Peak Insulin Response Research Articles

Pancreatic beta-cell function in CAPD.

Pancreatic beta-cell function was evaluated in uraemic patients by measuring beta-cell peptides in the peripheral blood after intravenous glucagon (1 mg) stimulation. Patients in chronic renal failure, patients on haemodialysis, and both new and established subjects on continuous ambulatory peritoneal dialysis (CAPD) (10 in each group) were studied and compared to 8 healthy controls. Fasting glucose (3.6-4.4 mmol/l) and insulin concentrations (9.5-11.7 mU/l) were normal and did not differ between the uraemic groups, but c-peptide concentrations were markedly increased in uremia (1.84-2.38 nmol/l) compared to controls (0.48 nmol/l). Following glucagon stimulation an exaggerated blood glucose response with delayed glucose peak was observed, while the peak insulin response to glucagon was normal; however, the return to basal concentrations was delayed in uraemia. The c-peptide response was also exaggerated and peak concentrations in uraemic subjects (3.0-4.3 nmol/l) were significantly greater than controls (1.5 nmol/l). The response of CAPD patients was similar to those on haemodialysis and non-dialysed uraemic patients. The abnormalities seen were due to uraemia, and CAPD treatment had no specific adverse effect on beta-cell function. Thus, from this data there was no evidence that CAPD per se is detrimental to beta-cell integrity.

Insulin production following injury and sepsis.

It is known that alterations in insulin metabolism following injury and infection result in depression of insulin levels and the development of insulin resistance. In order to further study insulin during septic and traumatic stress, we estimated insulin production in control (Group 1, n = 6), postoperative (Group 2, n = 5), and postoperative-septic (Group 3, n = 8) human subjects by measuring the 24-hour urinary C-peptide excretion. In addition, basal and peak glucose and insulin levels in response to a standard (0.5 gm/kg) intravenous glucose stimulus were measured immediately thereafter to determine if insulin levels reflected insulin production. Basal insulin for Groups 1, 2, and 3 (16 +/- 8.4, 10 +/- 3.4, 9.5 +/- 4.4 microU/ml +/- SD, respectively) were not substantially different. Peak insulin response to glucose infusion declined from Groups 1 to 3 (51 +/- 14, 42.4 +/- 31, 20.4 +/- 6.8 microU/ml, respectively) with Group 3 exhibiting a significantly decreased mean peak level compared to the other groups. Corresponding C-peptide excretion rates increased from Groups 1 to 3 (28.3 +/- 15.3, 63.7 +/- 27.6, 121.3 +/- 95.2 micrograms/day, respectively) with Group 3 exhibiting a significantly (p less than 0.05) higher level than Group 1. These data suggest that low insulin levels which may be evident in injured or septic patients not in shock reflect increased clearance and not decreased production.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of insulin secretion after pancreas autotransplantation by oral or intravenous glucose challenge.

Segmental pancreatic autotransplantation is accompanied by surgical alterations to the pancreas that may have consequences for carbohydrate metabolism. Four mongrel dogs were evaluated before operation and sequentially until 40 weeks after total pancreatectomy and autotransplantation of the splenic lobe of the pancreas with bolus intravenous and oral administration. Intravenous glucose tolerance test (IVGTT) (0.5 g/kg) revealed maintenance of fasting euglycemia for as long as 40 weeks after operation. Peak glucose and integrated glucose values did not show significant changes as a result of autotransplantation. Following transplantation, a delayed peak insulin response was seen; however, basal, peak, and integrated insulin values were largely unaltered. Only K values, a measure of glucose disposal, showed severe alterations (2.44 +/- 0.21 before operation to 1.24 +/- 0.30 at 40 weeks after operation). Oral glucose tolerance tests (OGTT) (2.0 g/kg) demonstrated an increased peak hyperglycemic response after autotransplantation with increased integrated glucose responses. Insulin levels remained at those levels seen before operation, and glucose-dependent insulinotropic polypeptide (GIP) responses were unchanged during the OGTT as late as 20 weeks after operation. In conclusion, pancreas autotransplantation after total pancreatectomy results in significant metabolic alterations that the IVGTT fails to detect with absolute glucose or insulin levels. However, K values are significantly lowered, which indicates alterations in cellular glucose transport. The OGTT demonstrates hyperglycemia without increased insulin or GIP levels, which suggests an altered beta cell response to the enteric stimulus of insulin release. These changes are nonetheless well tolerated by animals that have remained clinically healthy and euglycemic in the basal state.

