Effects of insulin on adipose tissue blood flow in man
Open accessAbstract
Adipose tissue blood flow (ATBF) rises after nutrient ingestion. It is not clear whether this is due to insulin. The aim of this study was to investigate the role of insulin in the regulation of subcutaneous ATBF. We have investigated the role of insulin in the regulation of ATBF in normal, healthy subjects in a three‐step procedure to determine the functional level at which insulin may potentially exert its effect. Fifteen subjects were studied on two occasions. On the first visit, 75 g oral glucose was given. In the second, similar plasma concentrations of insulin and glucose were achieved by dynamic intravenous infusions of insulin and glucose. The increase in ATBF after oral glucose (4.2 ± 1.4 ml min−1 (100 g tissue)−1, P= 0.01) was significantly greater (P < 0.05) than that after intravenous infusions (1.5 ± 0.6 ml min−1 (100 g tissue)−1P < 0.05). For the local delivery of potentially vasoactive substances and simultaneous measurement of ATBF, we describe a novel combination of methods, which we have called ‘microinfusion’. We have used this technique to show that locally infused insulin, even at pharmacological concentrations, had no demonstrable effect on ATBF in nine subjects. We conclude that whilst insulin does not have a direct effect on ATBF, it is likely to be an important mediator, possibly acting via sympathetic activation. In the postprandial state, other candidate peptides and hormones are also likely to play important roles.
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Written from the paper’s full text.
TL;DR
In healthy subjects, oral glucose increased adipose tissue blood flow (ATBF) more than matched intravenous insulin–glucose, while locally infused insulin had no demonstrable effect on ATBF. The authors conclude insulin does not act directly on ATBF but may mediate the postprandial increase indirectly, possibly via sympathetic activation.
Key findings
- ATBF absolute increase was 4.2 ± 1.4 ml min−1 (100 g tissue)−1 after oral glucose versus 1.5 ± 0.6 ml min−1 (100 g tissue)−1 after i.v. insulin–glucose (*P* < 0.05); ATBF AUC was 556 ± 144 versus 327 ± 84 ml min−1 (100 g tissue)−1 (180 min)−1 (*P* < 0.005).
- In four subjects, a hyperinsulinaemic, euglycaemic regimen increased ATBF by 7.8 ± 2.3 ml min−1 (100 g tissue)−1, indicating no additional effect of hyperglycaemia.
- In nine subjects, microinfused insulin at low and high local concentrations produced no significant difference in ATBF versus diluent, and the oral glucose response did not differ between insulin and control sites (iAUC 93.7 ± 37.6 versus 99.6 ± 23.9 ml min−1 (100 g tissue)−1 (60 min)−1).
- The increase in plasma noradrenaline from baseline to 30 min correlated with absolute ATBF increase (*r*s = 0.53, *P* = 0.05) but not with increase in plasma insulin (*r*s = −0.17, *P* = 0.56).
Methods
- Fifteen healthy subjects (10 male, 5 female; median age 32 years, median BMI 23.6 kg m−2) were studied twice: once with 75 g oral glucose and once with dynamic intravenous insulin–glucose infusions designed to mimic the oral glucose plasma insulin and glucose concentrations.
- ATBF was measured by the 133Xe washout technique; additional protocols included a hyperinsulinaemic, euglycaemic regimen in four subjects and paired-site microinfusion studies in nine subjects, with isoprenaline validation in four volunteers.
- Analyses used repeated-measures ANOVA, AUC/iAUC, Spearman rank correlation, Mann-Whitney *U* test, and Student’s paired *t* test.
Limitations
- Stated in the paper: the microinfusion technique cannot determine the exact “sphere of influence” of insulin compared with xenon, so it can only give qualitative estimates of function.
- Evident from the text: the euglycaemic clamp and microinfusion substudies were small (*n* = 4 and *n* = 9), and the noradrenaline analysis combined only 14 subjects.
- Evident from the text: participants were healthy and mostly lean, so findings may not generalize to obesity, insulin resistance, or type 2 diabetes.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 9 cited sources checked · 0 supported · 0 flagged
- Findingown data
Locally infused insulin, even at pharmacological concentrations, has no demonstrable effect on ATBF.
“we used this technique, which we refer to as microinfusion, to show that locally infused insulin, even at pharmacological concentrations, had no demonstrable effect on ATBF.”
Quote in the paperSubstantial claim - Findingown data
The ATBF seen after institution of hyperinsulinaemia is sometimes short-lived, lasting from 20 to 40 min.
“Using our sensitive technique of measuring ATBF over 10 min intervals, we have also observed that the ATBF seen after institution of hyperinsulinaemia is sometimes short-lived, lasting from 20 to 40 min.”
