Blood glucose control and insulin clearance in unrestrained diabetic dogs portally infused with a portable insulin delivery system

Abstract

Long term glucose control in pancreatectomised dogs has been obtained with portal insulin therapy. When compared to a previous similar study using peripheral infusions, 20% less exogenous insulin was required and peripheral fasting insulin levels were 30% lower. Animals (n = 5) were unrestrained, conscious and carried a programmable insulin pump for 163-224 days. In the post-absorptive state blood glucose was normal (87 _+ 5 mg/dl) as was plasma insulin (10 + 1 mU/1) with porcine insulin infused at a basal rate of 0.36 _+ 0.01 mU/kg/min. Following ingestion of a standard mixed meal the infusion rate was increased to 2.47 + 0.09 mU/kg/ rain for 71/2 h resulting in post-prandial normalisation of blood glucose. Peripheral plasma insulin levels were twice normal during the post-prandial infusion, but only half those previously reported with peripheral infusions. Insulin clearance rates were 37 ml/kg/min in the basal state and rose significantly post-prandially. In the absence of extra mealtime insulin the clearance rate was unaffected by the resulting post-prandial hyperglycaemia and similar to values observed with insulin infused peripherally at 0.45 + 0.03 mU/kg/min. No significant increase in the post-prandial rate of insulin clearance relative to the fasting rate was observed with peripherally administered insulin. It was thus concluded that portal insulin replacement in pancreatectomised dogs could normalise both blood glucose and insulin in the fasting state, but post-prandial peripheral insulin levels remained elevated.

The effect of portal and peripheral insulin delivery on carbohydrate and lipid metabolism in a miniature pig model of human IDDM

“…Isoglycaemic hyperinsulinaemic clamp data in normal and diabetic pigs after 4 weeks of peripheral and hepatic insulin delivery can remove between 50 and 75 % of insulin in the fasting state [55]. A lack of agreement exists among previous animal investigations, performed in rodents or dogs, concerning whether or not insulin delivery by the peripheral route results, as in our study, in raised [3,7,9,13,[17][18][19][20][21] or unchanged [2,6,11,[14][15][16] peripheral insulin levels. Studies in man comparing intraperitoneal and subcutaneous insulin delivery have similarly yielded conflicting results relating to the extent of systemic insulinisation [23][24][25][26][27][28]56].…”

“…A number of investigations have supported the concept that only portal insulin delivery can sustain normal insulin responsiveness [13,18,20]. Others, however, have yielded contradictory findings [2,4,7,11,14,17,19].…”

Differential effects of oral, peripheral intravenous, and intraportal glucose on hepatic glucose uptake and insulin and glucagon extraction in conscious dogs.

“…The explanations for these discrepancies are not apparent, but it should be emphasized that different techniques and experimental models have been used and hepatic extraction of insulin was assessed by indirect measurements. In conscious pancreatectomized dogs, Goriya et al (38) reported greater hepatic insulin extraction after ingestion of a mixed meal and intraportal insulin infusion compared with peripheral intravenous insulin infusion. They attributed the difference to the higher portal vein insulin and glucose levels.…”

Glucose ingestion in dogs alters the hepatic extraction of insulin. In vivo evidence for a relationship between biologic action and extraction of insulin.

“…end sampling catheters were placed in the portal and hepatic veins of seven mongrel dogs (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) kg; mean weight 22±1.6 kg) according to the methods described by Cherrington et al (10). The portal vein catheter was introduced via the spleen and secured in the portal vein just before its bifurcation into right and left branches in the porta hepatis.…”