Targeting insulin to the liver corrects defects in glucose metabolism caused by peripheral insulin delivery

Edgerton, Dale S.; Scott, Melanie; Farmer, Ben; Williams, Phillip E.; Madsen, Peter; Kjeldsen, Thomas; Brand, Christian; Fledelius, Christian; Nishimura, Erica; Cherrington, Alan D.

doi:10.1172/jci.insight.126974

Cited by 46 publications

(39 citation statements)

References 91 publications

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“…[1][2][3] The aberrant production of reactive oxygen species (ROS), due to hyperglycaemia, is considered to be the central element of oxidative stress and, ultimately, plays an important role in the pathogenesis of T1DM, its progression and ultimately micro-and macrovascular complications. With CIPII, insulin is infused directly in the intraperitoneal (IP) space resulting in higher concentrations of insulin in the portal vein catchment area, higher hepatic insulin extraction and lower peripheral plasma insulin concentrations compared with SC insulin administration.…”

Section: Currently Continuous Intraperitoneal Insulin Infusion (Cipimentioning

confidence: 99%

“…With CIPII, insulin is infused directly in the intraperitoneal (IP) space resulting in higher concentrations of insulin in the portal vein catchment area, higher hepatic insulin extraction and lower peripheral plasma insulin concentrations compared with SC insulin administration. [1][2][3] The aberrant production of reactive oxygen species (ROS), due to hyperglycaemia, is considered to be the central element of oxidative stress and, ultimately, plays an important role in the pathogenesis of T1DM, its progression and ultimately micro-and macrovascular complications. [4][5][6][7] Insulin has a pivotal role in the ROS production in T1DM through its effects on glucose-, IGF1-, lipid metabolism and its direct impact on the endothelium.…”

Section: Introductionmentioning

confidence: 99%

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Different routes of insulin administration do not influence serum free thiols in type 1 diabetes mellitus

Dijk

Waanders

Logtenberg

et al. 2019

Endocrino Diabet & Metabol

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Aims Intraperitoneal (IP) insulin administration is a last‐resort treatment option for selected patients with type 1 diabetes mellitus (T1DM). As the IP route of insulin administration mimics the physiology more closely than the subcutaneous (SC) route, we hypothesized that IP insulin would result in less oxidative stress (expressed as systemic level of free sulphydryl (R‐SH) content) compared to SC insulin in subjects with T1DM. Materials and methods Prospective, observational case‐control study. Serum thiol measurements were performed at baseline and at 26 weeks in age‐ and gender‐matched patients with T1DM. Serum‐free thiols, compounds with a R‐SH group that are readily oxidized by reactive oxygen species, are considered to be a marker of systemic redox status. Results A total of 176 patients, 39 of which used IP and 141 SC insulin therapy were analysed. Mean baseline R‐SH concentration was 248 (31) μmol/L. In multivariable analysis, the route of insulin therapy had no impact on baseline R‐SH levels. The estimated geometric mean concentrations of R‐SH did not differ significantly between both groups: 264 (95% CI 257, 270) for the IP group and 258 (95% CI 254, 261) for the SC group with a difference of 6 (95% CI −2, 14) μmol/L. Conclusions Based on R‐SH as a marker of systemic oxidative stress, these findings demonstrate that the route of insulin administration, IP or SC, does not influence systemic redox status in patients with T1DM.

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Section: Currently Continuous Intraperitoneal Insulin Infusion (Cipimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Different routes of insulin administration do not influence serum free thiols in type 1 diabetes mellitus

Dijk

Waanders

Logtenberg

et al. 2019

Endocrino Diabet & Metabol

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“…A consequence is that, despite adequate dose of insulin to normalize blood glucose, this does not result in an increase in IGF-1. (16,17) Although controversial, peripheral levels of insulin could increase glucose uptake in bone, thereby stimulating bone turnover. (18,19) Osteoblast-derived BTMs such as OCN and alkaline phosphatase (ALP) have received the greatest amount of focus in understanding reductions in bone quality with diabetes, in part because of the bone-pancreas feedback loop.…”

Section: Introductionmentioning

confidence: 99%

“…A consequence is that, despite adequate dose of insulin to normalize blood glucose, this does not result in an increase in IGF‐1. ( 16,17 ) Although controversial, peripheral levels of insulin could increase glucose uptake in bone, thereby stimulating bone turnover. ( 18,19 )…”

