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Biomedical subjects

R N Bergman

Publications and source records attributed to R N Bergman.

At least 127 records · Page 7Linked to original sources
PubMed1991

Intravenous insulin infusion to simulate subcutaneous absorption. Bioavailability and metabolic sequelae.

OBJECTIVE: To determine the bioavailability and bioactivity of subcutaneously injected insulin. RESEARCH DESIGN AND METHODS: A randomized block design with six male mongrel dogs as subjects. In protocol 1, purified pork insulin was infused intravenously to simulate the pattern of appearance in the blood that would have been expected from subcutaneous injection. Three intravenous doses (0.05, 0.10, and 0.15 U/kg) were infused on separate days in a pattern (0-300 min) designed to approximately simulate the absorption rate of subcutaneously injected insulin. In protocol 2, interscapular subcutaneous injections of pork insulin at 0.10 U/kg were made. RESULTS: Integrated insulin, decrement in plasma glucose, and maximal glucose clearance for subcutaneous injection experiments were similar to intravenous infusion of equal dose (P greater than 0.10) but significantly different from low-dose infusions (P less than 0.025). Similar results were observed for hepatic glucose output and glucose uptake. Hypoglycemia elicited counterregulatory responses that appeared to be under a threshold differentiated at a plasma glucose of approximately 3 mM. Integrated insulin was plotted against insulin dose to create dose-response curves for intravenous data. The curve was then used to predict the actual appearance rate of insulin in plasma for subcutaneous injection. The estimated bioavailability of subcutaneous insulin was 103.0 +/- 10.5% of the injected dose. CONCLUSIONS: We concluded that, in dogs, insulin delivered subcutaneously in the interscapular area is not significantly degraded before absorption, resulting in metabolic effects equal to intravenous insulin infusion of equivalent dose.

Animals↗
PubMed1990

Insulin sensitivity and B-cell responsiveness to glucose during late pregnancy in lean and moderately obese women with normal glucose tolerance or mild gestational diabetes.

We used the minimal model technique to obtain concurrent measurements of whole-body insulin sensitivity and pancreatic B-cell responsiveness to glucose during the third trimester of pregnancy. Insulin sensitivity in normal pregnant women (n = 8) was reduced to only one third that of a group of nonpregnant women (n = 7) of similar age and relative weight. This marked insulin resistance was compensated by reciprocal enhancement of the first and second-phase insulin responses to intravenous glucose, which were increased threefold as compared with the nonpregnant women. Women with gestational diabetes mellitus (n = 16) had mean insulin sensitivity that was similar to that of the normal pregnant group, which indicates that insulin action was appropriate for the late phase of pregnancy in the gestational diabetic group. By contrast, the mean first-phase insulin response was significantly reduced in women with gestational diabetes mellitus, as compared with that of normal pregnant women (p less than 0.001). However, approximately one fifth of the group with gestational diabetes mellitus had first-phase responses that did not fall below the 95% confidence interval for the mean in normal pregnant women. The mean second-phase response was also lower in the group with gestational diabetes, although the difference was of borderline statistical significance (p less than 0.09). Our findings reveal the quantitative nature of the reciprocal changes in insulin sensitivity and B-cell function that normally accompany late pregnancy. They further indicate that during the third trimester, mild gestational diabetes is characterized by an impairment of pancreatic B-cell function rather than an exaggeration of the normal insulin resistance of late pregnancy.

Adult↗
PubMed1990

Diminished insulin sensitivity and increased insulin response in nonobese, nondiabetic Mexican Americans.

