Functional and metabolic perturbations in isolated pancreatic islets from the GK rat, a genetic model of noninsulin-dependent diabetes.

Giroix, M.H.; Vesco, L; Portha, Bernard

doi:10.1210/endo.132.2.8425496

Cited by 70 publications

(35 citation statements)

References 21 publications

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“…The results agree with previous studies (Giroix et al 1993, Nagamatsu et al 1999 and suggest that the depletion of secreted constituents in -cells does not arise from a failure to recognize glucose as an activator of prohormone biosynthesis and granule biogenesis. Rather it points to an inability of the -cell population as a whole to meet the demands upon insulin secretion imposed by chronic hyperglycemia in vivo.…”

Section: Discussionsupporting

confidence: 92%

Proinsulin processing in the diabetic Goto-Kakizaki rat

Guest¹,

Abdel‐Halim²,

Gross³

et al. 2002

Journal of Endocrinology

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The biosynthesis and processing of proinsulin was investigated in the diabetic Goto-Kakizaki (GK) rat. Immunofluorescence microscopy comparing GK and Wistar control rat pancreata revealed marked changes in the distribution of -cells and pronounced -cell heterogeneity in the expression patterns of insulin, prohormone convertases PC1, PC2, carboxypeptidase E (CPE) and the PC-binding proteins 7B2 and ProSAAS. Western blot analyses of isolated islets revealed little difference in PC1 and CPE expression but PC2 immunoreactivity was markedly lower in the GK islets. The processing of the PC2-dependent substrate chromogranin A was reduced as evidenced by the appearance of intermediates. No differences were seen in the biosynthesis and post-translational modification of PC1, PC2 or CPE following incubation of islets in 16·7 mM glucose, but incubation in 3·3 mM glucose resulted in decreased PC2 biosynthesis in the GK islets. The rates of biosynthesis, processing and secretion of newly synthesized (pro)insulin were comparable. Circulating insulin immunoreactivity in both Wistar and GK rats was predominantly insulin 1 and 2 in the expected ratios with no (pro)insulin evident. Thus, the marked changes in islet morphology and PC2 expression did not impact the rate or extent of proinsulin processing either in vitro or in vivo in this experimental model.

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Section: Discussionsupporting

confidence: 92%

Proinsulin processing in the diabetic Goto-Kakizaki rat

Guest¹,

Abdel‐Halim²,

Gross³

et al. 2002

Journal of Endocrinology

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“…It should be noted that, in contrast to our findings, rats from the Paris colony of GK rats have demonstrated a pronounced decrease in islet volume at a very early age (Movassat et al 1995). It could be assumed that such a decrease contributes to the glucose intolerance in these animals (Giroix et al 1993). # P<0·05 and ## P<0·01 when compared with the corresponding value for the whole pancreas of the same strain.…”

Section: Discussionmentioning

confidence: 92%

“…The exact mechanism behind the impaired glucose-induced insulin release in the GK rat is unclear. However, it seems to be related to abnormalities in glucose metabolism and stimulus-secretion coupling within the -cells (Giroix et al 1993, Östenson et al 1993a, 1993b, Hughes et al 1994, MacDonald et al 1996, Ling et al 1998. F 1 hybrids between GK rats and Wistar rats are glucose-intolerant with impaired glucosestimulated insulin release (Abdel-Halim et al 1994).…”

Section: Introductionmentioning

confidence: 99%

Lack of compensatory increase in islet blood flow and islet mass in GK rats following 60% partial pancreatectomy

Svensson

Östenson²,

Bodin³

et al. 2005

Journal of Endocrinology

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The effects of a 60% partial pancreatectomy were studied in hyperglycemic GK (Goto-Kakizaki) rats. Partial pancreatectomy or a sham operation was performed on 12-weekold female Wistar rats, GK rats or hybrids between male GK rats and female Wistar rats. Measurements of pancreatic blood flow and islet blood flow were performed by a microsphere technique 2 weeks after surgery. Glucose tolerance was decreased in hybrid compared with Wistar rats, and in GK rats compared with both hybrid and Wistar rats before surgery. Partial pancreatectomy induced minor changes in glucose tolerance. Wistar rats had a decreased islet mass following partial pancreatectomy. Both hybrid and GK rats showed a significant decrease in relative islet volume, but only GK rats in total islet mass, compared with Wistar rats 2 weeks after surgery. Pancreatic blood flow and islet blood flow did not significantly differ between sham-operated Wistar, hybrid or GK rats. After partial pancreatectomy, islet blood flow in relation to islet mass increased 3-fold in Wistar rats and 2-fold in hybrid rats. In contrast, GK rats showed no increase in islet blood flow following partial pancreatectomy. It is concluded that compensatory mechanisms after partial pancreatectomy are operating less efficiently in hybrid and GK rats.

