Voluntary physical activity and leucine correct impairments in muscle protein synthesis in partially pancreatectomised rats.

AIMS/HYPOTHESIS: Poorly controlled type 1 diabetes mellitus can cause reduced skeletal muscle mass and weakness during adolescence, which may affect long-term management of the disease. The aim of this study was to determine whether regular voluntary physical activity and leucine feeding restore rates of protein synthesis and deficits in skeletal muscle mass in a young, hypoinsulinaemic/hyperglycaemic rat model of diabetes. METHODS: Four-week-old male Sprague-Dawley rats were partially pancreatectomised (Px) to induce hypoinsulinaemia/hyperglycaemia and housed with/without access to running wheels for 3 weeks (n = 12-14/group). Sham surgery rats (shams) served as sedentary controls (n = 18). Protein synthesis and markers of protein anabolism were assessed in the fasted state and following leucine gavage. Fibre type and cross-sectional areas of the gastrocnemius muscle were measured using a metachromatic ATPase stain. RESULTS: Compared with sedentary behaviour, regular activity lowered fasting glycaemia and reduced fed hyperglycaemia in Px rats. Active-Px rats, which ran 2.2 ± 0.71 km/night, displayed greater muscle mass and fibre areas similar to shams, while sedentary-Px rats displayed a 20-30% loss in muscle fibre areas. Muscle protein synthesis (basal and in response to leucine gavage) was impaired in sedentary-Px (by ~65%), but not in active-Px rats, when compared with shams. Following leucine gavage, the phosphorylation status of eIF4E binding protein 1 (4E-BP1) and ribosomal S6 kinase 1 (S6K1), markers of mammalian target of rapamycin complex 1 (mTORC1) signalling, increased in shams (by two- and ninefold, respectively) and in active-Px (1.5- and fourfold, respectively) rats, but not in sedentary-Px rats. CONCLUSION/INTERPRETATION: Moderate physical activity in young Px rats normalises impairments in skeletal muscle growth and protein synthesis. These findings illustrate the critical compensatory role that modest physical activity and targeted nutrition can have on skeletal muscle growth during periods of hypoinsulinaemia in adolescent diabetes.

Regulation of glucagon secretion by zinc: lessons from the ß cell-specific Znt8 knockout mouse model.

In type-2 diabetes, hyperglucagonaemia aggravates elevated blood glucose levels. Relative to our knowledge of the ß-cell and insulin secretion, there remains a limited understanding of glucagon secretion in α-cells. Regulation of glucagon may be dependent on a combination of factors, which include direct glucose sensing by the α-cell, innervations from the autonomic nervous system and potential 'paracrine' actions by hormones and factors that are released by adjacent endocrine cells within the islets. The list of potential 'paracrine' regulators within the islet includes insulin, somatostatin, γ-aminobutyric acid, glutamate and zinc. Zinc crystallises with insulin in ß-cells and is co-secreted with insulin. In the scientific literature, the effect of exogeneous zinc on glucagon secretion has been debated. Here, we confirm that an increase in exogeneous zinc does inhibit glucagon secretion. To determine if there are physiological effects of zinc on glucagon secretion we used a ß-cell-specific ZnT8 knockout (Znt8BKO) mouse model. Znt8BKO mice, despite showing lower granular zinc content in ß-cells, showed no changes in fasted plasma glucagon levels and glucose regulated glucagon secretion. These findings suggest that zinc secreted from ß-cell does not regulate glucagon secretion.