The contributions of diminished insulin sensitivity and decreased insulin response to the development of non-insulin-dependent diabetes mellitus (NIDDM) remain controversial. Nondiabetics in high-risk populations for NIDDM, including Pima Indians and Mexican Americans, are characterized by obesity and hyperinsulinemia relative to nondiabetics in the lower-risk white population. However, it is not clear to what extent diminished insulin sensitivity in the high-risk groups reflects obesity per se or is an inherent characteristic of these groups. Insulin sensitivity and secretion were determined in 10 nonobese, normoglycemic Mexican Americans (mean body mass index [BMI], 23.8 kg/m2) and 11 normoglycemic non-Hispanic whites (mean BMI, 22.5 kg/m2) using the intravenous glucose tolerance test (IVGTT) and the minimal model approach of Bergman et al. Age, BMI, sum of skinfolds, and the ratio of waist-to-hip circumference (WHR) were similar in both ethnic groups. Mexican Americans had decreased insulin sensitivity compared with non-Hispanic whites (4.06 +/- 0.72 in Mexican Americans v 7.56 +/- 1.13 in non-Hispanic whites, P = .017). The areas under the C-peptide and insulin curves were significantly greater in Mexican Americans than in non-Hispanic whites (P less than .01), suggesting greater insulin secretion in the former. This study provides evidence for diminished insulin sensitivity and increased insulin response in young, nonobese, normoglycemic Mexican Americans.

Analysis of Variance↗
PubMed1990

Peripheral effects of insulin dominate suppression of fasting hepatic glucose production.

Insulin may suppress hepatic glucose production directly, or indirectly via suppression of release of gluconeogenic substrates from extrasplanchnic tissues. To compare these mechanisms, we performed insulin dose-response experiments in conscious dogs at euglycemia, during somatostatin infusion, and intraportal glucagon replacement. Insulin was sequentially infused either intraportally (0.05, 0.20, 0.40, 1.0, 1.4, and/or 3.0; protocol I) or systemically at half the intraportal rate (0.025, 0.10, 0.20, 0.50, 0.70, and/or 1.5 mU.min-1.kg-1; protocol II). Exogenous glucose infused during clamps was labeled with 3-[3H]glucose (2 microCi/g) to prevent a fall in plasma specific activity (P greater than 0.2) that may have contributed to previous underestimations of hepatic glucose output (HGO). Portal insulins were up to threefold higher during intraportal infusion, but peripheral insulin levels were not different between the intraportal and systemic protocols [7 +/- 5 vs. 9 +/- 1, 12 +/- 4 vs. 13 +/- 6, 16 +/- 3 vs. 27 +/- 5, 70 +/- 23 vs. 48 +/- 8, 83 +/- 3 vs. 86 +/- 21, and 128 vs. 120 +/- 14 microU/ml for paired insulin doses; P greater than 0.06 by analysis of variance (ANOVA)]. Despite higher portal insulin levels in protocol I, HGO suppression was equivalent in the two protocols when systemic insulin was matched, from 3.3 +/- 0.1 to near-total suppression at 0.3 mg.min-1.kg-1 at the highest insulin infusion rate (3.0 mU.min-1.kg-1; P less than 0.0001) with intraportal insulin, from 2.9 +/- 0.8 to -0.8 +/- 0.2 mg.min-1.kg-1 in protocol II (P less than 0.001). Suppression of HGO was similar at matched systemic insulin, regardless of portal insulin, suggesting the primacy of insulin's action on the periphery in its restraint of hepatic glucose production.

Analysis of Variance↗
PubMed1990

Enhancement of hepatic glycogen by gluconeogenic precursors: substrate flux or metabolic control?

After a meal or glucose load, most carbons of hepatic glycogen are derived from gluconeogenesis. In vitro, hepatic glycogen accumulation is sluggish with glucose alone but markedly enhanced in the presence of gluconeogenic substrates. These findings conflict with the classical view that glucose is the major precursor of hepatic glycogen and have been termed the "glucose paradox." In this review, we attempt to elucidate the central mechanism underlying the glucose paradox by critically examining the in vitro data of hepatic glycogen accumulation. Our analysis is inconsistent with the current hypothesis that glucose phosphorylation is rate limiting for hepatic glycogen accumulation from glucose and that gluconeogenesis enhances glycogen accumulation primarily by increasing substrate flux to the hepatic glucose 6-phosphate pool. Instead, our analysis leads us to the conclusion that the rate-limiting step is the net incorporation of glucose 6-phosphate into glycogen, which is synergistically facilitated with glucose and gluconeogenic substrates. Thus gluconeogenic substrates are involved in the regulation of key enzyme(s) of glycogen metabolism. In addition, in the livers from fasted rats there is substantial cycling through glycogen, and that suppression of glycogen degradation may be a major mechanism in the enhancement of glycogen accumulation by gluconeogenic substrates. Thus we propose a specific hypothesis of the role of gluconeogenic substrates in glycogen metabolism (i.e., inhibition of phosphorylase), which can be tested by future studies.

