title: 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.
abstract: OBJECTIVE
  Previous studies on isolated islets have demonstrated tight coupling between calcium (Ca(2+)) 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 (Ca(2+)/metabolic coupling process [CMCP]) by Ca(2+) 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 Ca(2+)-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 Ca(2+) 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 Ca(2+) channel blockade coincided with decreased fasting plasma insulin concentrations observed in rats 3 weeks after the onset of hyperglycaemia.
  
  
  CONCLUSIONS
  These results suggest that phenotypic impairment of diabetic islets in the UCD-T2DM rat is downstream of Ca(2+) 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.
authors: Diabetes and Obesity Center of Excellence, University of Washington, 850 Republican Street, Seattle, WA 98109-8055, USA.
authors: A M
authors: AM
authors: Rountree
authors: B J
authors: BJ
authors: Reed
authors: B P
authors: BP
authors: Cummings
authors: S-R
authors: SR
authors: Jung
authors: K L
authors: KL
authors: Stanhope
authors: J L
authors: JL
authors: Graham
authors: S C
authors: SC
authors: Griffen
authors: R L
authors: RL
authors: Hull
authors: P J
authors: PJ
authors: Havel
authors: I R
authors: IR
authors: Sweet
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D008297:Male; D010101:Oxygen Consumption; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D007328:Insulin; D045304:Cytochromes c; D005947:Glucose; D002118:Calcium
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