Obesity causes insulin resistance (IR) through systemic low-grade inflammation and can lead to type 2 diabetes mellitus (T2DM). However, the mechanisms that cause IR and T2DM in non-obese individuals are unclear. The Goto-Kakizaki (GK) rat develops IR spontaneously and is a model of non-obese T2DM. These rats exhibit hyperglycemia beginning at weaning and exhibit lower body mass than control Wistar rats. Herein, we tested the hypothesis that macrophages of GK rats are permanently in a pro-inflammatory state, which may be associated with a systemic inflammation condition that mimics the pathogenesis of obesity-induced T2DM. Using eighteen-week-old GK and control Wistar rats, we investigated the proportions of M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages isolated from the peritoneal cavity. Additionally, the production of inflammatory cytokines and reactive oxygen species (ROS) in cultured macrophages under basal and stimulated conditions was assessed. It was found that phorbol myristate acetate (PMA) stimulation increased GK rat macrophage ROS production 90-fold compared to basal levels. This response was also three times more pronounced than in control cells (36-fold). The production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), tended to be upregulated in cultured macrophages from GK rats under basal conditions. Macrophages from GK rats produced 1.6 times more granulocyte-macrophage colony-stimulating factor (GM-CSF), 1.5 times more monocyte chemoattractant protein-1 (MCP-1) and 3.3 times more TNF-α than control cells when stimulated with lipopolysaccharide (LPS) (p = 0.0033; p = 0.049; p = 0.002, respectively). Moreover, compared to control cells, GK rats had 60% more M1 (p = 0.0008) and 23% less M2 (p = 0.038) macrophages. This study is the first to report macrophage inflammatory reprogramming towards a pro-inflammatory state in GK rats.

Background/Objectives: Goto-Kakizaki (GK) rats exhibit insulin resistance and type 2 diabetes mellitus (T2DM) without obesity. This study explored the effects of ω-3 fatty acid supplementation on T lymphocyte polarization in Wistar (WT) and GK rats. Methods: They were administered ω-3 fatty acid-rich fish oil (FO) containing eicosapentaenoic (540 mg/g) and docosahexaenoic acids (100 mg/g) by oral gavage at 2 g/kg, thrice a week for 8 weeks. The control groups (WT CT and GK CT) received the same volume of water. The following groups were investigated: GK CT, n = 14; GK ω-3, n = 15; Wistar CT, n = 15; and Wistar ω-3, n = 11. Glucose and insulin tolerance tests (GTT and ITT) were performed. Fasting plasma insulinemia and glycemia were measured. After euthanasia, the lymphocytes were extracted from the mesenteric lymph nodes. Results: The results showed that GK rats supplemented with FO had significantly improved glucose tolerance and insulin sensitivity (kITT). It also promoted greater polarization of lymphocytes toward T regulatory (Treg) features and a reduction in Th1 and Th17 profiles. Additionally, the GK ω-3 group exhibited lower cell proliferation, decreased pro-inflammatory cytokines, and increased IL-10 levels compared to the GK control. Conclusions: In conclusion, FO supplementation benefited GK rats by improving glucose intolerance, suppressing insulin resistance, and modulating lymphocytes toward Treg polarization.

The Goto-Kakizaki (GK) rat is a non-obese experimental model of type 2 diabetes mellitus (T2DM) that allows researchers to monitor diabetes-induced changes without jeopardizing the effects of obesity. This rat strain exhibits notable gastrointestinal features associated with T2DM, such as marked alterations in intestinal morphology, reduced intestinal motility, slow transit, and modified microbiota compared to Wistar rats. The primary treatments for diabetic patients include administration of hypoglycemic agents and insulin, and lifestyle changes. Emerging procedures, including alternative therapies, metabolic surgeries, and modulation of the intestinal microbiota composition, have been shown to improve the diabetic state of GK rats. This review describes the morpho-physiological diabetic-associated features of the gastrointestinal tract (GIT) of GK rats. We also describe promising strategies, e.g., metabolic surgery and modulation of gut microbiota composition, used to target the GIT of this animal model to improve the diabetic state.

Obesity causes insulin resistance (IR) through systemic low-grade inflammation and can lead to type 2 diabetes mellitus (T2DM). However, the mechanisms that cause IR and T2DM in non-obese individuals are unclear. The Goto-Kakizaki (GK) rat develops IR spontaneously and is a model of non-obese T2DM. These rats exhibit hyperglycemia beginning at weaning and exhibit lower body mass than control Wistar rats. Herein, we tested the hypothesis that macrophages of GK rats are permanently in a pro-inflammatory state, which may be associated with a systemic inflammation condition that mimics the pathogenesis of obesity-induced T2DM. Using eighteen-week-old GK and control Wistar rats, we investigated the proportions of M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages isolated from the peritoneal cavity. Additionally, the production of inflammatory cytokine and reactive oxygen species (ROS) in cultured macrophages under basal and stimulated conditions was assessed. It was found that phorbol myristate acetate (PMA) stimulation increased GK rat macrophage ROS production by 90-fold compared to basal levels. This response was also three times more pronounced than in control cells (36-fold). The production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), tended to be upregulated in cultured macrophages from GK rats under basal conditions. Macrophages from GK rats produced 1.6 times more granulocyte-macrophage colony-stimulating factor (GM-CSF), 1.5 times more monocyte chemoattractant protein-1 (MCP-1) and 3.3 times more TNF-α than control cells when stimulated with lipopolysaccharide (LPS) (p = 0.0033; p = 0.049; p = 0.002, respectively). Moreover, compared to control cells, GK rats had 60% more M1 (p = 0.0008) and 23% less M2 (p = 0.038) macrophages. This study is the first to report macrophage inflammatory reprogramming towards a pro-inflammatory state in GK rats.

Diabetes mellitus is associated with changes in intestinal morphology and the enteric nervous system. We previously reported constipation in Goto-Kakizaki (GK) rats, a non-obese model for type 2 diabetes mellitus. Aim: The morpho-quantitative analysis of myenteric plexus neurons in the small and large intestines of 120-day-old male GK rats was investigated. Methods: The diabetes was confirmed by high fasting blood glucose levels. The myenteric plexus was evaluated through wholemount immunofluorescence. The morpho-quantitative analyses included evaluating neuronal density (neurons per ganglion) of the total neuronal population, the cholinergic and nitrergic subpopulations, and enteric glial cells per ganglion. The cell body area of 100 neurons per segment per animal was measured. Results: The total neurons and nitrergic subpopulation were unaltered in the GK rats’ small and large intestines. The cholinergic subpopulation exhibited decreased density in the three segments of the small intestine and an increased number in the proximal colon of the GK rats. The number of enteric glial cells increased in the ileum of the GK rats, which could indicate enteric gliosis caused by the intestinal inflammatory state. The area of the cell body was increased in the total neuronal population of the jejunum and ileum of the GK rats. Frequency histograms of the cell body area distribution revealed the contribution of cholinergic neurons to larger areas in the jejunum and nitrergic neurons in the ileum. Conclusion: The constipation previously reported in GK rats might be explained by the decrease in the density of cholinergic neurons in the small intestine of this animal model.