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 language | English (US) |
|---|---|
| Pages (from-to) | 803-813 |
| Number of pages | 11 |
| Journal | Diabetologia |
| Volume | 56 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2013 |
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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 journal › Article
}
TY - JOUR
T1 - 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
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.
KW - Calcium
KW - Hyperglycaemia
KW - Insulin secretion
KW - Islets
KW - Oxygen consumption
UR - http://www.scopus.com/inward/record.url?scp=84876500331&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84876500331&partnerID=8YFLogxK
U2 - 10.1007/s00125-012-2808-6
DO - 10.1007/s00125-012-2808-6
M3 - Article
VL - 56
SP - 803
EP - 813
JO - Diabetologia
JF - Diabetologia
SN - 0012-186X
IS - 4
ER -