Uniphasic insulin-secretory response in the pancreatic vein of dogs after an enteric glucose load.

The insulin secretory response to an enteric glucose load was measured in 11 dogs after intrajejunal instillation of a 25 per cent glucose solution (1.75 gm./kg.) in five minutes. Insulin outflow rate was measured every minute for 10 minutes, then at increasing intervals through 60 minutes. Starting at two minutes after onset of glucose loading, mean arterial plasma glucose rose steadily throughout the hour. This was paralleled by a similarly progressive rise in mean pancreatic venous plasma insulin output starting at seven minutes and peaking at 50 minutes, despite partial masking by a simultaneous fall in pancreatic venous plasma flow rate after the fourth minute. The data indicate that the normal insulin response to an enterically administered glucose stimulus is a smoothly rising uniphasic one, in contrast to the typical biphasic insulin response to a "square-wave" intravenous glucose stimulus.

Influence of antecedent carbohydrate intake on the biphasic insulin response to intravenous glucose.

The insulin secretory response to a sudden and sustained intravenous glycemic stimulus was measured in three groups of dogs whose antecedent carbohydrate intake ranged from zero to 300 or more grams daily. Insulin outflow rate from the pancreaticoduodenal vein was measured every minute for ten minutes, then at increasing intervals through sixty minutes. It was found that starvation erased the first phase of the biphasic insulin response shown by dogs on ordinary carbohydrate intake and that high-carbohydrate intake abolished the trough between the two phases. The data suggest that, during truly physiologic stimulation of insulin secretion, the latter represents the final stage of a continuum of hormonal synthesis, storage, and release, rather than emanating from one of two separate pools of fast-versus-slow insulin secretion.

Confirmation of impaired early insulin response to glycemic stimulus in nonobese mild diabetics.

The initial insulin responses of nonobese normal subjects and mild diabetics were analyzed during and after five-minute and two-minute infusions of 0.5 gm. per kilogram of glucose by vein. It was found that the two-minute injection elicited faster and significantly higher absolute hormonal output in both normals and diabetics, and that on both tests the normal subjects secreted significantly more insulin than did the mild diabetics. Comparison of respective "insulinogenic indexes" (net insulin output per unit of glycemic stimulus) showed that the corrected early insulin responses were in fact the same on both the five-minute and two-minute tests in normal subjects, and also in mild diabetics; but that the corrected insulin output was still twice as great in control subjects on both tests. It was also found that obese mild diabetics had significantly greater absolute insulin responses to both the five-minute and two-minute glucose injections than did their nonobese counterparts. These findings reconfirm that the earliest clinically recognizable state of diabetes mellitus is characterized by an impaired initial insulin secretory response to glycemic stimulus. They also indicate that valid interpretations of the influence of mild diabetes per se on the early insulin response can only be drawn from data obtained in nonobese individuals. Diabetes 24:17-24, January, 1975.

Insulin secretion in response to glycemic stimulus: relation of delayed initial release to carbohydrate intolerance in mild diabetes mellitus.

Insulin secretory responses to paired intravenous and oral glucose loads were determined in 38 nonobese individuals classified as normal (nondiabetic) subjects, "mild" diabetics (fasting blood glucose below 105 mg per 100 ml), or "moderate" diabetics (fasting glucose below 192 mg per 100 ml). Studies were also performed in 29 obese persons who were similarly grouped. The intravenous load was given to assess the alacrity of hormonal release after glycemic stimulus, and the oral glucose to determine how the speed of initial insulinogenesis modifies the disposition of ingested carbohydrate. In the nonobese group, normal subjects responded to massive hyperglycemia after rapid injection of glucose with immediate and maximal outpouring of insulin, in contrast to a desultory insulinogenic response in patients with mild diabetes, and no initial response at all in moderate diabetics. During oral glucose tolerance tests, the much faster clearance of blood sugar in nondiabetic subjects was actually associated with lower absolute insulin output than was found in mildly diabetic patients, since the latter exhibited delayed hyperinsulinemia in concert with prolonged hyperglycemia. Moderate diabetics never showed excessive insulin release despite even greater hyperglycemia. An empirical "insulinogenic index," the ratio relating enhancement of circulating insulin to magnitude of corresponding glycemic stimulus, was used to compare the secretory capacities of respective groups. Despite the higher absolute hormonal output after oral glucose in mild diabetics, the index revealed that insulin release in normal subjects was proportionally more than twice as great. This relatively greater normal secretory response declared itself shortly after the administration of glucose by either route, and was maintained throughout both tests. In the 29 obese individuals, differences among groups were essentially the same as in persons of normal weight. Obese nondiabetics did show much larger absolute insulinogenic responses during both tests than did nonobese controls. Since corresponding glucose tolerance curves were also higher, the mean insulinogenic indexes for obese subjects were not statistically greater. Moreover, when comparable glucose curves of obese and nonobese controls