Short-term hyperglycemia and hyperinsulinemia improve insulin action but do not alter glucose action in normal humans

1992 ◽  
Vol 262 (4) ◽  
pp. E518-E523 ◽  
Author(s):  
S. E. Kahn ◽  
R. N. Bergman ◽  
M. W. Schwartz ◽  
G. J. Taborsky ◽  
D. Porte
Keyword(s):  
Insulin Sensitivity ◽  
Basal Insulin ◽  
Insulin Action ◽  
Insulin Response ◽  
Glucose Infusion ◽  
Glucose Disposal ◽  
Second Phase ◽  
Insulin Effect ◽  
Glucose Effectiveness ◽  
Mild Hyperglycemia

Tissue glucose uptake occurs by insulin-dependent and insulin-independent mechanisms. To evaluate the effect of mild hyperglycemia and hyperinsulinemia on the parameters responsible for glucose disposal, glucose (1.17 mmol/min) or saline was infused into six healthy male subjects (age 25-38 yr, body mass index 22.1-26.3 kg/m2) for 24 h. Thereafter, while the infusion continued, indexes of insulin sensitivity (SI), glucose effectiveness at basal insulin (SG), basal insulin effect (BIE = SI x basal insulin), and glucose effectiveness at zero insulin (GEZI = SG - BIE) were measured using Bergman's minimal model of insulin action. GEZI provides a measure of the efficiency of glucose to accelerate its own disposal independent of insulin. Twenty-four hours of glucose infusion increased the basal plasma glucose (5.1 +/- 0.1 to 6.4 +/- 0.2 mM, P = 0.001) and insulin (79 +/- 8 to 174 +/- 31 pM, P less than 0.05) levels. Hyperglycemia was also associated with an increase in the insulin response, predominantly in the second-phase component (138 +/- 31 to 258 +/- 66 pM, P less than 0.05). SI (4.8 +/- 1.0 to 8.2 +/- 1.6 x 10(-5) min-1.pM-1, P less than 0.05) and SG (1.7 +/- 0.1 to 2.5 +/- 0.3 x 10(-2) min-1, P less than 0.05) both increased after glucose infusion. The increase in SG was entirely due to the combined increase in basal insulin and insulin sensitivity (BIE 0.4 +/- 0.1 to 1.2 +/- 0.1 x 10(-2) min-1, P = 0.001) since GEZI did not change at all (1.3 +/- 0.1 vs. 1.3 +/- 0.3 x 10(-2) min-1, P = not significant). From these data we conclude that, in normal subjects, the mild hyperglycemia and hyperinsulinemia occurring during a prolonged glucose infusion improves glucose disposal in the basal state by increasing insulin secretion and insulin sensitivity but does not enhance glucose effectiveness independent of insulin. Both of these changes thus tend to minimize the development of hyperglycemia.

scholarly journals Effect of Insulin on Proximal Tubules Handling of Glucose: A Systematic Review

2020 ◽  
Vol 2020 ◽  
pp. 1-17 ◽  
Author(s):  
Ricardo Pereira-Moreira ◽  
Elza Muscelli
Keyword(s):  
Glucose Transport ◽  
Insulin Action ◽  
Current Knowledge ◽  
Sglt2 Inhibitor ◽  
Proximal Tubules ◽  
Human Studies ◽  
Glucose Disposal ◽  
Diabetic Patients ◽  
Insulin Effect ◽  
Renal Gluconeogenesis