The endocrine function of heterotopic islets of Langerhans.

AbstractIslets of Langerhans may be removed from the pancreatic environment and transferred as autografts to a heterotopic site such as the spleen or liver. The success of such grafts has been equated with normoglycemia but success in dogs has been variable. We have developed a model of canine islet autografting that entails total pancreatectomy, preparation of a pancreatic suspension by perfusion of the pancreatic duct with collagenase, and delivery of the autograft to the spleen by reflux through tributaries of the splenic vein. In this study, fasting insulin response to intravenous glucose (0.5 g/kg), tolbutamide (0.5 g), glucagon (1.0 mg), and arginine (460 mg/kg) was measured before and 3 weeks after intrasplenic islet autografts. The 5 animals studied achieved fasting normoglycemia immediately; therefore, they were successful grafts. The response to glucose, however, was distinctly abnormal with statistically different peripheral insulin levels at 1, 3, 5, and 10 minutes. The insulin response was graphed, the area under the curve determined, and the integrated response was only 20% of preoperative controls. This diminished insulin response was reflected in impaired glucose clearance with a K value of 1.95 ± 0.24 in grafted animals compared to 3.12 ± 0.74 in preoperative controls. Peak insulin responses, however, to tolbutamide (70.4% of normal), glucagon (85.4%), and arginine (94.7%) were not statistically different in grafted animals compared to controls. The disparity of beta cell response to these various secretagogues suggests significant alteration of beta cell function either as a consequence of heterotopic placement, grafting injury, or accommodation to reduced islet number. Comparison of these data with those obtained in other systems supports some sort of accommodation to explain these beta cell changes.

Insulin deficiency in non-insulin-dependent diabetics

In this study, the prevalence of severe insulin deprivation amongst 104 non-insulin-dependent diabetes mellitus (NIDDM) patients was determined using a mixed meal pancreatic stimulation test (2.4 MJ). Of the 104 patients, 62 were recently diagnosed and 42 had been diabetic for between 1 and 40 years, but were not adequately controlled on diet and oral hypoglycaemic agents. Twenty-one (34%) of the recently diagnosed patients and 13 (31%) of the poorly controlled patients had peak post-testmeal insulin responses less than 160 pmol/l (less than 23 mU/l)--values 3 SD below normal--and were therefore considered to have severe blunting of beta cell response to nutrient secretagogues. Amongst recently diagnosed diabetics, these patients, as a group, had higher blood glucose levels (P less than 0.05) and lower body weights (P less than 0.01) but overall these parameters correlated poorly with insulin responses. Islet cell antibodies were positive in only one patient, whereas they were present in three others with less severe insulin secretory defects. For the treated diabetics, insulin release showed very low non-significant correlations with duration of diabetes, age, weight and glycaemic control. Islet cell antibodies were present in five patients, one only showing peak insulin values less than 160 pmol/l. These data suggest that about one-third of new diabetics and one-third of treated diabetics with poor glycaemic control are insulin deficient. Clinical and biochemical parameters, including islet cell antibodies, appear to be of no value in identifying this sub-group requiring insulin therapy. Their early recognition is best facilitated by routine pancreatic function tests.

Does 1,25-dihydroxyvitamin D participate in the regulation of hormone release from endocrine glands?

The presence of receptors for 1,25-dihydroxyvitamin D3 in the pituitary, pancreas, testis, and ovary has raised the question of a possible direct role for 1,25-dihydroxyvitamin D (1,25(OH)2D) in the regulation of hormone synthesis and secretion. To evaluate this problem, six children with the syndrome of resistance to 1,25(OH)2D with rickets and alopecia underwent dynamic tests of insulin, TSH, PRL, GH, and testosterone secretion. Oral glucose loading resulted in normal glucose curves, subnormal peak insulin responses of 12-20 microU/ml in three hypocalcemic patients, and normal peak serum insulin values of 30-40 microU/ml in two normocalcemic patients. Basal serum, TSH, PRL, T4, and T3 concentrations were normal in all patients. Peak serum TSH values after TRH were 11-17 and 16-32 microU/ml in the hypo- and normocalcemic patients, respectively. The PRL response to TRH stimulation in either hypocalcemic or normocalcemic patients was normal [mean 26.2 +/- 5.1 (SD) ng/ml]. Peak serum GH levels were greater than 8 ng/ml in all five patients studied after one or more of the various stimuli. Serum testosterone concentrations after hCG stimulation were normal in the three patients studied (4.1-8.0 ng/ml). Thus, in children with resistance to 1,25(OH)2D, we could find no significant abnormalities in hormone secretion from the pituitary, pancreas, and testis apart from those presumably due to the hypocalcemia itself.