Animals↗
PubMed1990

Kinetics and specificity of insulin uptake from plasma into cerebrospinal fluid.

To characterize the relationship between insulin levels in plasma and those in cerebrospinal fluid (CSF), we studied the kinetics of both the uptake of insulin into CSF from plasma and the turnover of insulin within the CSF compartment. Sustained physiological levels of euglycemic hyperinsulinemia (plasma insulin approximately 500 pM) did not alter CSF insulin levels within the 1st h, but by 90 min a significant increase was observed (P less than 0.01). During graded hyperinsulinemic clamps (mean plasma insulin approximately 500-15,000 pM), CSF insulin rose in a dose-dependent fashion. This rise was characterized by an initial delay followed by a continuous increase for the next 150 min. We also found that after brief, high-dose intravenous insulin infusions, the t1/2 of CSF insulin was 143 +/- 7 min (means +/- SE; n = 4), similar to that of CSF turnover by bulk flow. To test the specificity of CSF insulin uptake from plasma, we compared this uptake during intravenous insulin infusions with that of proinsulin, a peptide with reduced affinity for the insulin receptor. We observed a significantly lower increment of CSF proinsulin levels over 180 min (13.6 +/- 1.6 pM; means +/- SE; n = 4) compared with that of insulin (22.4 +/- 0.6 pM; n = 4; P less than 0.01), despite plasma proinsulin levels higher than insulin (1,890 +/- 287 vs. 1,283 +/- 192 pM; P less than 0.001). When corrected for the difference in plasma levels, the uptake of insulin was fivefold greater than that of proinsulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

The modified minimal model: application to measurement of insulin sensitivity in children.

The modified minimal model (MMM), a recently introduced method that assesses insulin sensitivity (SI) by a computed mathematical analysis of the relation between the change in insulin and glucose clearance after a bolus of iv glucose, followed 20 min later by a bolus of tolbutamide, has been standardized in adults, but this method has not been validated in children. We performed an abbreviated 90-min MMM test in 50 children who were siblings of patients with insulin-dependent diabetes mellitus and 7 healthy adult volunteers and compared the results to the standard 180-min MMM test in 11 of these subjects. The cohort consisted of 29 prepubertal children [16 males and 13 females; 8.7 +/- 2.0 (mean +/- SEM) yr old]; 16 pubertal children defined as less than 17 yr of age and Tanner stage 2-5 (8 males and 8 females; 13.4 +/- 1.8 yr old), and 12 postpubertal subjects (7 males and 5 females; 18.2 +/- 0.9 yr old), with no significant difference in the weight for length index (WLI) among the 3 groups and with sera of all subjects negative for islet cell antibodies and insulin autoantibodies. The test procedure consisted of 3 baseline blood samples over 30 min, followed at zero time by 0.3 g/kg 25% dextrose infused iv over 1 min and an iv injection of tolbutamide (5 mg/kg) 20 min later; sequential blood samples for glucose and insulin measurements were withdrawn from zero time until completion 90 or 180 min later. In the 11 subjects who underwent both the standard and the abbreviated tests, there was no significant difference between the SI estimated by the 2 methods provided that glucose and insulin values were interpolated at 180 min during the computer calculations of the abbreviated test. Using the 90-min abbreviated test, the SI of the pubertal subjects (2.92 +/- 0.45) was markedly less than that of the prepubertal subjects (6.57 +/- 0.45; P = 0.0001). While the postpubertal group value of 4.63 +/- 0.86 was significantly higher than that of the pubertal group (P = 0.0001), the pre- and postpubertal groups remained significantly different (P = 0.0001). The 10 obese subjects with WLI greater than 120% had a lower SI (3.5 +/- 0.53) than the 47 nonobese subjects with WLI less than 120% (SI = 5.48 +/- 0.42; P less than 0.04), and there was a negative correlation between SI and WLI. None of the study subjects experienced symptomatic hypoglycemia during the test.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1990