Section: Introductionmentioning

confidence: 99%

Acute Hyperinsulinemia Alters Bone Turnover in Women and Men With Type 1 Diabetes

et al. 2020

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Type 1 diabetes (T1D) increases fracture risk across the lifespan. The low bone turnover associated with T1D is thought to be related to glycemic control, but it is unclear whether peripheral hyperinsulinemia due to dependence on exogenous insulin has an independent effect on suppressing bone turnover. The purpose of this study was to test the bone turnover marker (BTM) response to acute hyperinsulinemia. Fifty‐eight adults aged 18 to 65 years with T1D over 2 years were enrolled at seven T1D Exchange Clinic Network sites. Participants had T1D diagnosis between age 6 months to 45 years. Participants were stratified based on their residual endogenous insulin secretion measured as peak C‐peptide response to a mixed meal tolerance test. BTMs (CTX, P1NP, sclerostin [SCL], osteonectin [ON], alkaline phosphatase [ALP], osteocalcin [OCN], osteoprotegerin [OPG], osteopontin [OPN], and IGF‐1) were assessed before and at the end of a 2‐hour hyperinsulinemic‐euglycemic clamp (HEC). Baseline ON (r = −0.30, p = .022) and OCN (r = −0.41, p = .002) were negatively correlated with age at T1D diagnosis, but baseline BTMs were not associated with HbA1c. During the HEC, P1NP decreased significantly (−14.5 ± 44.3%; p = .020) from baseline. OCN, ON, and IGF‐1 all significantly increased (16.0 ± 13.1%, 29.7 ± 31.7%, 34.1 ± 71.2%, respectively; all p < .001) during the clamp. The increase in SCL was not significant (7.3 ± 32.9%, p = .098), but the decrease in CTX (−12.4 ± 48.9, p = .058) neared significance. ALP and OPG were not changed from baseline (p = .23 and p = .77, respectively). Baseline ON and SCL were higher in men, but OPG was higher in women (all p ≤ .029). SCL was the only BTM that changed differently in women than men. There were no differences in baseline BTMs or change in BTMs between C‐peptide groups. Exogenous hyperinsulinemia acutely alters bone turnover, suggesting a need to determine whether strategies to promote healthy remodeling may protect bone quality in T1D. © 2020 American Society for Bone and Mineral Research © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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“…The whole-body glucose disposal Rd in the present study included the glucose uptake by muscle, adipose tissue, brain and liver etc., and the Rd elevation was tightly integrated with GP suppression but the glucose uptake contribution to Rd between different tissues could be heterogeneous and dynamic under different conditions, i.e. if insulin infused through portal vein system, the glucose uptake was equally divided into liver and muscles, but if insulin infused into peripheral vein system, the glucose uptake by muscles was four-fold greater than by liver 14 . In this study, we only testified the part of GP suppression with Rd elevation in the GP-Rd inverse coupling as the other part of GP elevation with Rd suppression, i.e.…”

mentioning

confidence: 99%

Glucose Production and Glucose Disposal Integrated by an Intrinsic Inverse Coupling in Vivo: hypothesis of inter-organ reflex on glucose regulation

Liu

Zou

Xing

et al. 2020

Preprint

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Glucose production (GP) and glucose disposal (Rd) are two decisive and fundamental parameters in glucose turnover and in glucose homeostasis regulation. In conventional theory, GP and Rd were responsive to regulatory factors respectively and independently of each other. Even though GP and Rd responded in reverse to insulin, GP for suppression and Rd for elevation, these inverse alterations used to be attributed to insulin multiple functions both on hepatic GP, directly or indirectly, and on whole-body glucose Rd. However, in the present study, we found GP and Rd were inversely coupled intrinsically no matter which side was the target of insulin by comparison of Rd and GP data pairs between peripheral vein insulin infusion protocol and portal vein insulin infusion protocol in rats. Furthermore, neither circulating NEFA nor HFD induced resistance broke the GP-Rd inverse coupling, but both of them reduced the responses of both GP and Rd to insulin. In conclusion, we provide the evidence that GP and Rd are two coupled parameters in vivo and they alter in reverse simultaneously, the mechanism under which needs further investigation but we tend to believe an inter-organ neural reflex was involved.

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Targeting insulin to the liver corrects defects in glucose metabolism caused by peripheral insulin delivery

Cited by 46 publications

References 91 publications

Different routes of insulin administration do not influence serum free thiols in type 1 diabetes mellitus

Different routes of insulin administration do not influence serum free thiols in type 1 diabetes mellitus

Acute Hyperinsulinemia Alters Bone Turnover in Women and Men With Type 1 Diabetes

Glucose Production and Glucose Disposal Integrated by an Intrinsic Inverse Coupling in Vivo: hypothesis of inter-organ reflex on glucose regulation

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