The rate of starch hydrolysis in vitro does not predict the metabolic responses to legumes in vivo

The aim of this study was to determine whether legumes in a physical form which is rapidly digested in vitro give rise to proportionately greater metabolic responses in vivo than legumes which are slowly digested in vitro. Samples of cooked whole and ground lentils were incubated in vitro with pancreatic amylase for 30 min and the percentage starch hydrolysis determined. Grinding the lentils before cooking resulted in a 5-fold increase in the rate of starch hydrolysis (whole lentils 12.1%, ground lentils 60.9%). For the in vivo studies six healthy, young, lean subjects consumed two test meals containing 50 g starch: whole lentils and lentils that had been ground finely before cooking. Postprandial glucose and insulin responses were measured over 4 h. Peak glucose and insulin responses occurred 60 min postprandially for the whole lentils and 30 min postprandially for ground lentils. Although the increase in plasma glucose after ground lentils (1.6 mM) was significantly higher (p < 0.025) than that after whole lentils (0.9 mM), there was no difference in the magnitude of the insulin responses. These results indicate that, unlike for cereals, the rate of intestinal starch hydrolysis is not the major factor determining the metabolic responses to legumes. By virtue of their low postprandial glucose and insulin responses, irrespective of their physical form and digestibility, legumes would appear to be ideal for inclusion in the diet of diabetics.

Blunted pancreatic polypeptide responses in children with obesity of Prader-Willi syndrome.

Serum pancreatic polypeptide (PP), gastric inhibitory polypeptide (GIP), insulin and glucose responses to meal stimulation were studied in 10 normal weight patients, 13 normal obese patients and 7 patients with Prader-Willi syndrome (PWS) associated obesity. Serum and plasma concentrations of PP, glucose, insulin and GIP were obtained at 15 min intervals from 0-180 min. after a 275 K calorie meal. Basal and peak responses of glucose, for patients with PWS were significantly lower when compared to normal or obese controls. Basal and peak insulin responses in PWS were significantly greater than those of the normal controls but still less than those of the obese controls. Basal GIP concentrations in the patients with PWS were significantly less than normals and their peak response was less than the obese control group. No significant differences in basal or peak PP responses were noted between normal and obese controls. All 7 patients with PWS had abnormal PP responses. Five failed to show significant PP release after the stimulation; one had a peak response to 130 pg/ml while the 7th patient (PB) had an exaggerated response to 2000 pg/ml. The 6 patients with low or no response had basal PP values of 62 +/- 12 pg/ml and a mean PP peak response of 78 +/- 15 pg/ml. This observation of blunted PP response in a human model of hyperphagia and obesity parallels the animal models and suggests PP may have a significant role in appetite control.

Effect of total parenteral nutrition on gut hormone release in humans

Prolonged absence of food from the gut is said to cause hypoplasia of the intestine and pancreas. Whether gut and pancreatic hormone secretion is correspondingly altered is not known. As total parenteral nutrition (TPN) and nil per os is now used to treat many gastrointestinal disorders, we investigated what effect intralumenal starvation of the gut, yet adequate nutritional support had on gastrointestinal and pancreatic hormonal release in humans. Gut hormone release was studied before and after a standard meal in 9 patients with Crohn's disease treated by nil per os and TPN for a mean of 25 days (range 18–52). Subsequently after a variable period of normal oral diet (mean 156 days; range 38–395), the same meal study was repeated. Fasting and peak postprandial concentrations of gastrin, motilin, GIP, secretin, pancreatic polypeptide, pancreatic glucagon, and VIP immediately after a period of nil per os and TPN (NPO-TPN) were not significantly different from the second meal study after refeeding (RF) and were equivalent to levels observed in healthy subjects. Although the postprandial rise in glucose was identical with both meals, after NPO-TPN the peak insulin response was significantly (p < 0.001) lower than the normal levels after refeeding. With both meals, basal enteroglucagon was similar, yet a significantly (p < 0.01) higher peak level occurred after NPO-TPN. To assess the effect of TPN (mean 22 days, range 18–25) on gut hormone release, we also undertook sequential hormone measurements before, during, and after TPN in 8 other patients. No significant change in plasma gastrin, motilin, pancreatic polypeptide, GIP, secretin, or enteroglucagon was observed as a consequence of TPN. Thus after TPN and nil per os in humans the fasting and postprandial gut endocrine response is well maintained. Higher postprandial levels of enteroglucagon may reflect greater ileal exposure to the nutrient load as a consequence of decreased transit time, while the diminished insulin response, yet identical, glucose levels may point to peripheral insulin hypersensitivity after TPN.

