Loss of coupling between calcium influx, energy consumption and insulin secretion associated with development of hyperglycaemia in the UCD-T2DM rat model of type 2 diabetes

A. M. Rountree, B. J. Reed, B. P. Cummings, S. R. Jung, Kimber Stanhope, J. L. Graham, S. C. Griffen, R. L. Hull, Peter J Havel, I. R. Sweet

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Aims/hypothesis: Previous studies on isolated islets have demonstrated tight coupling between calcium (Ca2+) influx and oxygen consumption rate (OCR) that is correlated with insulin secretion rate (ISR). To explain these observations, we have proposed a mechanism whereby the activation of a highly energetic process (Ca2+/metabolic coupling process [CMCP]) by Ca2+ mediates the stimulation of ISR. The aim of the study was to test whether impairment of the CMCP could play a role in the development of type 2 diabetes. Methods: Glucose- and Ca2+-mediated changes in OCR and ISR in isolated islets were compared with the time course of changes of plasma insulin concentrations observed during the progression to hyperglycaemia in a rat model of type-2 diabetes (the University of California at Davis type 2 diabetes mellitus [UCD-T2DM] rat). Islets were isolated from UCD-T2DM rats before, 1 week, and 3 weeks after the onset of hyperglycaemia. Results: Glucose stimulation of cytosolic Ca2+ and OCR was similar for islets harvested before and 1 week after the onset of hyperglycaemia. In contrast, a loss of decrement in islet OCR and ISR in response to Ca2+ channel blockade coincided with decreased fasting plasma insulin concentrations observed in rats 3 weeks after the onset of hyperglycaemia. Conclusions/interpretation: These results suggest that phenotypic impairment of diabetic islets in the UCD-T2DM rat is downstream of Ca2+ influx and involves unregulated stimulation of the CMCP. The continuously elevated levels of CMCP induced by chronic hyperglycaemia in these islets may mediate the loss of islet function.

Original languageEnglish (US)
Pages (from-to)803-813
Number of pages11
JournalDiabetologia
Volume56
Issue number4
DOIs
StatePublished - Apr 2013

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Hyperglycemia
Type 2 Diabetes Mellitus
Insulin
Calcium
Oxygen Consumption
Glucose
Fasting

Keywords

  • Calcium
  • Hyperglycaemia
  • Insulin secretion
  • Islets
  • Oxygen consumption

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Loss of coupling between calcium influx, energy consumption and insulin secretion associated with development of hyperglycaemia in the UCD-T2DM rat model of type 2 diabetes. / Rountree, A. M.; Reed, B. J.; Cummings, B. P.; Jung, S. R.; Stanhope, Kimber; Graham, J. L.; Griffen, S. C.; Hull, R. L.; Havel, Peter J; Sweet, I. R.

In: Diabetologia, Vol. 56, No. 4, 04.2013, p. 803-813.

Research output: Contribution to journalArticle

Rountree, A. M. ; Reed, B. J. ; Cummings, B. P. ; Jung, S. R. ; Stanhope, Kimber ; Graham, J. L. ; Griffen, S. C. ; Hull, R. L. ; Havel, Peter J ; Sweet, I. R. / Loss of coupling between calcium influx, energy consumption and insulin secretion associated with development of hyperglycaemia in the UCD-T2DM rat model of type 2 diabetes. In: Diabetologia. 2013 ; Vol. 56, No. 4. pp. 803-813.
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AU - Rountree, A. M.

AU - Reed, B. J.

AU - Cummings, B. P.

AU - Jung, S. R.

AU - Stanhope, Kimber

AU - Graham, J. L.

AU - Griffen, S. C.

AU - Hull, R. L.

AU - Havel, Peter J

AU - Sweet, I. R.

PY - 2013/4

Y1 - 2013/4

N2 - Aims/hypothesis: Previous studies on isolated islets have demonstrated tight coupling between calcium (Ca2+) influx and oxygen consumption rate (OCR) that is correlated with insulin secretion rate (ISR). To explain these observations, we have proposed a mechanism whereby the activation of a highly energetic process (Ca2+/metabolic coupling process [CMCP]) by Ca2+ mediates the stimulation of ISR. The aim of the study was to test whether impairment of the CMCP could play a role in the development of type 2 diabetes. Methods: Glucose- and Ca2+-mediated changes in OCR and ISR in isolated islets were compared with the time course of changes of plasma insulin concentrations observed during the progression to hyperglycaemia in a rat model of type-2 diabetes (the University of California at Davis type 2 diabetes mellitus [UCD-T2DM] rat). Islets were isolated from UCD-T2DM rats before, 1 week, and 3 weeks after the onset of hyperglycaemia. Results: Glucose stimulation of cytosolic Ca2+ and OCR was similar for islets harvested before and 1 week after the onset of hyperglycaemia. In contrast, a loss of decrement in islet OCR and ISR in response to Ca2+ channel blockade coincided with decreased fasting plasma insulin concentrations observed in rats 3 weeks after the onset of hyperglycaemia. Conclusions/interpretation: These results suggest that phenotypic impairment of diabetic islets in the UCD-T2DM rat is downstream of Ca2+ influx and involves unregulated stimulation of the CMCP. The continuously elevated levels of CMCP induced by chronic hyperglycaemia in these islets may mediate the loss of islet function.

AB - Aims/hypothesis: Previous studies on isolated islets have demonstrated tight coupling between calcium (Ca2+) influx and oxygen consumption rate (OCR) that is correlated with insulin secretion rate (ISR). To explain these observations, we have proposed a mechanism whereby the activation of a highly energetic process (Ca2+/metabolic coupling process [CMCP]) by Ca2+ mediates the stimulation of ISR. The aim of the study was to test whether impairment of the CMCP could play a role in the development of type 2 diabetes. Methods: Glucose- and Ca2+-mediated changes in OCR and ISR in isolated islets were compared with the time course of changes of plasma insulin concentrations observed during the progression to hyperglycaemia in a rat model of type-2 diabetes (the University of California at Davis type 2 diabetes mellitus [UCD-T2DM] rat). Islets were isolated from UCD-T2DM rats before, 1 week, and 3 weeks after the onset of hyperglycaemia. Results: Glucose stimulation of cytosolic Ca2+ and OCR was similar for islets harvested before and 1 week after the onset of hyperglycaemia. In contrast, a loss of decrement in islet OCR and ISR in response to Ca2+ channel blockade coincided with decreased fasting plasma insulin concentrations observed in rats 3 weeks after the onset of hyperglycaemia. Conclusions/interpretation: These results suggest that phenotypic impairment of diabetic islets in the UCD-T2DM rat is downstream of Ca2+ influx and involves unregulated stimulation of the CMCP. The continuously elevated levels of CMCP induced by chronic hyperglycaemia in these islets may mediate the loss of islet function.

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KW - Insulin secretion

KW - Islets

KW - Oxygen consumption

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