Renal proximal tubules reabsorb glucose from the glomerular filtrate and release it back into the circulation. Modulation of glomerular filtration and renal glucose disposal are some of the insulin actions, but little is known about a possible insulin effect on tubular glucose reabsorption. This review is aimed at synthesizing the current knowledge about insulin action on glucose handling by proximal tubules. Method. A systematic article selection from Medline (PubMed) and Embase between 2008 and 2019. 180 selected articles were clustered into topics (renal insulin handling, proximal tubule glucose transport, renal gluconeogenesis, and renal insulin resistance). Summary of Results. Insulin upregulates its renal uptake and degradation, and there is probably a renal site-specific insulin action and resistance; studies in diabetic animal models suggest that insulin increases renal SGLT2 protein content; in vivo human studies on glucose transport are few, and results of glucose transporter protein and mRNA contents are conflicting in human kidney biopsies; maximum renal glucose reabsorptive capacity is higher in diabetic patients than in healthy subjects; glucose stimulates SGLT1, SGLT2, and GLUT2 in renal cell cultures while insulin raises SGLT2 protein availability and activity and seems to directly inhibit the SGLT1 activity despite it activating this transporter indirectly. Besides, insulin regulates SGLT2 inhibitor bioavailability, inhibits renal gluconeogenesis, and interferes with Na+K+ATPase activity impacting on glucose transport. Conclusion. Available data points to an important insulin participation in renal glucose handling, including tubular glucose transport, but human studies with reproducible and comparable method are still needed.

scholarly journals Glucocorticoids and Insulin Sensitivity: Dissociation of Insulin’s Metabolic and Vascular Actions

2003 ◽  
Vol 88 (12) ◽  
pp. 6008-6014 ◽  
Author(s):  
C. G. Perry ◽  
A. Spiers ◽  
S. J. Cleland ◽  
G. D. O. Lowe ◽  
J. R. Petrie ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Insulin Action ◽  
Random Order ◽  
Glucose Disposal ◽  
High Dose ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Double Blind ◽  
High Dose Dexamethasone ◽  
Short Term Exposure ◽  
Healthy Males

Abstract Insulin sensitivity in tissues such as a skeletal muscle and fat is closely correlated with insulin action in the vasculature, but the mechanism underlying this is unclear. We investigated the effect of dexamethasone on insulin-stimulated glucose disposal and vasodilation in healthy males to test the hypothesis that a reduction in glucose disposal would be accompanied by a reduction in insulin action in the vasculature. We performed a double-blind, placebo-controlled, cross-over trial comparing insulin sensitivity (measured by the euglycemic hyperinsulinemic clamp) and vascular insulin action (measured by small vessel wire myography) in young healthy males allocated to placebo or 1 mg dexamethasone twice daily for 6 d, each in random order. Six days of dexamethasone therapy was associated with a 30% (95% confidence interval, 19.1–40.0%) fall in insulin sensitivity. Despite this, there was no difference in insulin-mediated vasodilation between phases. Dexamethasone had no effect on circulating markers of endothelial function, such as d-dimer, von Willebrand factor, and tissue plasminogen activator. By short-term exposure to high dose dexamethasone we were able to differentially affect the metabolic and vascular actions of insulin. This implies that, using this model, there is physiological uncoupling of the effects of insulin in different tissues.

scholarly journals Loss of PDGF-B activity increases hepatic vascular permeability and enhances insulin sensitivity

2011 ◽  
Vol 301 (3) ◽  
pp. E517-E526 ◽  
Author(s):  
Summer M. Raines ◽  
Oliver C. Richards ◽  
Lindsay R. Schneider ◽  
Kathryn L. Schueler ◽  
Mary E. Rabaglia ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Insulin Action ◽  
Basolateral Membrane ◽  
Tolerance Test ◽  
Whole Body ◽  
Glucose Disposal ◽  
Permeability Barrier ◽  
Loss Of Function ◽  
Transendothelial Transport