Acid-Induced Gastric Inhibitory Polypeptide Secretion in Man*

This study has assessed the effect of oral or intraduodenal HCl, administered alone or in combination with glucose, on gastric inhibitory polypeptide (GIP) and insulin secretion. Eight young males were given the following three oral tests: 30 g glucose, 150 cc 0.1 N HCl and the glucose-acid combination. Another group of eight controls received intraduodenal infusions of 20 g glucose, 75 cc 0.1 N HCl and their combination. All tests were performed in a random fashion at weekly intervals. When given alone, HCl did not influence glucose or insulin levels. However, HCl did produce an increase in GIP. The GIP response to acid was less than that to glucose and was delayed. The peak insulin and GIP responses with the glucose and glucose/acid combinations were similar with both the oral and intraduodenal routes. There was, however, a potentiation of both the GIP and insulin responses when intraduodenal acid was given with glucose. This effect on GIP and insulin was not evident with the oral glucose/acid load. It is concluded that HCl by itself is capable of stimulating GIP secretion. Since there was only a potentiation of insulin and GIP secretion when large doses of HCl were given together with glucose via the intraduodenal route, the physiological relevance of acid-induced GIP secretion remains to be resolved.

Insulin secretory dynamics after two consecutive intravenous stimulations with glucose and/or tolbutamide

Intravenous glucose and/or tolbutamide administered in two consecutive pulses 30 and 60 min apart to the same subjects using identical doses showed that insulin secretory response was altered during a subsequent stimulation and that this was modulated by the time factor. Insulin response was more sustained after the second glucose pulses and the insulin peak response was delayed and diminished if the second glucose dose was given 30 min after the first, but not if given 60 min later. It is suggested that the beta-cell membrane might remain partially depolarized above a certain glucose level or that a postulated signal relay mechanism might become saturated. Response to two tolbutamide pulses did not show these characteristics; however, the second insulin response was smaller than the first. When the first pulse was glucose and the second tolbutamide, or vice versa, the second responses were altogether different from those elicited by the double doses of either tolbutamide or glucose. To explain these characteristic patterns of insulin secretory dynamics, the existence of occult glucose receptors on the beta-cell that are opened up by tolbutamide was postulated. These studies do not support the two-pool theory, or at least restrict it to glucose-stimulated insulin response. The positive correlations between the first and the second insulin responses in all tests argue strongly against the existence of an insulin feedback mechanism in man.

Effect of methylene blue and thiol oxidants on pancreatic islet GSH/GSSG ratios and tolbutamide mediated insulin release in vitro

Methylene blue (an oxidant of NADPH), diamide (an oxidant of glutathion-SH [GSH]) and tertbutyl hydroperoxide (a substrate of glutathione peroxidase) significantly decreased the GSH content of pancreatic rat islets and decreased their GSH/GSSG ratio. They also significantly depressed the single peak insulin response to tolbutamide by the isolated perfused pancreas as well as its synergistic action with glucose in isolated pancreatic islets. These results suggest that the effect of tolbutamide alone and its synergistic action with glucose could depend on the islet NADPH and GSH. In addition it appears that augmentation of tolbutamide action by glucose in insulin release is mediated by the provision of additional NADPH and GSH through glucose metabolism.

