Increased β-cell mass by islet transplantation and PLAG1 overexpression causes hyperinsulinemic normoglycemia and hepatic insulin resistance in mice

Jeroen Declercq, Anujith Kumar, Janna A. Van Diepen, Irene O C M Vroegrijk, Conny Gysemans, Caterina Di Pietro, Peter J. Voshol, Chantal Mathieu, Nadine Ectors, Wim J M Van De Ven, Catherine M. Verfaillie

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

OBJECTIVE - It is believed that an organism remains normoglycemic despite an increase in the β-cell mass because of decreased insulin production by β-cells on a per-cell basis. However, some transgenic mouse models with β-cell hyperplasia suggest that insulin production remains excessive and that normoglycemia is maintained by insulin resistance. METHODS - Here, we investigated the effect of an increased β-cell mass on glycemia and insulin resistance by grafting excess normal islets in normoglycemic mice, as well as using targeted PLAG1 expression in β-cells, which leads to β-cell expansion. RESULTS - In both models, fasting plasma insulin levels were increased, even though animals were normoglycemic. After an intraperitoneal glucose tolerance test, plasma insulin levels increased, which was associated with improved glucose clearing. Under these conditions, normoglycemia is maintained by hepatic insulin resistance as demonstrated by hyperinsulinemic euglycemic clamp experiments. CONCLUSIONS - In conclusion, we demonstrate that when excess β-cells are grafted, insulin production on a per β-cell basis is not sufficiently decreased, leading to hyperinsulinemia and hepatic insulin resistance. This observation might be important for the design of stem cell-based islet replacement therapies.

Original languageEnglish
Pages (from-to)1957-1965
Number of pages9
JournalDiabetes
Volume59
Issue number8
DOIs
Publication statusPublished - 08-2010

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Islets of Langerhans Transplantation
Insulin Resistance
Liver
Insulin
Glucose Clamp Technique
Hyperinsulinism
Glucose Tolerance Test
Transgenic Mice
Hyperplasia
Fasting
Stem Cells
Glucose

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Declercq, J., Kumar, A., Van Diepen, J. A., Vroegrijk, I. O. C. M., Gysemans, C., Di Pietro, C., ... Verfaillie, C. M. (2010). Increased β-cell mass by islet transplantation and PLAG1 overexpression causes hyperinsulinemic normoglycemia and hepatic insulin resistance in mice. Diabetes, 59(8), 1957-1965. https://doi.org/10.2337/db09-1446
Declercq, Jeroen ; Kumar, Anujith ; Van Diepen, Janna A. ; Vroegrijk, Irene O C M ; Gysemans, Conny ; Di Pietro, Caterina ; Voshol, Peter J. ; Mathieu, Chantal ; Ectors, Nadine ; Van De Ven, Wim J M ; Verfaillie, Catherine M. / Increased β-cell mass by islet transplantation and PLAG1 overexpression causes hyperinsulinemic normoglycemia and hepatic insulin resistance in mice. In: Diabetes. 2010 ; Vol. 59, No. 8. pp. 1957-1965.
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abstract = "OBJECTIVE - It is believed that an organism remains normoglycemic despite an increase in the β-cell mass because of decreased insulin production by β-cells on a per-cell basis. However, some transgenic mouse models with β-cell hyperplasia suggest that insulin production remains excessive and that normoglycemia is maintained by insulin resistance. METHODS - Here, we investigated the effect of an increased β-cell mass on glycemia and insulin resistance by grafting excess normal islets in normoglycemic mice, as well as using targeted PLAG1 expression in β-cells, which leads to β-cell expansion. RESULTS - In both models, fasting plasma insulin levels were increased, even though animals were normoglycemic. After an intraperitoneal glucose tolerance test, plasma insulin levels increased, which was associated with improved glucose clearing. Under these conditions, normoglycemia is maintained by hepatic insulin resistance as demonstrated by hyperinsulinemic euglycemic clamp experiments. CONCLUSIONS - In conclusion, we demonstrate that when excess β-cells are grafted, insulin production on a per β-cell basis is not sufficiently decreased, leading to hyperinsulinemia and hepatic insulin resistance. This observation might be important for the design of stem cell-based islet replacement therapies.",
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Declercq, J, Kumar, A, Van Diepen, JA, Vroegrijk, IOCM, Gysemans, C, Di Pietro, C, Voshol, PJ, Mathieu, C, Ectors, N, Van De Ven, WJM & Verfaillie, CM 2010, 'Increased β-cell mass by islet transplantation and PLAG1 overexpression causes hyperinsulinemic normoglycemia and hepatic insulin resistance in mice', Diabetes, vol. 59, no. 8, pp. 1957-1965. https://doi.org/10.2337/db09-1446

