Study of blood glucose and insulin infusion rate in real-time in diabetic rats using an artificial pancreas system

Abstract

Artificial pancreas system (APS) is an emerging new treatment for type 1 diabetes mellitus. The aim of this study was to develop a rat APS as a research tool and demonstrate its application. We established a rat APS using Medtronic Minimed Pump 722, Medtronic Enlite sensor, and the open artificial pancreas system as a controller. We tested different dilutions of Humalog (100 units/ml) in saline ranged from 1:3 to 1:20 and determined that 1:7 dilution works well for rats with ~500g bodyweight. Blood glucose levels (BGL) of diabetic rats fed with chow diet (58% carbohydrate) whose BGL was managed by the closed-loop APS for the total duration of 207h were in euglycemic range (70–180 mg/dl) for 94.5% of the time with 2.1% and 3.4% for hyperglycemia (>180mg/dl) and hypoglycemia (<70 mg/dl), respectively. Diabetic rats fed with Sucrose pellets (94.8% carbohydrate) for the experimental duration of 175h were in euglycemic range for 61% of the time with 35% and 4% for hyperglycemia and hypoglycemia, respectively. Heathy rats fed with chow diet showed almost a straight line of BGL ~ 95 mg/dl (average 94.8 mg/dl) during the entire experimental period (281h), which was minimally altered by food intake. In the healthy rats, feeding sucrose pellets caused greater range of BGL in high and low levels but still within euglycemic range (99.9%). Next, to study how healthy and diabetic rats handle supra-physiological concentrations of glucose, we intraperitoneally injected various amounts of 50% dextrose (2, 3, 4g/kg) and monitored BGL. Duration of hyperglycemia after injection of 50% dextrose at all three different concentrations was significantly greater for healthy rats than diabetic rats, suggesting that insulin infusion by APS was superior in reducing BGL as compared to natural insulin released from pancreatic β-cells. Ex vivo studies showed that islets isolated from diabetic rats were almost completely devoid of pancreatic β-cells but with intact α-cells as expected. Lipid droplet deposition in the liver of diabetic rats was significantly lower with higher levels of triacylglyceride in the blood as compared to those of healthy rats, suggesting lipid metabolism was altered in diabetic rats. However, glycogen storage in the liver determined by Periodic acid-Schiff staining was not altered in diabetic rats as compared to healthy rats. A rat APS may be used as a powerful tool not only to study alterations of glucose and insulin homeostasis in real-time caused by diet, exercise, hormones, or antidiabetic agents, but also to test mathematical and engineering models of blood glucose prediction or new algorithms for closed-loop APS.

The Cardiometabolic Impact of Rebaudioside A Exposure during the Reproductive Stage

“…Glucose homeostasis was also not majorly affected by RebA consumption, except for a reduction in fasting glycemia at the end of the study, for values close to the lowest value of the rat’s euglycemic range (70–180 mg/dL) [ 13 ]. Sunanarunsawat and colleagues demonstrated increased insulin and decreased glucagon serum levels in diabetic rats, but not in the normoglycemic group, after receiving unspecified stevioside (0.25 g/kg body weight) or aqueous extract of Stevia rebaudiana (4.66 g/kg body weight) for 8 weeks [ 14 ].…”

Anti-Hyperglycemic and Hypoglycemic Activities of 80% Methanol Extract and Solvent Fractions of Ocimum lamiifolium Hochst Ex Benth. (Lamiaceae) Leaves in Mice

“…At the studied dose, the plant extracts have a lower risk of hypoglycemic shock, since severe and marked hypoglycemia are characterized in rodents as blood glucose levels less than 40 mg/dL and 40 to 60 mg/dL, respectively. 27 , 28 Because the 80% methanol extract contains a high concentration of tannins, saponins, steroids, terpenoids, flavonoids, and phenols, it may have antioxidant properties, hypoglycemic activity, and insulin-like effects that contribute to the significant reduction in blood glucose levels observed with these extracts. 22 The hypoglycemic activity in fractions is caused by medium-polarity phytochemicals such tannins, saponins, phenols, and steroids, whereas the hypoglycemic activity in crude extracts is caused by flavonoids, tannins, and phenols.…”

Antidiabetic Activities of 80% Methanol Extract and Solvent Fractions of Verbascum Sinaiticum Benth (Scrophulariaceae) Leaves in Mice

“…The plant extract has a lower risk of hypoglycemic shock at the tested dose levels of severe and marked hypoglycemia of less than 40 mg/dl and 40 to 60 mg/dl, respectively. 43 A significant reduction in blood glucose levels with some plant extracts might be due to their antioxidant properties or the hypoglycemic activity of phytochemical constituents. 44 , 45 …”

“…The plant extract has a lower risk of hypoglycemic shock at the tested dose levels of severe and marked hypoglycemia of less than 40 mg/dl and 40 to 60 mg/dl, respectively. 43 A significant reduction in blood glucose levels with some plant extracts might be due to their antioxidant properties or the hypoglycemic activity of phytochemical constituents. 44,45 An oral glucose tolerance test is a standard procedure that measures the clearance of an oral glucose load from the body or how quickly exogenous glucose can be cleared from the blood and is used in diagnosing diabetes mellitus.…”