Reversible Impairment of Glucose-Induced Insulin Secretion in SHR/N-<i>cp</i> Rats: Genetic Model of Type II Diabetes

Voyles, Nancy R.; Powell, Andrea M.; Timmers, Kim I.; Wilkins, Sam D; Bhathena, Sam J.; Hansen, Carl T.; Michaelis, Otho E.; Recant, Lillian

doi:10.2337/diab.37.4.398

Cited by 26 publications

(36 citation statements)

References 20 publications

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“…In contrast, perfusate containing 5.5 mmol/1 glucose (well below the normal plasma glucose value in rats) failed to achieve the same effect, indicating that the return of glucose-induced insulin secretion was not simply an effect of removing hyperglycaemia but instead depended on the absence (or possibly extremely low level) of glucose. The same observation has been made in other hyperglycaemic rodent models [15,22,23] suggesting that rapid restoration of glucose responsiveness in the presence of profound glucopoenia is a fundamental characteristic of hyperglycaemia-associated Beta-cell dysfunction. Some aspects of these findings need to be emphasized.…”

Section: Discussionsupporting

confidence: 53%

Beta-cell dysfunction in hyperglycaemic rat models: recovery of glucose-induced insulin secretion with lowering of the ambient glucose level

Leahy

Weir

1991

Diabetologia

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Summary. Glucose-induced insulin secretion is lost in the face of chronic hyperglycaemia. The same defect is present when normal rats are made hyperglycaemic by 48-h glucose infusions. Insulin secretory responses were mapped out during the post-infusion period in order to determine how long it takes for normal Beta-cell function to recover, and to identify factors which influence the rate of recovery. Male Sprague Dawley rats weighing 200-250 g were infused with 50% glucose or 77 mmol/1 NaC1 for 48 h. The glucose-infused rats were mildly hypoglycaemic for 14 h after the infusion ceased. Glucose-induced insulin secretion, absent at the end of the glucose infusion, was normal 6 h post-infusion. Such rapid recovery was not because of the short duration of hyperglycaemia; mild hypoglycaemia from a 5-h insulin infusion in 90% pancreatectomized rats resulted in a four-fold rise in glucose-induced insulin secretion. Under in vitro conditions, extreme glucose deprivation caused by perfusing the pancreas of glucose-infused rats with buffer devoid of glucose restored glucose-induced insulin secretion in just 37 min. Therefore, the suppression of glucose-induced insulin release by chronic hyperglycaemia is a dynamic situation that requires ongoing hyperglycaemia to prevent the reappearance of glucose responsiveness. This study shows recovery of glucose-induced insulin secretion after just 6 h of mild hypoglycaemia in vivo and even faster recovery with more severe glucose deprivation in vitro. Our results suggest that there is an inverse relationship between the rate of return of Betacell glucose responsiveness and the ambient glucose concentration.Key words: Animal models, Type 2 (non-insulin-dependent) diabetes mellitus, insulin secretion, insulin treatment, hypoglycaemia, islets of Langerhans.Normally, the plasma glucose concentration exerts the dominant influence over insulin secretion. Type 2 (noninsulin-dependent) diabetes mellitus is characterized by Beta cells which no longer respond to a changing glucose level [1][2][3][4]. We have proposed that glucose-induced insulin secretion is lost as a direct result of Beta cells being exposed to a chronically elevated glucose concentration [4,5]. Support for this idea has come from animal studies in which normal rats made hyperglycaemic through a variety of mechanisms develop a similar defect [6.9], and also that normalizing the plasma glucose concentration in these rats with phloridzin restores glucose-induced insulin secretion [10,11].Little is known about reversal of secretory defects in non-insulin-dependent diabetes mellitus except that restoration of euglycaemia often results in the reappearance of glucose-induced insulin release [4, 12-14]. The recovery time has not been mapped out, nor has much been learned about what conditions speed up or retard recovery. Animal models should theoretically provide a way to investigate this question, but reversal studies in hyperglycaemic rat models have provided conflicting results. Using in vitro techniques, glucose-induced insuli...

