Comparison of Insulin Secretory Patterns in Obese Nondiabetic LA/N-<i>cp</i> and Obese Diabetic SHR/N-<i>cp</i> Rats: Role of Hyperglycemia

Recant, Lillian; Voyles, Nancy R.; Timmers, Kim I.; Bhathena, Sam J.; Solomon, Darley; Wilkins, Sam D; Michaelis, Otho E.

doi:10.2337/diab.38.6.691

Cited by 12 publications

(5 citation statements)

References 13 publications

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“…The present data cannot entirely explain the differential effect of a 48-h hyperglycaemic period on the subsequent in vivo and in vitro insulin secretion that we and others reported previously [9,[18][19][20]. In particular, the in vivo insulin response to a low glucose concentration (8 mmol/1) was much higher in HG rats than in controls whereas this difference disappeared in vitro.…”

Section: Discussioncontrasting

confidence: 90%

In vivo and in vitro increased pancreatic beta-cell sensitivity to glucose in normal rats submitted to a 48-h hyperglycaemic period

Thibault

Guettet

et al. 1993

Diabetologia

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We investigated the importance of the level and the duration of glucose stimulation on the in vivo and in vitro insulin response to glucose in normal rats previously submitted to hyperglycaemia. Rats were made hyperglycaemic by a 48-h glucose infusion. Glucose-induced insulin secretion was investigated in vivo by a 20-min hyperglycaemic clamp and in vitro by the isolated perfused pancreas technique, 3 h after the end of the in vivo glucose infusion. In glucose-infused rats, as compared to controls, in vivo incremental plasma insulin values above baseline integrated over the 20-min hyperglycaemic clamp (delta I) were five times higher during 8 mmol/l glucose clamp, only two times higher in 11 mmol/l glucose clamp and no different in 16.5 mmol/l. Compared to the controls, in vitro incremental plasma insulin concentration above baseline integrated over a 20-min period (delta I) in glucose-infused rats was 16 times higher in response to 2.8 mmol/l glucose, two times higher in response to 5.5 mmol/l, similar in response to 8.3 mmol/l and significantly lower in response to 16.5 mmol/l. In conclusion, our data suggest that a 48-h hyperglycaemic period results in an increased response of the pancreatic beta cell to low glucose. The response is immediately maximal and can not be increased with higher glucose concentrations. This situation could explain the apparent minimal effect of high concentrations on in vitro insulin secretion in previously hyperglycaemic rats and may provide insights into the sequence of events leading to the impairment of beta-cell function in Type 2 (non-insulin-dependent) diabetes mellitus.

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Section: Discussioncontrasting

confidence: 90%

In vivo and in vitro increased pancreatic beta-cell sensitivity to glucose in normal rats submitted to a 48-h hyperglycaemic period

Thibault

Guettet

et al. 1993

Diabetologia

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“…The hyperinsulinemia can be exacerbated by a high-sucrose diet [105]. In 5-month old male rats, plasma insulin levels are 6 times higher than those of their lean controls [58].…”

Section: Introductionmentioning

confidence: 99%

Leptin- and Leptin Receptor-Deficient Rodent Models: Relevance for Human Type 2 Diabetes

Wang¹,

Chandrasekera

Pippin

2014

CDR

423

348

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Among the most widely used animal models in obesity-induced type 2 diabetes mellitus (T2DM) research are the congenital leptin- and leptin receptor-deficient rodent models. These include the leptin-deficient ob/ob mice and the leptin receptor-deficient db/db mice, Zucker fatty rats, Zucker diabetic fatty rats, SHR/N-cp rats, and JCR:LA-cp rats. After decades of mechanistic and therapeutic research schemes with these animal models, many species differences have been uncovered, but researchers continue to overlook these differences, leading to untranslatable research. The purpose of this review is to analyze and comprehensively recapitulate the most common leptin/leptin receptor-based animal models with respect to their relevance and translatability to human T2DM. Our analysis revealed that, although these rodents develop obesity due to hyperphagia caused by abnormal leptin/leptin receptor signaling with the subsequent appearance of T2DM-like manifestations, these are in fact secondary to genetic mutations that do not reflect disease etiology in humans, for whom leptin or leptin receptor deficiency is not an important contributor to T2DM. A detailed comparison of the roles of genetic susceptibility, obesity, hyperglycemia, hyperinsulinemia, insulin resistance, and diabetic complications as well as leptin expression, signaling, and other factors that confound translation are presented here. There are substantial differences between these animal models and human T2DM that limit reliable, reproducible, and translatable insight into human T2DM. Therefore, it is imperative that researchers recognize and acknowledge the limitations of the leptin/leptin receptor-based rodent models and invest in research methods that would be directly and reliably applicable to humans in order to advance T2DM management.