Increased β-cell mass by islet transplantation and PLAG1 overexpression causes hyperinsulinemic normoglycemia and hepatic insulin resistance in mice. / Declercq, Jeroen; Kumar, Anujith; Van Diepen, Janna A.; Vroegrijk, Irene O C M; Gysemans, Conny; Di Pietro, Caterina; Voshol, Peter J.; Mathieu, Chantal; Ectors, Nadine; Van De Ven, Wim J M; Verfaillie, Catherine M.

In: Diabetes, Vol. 59, No. 8, 08.2010, p. 1957-1965.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Increased β-cell mass by islet transplantation and PLAG1 overexpression causes hyperinsulinemic normoglycemia and hepatic insulin resistance in mice

AU - Declercq, Jeroen

AU - Kumar, Anujith

AU - Van Diepen, Janna A.

AU - Vroegrijk, Irene O C M

AU - Gysemans, Conny

AU - Di Pietro, Caterina

AU - Voshol, Peter J.

AU - Mathieu, Chantal

AU - Ectors, Nadine

AU - Van De Ven, Wim J M

AU - Verfaillie, Catherine M.

PY - 2010/8

Y1 - 2010/8

N2 - OBJECTIVE - It is believed that an organism remains normoglycemic despite an increase in the β-cell mass because of decreased insulin production by β-cells on a per-cell basis. However, some transgenic mouse models with β-cell hyperplasia suggest that insulin production remains excessive and that normoglycemia is maintained by insulin resistance. METHODS - Here, we investigated the effect of an increased β-cell mass on glycemia and insulin resistance by grafting excess normal islets in normoglycemic mice, as well as using targeted PLAG1 expression in β-cells, which leads to β-cell expansion. RESULTS - In both models, fasting plasma insulin levels were increased, even though animals were normoglycemic. After an intraperitoneal glucose tolerance test, plasma insulin levels increased, which was associated with improved glucose clearing. Under these conditions, normoglycemia is maintained by hepatic insulin resistance as demonstrated by hyperinsulinemic euglycemic clamp experiments. CONCLUSIONS - In conclusion, we demonstrate that when excess β-cells are grafted, insulin production on a per β-cell basis is not sufficiently decreased, leading to hyperinsulinemia and hepatic insulin resistance. This observation might be important for the design of stem cell-based islet replacement therapies.

AB - OBJECTIVE - It is believed that an organism remains normoglycemic despite an increase in the β-cell mass because of decreased insulin production by β-cells on a per-cell basis. However, some transgenic mouse models with β-cell hyperplasia suggest that insulin production remains excessive and that normoglycemia is maintained by insulin resistance. METHODS - Here, we investigated the effect of an increased β-cell mass on glycemia and insulin resistance by grafting excess normal islets in normoglycemic mice, as well as using targeted PLAG1 expression in β-cells, which leads to β-cell expansion. RESULTS - In both models, fasting plasma insulin levels were increased, even though animals were normoglycemic. After an intraperitoneal glucose tolerance test, plasma insulin levels increased, which was associated with improved glucose clearing. Under these conditions, normoglycemia is maintained by hepatic insulin resistance as demonstrated by hyperinsulinemic euglycemic clamp experiments. CONCLUSIONS - In conclusion, we demonstrate that when excess β-cells are grafted, insulin production on a per β-cell basis is not sufficiently decreased, leading to hyperinsulinemia and hepatic insulin resistance. This observation might be important for the design of stem cell-based islet replacement therapies.

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