874 INSULIN RECEPTORS IN CYSTIC FIBROSIS (CF): INCREASE IN RECEPTOR NUMBER MAY EXPLAIN INSULIN SENSITIVITY

Specific 125I insulin binding to circulating monocytes was studied in a group of 13 patients with CF, 4 of whom were insulin dependent. Nine untreated patients had mild carbohydrate intolerance in response to oral glucose as compared to controls (201±26mg/dl vs.103±6 M±SEm at 2h; 144±26 vs.92±5 at 3h). The peak insulin response was delayed to 2 hours in CF and lower than the one hour peak of normals (44mIU/ml vs.66mIU/ml). Calculated insulinogenic index, II (∑Δinsulin/∑Δglucose) was lower for CF than controls (0.21±0.05 vs.0.37±0.04 p<0.01), indicating enhanced insulin sensitivity. Scatchard analysis of insulin binding revealed a marked increase in receptor sites in untreated CF patients as compared to controls; 44,000 sites/cell vs. 25,000 sites/cell. Specific insulin binding at tracer concentrations (0.3ng/ml) was lower in CF 3.14% vs.5.14%, and the calculated affinity constant for binding (Ke) was reduced, 0.8x108 M−1 vs. 2.5x108 M−1. Insulin treated patients did not have lower receptor numbers or altered affinity as compared to the untreated. Thus 1) in CF diminished insulin secretion is associated with an increased number of receptor sites 2) increased binding sites would explain sensitivity to endogenous insulin, as demonstrated by the decreased II as well as to exogenous insulin (reported by others) 3) the consequences of the substantial increase in receptor number may be offset somewhat by reduced receptor affinity.

Loss of Insulin Response to Ingested Amino Acids After Jejunoileal Bypass Surgery for Morbid Obesity

Amino acid tolerance tests were performed before and after jejunoileal bypass surgery for morbid obesity to determine whether an enteric factor(s) originating in the bypassed jejunum and/or ileum potentiates the insulin response to oral nitrogen loading. Preoperatively a 30-gm. mixture of amino acids given orally evoked a larger peak insulin than an intravenous load yielding comparable plasma amino acid elevations (82 +/- 17 muU./ml versus 38 +/- 8 muU./ml., p less than 0.05). Four months after operation, basal insulin concentrations were 46 per cent (p less than 0.001) of preoperative values. After surgery the response to intravenous amino acids was preserved when expressed as percentage increase above basal. In contrast, the peak increment and the percentage increase in insulin secretion after 30-gm. oral amino acid loading was significantly blunted (p less than 0.005). A smaller amino acid load (16.5 gm.) was given preoperatively to duplicate the plasma amino acid elevations seen postoperatively with the 30-gm. mixture given by mouth. The insulin response postoperatively was still significantly lower (167 +/- 33 per cent versus 98 +/- 16 per cent, p less than 0.05). After various explanations for the diminished postoperative insulin release following oral amino acid ingestion are considered, the results are best explained by the loss of an enteric insulinotrophic factor(s) normally released by the bypassed portions of jejunum or ileum in response to ingested protein.

Glucose tolerance and insulin response in diabetes mellitus of dogs

ABSTRACTThe low dose intravenous glucose tolerance test (IVGTT) and the insulin response to the glucose load were performed in a series of twenty–two diabetic dogs. All diabetic dogs were characterized by glucose intolerance as expressed by an abnormal half time (Tl/2) or fractional turnover rate (k) for glucose clearance. On the basis of the initial insulin level (Io), the insulin peak response (Ip) and the insulinogenic index (I/G), the dogs were classified into three types. Type I dogs were characterized by a low Io, low Ip and low I/G in response to glucose, similar to the juvenile form of diabetes in humans. Type II dogs were characterized by a normal or high Io, but also with a low Ip and a low I/G which are some of the features of the maturity onset form. Type III dogs were characterized by a normal Io and a normal or delayed response to glucose as seen in chemical diabetes. It is suggested that these types represent stages in the natural history of the development of diabetes mellitus in dogs.

Deranged insulin-secretory dynamics in offspring of two diabetic parents after double stimulation with intravenous glucose.

Nine offspring of two diabetic parents and 18 normals were studied with two intravenous glucose loads (o.5 gm./kg. body weight), 60 minutes apart. By thus stressing the beta cell, subtle defects could be identified in the prediabetics: (1) An inverse relationship between insulin peak response and insulin concentration 60 minutes postglucose was seen, a phenomenon exactly the opposite to that seen in normals. (2) Insulin peak response was delayed slightly after the first pulse and significantly after the second. (3) A less effective handling of the glucose load when compared with normals was brought out by the second stimulation. (4) There was a significant reduction in the insulin response per unit change in glucose after the first glucose pulse that was accentuated after the second pulse. This double-stimulation technique amplifies previously detected slight but significant defects in insulin secretion that might help to identify a diabetes-prone population.

