Hypothalamic and Striatal Insulin Action Suppresses Endogenous Glucose Production and May Stimulate Glucose Uptake During Hyperinsulinemia in Lean but Not in Overweight Men
Abstract
Intranasal spray application facilitates insulin delivery to the human brain. Although brain insulin modulates peripheral metabolism, the mechanisms involved remain elusive. Twenty-one men underwent two hyperinsulinemic-euglycemic clamps with d-[6,6-2H2]glucose infusion to measure endogenous glucose production and glucose disappearance. On two separate days, participants received intranasal insulin or placebo. Insulin spillover into circulation after intranasal insulin application was mimicked by an intravenous insulin bolus on placebo day. On a different day, brain insulin sensitivity was assessed by functional MRI. Glucose infusion rates (GIRs) had to be increased more after nasal insulin than after placebo to maintain euglycemia in lean but not in overweight people. The increase in GIRs was associated with regional brain insulin action in hypothalamus and striatum. Suppression of endogenous glucose production by circulating insulin was more pronounced after administration of nasal insulin than after placebo. Furthermore, glucose uptake into tissue tended to be higher after nasal insulin application. No such effects were detected in overweight participants. By increasing insulin-mediated suppression of endogenous glucose production and stimulating peripheral glucose uptake, brain insulin may improve glucose metabolism during systemic hyperinsulinemia. Obese people appear to lack these mechanisms. Therefore, brain insulin resistance in obesity may have unfavorable consequences for whole-body glucose homeostasis.
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Previous findings from healthy men indicate that brain insulin most likely modulates both endogenous glucose production and glucose disappearance.
“Previous findings from healthy men indicate that brain insulin most likely modulates both3.”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [3]
Studies on brain insulin action increasing whole-body insulin sensitivity were mainly performed in lean men.
“these studies were mainly performed in lean men3,4”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [3]
Brain insulin action increases whole-body insulin sensitivity.
“brain insulin action increases whole-body insulin sensitivity”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [3]
In healthy men, insulin action in the brain stimulates glucose uptake into peripheral tissues.
“and stimulates glucose uptake into peripheral tissues3”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [3]
In healthy men, insulin action in the brain suppresses endogenous glucose production.
“Studies performed in healthy men found that insulin action in the brain suppresses endogenous glucose production3,11”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [3]
The current study corroborates that insulin action in the human brain modulates peripheral insulin sensitivity.
“The current study corroborates that insulin action in the human brain modulates peripheral insulin sensitivity3,4,11”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [3]
In lean women, the effects on peripheral insulin sensitivity in the follicular phase were comparable in timing and magnitude to previous findings obtained in lean men.
“Here, the effects on peripheral insulin sensitivity were comparable in timing and magnitude to previous findings obtained in lean men3,4.”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [3]
Insulin action in the human brain modulates peripheral insulin sensitivity.
“The current study corroborates that insulin action in the human brain modulates peripheral insulin sensitivity3,4,11”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [3]
Insulin-induced response of hypothalamic cerebral blood flow is a readout for hypothalamic insulin action.
“On the basis of our previous findings3,8, we assessed the insulin-induced response of hypothalamic cerebral blood flow (CBF) as a readout for hypothalamic insulin action.”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [3]
Insulin action in the hypothalamus has a crucial role in the modulation of whole-body glucose metabolism.
“In line with experimental evidence from animals30, previous correlational findings from humans indicate a crucial role of insulin action in the hypothalamus for the modulation of whole-body glucose metabolism3,4.”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [3]
CBF was extracted from the hypothalamus as the region of interest, based on recent findings.
“CBF was extracted from the hypothalamus as our region of interest, based on recent findings3,8.”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [3]
fMRI measurements indicated involvement of the hypothalamus and striatum in the glucoregulatory effects of IN insulin, which were not found in obese individuals.
“the fMRI measurements indicated an involvement of the hypothalamus and striatum in these glucoregulatory effects of IN insulin, which, notably, were not found in obese individuals”
From Intranasal insulin (2021) · cites this paper as [80]
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- Authors
- Heni, M., Wagner, R., Kullmann, S., Gancheva, S., Roden, M., Peter, A., Stefan, N., Preissl, H., Häring, H.-U., & Fritsche, A.
- Affiliations
- German Center for Diabetes Research (DE)
- Deutsches Diabetes-Zentrum e.V. (DE)
- Helmholtz Munich (DE)
- Corresponding author
- Heni, Martin
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2017-02-07
- Volume
- 66
- Issue
- 7
- Pages
- 1797-1806
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2586809204
- Cited by
- 115
- References
- 43
- Citations by year
- 2026: 10 · 2025: 7 · 2024: 13 · 2023: 10 · 2022: 11 · 2021: 12 · 2020: 15 · 2019: 14 · 2018: 19 · 2017: 4
- FWCI
- 14.56
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Site cant be reached (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Funders
- Federal Ministry of Education and Research (01GI0925)
- Helmholtz-Gemeinschaft (Helmholtz Alliance ICEMED-Imaging and Curing Environmental Metabolic Diseases)
- European Foundation for the Study of Diabetes (Rising Star award supported by Novo Nordisk)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- hypothalamus, striatum, endogenous glucose production, glucose uptake, hyperinsulinemia, intranasal insulin, brain insulin resistance, obesity, glucose metabolism, glucose homeostasis
- MeSH terms
- Adult, Blood Glucose, Brain, Deuterium, Gluconeogenesis, Glucose, Humans, Hypoglycemic Agents, Hypothalamus, Insulin, Magnetic Resonance Imaging, Male, Thinness, Glucose Clamp Technique, Case-Control Studies, Neostriatum, Overweight, Young Adult, Functional Neuroimaging
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