Hepatic vasculature is not thought to pose a permeability barrier for diffusion of macromolecules from the bloodstream to hepatocytes. In contrast, in extrahepatic tissues, the microvasculature is critically important for insulin action, because transport of insulin across the endothelial cell layer is rate limiting for insulin-stimulated glucose disposal. However, very little is known concerning the role in this process of pericytes, the mural cells lining the basolateral membrane of endothelial cells. PDGF-B is a growth factor involved in the recruitment and function of pericytes. We studied insulin action in mice expressing PDGF-B lacking the proteoglycan binding domain, producing a protein with a partial loss of function (PDGF-B ret/ ret). Insulin action was assessed through measurements of insulin signaling and insulin and glucose tolerance tests. PDGF-B deficiency enhanced hepatic vascular transendothelial transport. One outcome of this change was an increase in hepatic insulin signaling. This correlated with enhanced whole body glucose homeostasis and increased insulin clearance from the circulation during an insulin tolerance test. In obese mice, PDGF-B deficiency was associated with an 80% reduction in fasting insulin and drastically reduced insulin secretion. These mice did not have significantly higher glucose levels, reflecting a dramatic increase in insulin action. Our findings show that, despite already having a high permeability, hepatic transendothelial transport can be further enhanced. To the best of our knowledge, this is the first study to connect PDGF-B-induced changes in hepatic sinusoidal transport to changes in insulin action, demonstrating a link between PDGF-B signaling and insulin sensitivity.

scholarly journals PACAP stimulates insulin secretion but inhibits insulin sensitivity in mice

1998 ◽  
Vol 274 (5) ◽  
pp. E834-E842 ◽  
Author(s):  
Karin Filipsson ◽  
Giovanni Pacini ◽  
Anton J. W. Scheurink ◽  
Bo Ahrén
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Elimination Rate ◽  
Insulin Response ◽  
Area Under The Curve ◽  
Glucose Disposal ◽  
Sensitivity Index ◽  
Maximal Effect ◽  
Intravenous Glucose

Although pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates insulin secretion, its net influence on glucose homeostasis in vivo has not been established. We therefore examined the action of PACAP-27 and PACAP-38 on insulin secretion, insulin sensitivity, and glucose disposal as derived from the minimal model of glucose disappearance during an intravenous glucose tolerance test in anesthetized mice. PACAP-27 and PACAP-38 markedly and equipotently potentiated glucose-stimulated insulin secretion, with a half-maximal effect at 33 pmol/kg. After PACAP-27 or PACAP-38 (1.3 nmol/kg), the acute (1–5 min) insulin response was 3.8 ± 0.4 nmol/l (PACAP-27) and 3.3 ± 0.3 nmol/l (PACAP-38), respectively, vs. 1.4 ± 0.1 nmol/l after glucose alone ( P < 0.001), and the total area under the curve for insulin (AUCinsulin) was potentiated by 60% ( P < 0.001). In contrast, PACAP-27 and PACAP-38 reduced the insulin sensitivity index (SI) [0.23 ± 0.04 10−4min−1/(pmol/l) for PACAP-27 and 0.29 ± 0.06 10−4min−1/(pmol/l) for PACAP-38 vs. 0.46 ± 0.02 10−4min−1/(pmol/l) for controls ( P < 0.01)]. Furthermore, PACAP-27 or PACAP-38 did not affect glucose elimination determined as glucose half-time or the glucose elimination rate after glucose injection or the area under the curve for glucose. Moreover, glucose effectiveness and the global disposition index (AUCinsulin times SI) were not affected by PACAP-27 or PACAP-38. Finally, when given together with glucose, PACAP-27 did not alter plasma glucagon or norepinephrine levels but significantly increased plasma epinephrine levels. We conclude that PACAP, besides its marked stimulation of insulin secretion, also inhibits insulin sensitivity in mice, the latter possibly explained by increased epinephrine. This complex action explains why the peptide does not enhance glucose disposal.