Carbohydrate Metabolism and Capillary Basement-membrane Thickness in Children: II. Longitudinal Studies

Longitudinal biochemical and histologic studies were carried out in 11 children receiving oral hypoglycemic agents. There were five "suspected" diabetics (with evidence of glucose intolerance but without repeated fasting hyperglycemia) and six diabetics. Mean fasting plasma glucose (FPG) values showed no significant change during treatment with phenformin alone. The mean FPG decreased significantly within six to 10 weeks after addition of tolazamide to the regimen, but the decrease was not sustained during long-term observation (seven months to four years). Glucose disappearance rate (K) generally increased as FPG decreased, but the number of observations was smaller, and mean values showed no significant change. Mean values for fasting plasma insulin and for peak insulin response to intravenously administered glucose did not change significantly. Changes in capillary basement membrane thickness (BMT) were found to be statistically significant in a number of individual instances. Decreasing BMTs were associated with increasing Ks and vice versa. A similar trend was apparent among other patients, in whom individual changes in BMT were not statistically significant. The pooled data were therefore subjected to chi-square analysis; K and average BMT were found to change in opposite directions (P less than 0.001); a similar relationship held for K and minimum BMT (P less than 0.05). But K and BMT did not correlate well as regards magnitude of change. Influences of phenformin and tolazamide on these changes could not be evaluated. Both BMT and K may be influenced by many complex variables, but the present findings indicate that glucose tolerance and BMT have a close interdependence.

The influence of oral glucose loading on the insulin response to i.v. glucagon in children and adolescents

Fourteen children and adolescents with slight constitutional growth retardation (12 males and two females) aged from 7 1 2 to 18 1 2 , yr underwent an oral glucose tolerance test (OGTT 1.75 g/Kg followed at 180 min by an i.v. glucagon injection (0.03 mg/Kg). On a separate occasion these children underwent a simple i.v. glucagon test. Comparing the glucose and insulin response in the two glucagon tests for each child we found that whereas in the single test the blood glucose rose slowly with a peak at 30 min, in the combined test the peak was at 5 min. The mean peak values were similar ( 129 and 121 mg 100 ml ). The mean peak insulin response in the single test was 70 μU/ml (at 2 min) as compared to 253 μU/ml (at 2 min) in the combined test. Our studies provide further evidence for a direct effect of glucagon on insulin release and that glucose preloading augments this effect, without relation to the concomitant blood glucose concentrations.

THE INFLUENCE OF ORAL GLUCOSE LOADING ON THE INSULIN RESPONSE TO I.V. GLUCAGON IN CHILDREN AND ADOLESCENTS

Fourteen children and adolescents (12 males and 2 females) aged from 7 6/12 to 18 6/12 years underwent an oral glucose tolerance test (OGTT 1.75 g/kg) followed at 180 min by i.v. glucagon injection (0.03 mg/kg). On a separate occasion these children underwent a simple i.v. glucagon test. Combining the glucose and insulin response in the two glucagon tests for each child we found that whereas in the single test the blood glucose rose slowly with a peak at 39 min, in the combined test the peak was at 5 min. The mean peak values were similar (129 and 121 mg%). The mean peak insulin response in the single test was 79 mIU/ml (at 2 min) as compared to 253 mIU/ml (at 2 min ) in the combined test. Our studies provide further evidence for a direct effect of glucagon on insulin release and that glucose preloading augments this effect, without relation to the blood glucose concentrations.Established Investigator of The Chief Scientist's Bureau of Health

Effect of intravenously administered glucose on glucagon and insulin secretion during fat absorption

The intravenous infusion of glucose was found to alter profoundly the response of insulin and glucagon to an intraduodenally administered fat meal in conscious dogs from that of dogs given only intravenous saline as a control. In the latter, insulin rose only 4 μU/ml and glucagon rose from 142 SEM ± 8 to a peak of 221 pg/ml SEM ± 50. When glucose was infused, raising plasma glucose above 170 mg 100 ml , the administration of fat was associated with a rise in mean insulin to 344 μU/ml, and glucagon remained suppressed by hyperglycemia to below baseline levels, despite the fat meal. The peak insulin response to a fat meal plus glucose infusion was more than three times the peak level observed when glucose was infused alone without a meal or with a nonabsorbable intraduodenal volume load in the form of mineral oil. This suggests that the absorption of fat elicits an entero-insular signal that is greatly potentiated by exogenous glucose. These glucose-induced changes in the hormonal response to a fat meal may mediate certain of the metabolic effects of carbohydrates.