Treatment with a somatostatin analog decreases pancreatic B-cell and whole body sensitivity to glucose.

To determine the specific alteration in B-cell function caused by a somatostatin analog in man and to determine the effect of the induced insulin deficiency on insulin action, we administered octreotide (SMS 201-995; 50 micrograms twice daily) to nine healthy male subjects, aged 24-35 yr. B-Cell function was assessed by measuring the acute insulin response (AIR) to glucose (AIRglucose) at fasting glucose and to arginine (AIRarg) at glucose concentrations of fasting, approximately 14 and more than 28 mM after 2 (n = 7) and 8 days (n = 9) of octreotide. The AIRarg at more than 28 mM glucose (AIR500) is an estimate of B-cell secretory capacity, while the glucose level at which 50% of AIR500 occurs is termed PG50 and can provide an estimate of B-cell glucose sensitivity. Insulin sensitivity and the parameters describing glucose disposal were measured using Bergman's minimal model. Octreotide administration resulted in the development of mild fasting hyperglycemia, marked fasting hypoinsulinemia, as well as a marked reduction in AIRglucose [mean +/- SE; pretreatment, 260 +/- 48 pM; 1 day, 62 +/- 14 pM (P less than 0.005 vs. pretreatment); 8 days, 62 +/- 7 pM (P less than 0.005 vs. pretreatment)]. In addition, there was an associated marked reduction in iv glucose tolerance. While the AIRarg at fasting glucose (pretreatment, 233 +/- 27 pM; 2 days, 144 +/- 27 pM; 8 days 281 +/- 55 pM) and AIR500 (pretreatment 1000 +/- 178 pM; 2 days, 651 +/- 82 pM; 8 days, 1041 +/- 219 pM) remained unchanged, the AIRarg at 14 mM decreased significantly during octreotide [pretreatment 986 +/- 178 pM; 2 days, 363 +/- 62 pM (P less than 0.001 vs. pretreatment); 8 days, 623 +/- 130 pM (P less than 0.005 vs. pretreatment)], resulting in a rightward shift of the dose-response curve such that the estimated PG50 increased from 8.8 +/- 0.6 to 12.9 +/- 1.3 mM (P less than 0.05) after 2 days and was maintained for 8 days (11.2 +/- 0.8 mM; P less than 0.05 vs. pretreatment). Despite the development of marked insulin deficiency, the insulin sensitivity index (SI) did not change significantly (pretreatment, 11.34 +/- 1.59 x 10(-5); 1 day, 10.01 +/- 2.28 x 10(-5); 7 days, 9.65 +/- 1.69 x 10(-5) min-1/pM).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1990

Minimal model analysis of intravenous glucose tolerance test-derived insulin sensitivity in diabetic subjects.

