Simulated first-phase insulin release using Humulin or insulin analog HIM2 is associated with prolonged improvement in postprandial glycemia

Abstract

We examined the extent to which priming the liver with a pulse of Humulin or the insulin analog hexyl-insulin monoconjugate 2 (HIM2) reduces postprandial hyperglycemia. Somatostatin (0.5 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) was given with basal intraportal insulin and glucagon for 4.5 h into three groups of 42-h-fasted conscious dogs. From 0 -5 min, group 1 (BI, n ϭ 6) received saline, group 2 (HI, n ϭ 6) received a Humulin pulse (10 mU ⅐ kg Ϫ1 ⅐ min Ϫ1 ), and group 3 (HIM2, n ϭ 6) received a HIM2 pulse (10 mU ⅐ kg Ϫ1 ⅐ min Ϫ1 ). Duodenal glucose was infused (5.0 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ) from 15 to 270 min. Arterial insulin in BI remained basal (6 Ϯ 1 U/ml) and peaked at 52 Ϯ 15 (HI) and 164 Ϯ 44 U/ml (HIM2) and returned to baseline by 30 and 60 min, respectively. Arterial plasma glucose plateaued at 265 Ϯ 20, 214 Ϯ 15, and 193 Ϯ 14 mg/dl in BI, HI, and HIM2. Glucose absorption was similar in all groups. Significant net hepatic glucose uptake occurred at 85, 55, and 25 min in BI, HI, and HIM2, respectively. Nonhepatic glucose clearance at 270 min differed among groups (BI, HI, HIM2): 0.62 Ϯ 0.11, 0.76 Ϯ 0.26, and 1.61 Ϯ 0.29 ml ⅐ kg Ϫ1 ⅐ min Ϫ1 (P Ͻ 0.05). A brief (5-min) insulin pulse improved postprandial glycemia, stimulating hepatic glucose uptake and prolonging enhancement of nonhepatic glucose clearance. HIM2 was more effective than Humulin, perhaps because its lowered clearance caused higher levels at the liver and periphery and its biological activity was not reduced proportionally to its decreased clearance.hexyl-insulin monoconjugate 2; insulin action SUBCUTANEOUSLY ADMINISTERED INSULIN is initially absorbed into the peripheral circulation of individuals with diabetes, resulting in fat and muscle being exposed to higher insulin levels than the liver. This peripheral hyperinsulinemia predisposes to hypoglycemia and is thought to be linked to weight gain and other metabolic abnormalities, which in turn lead to microvascular and macrovascular disease (15). If insulin could be given orally, the normal portal vein/arterial insulin distribution would be restored. It has been shown that agents capable of rapidly increasing the insulin concentration in response to a glucose challenge are good regulators of hepatic glucose metabolism and are more effective controllers of postprandial glucose concentrations than peripherally delivered insulin (3). An oral insulin would eliminate the disproportionately high peripheral insulin levels while still delivering adequate amounts of insulin to the liver, thereby potentially being useful as a new therapeutic agent.The release of insulin in response to a glucose challenge is biphasic in nature, with an early phase and a late phase. The early phase consists of two parts: a cephalic phase and a first phase. The cephalic phase is rapid (Յ2 min after a meal) yet very small, increasing arterial plasma insulin levels by only ϳ5 U/ml. The more pronounced first phase occurs 5-10 min postprandially and is dependent on the amount of glucose present. The liver responds quickly, such that the first-phas...

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