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“…Malaisse, unpublished observation). Moreover, in the GK M.-H. Giroix et al: Glycolysis in pancreatic islets rats, the islet insulin content is little affected when related to either the protein or DNA content [17], suggesting a near normal relative contribution of beta cells to the total islet mass.…”

Section: Discussionmentioning

confidence: 93%

“…This negative finding strongly suggests that any anomaly in hexose transport, leading for instance to a delayed equilibration of D-glucose concentration across the beta-cell plasma membrane, is not sufficient to account for impaired insulin release under near steadystate conditions. It is known from previous studies that glucose-stimulated insulin release is impaired in the islets from STZ and GK rats [16,17].…”

Section: Discussionmentioning

confidence: 99%

Preferential alteration of oxidative relative to total glycolysis in pancreatic islets of two rat models of inherited or acquired Type 2 (non-insulin-dependent) diabetes mellitus

Giroix

Sener²,

Portha

et al. 1993

Diabetologia

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Summary. In islets from both adult rats injected with streptozotocin during the neonatal period and spontaneously diabetic rats obtained by repeated selective breedings (GK rats), the ratio between D-[3, 4-14C]glucose oxidation and D-[5-3H]glucose conversion to 3HOH was 25 % lower than in islets from control rats, indicating an impaired contribution of oxidative to total glycolysis. No primary defect in the Krebs cycle was found in the islets of diabetic rats, as judged from the ratio between either D-[2-14C]glucose or D-[6-~4C]glucose and D-[3, 4-~4C]glucose oxidation. Therefore, we propose that a preferential alteration of oxidative glycolysis in the pancreatic beta cell may contribute to the impairment of glucose-induced insulin release not only in a cytotoxic but also in a spontaneous model of non-insulin-dependent diabetes mellitus.Key words: Pancreatic islets, GK rats, streptozotocin, glucose metabolism.The impairment of glucose-induced insulin release in noninsulin-dependent diabetes mellitus has been suggested to be caused by a defect of D-glucose transport across the islet beta-cell plasma membrane [1,2]. It is also conceivable, however, that such an impairment is due to a more distal anomaly in D-glucose metabolism, e.g. at the level of its phosphorylation or oxidative catabolism. The present report reveals that, in two experimental models of non-insulin-dependent diabetes, namely in adult rats injected with streptozotocin during the neonatal period (STZ rats) and in spontaneously glucose-intolerant rats [3,4] obtained by selective breeding over numerous generations (GK rats), the oxidation of D-[3, 4-14C]glucose by pancreatic islets is impaired even when expressed relative to total glycolytic flux. Therefore, we propose that a perturbation of mitochondrial oxidative events, rather than hexose transport, plays an essential role in the secretory defect. Materials and methodsControl Wistar rats, animals injected with STZ [5] during the neonatal period (STZ rats) and GK rats [6] were given free access to food [7]. The rats were weighed and then decapitated. Blood was col~ lected in heparinized tubes for the measurement of plasma glucose by the glucose oxidase method [8] and plasma insulin by radioimmunoassay [9]. In each experiment, islets were isolated by the collagenase method [10] from the pancreas of two rats in each group. Two groups of ten islets each were used for the measurement of islet protein and insulin content [10,11]. For the measurement of t4C-labelled D-glucose oxidation and D-[5-3H]glucose utilization, groups of ten islets each were incubated for 120 min at 37 ~ in 40 gt of a bicarbonate-buffered medium [10] containing bovine serum albumin (5 mg/ml). In some experiments, the incubation medium was deprived of CaC12 and contained 0.5 mmol/1EGTA. The production of ~4CO2 and 3HOH was measured as previously described [12]. The acidified medium containing the islets was stored at -20 ~ and later examined for its content in z4C-labelled amino acids and acidic metabolites separated by ion-exchan...

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Functional and metabolic perturbations in isolated pancreatic islets from the GK rat, a genetic model of noninsulin-dependent diabetes.

Cited by 70 publications

References 21 publications

Proinsulin processing in the diabetic Goto-Kakizaki rat

Proinsulin processing in the diabetic Goto-Kakizaki rat

Lack of compensatory increase in islet blood flow and islet mass in GK rats following 60% partial pancreatectomy

Preferential alteration of oxidative relative to total glycolysis in pancreatic islets of two rat models of inherited or acquired Type 2 (non-insulin-dependent) diabetes mellitus

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