Although minimal model analysis of frequently sampled iv glucose tolerance tests (FSIGTs) to measure insulin sensitivity is well recognized, application has been limited by the need for endogenous insulin secretion. In the present study we determined whether use of exogenous insulin could permit minimal model assessment of insulin sensitivity (SI) to be extended to diabetic subjects. Normal volunteers had separate FSIGT assessments supplemented with both tolbutamide and insulin to accelerate glucose disappearance, while diabetics had a FSIGT supplemented only with insulin. There was a strong and highly significant correlation between the two assessments in normal subjects (r = 0.87; P less than 0.001), and the rank order of SI generally was maintained with the two assessments over a 3-fold range of SI; however, insulin-determined SI was 16% lower (3.4 +/- 0.4 vs. 4.1 +/- 0.4 x 10(-4) min/microU.microL; P less than 0.01). Diabetic subjects had markedly lower insulin sensitivity than controls (SI = 0.61 +/- 0.16; P less than 0.0001). Across all subjects, the level of fasting serum glucose was correlated inversely with both insulin sensitivity (r = -0.62; P less than 0.05) and acute insulin responses (r = -0.72; P less than 0.02); however, insulin sensitivity in diabetic subjects with little insulin secretion (0.6 +/- 0.2) was comparable to insulin sensitivity in diabetic subjects with near-normal responses (0.6 +/- 0.3). In subjects with fasting hyperglycemia, there were significant correlations between insulin sensitivity and body mass index, percent fat mass, and waist/hip ratio (all P less than 0.03). Among all female subjects, there was also a strong correlation between insulin sensitivity and upper body obesity, as measured by waist/hip ratio (r = -0.68; P less than 0.02). Model parameters also permitted glucose uptake to be estimated in diabetic vs. normal subjects at comparable hyperglycemia (11.1 mmol/L). Total glucose uptake was decreased in diabetic subjects (5.2 +/- 0.8 vs. 12.7 +/- 1.7 mg/min.kg in normals; P less than 0.001), insulin-dependent glucose uptake was diminished to a greater extent (1.3 +/- 0.4 vs. 6.2 +/- 1.2) than noninsulin-independent glucose uptake (3.9 +/- 0.5 vs. 6.4 +/- 0.9; both P less than 0.02). Administration of insulin permits minimal model FSIGT analysis to be applied to diabetic as well as normal subjects, yielding information about both insulin- and noninsulin-mediated glucose uptake as well as insulin sensitivity and insulin secretion.

Adult↗
PubMed1990

Determination of portal insulin absorption from peritoneum via novel nonisotopic method.

The absorption mechanism of insulin administered in the peritoneal cavity (IP) is of current interest because of the near availability of implantable insulin-infusion devices for the treatment of diabetes. To determine the fraction of insulin absorbed by the portal circulation after IP administration, a novel nonisotopic method is described. Conscious fasting diabetic dogs were studied at normoglycemia via the euglycemic insulin-clamp method. Posthepatic appearance of insulin and C-peptide were measured in peripheral blood during IP or intravenous (IV) equimolar infusion of insulin and C-peptide at two sequential 3-h infusion rates of 3.2 and 12.8 pmol.kg-1.min-1. Prior studies have shown that 40-60% of portal insulin is extracted at first pass by the liver, whereas C-peptide is not extracted. Thus, the fraction (F) of IP insulin not taken up by liver at first pass and consequently the fraction absorbed by the portal circulation can be derived from insulin (I) and C-peptide (C) plasma concentration values at steady state with a monocompartmental model where F = (IIP/IIV)(CIV/CIP). The mean +/- SE value of F was 49.7 +/- 8.8%. Glucose disappearance rates were lower with IP than IV infusion but similar when peripheral insulin levels were matched. We conclude that IP insulin is almost entirely absorbed by the portal circulation and induces lower glucose disappearance rates than IV insulin because of lower peripheral circulating insulin levels. Whether these properties make the IP route a more appropriate route for insulin therapy than the subcutaneous or IV routes remains to be established.

Absorption↗
PubMed1990

The role of the transcapillary insulin transport in the efficiency of insulin action: studies with glucose clamps and the minimal model.

