The induction of stable obese type 2 diabetes in pigs

To follow the natural course of obese type 2 diabetes in a pig model, the pig needs to become obese first and subsequently develop diabetes. The obese phenotype should express characteristics of the metabolic syndrome, also called the pre-diabetic state. Characteristics of metabolic syndrome include visceral obesity, glucose intolerance, insulin resistance, disturbed insulin secretion, high blood pressure and dyslipidemia (elevated LDL-cholesterol and triglycerides). Once metabolic syndrome is established in pigs by ad libitum feeding of a high energy Western diet, diabetes should evolve and superimpose on the phenotype of the metabolic syndrome model, resulting in overt obese type 2 diabetes. This is easier said than done. Pigs do not easily develop obese type 2 diabetes spontaneously, at least not in the time frame of 1 or 2 years. Whereas obese metabolic syndrome can be induced in adult Gottingen minipigs within a time period of 4-6 months, overt diabetes does not develop spontaneously due to the robustness and flexibility of the porcine pancreas. The large (over)capacity of the pancreatic beta-cells to produce insulin leads to the ability to compensate for insulin resistance and to avoid hyperglycaemia for prolonged times. Young healthy pigs fed a low fat, low sugar diet require a (chemically-induced) reduction of ~95% of their total pancreatic beta-cell mass in order to observe hyperglycaemia (>10 mmol/l). For instance, in young growing Landrace pigs, insulin staining area of the pancreas was lower by 93% (P<0.001) in streptozotocin-induced diabetes (0.12±0.02%) compared to healthy control (1.63±0.21%) pigs and compared to pigs with metabolic syndrome (2.33±0.21%). In fact, total beta-cell mass increased in pigs with metabolic syndrome by 43% (P<0.05) compared to control pigs, showing the flexibility of porcine pancreatic beta-cells to deal with metabolic stress. This flexibility of the beta-cells is not related to (young) age because we have observed the same phenomenon in adult Gottingen minipigs. Insulin staining area of the pancreas was higher (1.80±1.13%) in adult minipigs by 58% compared to control (1.14±0.39%) minipigs. Although functional defects in glucose-induced insulin secretion could be detected in minipigs with metabolic syndrome, these defects were too small to induce diabetes. With respect to the induction of diabetes by streptozotocin in minipigs with metabolic syndrome, insulin staining area of the pancreas was lower by 73% in obese type 2 diabetic minipigs (0.48±0.46) compared to minipigs with metabolic syndrome (1.80±1.13%). Compared to young lean Landrace pigs, adult obese minipigs require 2-fold less streptozotocin to induce diabetes. In line with this, young lean Landrace pigs require a 93% reduction in total beta-cell mass whereas adult obese minipigs require a reduction of 73% to induce diabetes. Taken together, these results indicate that the pancreatic beta-cells of adult obese minipigs truly represent a pre-diabetic state. In addition, we now have shown that adult obese minipigs with type 2 diabetes can be maintained for many months without medication, with stable food intake, body weight and hyperglycaemia, thereby representing stable obese type 2 diabetes.