Non-obese Diabetic Goto-Kakizaki Rats Research Articles

Reviewing physical exercise in non-obese diabetic Goto-Kakizaki rats.

There is a high incidence of non-obese type 2 diabetes mellitus (non-obese-T2DM) cases, particularly in Asian countries, for which the pathogenesis remains mainly unclear. Interestingly, Goto-Kakizaki (GK) rats spontaneously develop insulin resistance (IR) and non-obese-T2DM, making them a lean diabetes model. Physical exercise is a non-pharmacological therapeutic approach to reduce adipose tissue mass, improving peripheral IR, glycemic control, and quality of life in obese animals or humans with T2DM. In this narrative review, we selected and analyzed the published literature on the effects of physical exercise on the metabolic features associated with non-obese-T2DM. Only randomized controlled trials with regular physical exercise training, freely executed physical activity, or skeletal muscle stimulation protocols in GK rats published after 2008 were included. The results indicated that exercise reduces plasma insulin levels, increases skeletal muscle glycogen content, improves exercise tolerance, protects renal and myocardial function, and enhances blood oxygen flow in GK rats.

Exercise training impacts exercise tolerance and bioenergetics in gastrocnemius muscle of non-obese type-2 diabetic Goto-Kakizaki rat in vivo

The functional and bioenergetics impact of regular physical activity upon type-2 diabetic skeletal muscle independently of confounding factors of overweight remains undocumented. Here, gastrocnemius muscle energy fluxes, mitochondrial capacity and mechanical performance were assessed noninvasively and longitudinally in non-obese diabetic Goto-Kakizaki rats using magnetic resonance (MR) imaging and dynamic 31-phosphorus MR spectroscopy (31P-MRS) throughout a 6-min fatiguing bout of exercise performed before, in the middle (4-week) and at the end of an 8-week training protocol consisting in 60-min daily run on a treadmill. The training protocol reduced plasmatic insulin level (−61%) whereas blood glucose and non-esterified fatty acids levels remained unaffected, thereby indicating an improvement of insulin sensitivity. It also increased muscle mitochondrial citrate synthase activity (+45%) but this increase did not enhance oxidative ATP synthesis capacity in working muscle in vivo while glycolytic ATP production was increased (+33%). On the other hand, the training protocol impaired maximal force-generating capacity (−9%), total amount of force produced (−12%) and increased ATP cost of contraction (+32%) during the fatiguing exercise. Importantly, these deleterious effects were transiently worsened in the middle of the 8-week period, in association with reduced oxidative capacity and increased basal [Pi]/[PCr] ratio (an in vivo biomarker of muscle damage). These data demonstrate that the beneficial effect of regular training on insulin sensitivity in non-obese diabetic rat occurs separately from any improvement in muscle mitochondrial function and might be linked to an increased capacity for metabolizing glucose through anaerobic process in exercising muscle.

The Sodium Glucose Cotransporter 2 Inhibitor Ipragliflozin Promotes Preferential Loss of Fat Mass in Non-obese Diabetic Goto–Kakizaki Rats

Sodium glucose cotransporter 2 (SGLT2) inhibitors improve hyperglycemia in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion. In addition to their antihyperglycemic effect, SGLT2 inhibitors also reduce body weight and fat mass in obese and overweight patients with T2DM. However, whether or not SGLT2 inhibitors similarly affect body composition of non-obese patients with T2DM remains unclear. In this study, we investigated the effect of the SGLT2 inhibitor ipragliflozin on body composition in a Goto-Kakizaki (GK) rat model of non-obese T2DM. GK rats were treated with ipragliflozin once daily for 9 weeks, starting at 23 weeks of age. Body composition was then analyzed using dual-energy X-ray absorptiometry. Treatment with ipragliflozin increased urinary glucose excretion, reduced hemoglobin A1c (HbA1c) levels and suppressed body weight gain as the dose increased. Body composition analysis revealed that body fat mass was lower in the ipragliflozin-treated groups than in the control group, while lean body mass and bone mineral contents were comparable between groups. Thus, an SGLT2 inhibitor ipragliflozin was found to promote preferential loss of fat mass in a rat model of non-obese T2DM. Ipragliflozin might also promote preferential loss of fat in non-obese patients with T2DM.

Abnormalities in the Fiber Composition and Capillary Architecture in the Soleus Muscle of Type 2 Diabetic Goto-Kakizaki Rats

Type 2 diabetes mellitus is linked to impaired skeletal muscle glucose uptake and storage. This study aimed to investigate the fiber type distributions and the three-dimensional (3D) architecture of the capillary network in the skeletal muscles of type 2 diabetic rats. Muscle fiber type transformation, succinate dehydrogenase (SDH) activity, capillary density, and 3D architecture of the capillary network in the soleus muscle were determined in 36-week-old Goto-Kakizaki (GK) rats as an animal model of nonobese type 2 diabetes and age-matched Wistar (Cont) rats. Although the soleus muscle of Cont rats comprised both type I and type IIA fibers, the soleus muscle of GK rats had only type I fibers. In addition, total SDH activity in the soleus muscle of GK rats was significantly lower than that in Cont rats because GK rats had no high-SDH activity type IIA fiber in the soleus muscle. Furthermore, the capillary diameter, capillary tortuosity, and microvessel volume in GK rats were significantly lower than those in Cont rats. These results indicate that non-obese diabetic GK rats have muscle fiber type transformation, low SDH activity, and reduced skeletal muscle capillary content, which may be related to the impaired glucose metabolism characteristic of type 2 diabetes.

The Changes of Pro-opiomelanocortin Neurons in Type 2 Diabetes Mellitus Rats After Ileal Transposition: The Role of POMC Neurons

BackgroundIleal transposition (IT) can effectively resolve obesity and improve type 2 diabetes. IT is associated with increased glucagon-like peptide 1 secretion. The mechanisms mediating the effects of IT on obesity and diabetes remain undefined. Given the role of pro-opiomelanocortin neurons in energy balance, we sought to determine its potential role in these processes. MethodsTwenty non-obese diabetic Goto–Kakizaki rats underwent either IT or sham operation. Various measures including food intake, body weight, fasting plasma glucose, glucagon-like peptide 1 level, activated pro-opiomelanocortin neuron number, and pro-opiomelanocortin mRNA expression were evaluated. ResultsThe IT group demonstrated significantly improved plasma glucose homeostasis with increased glucagon-like peptide 1 secretion. The IT group ate less and demonstrated reduced body weight gain over time. These effects were also associated with increased central neuronal activity with increased pro-opiomelanocortin and derivative gene expression in the hypothalamus and increased protein expression in the pituitary gland. ConclusionsMore pro-opiomelanocortin neurons in the hypothalamus of diabetes rats were activated after ileal transposition. These data suggest a potential important role for pro-opiomelanocortin neurons in the resolution of diabetes after IT.

Dietary Supplementation with Epigallocatechin Gallate Elevates Levels of Circulating Adiponectin in Non-Obese Type-2 Diabetic Goto-Kakizaki Rats

Epigallocatechin gallate (EGCG) reportedly enhances plasma adiponectin levels in models of insulin resistance and obesity. In this study, we found that EGCG increases plasma adiponectin levels and decreases plasma triacylglycerol levels in non-obese diabetic Goto-Kakizaki rats with insulin secretory dysfunction. These results suggest that EGCG ameliorates lipid metabolic abnormality even in non-obese rats, probably by increasing adiponectin production.