Insulin action to augment glucose utilization (Rd) and suppress endogenous glucose production is not directly determined by changing plasma insulin, but rather by that insulin which traverses the capillary endothelial boundary to enter the interstitial space bathing insulin-sensitive cells. We have examined the importance of transcapillary insulin transport to the efficiency of insulin action by sampling insulin in thoracic duct lymph, believed to represent interstitial fluid, during euglycemic glucose clamps or intravenous glucose tolerance tests (IVGTTs) in conscious dogs. During clamps (insulin infusion: 0.6 mU/min per kg), we observed a 3:2 gradient between plasma and lymph insulin both at basal and at hyperinsulinemic steady state, which was reestablished after termination of infusion. No such gradient was observed for inulin, a non-metabolizable diffusionary marker infused along with insulin. Furthermore, lymph insulin was proportional to Rd during clamps, and these two independently measured variables were strongly correlated (r = 0.96). These results indicate that transcapillary insulin transport is rate-limiting for insulin action during clamps. Compartmental analysis of insulin and inulin data was consistent with receptor-mediated transport of insulin across capillary endothelium from plasma to interstitium. Glucose tolerance tests were subjected to minimal model analysis, which yields the insulin sensitivity index (SI) and X(t), the rate of net glucose disposition during the intravenous test. Preliminary data reveal a striking similarity between the time courses of X and measured lymph insulin during IVGTTs, evidence that interstitial insulin is virtually at equilibrium with the rate of glucose uptake. Thus, even in the non-steady state, transendothelial insulin transport is the rate determining step for insulin action.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Glucose phosphorylation is not rate limiting for accumulation of glycogen from glucose in perfused livers from fasted rats.

Incorporation of Glc and Fru into glycogen was measured in perfused livers from 24-h fasted rats using [6-3H]Glc and [U-14C]Fru. For the initial 20 min, livers were perfused with low Glc (2 mM) to deplete hepatic glycogen and were perfused for the following 30 min with various combinations of Glc and Fru. With constant Fru (2 mM), increasing perfusate Glc increased the relative contribution of Glc carbons to glycogen (7.2 +/- 0.4, 34.9 +/- 2.8, and 59.1 +/- 2.7% at 2, 10, and 20 mM Glc, respectively; n = 5 for each). During perfusion with substrate levels seen during refeeding (10 mM Glc, 1.8 mumol/g/min gluconeogenic flux from 2 mM Fru), Fru provided 54.7 +/- 2.7% of the carbons for glycogen, while Glc provided only 34.9 +/- 2.8%, consistent with in vivo estimations. However, the estimated rate of Glc phosphorylation was at least 1.10 +/- 0.11 mumol/g/min, which exceeded by at least 4-fold the glycogen accumulation rate (0.28 +/- 0.04 mumol of glucose/g/min). The total rate of glucose 6-phosphate supply via Glc phosphorylation and gluconeogenesis (2.9 mumol/g/min) exceeded reported in vivo rates of glycogen accumulation during refeeding. Thus, in perfused livers of 24-h fasted rats there is an apparent redundancy in glucose 6-phosphate supply. These results suggest that the rate-limiting step for hepatic glycogen accumulation during refeeding is located between glucose 6-phosphate and glycogen, rather than at the step of Glc phosphorylation or in the gluconeogenic pathway.

Animals↗
PubMed1989

Insulin transport across capillaries is rate limiting for insulin action in dogs.

