THE GOTO -KAKIZAKI RAT: A MODEL OF NON -OBESE TYPE 2 DIABETES MELLITUS AND ITS COMORBIDITIES

Resumo

Type 2 Diabetes mellitus (T2DM) is characterized by peripheral insulin resistance, often triggered by excess body mass. However, worldwide, the T2DM phenotype without obesity represents 10 - 15% of patients, corresponding to more than 70 million people. In Japan, 60% of the population with T2DM are not obe se. The non -obese T2DM GK rat was developed in 1975 at Tohoku University in Sendai, Japan, by Goto, Kakizaki, and Masaki through selective breeding of glucose- intolerant Wistar rats with hyperglycemia. GK rat exhibits typical manifestations of T2DM: chronic inflammation, moderate hyperglycemia, glucose intolerance, peripheral insulin resistance, hyperinsulinemia, impaired glucose-induced insulin secretion, reduced pancreatic β -cell function and number, increased hepatic gluconeogenesis, and elevated plasma lipid levels. The GK rat also develops chronic comorbidities, allowing examination of the intrinsic complications of T2DM. Herein, a literature review was conducted in the PubMed and Google Scholar databases using the descriptors "Goto -Kakizaki rat" combin ed with "type 2 diabetes mellitus," "diabetic cardiomyopathy," "diabetic nephropathy," "diabetic retinopathy," "diabetic neuropathy," "autonomic neuropathy," "cognitive dysfunction," "neurodegeneration," "insulin resistance," "oxidative stress," "hepatic s teatosis," "bone loss," and "erectile dysfunction”, with no time restriction. Only original English-language articles that employed the GK rat to investigate chronic conditions were included. The GK rat develops a multisystemic spectrum of chronic complications: progressive left ventricular hypertrophy, diastolic dysfunction, myocardial fibrosis, and endothelial dysfunction. Nephropathy, proteinuria, hyperfiltration, and moderate glomerular impairments were also reported. Retinopathy was associated with the transmigration of inflammatory cells across the blood-retinal barrier and progressive microvascular changes in GK rats. Neuropathies with structural remodeling of intracardiac ganglia, impaired sciatic nerve regeneration with sex differences, and corneal neuropathy with delayed epithelial healing were described. Morphological remodeling of the small intestine, constipation, and alterations in the cholinergic myenteric plexus were reported, indicating enteric dysautonomia. Concerning neurodegenerative signs , about 11% reduction in the number of cortical neurons, accompanied by microglial activation, was observed, along with impairment of adult hippocampal neurogenesis and spatial memory. Transcriptomic changes in brain regions revealed molecular pathways con necting central insulin resistance to Alzheimer 's-like disease. Osteopathy with reduction in trabecular bone mineral density, hepatic steatosis, and erectile dysfunction was also described. So, the GK rat model enables investigation of pathophysiological mechanisms intrinsic to chronic hyperglycemia and its associated comorbidities in non-obese T2DM.