Specific adaptations in muscle and adipose tissue in response to chronic systemic glucose oversupply in rats

1997 ◽  
Vol 273 (1) ◽  
pp. E1-E9 ◽  
Author(s):  
D. R. Laybutt ◽  
D. J. Chisholm ◽  
E. W. Kraegen
Keyword(s):  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Glucose Infusion ◽  
Whole Body ◽  
Glucose Disposal ◽  
Saline Control ◽  
Slow Increase ◽  
Glucose Clearance

Rats minimize hyperglycemia during chronic glucose infusion, but the metabolic processes are unclear. We investigated the tissues involved and the role of altered insulin sensitivity. Cannulated rats were infused with glucose (40 mg.kg-1.min-1) for 1 or 4 days or with saline (control). Hyperglycemia at 1 day (15.3 +/- 1.0 mM) was absent at 4 days (7.5 +/- 0.3 mM), but hyperinsulinemia persisted. Whole body glucose disposal was similarly elevated at 1 and 4 days, implying increased glucose clearance at 4 days (2-fold, P < 0.001). Muscle glucose uptake and glycogen content declined in glucose-infused rats from 1 to 4 days, whereas white adipose tissue (WAT) glucose uptake (6-fold, P < 0.001) and lipogenesis (3-fold, P < 0.001) increased. Muscle and liver triglyceride were doubled at both 1 and 4 days (P < 0.05 vs. control). Insulin sensitivity (assessed during euglycemic clamps) decreased in muscle to 34% of control at 1 and 4 days (P < 0.001 vs. control) and increased fivefold in WAT from 1 to 4 days (P < 0.05). Thus chronic glucose infusion results in a slow increase in efficiency of glucose clearance with enhanced WAT glucose uptake, lipogenesis, and insulin action. In contrast, the adaptation reduces glucose oversupply to muscle. Muscle shows sustained insulin resistance, with lipid accumulation a possible contributing factor.

Perioperative insulin and glucose infusion maintains normal insulin sensitivity after surgery

1998 ◽  
Vol 275 (1) ◽  
pp. E140-E148 ◽  
Author(s):  
Jonas O. Nygren ◽  
Anders Thorell ◽  
Mattias Soop ◽  
Suad Efendic ◽  
Kerstin Brismar ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Metabolic Response ◽  
Elective Surgery ◽  
Substrate Utilization ◽  
Glucose Infusion ◽  
Whole Body ◽  
Glucose Disposal ◽  
Control Group ◽  
Insulin Group ◽  
Postoperative Changes

Elective surgery was performed after overnight fasting, a routine that may affect the metabolic response to surgery. We investigated the effects of insulin and glucose infusions before and during surgery on postoperative substrate utilization and insulin sensitivity. Seven patients were given insulin and glucose infusions 3 h before and during surgery (insulin group), and a control group of six patients underwent surgery after fasting overnight. Insulin sensitivity and glucose kinetics (d-[6,6-2H2]glucose) were measured before and immediately after surgery using a hyperinsulinemic, normoglycemic clamp. Glucose infusion rates and whole body glucose disposal decreased after surgery in the control group (−40 and −29%, respectively), whereas no significant change was found in the insulin group (+16 and +25%). Endogenous glucose production remained unchanged in both groups. Postoperative changes in cortisol, glucagon, fat oxidation, and free fatty acids were attenuated in the insulin group (vs. control). We conclude that perioperative insulin and glucose infusions minimize the endocrine stress response and normalize postoperative insulin sensitivity and substrate utilization.

Insulin action and secretion in endurance-trained and untrained humans

1987 ◽  
Vol 63 (6) ◽  
pp. 2247-2252 ◽  
Author(s):  
D. S. King ◽  
G. P. Dalsky ◽  
M. A. Staten ◽  
W. E. Clutter ◽  
D. R. Van Houten ◽  
...  
Keyword(s):  
Insulin Action ◽  
Plasma Insulin ◽  
Insulin Response ◽  
Fat Free Mass ◽  
Glucose Disposal ◽  
Trained Subjects ◽  
Hyperglycemic Clamp ◽  
Significant Difference ◽  
Increased Sensitivity ◽  
Glucose Disposal Rate