Quote in the paperNot a substantial claim - Findingown data
Increased systemic concentrations of insulin mediate an increase in adipose tissue blood flow (ATBF) that is independent of the gut.
“In these studies, we have clearly shown that increased systemic concentrations of insulin mediate an increase in ATBF that is independent of the gut”
Quote in the paperSubstantial claim - Findingown data
Plasma C-peptide concentrations decreased during the euglycaemic insulin-glucose regimen.
“There was a decrease in C-peptide concentrations during the euglycaemic clamp; values were 0.53 ± 0.11, 0.24 ± 0.04, 0.19 ± 0.02 and 0.20 ± 0.02 nmol l−1, at 0, 60, 120 and 180 min, respectively, indicating limited endogenous insulin production.”
Quote in the paperNot a substantial claim - Findingown data
The ATBF response to oral glucose was not dependent on the local insulin concentration.
“The magnitude of increase after oral glucose was also not significantly different (iAUC was 93.7 ± 37.6 and 99.6 ± 23.9 ml min−1 (100 g tissue)−1 (60 min)−1 for insulin and control sites, respectively); thus, the response to the oral glucose was not dependent on the local insulin concentration.”
Quote in the paperSubstantial claim
- Findingown data
Plasma glucose concentrations were kept euglycaemic during the i.v.eu insulin-glucose regimen.
“Plasma glucose concentrations were kept euglycaemic (mean fasting glucose was 5.13 ± 0.04 mmol l−1 and the value during the infusions was 4.63 ± 0.05 mmol l−1).”
Quote in the paperSubstantial claim - Findingnone given
Plasma insulin concentrations achieved by i.v.eu insulin-glucose were virtually identical to those with i.v. insulin-glucose administration.
“Plasma insulin concentrations achieved by i.v.eu insulin–glucose were virtually identical to those with i.v. insulin–glucose administration.”
Quote in the paperSubstantial claim - Findingown data
Baseline ATBF did not differ between the oral and intravenous visits.
“Baseline (overnight fasting) ATBF did not differ between visits (3.69 ± 0.46 and 3.02 ± 0.42 ml min−1 (100 g tissue)−1 after oral and i.v. glucose/insulin respectively).”
Quote in the paperNot a substantial claim - Findingown data
Locally infused insulin, even at pharmacological concentrations, had no demonstrable effect on ATBF in nine subjects.
“We have used this technique to show that locally infused insulin, even at pharmacological concentrations, had no demonstrable effect on ATBF in nine subjects.”
- Also stated in: § Microinfusion · hedged
“Calculation of iAUC of ATBF showed that there were no significant differences between the infusion of either low- or high-dose subcutaneous insulin infusion, compared with infusion of diluent on the control site, indicating that local administration of physiological and supra-physiological concentrations of insulin did not change the blood flow.”
Quote in the paperSubstantial claim - Also stated in: § Microinfusion · hedged
- Interpretationown data
Insulin per se does not seem to affect ATBF.
“In summary, we have shown that insulin *per se* does not seem to affect ATBF”
Quote in the paperSubstantial claim - Interpretationown data
The finding that locally infused insulin has no effect challenges the hypothesis that insulin has a direct effect on ATBF.
“Our finding challenges the hypothesis that insulin has a direct effect on ATBF.”
Quote in the paperSubstantial claim - Study design and conductreasoning
The microinfusion technique cannot determine the exact sphere of influence of the target molecule in comparison with xenon.
“However, with this technique, it is not possible to know the exact ‘sphere of influence’ of the target molecule in comparison with xenon.”
Quote in the paperSubstantial claim- Rests on an assumption: Lipophilic molecules such as xenon are taken up by adipocytes more quickly than hydrophilic molecules.
- Interpretationreasoning
Insulin is likely to stimulate ATBF via other mechanisms such as sympathetic activation.
“rather that insulin is likely to stimulate ATBF via other mechanisms such as sympathetic activation.”
Quote in the paperSubstantial claim - Interpretationown data
There was no additional effect of hyperglycaemia on ATBF during the euglycaemic insulin-glucose regimen.
“We found a pronounced absolute increase in ATBF during the i.v.eu insulin–glucose regimen, showing that there was no additional effect of hyperglycaemia.”
Quote in the paperSubstantial claim - Study design and conductreasoning
The microinfusion technique can only give qualitative estimates of function.
“Clearly, the technique can only give qualitative estimates of function.”
Quote in the paperSubstantial claim - Premisecitation
Extra-splanchnic tissues showed no significant increase in blood flow in response to oral glucose.