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“…Other investigators also concluded that a simple osmotic effect could not explain the massive hypersecretion in pancreas perfusions from glucose-infused rats (31). Third, nondiabetic genetically obese hyperinsulinemic rats (LA/N-cp/cp) also exhibit paradoxical secretion during pancreas perfusions (7) and in batch incubations of isolated islets (32), despite having normal blood glucose levels. Fourth, paradoxical hypersecretion appears to be inherently transient in isolated islets and wanes with time at 37°C, in either low or high Wanes with time at 37°C regardless of glucose (never seen in 2nd incubations) Partly mimicked by isolation of control islets in high glucose Partly reversed by isolation of infused islets in 0 glucose Persists after isolation in 0 glucose and lowglucose 1st incubation Most severe after continuous exposure of islets to high glucose Reversed by islet isolation in 0 glucose glucose.…”

Section: Discussionmentioning

confidence: 94%

“…Studies in our laboratory demonstrated that closely similar insulin secretory abnormalities were observed in perfused pancreases of genetically obese diabetic rats (SHR/N-cp [corpulent]) after 4 wk of hyperglycemia (6,7). However, when young hyperinsulinemic corpulent rats were studied before the development of hyperglycemia, the impaired insulin response to elevated glucose levels (desensitization) was not found (7), although the pancreases exhibited paradoxical secretion in low glucose.…”

mentioning

confidence: 76%

“…Although insulin secretion at physiological levels of glucose was increased, experimental islets secreted significantly less insulin than controls at 16.8 and 28 mM glucose, showing a reduction of 25-50% compared with control islets. This decreased maximum rate of release in high glucose, which has been called desensitization to glucose in numerous studies (mainly pancreas perfusions) in which only single low and high glucose concentrations were tested in each experiment (6)(7)(8)(9)(10)(11)(12)(13), was not demonstrable if, as is usually done in islet studies, the islets were isolated in glucose-free buffers. The ease of reversibility may be responsible for an apparent failure to demonstrate desensitization after culture of mouse islets in vitro in high glucose (38,39).…”

Section: Discussionmentioning

confidence: 98%

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Multiple Alterations in Insulin Responses to Glucose in Islets From 48-h Glucose-Infused Nondiabetic Rats

Timmers

Powell²,

Voyles³

et al. 1990

Diabetes

Self Cite

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To examine the biochemical mechanisms by which hyperglycemia produces insulin secretory abnormalities, we studied isolated islets from control rats and rats infused for 48 h with a 50% glucose solution. To preserve the effects of in vivo hyperglycemia during in vitro handling for islet isolation, our standard isolation procedure utilized buffers containing 16.8 mM glucose. Islets from infused rats released similar amounts of insulin in low or high glucose during first incubations at 37 degrees C (92.4 +/- 7.0 ng.10 islets-1.45 min-1 at 2.8 mM, 84.4 +/- 4.1 ng.10 islets-1.45 min-1 at 16.8 mM) in contrast with control (uninfused) islets (18.6 +/- 2.8 ng.10 islets-1.45 min-1 at 2.8 mM and 109.8 +/- 8.0 ng.10 islets-1.45 min-1 at 16.8 mM glucose) (P less than 0.01). Secretion by islets of glucose-infused rats was lower during 60-min second incubations at 28 mM glucose than in first incubations of the same islets in low glucose (P less than 0.01). This phenomenon is comparable to the paradoxical hypersecretion observed during the first 10-15 min of exposure of glucose-infused pancreas to low-glucose perfusions. Paradoxical secretion in low glucose waned rapidly, so that during second incubations at 37 degrees C, little immunoreactive insulin release occurred at 2.8 mM glucose, despite the persistence of two additional lesions. The glucose-insulin dose-response curves in second incubations showed a leftward shift for glucose-infused islets, with two- to threefold higher secretion at 5.6-8.4 mM glucose than control islets. This is termed sensitization to glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

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Comparison of Insulin Secretory Patterns in Obese Nondiabetic LA/N-cp and Obese Diabetic SHR/N-cp Rats: Role of Hyperglycemia

Cited by 12 publications

References 13 publications

In vivo and in vitro increased pancreatic beta-cell sensitivity to glucose in normal rats submitted to a 48-h hyperglycaemic period

In vivo and in vitro increased pancreatic beta-cell sensitivity to glucose in normal rats submitted to a 48-h hyperglycaemic period

Leptin- and Leptin Receptor-Deficient Rodent Models: Relevance for Human Type 2 Diabetes

Multiple Alterations in Insulin Responses to Glucose in Islets From 48-h Glucose-Infused Nondiabetic Rats

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