To evaluate insulin sensitivity and responsiveness, a two-stage hyperinsulinemic euglycemic clamp procedure (insulin infusions of 40 and 400 mU.m-2.min-1) was performed on 11 endurance-trained and 11 untrained volunteers. A 3-h hyperglycemic clamp procedure (plasma glucose approximately 180 mg/dl) was used to study the insulin response to a fixed glycemic stimulus in 15 trained and 12 untrained subjects. During the 40-mU.m-2.min-1 insulin infusion, the glucose disposal rate was 10.2 +/- 0.5 mg.kg fat-free mass (FFM)-1.min-1 in the trained group compared with 8.0 +/- 0.6 mg.kg FFM-1.min-1 in the untrained group (P less than 0.01). In contrast, there was no significant difference in maximally stimulated glucose disposal: 17.7 +/- 0.6 in the trained vs. 16.7 +/- 0.7 mg.kg FFM-1.min-1 in the untrained group. During the hyperglycemic clamp procedure, the incremental area for plasma insulin was lower in the trained subjects for both early (0–10 min: 140 +/- 18 vs. 223 +/- 23 microU.ml–1.min; P less than 0.005) and late (10–180 min: 4,582 +/- 689 vs. 8,895 +/- 1,316 microU.ml–1.min; P less than 0.005) insulin secretory phases. These data demonstrate that 1) the improved insulin action in healthy trained subjects is due to increased sensitivity to insulin, with no change in responsiveness to insulin, and 2) trained subjects have a smaller plasma insulin response to an identical glucose stimulus than untrained individuals.

scholarly journals Determining insulin sensitivity from glucose tolerance tests in Iberian and landrace pigs

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11014
Author(s):  
José Miguel Rodríguez-López ◽  
Manuel Lachica ◽  
Lucrecia González-Valero ◽  
Ignacio Fernández-Fígares
Keyword(s):  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Early Stage ◽  
Insulin Response ◽  
Area Under The Curve ◽  
Tolerance Test ◽  
Glucose Infusion ◽  
Sensitivity Index ◽  
Post Infusion

As insulin sensitivity may help to explain divergences in growth and body composition between native and modern breeds, metabolic responses to glucose infusion were measured using an intra-arterial glucose tolerance test (IAGTT). Iberian (n = 4) and Landrace (n = 5) barrows (47.0 ± 1.2 kg body weight (BW)), fitted with a permanent carotid artery catheter were injected with glucose (500 mg/kg BW) and blood samples collected at -10, 0, 5, 10, 15, 20, 25, 30, 45, 60, 90, 120 and 180 min following glucose infusion. Plasma samples were analysed for insulin, glucose, lactate, triglycerides, cholesterol, creatinine, albumin and urea. Insulin sensitivity indices were calculated and analysed. Mean plasma glucose, creatinine and cholesterol concentrations were lower (P < 0.01) in Iberian (14, 68 and 22%, respectively) than in Landrace pigs during the IAGTT. However, mean plasma insulin, lactate, triglycerides and urea concentrations were greater (P < 0.001) in Iberian (50, 35, 18 and 23%, respectively) than in Landrace pigs. Iberian pigs had larger area under the curve (AUC) of insulin (P < 0.05) or tended to a greater AUC of lactate (P < 0.10), and a smaller (P < 0.05) AUC for glucose 0-60 min compared with Landrace pigs. Indices for estimating insulin sensitivity in fasting conditions indicated improved β-cell function in Iberian compared with Landrace pigs, but no difference (P > 0.10) in calculated insulin sensitivity index was found after IAGTT between breeds. A time response (P < 0.05) was obtained for insulin, glucose and lactate so that maximum concentration was achieved at 10 and 15 min post-infusion for insulin (Iberian and Landrace pigs, respectively), immediately post-infusion for glucose, and 20 min post-infusion for lactate, decreasing thereafter until basal levels. There was no time effect for the rest of metabolites evaluated. In conclusion, growing Iberian pigs challenged with an IAGTT showed changes in biochemical parameters and insulin response that may indicate an early stage of insulin resistance.