“In contrast, extra-splanchnic tissues showed no significant increase in blood flow.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Brundin et al. 1996
Not checked in the free run.
- Study design and conductreasoning
A high dose of insulin was used at the tissue level to address concern about diffusion when comparing insulin with the physiological response of isoprenaline.
“When using insulin (large hydrophilic molecule), and comparing it with the physiological response of isoprenaline, we were aware of this concern and therefore we used, on a tissue level, a high dose of insulin.”
Quote in the paperSubstantial claim - Interpretationown data
The i.v. insulin-glucose regimen provided a useful model for oral ingestion of glucose whilst by-passing any effects of the gut.
“It therefore provided a useful model for the oral ingestion of glucose whilst by-passing any effects of the gut.”
Quote in the paperSubstantial claim- Rests on an assumption: The i.v. insulin–glucose regimen by-passes any effects of the gut.
- Study design and conductown data
The intravenous insulin-glucose regimen achieved similar plasma concentrations of insulin and glucose to those after oral glucose.
“In the second, similar plasma concentrations of insulin and glucose were achieved by dynamic intravenous infusions of insulin and glucose.”
- Also stated in: § Oral glucose and intravenous insulin–glucose administration · plain
“The intravenous administration of glucose and insulin achieved similar plasma concentrations of these metabolites.”
- Also stated in: § DISCUSSION · plain
“Then we used an i.v. insulin–glucose regimen, which was successful in replicating the plasma glucose and insulin concentrations achieved after the ingestion of oral glucose.”
Quote in the paperSubstantial claim - Also stated in: § Oral glucose and intravenous insulin–glucose administration · plain
- Premisecitation
Adipose tissue blood flow (ATBF) rises after nutrient ingestion.
“Adipose tissue blood flow (ATBF) rises after nutrient ingestion.”
- Also stated in: § Abstract · plain
“More recently, it has also been recognised that ATBF increases in response to nutritional stimuli.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Bülow et al. 1987
Not checked in the free run.
- cites Coppack et al. 1992
Not checked in the free run.
- cites Summers et al. 1998
Not checked in the free run.
- Also stated in: § Abstract · plain
- Interpretationown data
In the postprandial state, factors in addition to the increase in plasma insulin concentration must facilitate increased ATBF.
“These results show that in the postprandial state, factors in addition to the increase in plasma insulin concentration must facilitate increased ATBF.”
Quote in the paperSubstantial claim - Interpretationown data
Insulin does not have a direct effect on ATBF.
“We conclude that whilst insulin does not have a direct effect on ATBF, it is likely to be an important mediator, possibly acting via sympathetic activation.”
Quote in the paperSubstantial claim - Study design and conductown data
The microinfusion technique was successful for the local delivery of vasoactive agents.
“This indicated that the technique was successful for the local delivery of vasoactive agents and it was therefore used in subsequent experiments for the local administration of insulin to adipose tissue.”
Quote in the paperSubstantial claim
- May combine two claims. 4
- Classified as probably not a substantial claim. 2
May combine two claims.
Findingown dataIn the study, there was a correlation between the increase in plasma noradrenaline and the increase in ATBF, but not between the increase in plasma insulin concentrations and the increase in noradrenaline.
“In agreement with the idea of increased sympathetic activation induced by an imposed hyperinsulinaemia, we found correlation between the increase of plasma noradrenaline and the increase in ATBF, but not between increase in plasma insulin concentrations and increase in noradrenaline.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataInsulin is likely to be an important mediator of the postprandial increase in ATBF, possibly acting via sympathetic activation.
“We conclude that whilst insulin does not have a direct effect on ATBF, it is likely to be an important mediator, possibly acting via sympathetic activation.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationFood intake or imposed hyperinsulinaemia induces sympathetic activation.
“It is well known that food intake ([Patel *et al.* 1999](#b18)) or imposed hyperinsulinaemia ([Anderson *et al.* 1991](#b1); [Vollenweider *et al.* 1993](#b27)) induces sympathetic activation.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Patel et al. 1999
Not checked in the free run.
- cites Anderson et al. 1991
Not checked in the free run.
- cites Vollenweider et al. 1993
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationLarge molecules diffuse more slowly through the extracellular space because molecular radius is inversely proportional to diffusivity (Stokes-Einstein equation).
“On one hand, large molecules will diffuse more slowly through the extracellular space as the molecular radius is inversely proportional to the diffusivity (Stokes-Einstein's diffusivity equation).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Stokes-Einstein's diffusivity equation
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).
InterpretationreasoningIn the postprandial state, other candidate peptides and hormones are also likely to play important roles in increasing ATBF.
