Postweaning development of diabetes in mice

Dubuc, Paul U.; Willis, Patricia

doi:10.1016/0026-0495(79)90016-7

Cited by 21 publications

(14 citation statements)

References 18 publications

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“…Until 21 days of age they are mildly hypoglycemic and have an increased tolerance to glucose (Dubuc 1976a;Dubuc and Willis 1979). Coincident with weaning (21-28 days of age) fasting hyperglycemia, glucose intolerance, and in vivo insulin 'insensitivity' are first detected (Dubuc and Willis 1979). The metabolic state progressively deteriorates with age and by about 12 weeks of age the most severe diabetes is observed (Bailey, Atkins, Flatt,Best and Matty 1977;Dubuc 1976b;Garthwaite,Martinson, Tseng,Hagen and Menahan 1980).…”

Section: Introductionmentioning

confidence: 95%

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Starvation and Age Effects on Glycoregulation and Hormone Levels of C57BL/6J ob/ob Mice

Dubuc¹,

Cahn²,

S³

et al. 1982

Horm Metab Res

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The contributions of insulin (IRI), glucagon (IRG), and corticosterone production to the glycemic changes associated with age and starvation were examined in 3 and 6 month old ob/ob and lean mice. Three month old ob/ob mice had elevated glucose levels under all feeding conditions, but in older obese mice basal hyperglycemia was evident only after 48 hours of food deprivation. These age differences in glycoregulation were not consistently related to changes of IRI, IRG, or corticosterone concentrations. Similarly, the mild diabetes associated with senescence in lean mice was only evident during food deprivation. This abnormality in glycoregulation was also independent of decreased IRI or elevated diabetogenic hormone concentrations. Our results indicate that there is no simple hormonal basis for the partial remission of diabetes in older ob/ob mice, or for the development of mild diabetes in aging lean mice. Additionally, these data suggest that the tissue 'resistance' that is associated with chronic insulin overproduction might also develop in response to persistent overproduction of other metabolically-active hormones.

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Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Starvation and Age Effects on Glycoregulation and Hormone Levels of C57BL/6J ob/ob Mice

Dubuc¹,

Cahn²,

S³

et al. 1982

Horm Metab Res

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“…Mutation of the gene encoding leptin in mice ( Lep ob/ob ) results in a deficiency of leptin, and increases in hyperphagia and adiposity [1]. In addition, loss of leptin also impairs glucose homeostasis, manifesting as glucose intolerance, and, at times, fasting hyperglycemia in mice greater than 8 weeks of age [2]. In both Lep ob/ob and mice lacking leptin receptors ( Lepr db/db ), hyperinsulinemia occurs prior to increases in body weight and fasting glucose levels [2], [3], [4], possibly as a result of removal of leptin's inhibitory effects on insulin gene expression and secretion [5], [6].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, loss of leptin also impairs glucose homeostasis, manifesting as glucose intolerance, and, at times, fasting hyperglycemia in mice greater than 8 weeks of age [2]. In both Lep ob/ob and mice lacking leptin receptors ( Lepr db/db ), hyperinsulinemia occurs prior to increases in body weight and fasting glucose levels [2], [3], [4], possibly as a result of removal of leptin's inhibitory effects on insulin gene expression and secretion [5], [6]. Administration of exogenous leptin to Lep ob/ob mice results in attenuation of circulating insulin levels and improved fasting glycemia prior to reductions in body weight [7].…”

Section: Introductionmentioning

confidence: 99%

Suppressing hyperinsulinemia prevents obesity but causes rapid onset of diabetes in leptin-deficient Lepob/ob mice