scholarly journals Insulin Action, Glucose Homeostasis and Free Fatty Acid Metabolism: Insights From a Novel Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Darko Stefanovski ◽  
Naresh M. Punjabi ◽  
Raymond C. Boston ◽  
Richard M. Watanabe
Keyword(s):  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Insulin Action ◽  
Glucose Disposal ◽  
Parameter Estimates ◽  
Standardized Residuals ◽  
Standard Deviation Range ◽  
Free Fatty Acid Metabolism ◽  
Ffa Metabolism ◽  
Novel Model

Glucose and free fatty acids (FFA) are essential nutrients that are both partly regulated by insulin. Impaired insulin secretion and insulin resistance are hallmarks of aberrant glucose disposal, and type 2 diabetes (T2DM). In the current study, a novel model of FFA kinetics is proposed to estimate the role insulin action on FFA lipolysis and oxidation allowing estimation of adipose tissue insulin sensitivity (SIFFA). Twenty-five normal volunteers were recruited for the current study. To participate, volunteers had to be less than 40 years of age and have a body mass index (BMI) &lt; 30 kg/m2, and be free of medical comorbidity. The proposed model of FFA kinetics was used to analyze the data derived from the insulin-modified FSIGT. Mean fractional standard deviations of the parameter estimates were all less than 20%. Standardized residuals of the fit of the model to the FFA temporal data were randomly distributed, with only one estimated point lying outside the 2-standard deviation range, suggesting an acceptable fit of the model to the FFA data. The current study describes a novel one-compartment non-linear model of FFA kinetics during an FSIGT that provides an FFA metabolism insulin sensitivity parameter (SIFFA). Furthermore, the models suggest a new role of glucose as the modulator of FFA disposal. Estimates of SIFFA confirmed previous findings that FFA metabolism is more sensitive to changes in insulin than glucose metabolism. Novel derived indices of insulin sensitivity of FFA (SIFFA) were correlated with minimal model indices. These associations suggest a cooperative rather than competitive interplay between the two primary nutrients (glucose and FFA) and allude to the FFA acting as the buffer, such that glucose homeostasis is maintained.

Effects of growth hormone releasing hormone on insulin action and insulin secretion in a hypopituitary patient evaluated by the clamp technique

1992 ◽  
Vol 127 (1) ◽  
pp. 93-96 ◽  
Author(s):  
Silva Arslanian ◽  
Satish Kalhan
Keyword(s):  
Growth Hormone ◽  
Insulin Secretion ◽  
Insulin Action ◽  
Glucose Disposal ◽  
Second Phase ◽  
Growth Hormone Releasing Hormone ◽  
Releasing Hormone ◽  
Euglycemic Clamp ◽  
Hyperglycemic Clamp ◽  
Hyperinsulinemic Euglycemic Clamp

The effect of growth hormone releasing hormone (GHRH-44) therapy on insulin action and secretion was evaluated in a hypopituitary patient after one month and one year of treatment. Hepatic and peripheral insulin action was studied with the hyperinsulinemic-euglycemic clamp in combination with [6,6-2H2]glucose tracer infusion. First and second phase insulin secretion was assessed with the hyperglycemic clamp. Prior to GHRH-44 therapy the hypopituitary patient had higher insulin mediated glucose disposal rate and lower basal and stimulated insulin concentrations by more than two standard deviations from the mean of a control group. Following therapy there was no change in basal hepatic glucose production; however, there was evidence of diminished peripheral insulin action. This was manifested by decreased insulin mediated glucose disposal during the hyperinsulinemic-euglycemic clamp, and increased insulin secretion during the hyperglycemic clamp. We conclude that GHRH-44 therapy in this patient was associated with decreased peripheral insulin action which was compensated for by increased insulin secretion.

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