“In the postprandial state, other candidate peptides and hormones are also likely to play important roles.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationIncreased plasma noradrenaline concentration is a sign of sympathetic activation and is likely to derive from spillover in muscle and adipose tissue.
“A sign of that is an increased plasma concentration of noradrenaline, which is likely to derive from spillover in muscle and adipose tissue ([Patel *et al.* 1999](#b18)).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Patel et al. 1999
Not checked in the free run.
The paper relies on this without support.
Whether the postprandial rise in ATBF is due to insulin is not clear.
“It is not clear whether this is due to insulin.”
“The actual stimulus for this nutrient-related increase in ATBF is, however, not clear.”
The paper relies on this without support.
High glucose concentrations can affect blood flow (as observed in muscle).
“This protocol was designed to eliminate the potential effect of high glucose concentrations on ATBF, which has been observed in muscle blood flow.”
The paper relies on this without support.
The i.v. insulin–glucose regimen by-passes any effects of the gut.
“It therefore provided a useful model for the oral ingestion of glucose whilst by-passing any effects of the gut.”
The paper relies on this without support.
Locally infused insulin decreases adipose tissue lipolysis via inhibition of hormone-sensitive lipase, leading to decreased release of non-esterified fatty acids (NEFAs).
“Locally infused insulin is likely to decrease adipose tissue lipolysis via inhibition of hormone-sensitive lipase leading to decreased release of NEFAs.”
The paper relies on this without support.
Lipophilic molecules such as xenon are taken up by adipocytes more quickly than hydrophilic molecules.
“On the other hand lipophilic molecules, such as xenon, will be taken up by the adipocytes more quickly than hydrophilic molecules.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The postprandial increase in blood flow that is so frequently observed in lean individuals is dramatically reduced in obese individuals.
“the postprandial increase in blood flow that is so frequently observed in lean individuals is dramatically reduced in obese individuals (95,96)”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [95]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Reported insulin doses assume longer infusions than the protocol describes
MinorThe low-dose infusion is described as lasting 60 minutes before being replaced by the high-dose infusion at the same site. At 4 mU ml−1 and 2 μl min−1, that delivers 0.48 mU, not the reported 1.9 mU; the reported dose corresponds to 4 hours at the low rate.
“The total dose of insulin given during the 4 h exposure was 1.9 mU for the low dose insulin, and 0.19 U for the high dose insulin.”
“the diluent was switched to a low concentration insulin infusion (4 mU ml−1) at a rate of 2 μl min−1, which was maintained for 60 min. At the other site, the diluent infusion was continued. Then, the insulin infusion was increased to a high concentration (400 mU ml−1) at the same site for another 60 min”
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Body fat distribution and obesity
Lempesis, I. G. (2023) · doi:10.26481/dis.20231019ll
- Authors
- Karpe, F., Fielding, B. A., Ardilouze, J., Ilic, V., Macdonald, I. A., & Frayn, K. N.
- Affiliations
- University of Oxford (GB)
- Oxford Centre for Diabetes, Endocrinology and Metabolism (GB)
- University of Nottingham (GB)
- Corresponding author
- Karpe, Fredrik
- Venue
- The Journal of Physiology
- Publisher
- Wiley
- Published
- 2002-05
- Volume
- 540
- Issue
- 3
- Pages
- 1087-1093
- ISSN
- 0022-3751 (ISSN-L)
- 1469-7793
- PMC
- PMC2290270
- OpenAlex
- W1989799665
- Semantic Scholar
- 3ae5d93c9f48bd8399d0a155e8a6459c74a8ce3b
- Cited by
- 81
- References
- 31
- Citations by year
- 2025: 3 · 2023: 1 · 2022: 1 · 2021: 6 · 2020: 2 · 2018: 3 · 2017: 5 · 2016: 3 · 2015: 2 · 2014: 1 · 2013: 2 · 2012: 9
- FWCI
- 2.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Open Research (University of Surrey) (submittedVersion)
- Surrey Research Insight Open Access (The University of Surrey) (submittedVersion)
- Funders
- Wellcome Trust
- University of Nottingham
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- insulin, adipose tissue blood flow, subcutaneous adipose tissue, postprandial blood flow, oral glucose, microinfusion, sympathetic activation, vasoactive peptides
- MeSH terms
- Adipose Tissue, Administration, Oral, Blood Glucose, Fatty Acids, Nonesterified, Glucose, Humans, Hyperinsulinism, Infusions, Intravenous, Insulin, Isoproterenol, Kinetics, Regional Blood Flow, Time Factors, Glucose Clamp Technique
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