The spontaneously diabetic torii (SDT) fatty rat is a new model of type 2 diabetes
showing overt obesity, hyperglycemia and hyperlipidemia. With early onset of diabetes
mellitus, diabetic microvascular complications, including nephropathy, peripheral
neuropathy and retinopathy, are observed at young ages. In the present study, blood
glucose levels of female SDT fatty rats were controlled with phlorizin, a non-selective
SGLT inhibitor, to examine whether and how these complications are caused by
hyperglycemia. Phlorizin treatment adequately controlled plasma glucose levels during the
experiment. At 29 weeks of age, urinary albumin excretion considerably increased in SDT
fatty rats. Glomerulosclerosis and tubular pathological findings also indicate diabetic
nephropathy. These renal parameters tended to decrease with phlorizin; however, effects
were partial. Sciatic nerve conduction velocities were significantly delayed in SDT fatty
rats compared with Sprague-Dawley (SD) rats. Intraepidermal nerve fiber density, an
indicator of subclinical small nerve fiber neuropathy, significantly decreased in SDT
fatty rats. Retinal dysfunction (prolongation of peak latency for oscillatory potential in
electroretinograms) and histopathological eye abnormalities, including retinal folding and
mature cataracts were also observed. Both nerve and eye disorders were prevented with
phlorizin. These findings indicate that severe hyperglycemia mainly causes diabetic
complications in SDT fatty rats. However, other factors, such as hyperlipidemia and
hypertension, may affect diabetic nephropathy. These characteristics of diabetic
complications will become helpful in evaluating new drugs for diabetic complications using
SDT fatty rats.
Sarcopenia is the age-related decrease of muscle mass and function. Diabetes and obesity
are known to be risk factors that exacerbate sarcopenia, but the underlying mechanism of
diabetes-related sarcopenia is still unknown. Obese type 2 diabetes SDT fatty rats show
early onset of severe diabetes and there have been no reports on the characteristics of
their skeletal muscle. Therefore, pathophysiological analyses were performed for the
skeletal muscle in these rats. Diabetic male SDT fatty rats were sacrificed at 8, 16, 24,
32 and 40 weeks of age. Age-matched Sprague Dawley (SD) rats were used as the normal
control. In addition to biological blood parameters, the soleus and the extensor digitorum
longus muscles were examined for muscle weight, histopathology, and protein synthesis and
degradation. Muscle grip strength was also examined. These results revealed that the
muscle weights of the SDT fatty rats were significantly decreased from 16 weeks of age.
The mean cross-sectional area of muscle fibers in the SDT fatty rats decreased from 24
weeks of age. Increased intramyocellular lipid accumulation, identified by
immunohistochemistry for adipophilin and TEM, was observed in the SDT fatty rats from 8
weeks of age. Plasma insulin-like growth factor (IGF)-1 levels and muscle strength in the
SDT fatty rats decreased at 24 weeks of age and thereafter. These pathophysiological
findings have been reported both in sarcopenia in aged humans and in patients with
diabetes. In conclusion, the SDT fatty rat was considered to be a useful model for
analysis of diabetes-related sarcopenia.
G protein‐coupled receptor 119 (GPR119) expression in pancreatic β‐cells and intestinal L‐cells is a potential therapeutic target for the treatment of type 2 diabetes. Previously, we have reported that the GPR119 agonist JTP‐109192 improves glucose metabolism with single and repeated administration. Conversely, overexpression of the Gpr119 gene reportedly regulates cholesterol transporter expression in animal models, and a natural GPR119 agonist, oleoylethanolamide (OEA), improves atherosclerosis. Therefore, improving dyslipidaemia is considered a possible feature of GPR119 agonists. In the present study, the lipid‐lowering effect of JTP‐109192 was examined in BALB/c background spontaneously hyperlipidaemic (SHL) mice with repeated administration, once daily for 12 weeks. On repeated administration, JTP‐109192 revealed a cholesterol‐lowering effect and improved atherosclerosis following histopathological examination. With further investigation, the cholesterol‐lowering effect and subsequent antiatherosclerotic effect of JTP‐109192 was attributed to changes in intestinal cholesterol metabolism gene expression. Based on these results, JTP‐109192 represents a new potential antihypercholesterolaemic agent for the treatment of dyslipidaemia.
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