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Type II Diabetes Zebrafish Model

Type II Diabetes - Disease Pathology

Type II Diabetes is a condition that arises due to an environment of dysregulated glucose and fat metabolism. The key contributing factors are high fat and high carb diet with low metabolic profile of the individual. With physiological events, this leads to certain cells in the body no longer responding to the insulin’s signal to transport sugar into the cells. This condition is also accompanied by inability of the pancreas to produce enough insulin for cells that may be sensitive to insulin. As a result, sugar is not available to the cells, whilst the sugar is still present in the circulation. When high blood sugar is accompanied with a dysregulated triglyceride metabolism, it creates a milieu of increased risk of vascular disease such as atherosclerosis, driven by high cholesterol and triglycerides in the systemic circulation. Further events in the condition exacerbates into gut dysbiosis and inflammatory dysregulation of mitochondria. A continued high sugar in the vasculature further destroys retinal cells leading to retinopathy, similarly, destroying nephrons leading to nephropathy; high sugar has also shown to impair neuronal impulse conductivity that further leads to neuropathy observed as numbness in the condition. Therefore, type II diabetes is observed with high blood sugar, low glucose tolerance, fatigue, numbness and risk of cardiovascular disease, slow wound healing and progress into retinopathy, nephropathy, and neuropathy

Zebrafish as a model for Type II Diabetes

  • Zebrafish has a fully developed insulin synthesis β cells in pancreas.

  • High Fat, High carb diet fed zebrafish develops obesity with adipose tissue accumulation in the abdomen. The glucose response system such as glucose tolerance, fasting glucose and the triglyceride metabolic profile in zebrafish are similar as in humans.

  • Zebrafish models developed through high fat high carb diet with lack of insulin response has shown to have pathological hallmarks as observed in humans as in – low glucose tolerance, high blood glucose, slow wound healing, numbness, fatigue with retinopathy, nephropathy and neuropathy.

  • Triglyceride and cholesterol levels are increased in the blood. Zebrafish models of type II diabetes respond to metformin treatment.

Model Design for Therapeutic Strategies

Zebrafish model of type II diabetes is developed through high fat high carb diet feeding three times a day for a period of 8 weeks. Adults are dosed for a period of two weeks and screened after then for rescue.

Type II Diabetes Discovery Strategies using Zebrafish

​Current clinical endpoints have progress beyond achieving normoglycaemia but also looking at low cardiovascular risk such as composite end points.

  • Sodium-Glucose Cotransporter Type 2 Inhibitors:

    • For drugs targeting through these pathway, additional parameters such as serum creatinine for kidney function and serum levels of triglycerides can be measured via biochemistry. Genital infections can be measured in zebrafish through histology.

Glucagon-Like Peptide 1 Receptor:

  • For drugs targeting through this pathway, a key area to look at is pancreatitis. In zebrafish the pancreas is organized as a small group of cells which can be observed through histology. Sloughing of exterior cells, necrosis, loss of tissue architecture and shrinkage of cell membrane along with inflammatory infiltration in pancreatic cells are some of the early indicators that can be observed.

Dipeptidyl Peptidase IV:

  • For drugs targeting through this pathway, additional outcomes to measure would be gastrointestinal abnormalities and skin infections. Gastrointestinal abnormalities are observed as bloating through phenotype observations, or in advanced conditions as intestinal slough. Skin infections are observed as redness and haemorrhage phenotype in zebrafish.

Peroxisome proliferator-activated receptor-gamma Agonist

  • For drugs targeting through this pathway, additional outcomes could look at would be macular edema and heart failure. Macular edema could be evaluated by visual acuity tests or histology in zebrafish. Heart failure needs to be understood by late stage serum biomarkers or histology.

Type II Diabetes - Endpoint Readouts

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