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Section: Discussionsupporting

confidence: 53%

Beta-cell dysfunction in hyperglycaemic rat models: recovery of glucose-induced insulin secretion with lowering of the ambient glucose level

Leahy

Weir

1991

Diabetologia

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“…For example, the defective g-cells are isolated from hyperglycemic animals and maintained for several days at a basal glucose level before experimentation. It has been shown that hyperglycemia per se may be reponsible for the impaired ~' cell secretory response to glucose in glucoseinfused normal rats and in a genetic model of type II diabetes [17,18]. The alternative explanation of differences in the electrical abnormalities existing between the Jackson Laboratory colony and the Norwich colony is discarded by unpublished results from this laboratory showing similar patterns of electrical activity in both colonies.…”

Section: Discussionmentioning

confidence: 81%

Characterization of potassium channels in pancreatic β cells from ob/ob mice

Kukuljan

Atwater

1990

FEBS Letters

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The patch-clamp technique in the cell-attached mode was used to study the K channels present in the membrane of cultured pancreatic fl cells from ob/ob mice. Three types of K + channels were regularly observed, with conductances of 64, 20 and 146 pS. The conduction and kinetic properties of the 64 pS channel were similar to those of the ATP-sensitive potassium channel from normal fl cells. Furthermore, glucose blocked the activity of this channel at the same concentrations as that reported for normal cells. The 20 pS and the 146 pS were insensitive to glucose. The latter K + channel appears to be similar to the large conductance voltage-activated potassium channels described in normal rodent fl cells. Thus, potassium channels in ob/ob pancreatic fl cells in culture are in most respects normal. Other factors may account for the abnormal electrical response to glucose of ob/ob pancreatic islets, such as reversible impairment of their function in vivo or defects not related to potassium permeability.

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“…Plasma insulin levels (U/ml) after overnight fasting (F-Ins) and stimulated plasma insulin levels (S-Ins) 15 28 22 79 11 14 3 21 12 13 10 77 13 6 5 83 14 17 7 41 15 26 7 27 16 8 5 63 17 31 7 23 18 14 5 36 19 11 2 18 20 10 5 50 X 2 1 1 5 Total 486 220 45 …”

Section: Tablementioning

confidence: 99%

“…In contrast, the "control" strains of the GK, OLETF, and ZDF models are unrelated strains that do not share the same ancestry. A third feature that makes the Cohen rat stand out is that it is a nonobese model of diabetes, which allows dissociation of the confounding obesity factor from other diabetogenic genes (13)(14)(15).…”

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confidence: 99%

The Newly Inbred Cohen Diabetic Rat

et al. 2001

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The newly inbred Cohen diabetic rat is an exceptional experimental model of diet-induced type 2 diabetes mellitus that is the result of secondary inbreeding nearly 30 years after it originally had been established. Animals from the original colony were selectively inbred by stringent criteria for 10 additional generations, bringing overall inbreeding to >50 generations. The metabolic phenotypes of the resulting contrasting strains, designated as the Cohen diabetic-sensitive (CDs) and -resistant (CDr) rats, were characterized. The phenotype of the CDs strain that was fed a regular diet consisted of fasting normoglycemia, normal glucose tolerance to intraperitoneal glucose loading, normal fasting insulin levels, and a normal insulin response to glucose loading. In contrast, CDs rats that were fed a custom-prepared high-sucrose low-copper diabetogenic diet became overtly diabetic: fasting glucose levels were normal or elevated, and the blood glucose insulin response to glucose loading was markedly abnormal. CDr rats that were fed a regular or diabetogenic diet did not develop diabetes and maintained normal glucose tolerance and insulin secretion. A striking sex difference was observed in CDs rats that were fed a diabetogenic diet: males had a lower growth rate and a more severe glucose intolerance pattern than females. Gonadectomy shortly after weaning did not prevent the development of the diabetic phenotype in its early phase in either sex but markedly attenuated its expression in males at a later phase, abolishing the sex differences. Alternate-day feeding, as opposed to daily feeding, also attenuated the metabolic phenotype in males. The development of the diabetic phenotype in CDs rats that were fed a diabetogenic diet was not accompanied by obesity or hyperlipidemia. The genetic profile of the strains was established using 550 microsatellite markers evenly distributed throughout the rat genome. The rate of homozygosity within strain was >96%. The rate of polymorphism between the contrasting strains was 43%. We conclude that the metabolic phenotypes of the rebred colony of CDs and CDr rats and their genetic makeup render the Cohen diabetic rat a useful experimental model that is highly suitable for studying the interaction between nutritional-metabolic environmental factors and genetic susceptibility (sensitivity and resistance) for the development of type 2 diabetes. The model is also distinctively useful for investigating the effect of sex on the expression of the diabetic phenotype.

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Reversible Impairment of Glucose-Induced Insulin Secretion in SHR/N-cp Rats: Genetic Model of Type II Diabetes

Cited by 26 publications

References 20 publications

Beta-cell dysfunction in hyperglycaemic rat models: recovery of glucose-induced insulin secretion with lowering of the ambient glucose level

Beta-cell dysfunction in hyperglycaemic rat models: recovery of glucose-induced insulin secretion with lowering of the ambient glucose level

Characterization of potassium channels in pancreatic β cells from ob/ob mice

The Newly Inbred Cohen Diabetic Rat

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