D'souza¹,

Johnson²,

Clee³

et al. 2016

Molecular Metabolism

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ObjectiveHyperinsulinemia is commonly associated with obesity. Mice deficient in the adipose-derived hormone leptin (Lepob/ob) develop hyperinsulinemia prior to onset of obesity and glucose intolerance. Whether the excess of circulating insulin is a major contributor to obesity and impaired glucose homeostasis in Lepob/ob mice is unclear. It has been reported previously that diet-induced obesity in mice can be prevented by reducing insulin gene dosage. In the present study, we examined the effects of genetic insulin reduction in Lepob/ob mice on circulating insulin, body composition, and glucose homeostasis.MethodsLeptin expressing (Lepwt/wt) mice lacking 3 insulin alleles were crossed with Lepob/ob mice to generate Lepob/ob and Lepwt/wt littermates lacking 1 (Ins1+/+;Ins2+/−), 2 (Ins1+/+;Ins2−/−) or 3 (Ins1+/−;Ins2−/−) insulin alleles. Animals were assessed for body weight gain, body composition, glucose homeostasis, and islet morphology.ResultsWe found that in young Lepob/ob mice, loss of 2 or 3 insulin alleles reduced plasma insulin levels by 75–95% and attenuated body weight gain by 50–90% compared to Ins1+/+;Ins2+/−;Lepob/ob mice. This corresponded with ∼30% and ∼50% reduced total body fat in Ins1+/+;Ins2−/−;Lepob/ob and Ins1+/−;Ins2−/−;Lepob/ob mice, respectively. Loss of 2 or 3 insulin alleles in young Lepob/ob mice resulted in onset of fasting hyperglycemia by 4 weeks of age, exacerbated glucose intolerance, and abnormal islet morphology. In contrast, loss of 1,2 or 3 insulin alleles in Lepwt/wt mice did not significantly alter plasma insulin levels, body weight, fat mass, fasting glycemia, or glucose tolerance.ConclusionTaken together, our findings indicate that hyperinsulinemia is required for excess adiposity in Lepob/ob mice and sufficient insulin production is necessary to maintain euglycemia in the absence of leptin.

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“…This primary hyperinsulinemia is associated initially with hypoglycemia (29,30) and may elicit a series of compensatory mechanisms that culminate in the development of obesity and insulin resistance as ob/ob mice age. Because insulin facilitates fat deposition, the hyperinsulinemia likely contributes directly to obesity and together may promote insulin resistance and development of type 2 diabetes.…”

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confidence: 99%

Acute Disruption of Leptin Signaling in Vivo Leads to Increased Insulin Levels and Insulin Resistance

et al. 2011

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Leptin, an adipocyte-derived hormone, plays an essential role in the maintenance of normal body weight and energy expenditure, as well as glucose homeostasis. Indeed, leptin-deficient ob/ob mice are obese with profound hyperinsulinemia, insulin resistance, and often hyperglycemia. Interestingly, low doses of exogenous leptin can reverse the hyperinsulinemia and hyperglycemia in these animals without altering body weight. The hyperinsulinemia in ob/ob mice may result directly from the absence of leptin signaling in pancreatic β-cells and, in turn, contribute to both obesity and insulin resistance. Here, we acutely attenuated endogenous leptin signaling in normal mice with a polyethylene glycol (PEG)ylated mouse leptin antagonist (PEG-MLA) to determine the contribution of leptin signaling in the regulation of glucose homeostasis. PEG-MLA was either injected or continuously administered via osmotic minipumps for several days, and various metabolic parameters were assessed. PEG-MLA-treated mice had increased fasting and glucose-stimulated plasma insulin levels, decreased whole-body insulin sensitivity, elevated hepatic glucose production, and impaired insulin-mediated suppression of hepatic glucose production. Moreover, PEG-MLA treatment resulted in increased food intake and increased respiratory quotient without significantly altering energy expenditure or body composition as assessed by the lean:lipid ratio. Our findings indicate that alterations in insulin sensitivity occur before changes in the lean:lipid ratio and energy expenditure during the acute disruption of endogenous leptin signaling.

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Postweaning development of diabetes in mice

Cited by 21 publications

References 18 publications

Starvation and Age Effects on Glycoregulation and Hormone Levels of C57BL/6J ob/ob Mice

Starvation and Age Effects on Glycoregulation and Hormone Levels of C57BL/6J ob/ob Mice

Suppressing hyperinsulinemia prevents obesity but causes rapid onset of diabetes in leptin-deficient Lepob/ob mice

Acute Disruption of Leptin Signaling in Vivo Leads to Increased Insulin Levels and Insulin Resistance

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