This study examined the relationship between transcapillary insulin transport and insulin action in vivo. During euglycemic clamps (n = 7) in normal conscious dogs we simultaneously measured plasma and thoracic duct lymph insulin and glucose utilization (Rd). Clamps consisted of an activation phase with constant insulin infusion (0.6 mU/kg per min) and a deactivation phase. [14C]Inulin was infused as a passively transported control substance. While [14C]inulin reached an equilibrium between plasma and lymph, steady-state (ss) plasma insulin was higher than lymph (P less than 0.05) and the ratio of 3:2 was maintained during basal, activation, and deactivation phases: 18 +/- 2 vs. 12 +/- 1, 51 +/- 2 vs. 32 +/- 1, and 18 +/- 3 vs. 13 +/- 1 microU/ml. In addition, it took longer for lymph insulin to reach ss than plasma insulin during activation and deactivation: 11 +/- 2 vs. 31 +/- 5 and 8 +/- 2 vs. 32 +/- 6 min (P less than 0.02). Rd increased from 2.6 +/- 0.1 to a ss of 6.6 +/- 0.4 mg/kg per min within 50 +/- 8 min. There was a remarkable similarity in the dynamics of insulin in lymph and Rd: the time to reach ss for Rd was not different from lymph insulin (P greater than 0.1), and the relative increases of the two measurements were similar, 164 +/- 45% and 189 +/- 29% (P greater than 0.05). While there was only a modest correlation (r = 0.78, P less than 0.01) between Rd and plasma insulin, the dynamic changes of lymph insulin and Rd showed a strong correlation (r = 0.95, P less than 0.01). The intimate relationship between lymph insulin and Rd suggests that the transcapillary insulin transport is primarily responsible for the delay in Rd. Thus, transcapillary transport may be rate limiting for insulin action, and if altered, it could be an important component of insulin resistance in obesity and diabetes mellitus.

Animals↗
PubMed1989

Prehepatic beta-cell secretion during the intravenous glucose tolerance test in humans: application of a combined model of insulin and C-peptide kinetics.

A previously introduced method by which prehepatic beta-cell secretion is calculated in vivo from plasma measurements of insulin and C-peptide was applied to data derived from iv glucose tolerance tests performed in normal women. Prehepatic secretory rates calculated using the combined model appeared biphasic in nature after glucose injection. Basal insulin secretion was 63.9 +/- 9.8 pmol/min. The duration of first phase was approximately 5 min, with secretion reaching a peak of 2033 +/- 342 pmol/min. The first phase was followed by a significant refractory period in which the secretory rate fell below basal values. The magnitude of second phase secretion was small relative to first phase secretion and appeared pulsatile in nature. Total integrated insulin secretion was 22.2 +/- 2.7 nmol, of which first phase accounted for 32%, and second phase accounted for the remaining 68%. Total incremental integrated secretion was 10.6 +/- 1.4 nmol, accounting for approximately half of the total insulin secretion. Proportions of first and second phase secretion changed to 66.5% and 33.5%, respectively, with incremental data. This study shows that the combined model of insulin and C-peptide is capable of estimating prehepatic insulin secretion from the iv glucose tolerance test and may provide a useful tool to measure secretion in vivo under various pathological conditions.

Adult↗
PubMed1989

Lilly lecture 1989. Toward physiological understanding of glucose tolerance. Minimal-model approach.

Glucose tolerance depends on a complex interaction among insulin secretion from the beta-cells, clearance of the hormone, and the actions of insulin to accelerate glucose disappearance and inhibit endogenous glucose production. An additional factor, less well recognized, is the ability of glucose per se, independent of changes in insulin, to increase glucose uptake and suppress endogenous output (glucose effectiveness). These factors can be measured in the intact organism with physiologically based minimal models of glucose utilization and insulin kinetics. With the glucose minimal model, insulin sensitivity (SI) and glucose effectiveness (SG) are measured by computer analysis of the frequently sampled intravenous glucose tolerance test. The test involves intravenous injection of glucose followed by tolbutamide or insulin and frequent blood sampling. SI varied from a high of 7.6 x 10(-4) min-1.microU-1.ml-1 in young Whites to 2.3 x 10(-4) min-1.microU-1.ml-1 in obese nondiabetic subjects; in all of the nondiabetic subjects, SG was normal. In subjects with non-insulin-dependent diabetes mellitus (NIDDM), not only was SI reduced 90% below normal (0.61 +/- 0.16 x 10(-4) min-1.microU-1.ml-1), but in this group alone, SG was reduced (from 0.026 +/- 0.008 to 0.014 +/- 0.002 min-1); thus, defects in SI and SG are synergistic in causing glucose intolerance in NIDDM. One assumption of the minimal model is that the time delay in insulin action on glucose utilization in vivo is due to sluggish insulin transport across the capillary endothelium. This was tested by comparing insulin concentrations in plasma with those in lymph (representing interstitial fluid) during euglycemic-hyperinsulinemic glucose clamps. Lymph insulin was lower than plasma insulin at basal (12 vs. 18 microU/ml) and at steady state, indicating significant loss of insulin from the interstitial space, presumably due to cellular uptake of the insulin-receptor complex. Additionally, during clamps, lymph insulin changed more slowly than plasma insulin, but the rate of glucose utilization followed a time course identical with that of lymph (r = .96) rather than plasma (r = .71). Thus, lymph insulin, which may be reflective of interstitial fluid, is the signal to which insulin-sensitive tissues are responding. These studies support the concept that, at physiological insulin levels, the time for insulin to cross the capillary endothelium is the process that determines the rate of insulin action in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Increased beta-cell secretory capacity as mechanism for islet adaptation to nicotinic acid-induced insulin resistance.

