOS signaling pathways.

Hearing loss in middle-aged subjects with type 2 diabetes mellitus.

BACKGROUND: Complications of type 2 diabetes mellitus (T2DM) can result in hearing loss, which is characterized by high-frequency sensorineural hearing impairment and accelerated age-related decline of the right ear advantage. This investigation aimed to determine which auditory functions are affected in middle-aged subjects with T2DM and the change of the right ear advantage. METHODS: We assessed the auditory function of 50 diabetic and 50 healthy subjects using pure-tone audiometry, auditory brainstem response and otoacoustic emissions. RESULTS: Diabetic subjects showed elevated thresholds at 4000 Hz and 8000 Hz (p <0.01) and increased wave V and interwave I-V latencies (p <0.01) when compared to healthy subjects. Consistently, subjects with diabetes also had smaller distortion product otoacoustic emission amplitudes at 2.0, 3.0 and 4.0 kHz (p <0.01) and smaller transient otoacoustic emission amplitude in the right ear when compared to healthy controls (p <0.05). Meanwhile, the right ear transient otoacoustic emission amplitude of subjects with T2DM was smaller than the left ear at 4.0 kHz (p <0.05). CONCLUSIONS: Our data suggest that middle-aged subjects with T2DM have subclinical hearing loss, impaired auditory brainstem response and diminished otoacoustic emissions, and the peripheral right ear advantage is being lost in middle-aged subjects with T2DM.