To determine whether prolonged nicotinic acid (NA) administration produces insulin resistance and, if so, how the normal pancreatic islet adapts to prolonged insulin resistance, we administered incremental doses of NA to 11 normal men for 2 wk, ending at 2 g/day. Insulin sensitivity was measured with Bergman's minimal model. Islet function was evaluated by measurement of acute insulin (AIR) and glucagon (AGR) responses to arginine at three glucose levels. Insulin resistance was demonstrated and quantified by a marked drop in the insulin sensitivity index (Sl) from 6.72 +/- 0.77 to 2.47 +/- 0.36 x 10(-5) min-1/pM (P less than .0001) and resulted in a doubling of basal immunoreactive insulin levels (from 75 +/- 7 to 157 +/- 21 pM, P less than .001) with no change in fasting glucose (5.5 +/- 0.1 vs. 5.7 +/- 0.1 mM). Proinsulin levels also increased (from 9 +/- 1 to 15 +/- 2 pM, P less than .005), but the ratio of proinsulin to immunoreactive insulin did not change (12.7 +/- 1.9 vs. 10.3 +/- 1.9%). beta-Cell changes were characterized by increases in the AIR to glucose (from 548 +/- 157 to 829 +/- 157 pM, P less than .005) and in the AIR to arginine at the fasting glucose level (from 431 +/- 54 to 788 +/- 164 pM, P less than .05). At the maximal hyperglycemia level the AIR to arginine represents beta-cell secretory capacity, and this increased with administration of NA (from 2062 +/- 267 to 2630 +/- 363 pM, P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Response to deep hypoglycemia does not involve glucoreceptors in carotid perfused tissue.

In the present study we examined whether the magnified hormonal counter-regulatory response seen during deep hypoglycemia (40 mg/dl) could be attenuated by supplying the forebrain with glucose furnished through carotid infusion. Two protocols were performed in conscious dogs. In the first protocol we infused glucose bilaterally into the carotid circulation to produce a forebrain glycemia of 55 +/- 1 mg/dl (as reflected in the jugular vein), whereas systemic glycemia declined to 39 +/- 2 mg/dl. In the second protocol as a control we infused glucose into the systemic circulation at a rate matched to protocol 1 so that both systemic and jugular plasma glucose concentrations were equivalent to the systemic glucose concentrations in protocol 1 (jugular, 41 +/- 3 mg/dl; systemic, 40 +/- 2 mg/dl; P greater than 0.9). In spite of a substantial difference in forebrain glycemia (55 mg/dl compared with 41 mg/dl) there were no differences in the counter-regulatory responses of catecholamines or glucagon. In addition, through the use of radiolabeled microspheres, we defined the precise regions of the forebrain irrigated during bilateral intracarotid glucose infusions. The concentration of microspheres was high in the forebrain but very low in the hindbrain. Our results indicate that glucoreceptor cells in tissues perfused by carotid arteries may play a tautological role in the sympathetic response to hypoglycemia and imply that glucose-sensitive receptors must also be located elsewhere in the central nervous system or in the periphery.

Animals↗