Effect of genetic background on the capacity for islet cell replication in mice

Swenne, Ingemar; Andersson, Arne

doi:10.1007/bf00273912

Cited by 82 publications

(56 citation statements)

References 14 publications

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“…Thus, hyperinsulinemia was greater in the B6 mice, and this was associated with greater islet hyperplasia and an increase in ␤-cell mass that exceeded the levels observed in DBA mice. In fact, the hyperplasia in the B6 mice was greater than our earlier observations in DH mice on the mixed genetic background (19), which may be in part due to the greater ability of B6 islet cells to replicate (34). The milder response in the aging DBA mice may be related to loss of ␤-cells because of "vacuolation" in the islets, which limits the ability of the ␤-cells to synthesize and store insulin.…”

Section: Discussioncontrasting

confidence: 53%

Impact of Genetic Background on Development of Hyperinsulinemia and Diabetes in Insulin Receptor/Insulin Receptor Substrate-1 Double Heterozygous Mice

et al. 2003

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Type 2 diabetes is a complex disease in which genetic and environmental factors interact to produce alterations in insulin action and insulin secretion, leading to hyperglycemia. To evaluate the influence of genetic background on development of diabetes in a genetically susceptible host, we generated mice that are double heterozygous (DH) for knockout of the insulin receptor and insulin receptor substrate-1 on three genetic backgrounds (C57BL/6 [B6], 129Sv, and DBA). Although DH mice on all backgrounds showed insulin resistance, their phenotypes were dramatically different. B6 DH mice exhibited marked hyperinsulinemia and massive islet hyperplasia and developed early hyperglycemia, with 85% overtly diabetic by 6 months. By contrast, 129Sv DH mice showed mild hyperinsulinemia and minimal islet hyperplasia, and <2% developed diabetes. DBA mice had slower development of hyperglycemia, intermediate insulin levels, and evidence of islet degeneration, with 64% developing diabetes. Thus, mice carrying the same genetic defects on different backgrounds exhibited the full spectrum of abnormalities observed in humans with type 2 diabetes, which allowed for identification of potential loci that promote development of the diabetic phenotype. Diabetes 52: 1528 -1534, 2003 S everal common human disorders, including obesity, diabetes, hyperlipidemia, atherosclerosis, and hypertension, have complex patterns of inheritance with superimposed effects created by diet, level of exercise, and other environmental factors (1-3). Several monogenic forms of diabetes, including mutations in genes for insulin (4), the insulin receptor (5), maturity-onset diabetes of the young (6), and mitochondrial diabetes (7), have been identified and constitute Ͻ5% of all cases of type 2 diabetes. The genetic basis for the more common form(s) of type 2 diabetes remains elusive but is thought to be the result of interactions between genes controlling insulin resistance and ␤-cell function, environmental factors, and variations in other background genes (8).One approach toward defining the primary and background genes involved in type 2 diabetes and obesity is the use of naturally occurring rodent models (9,10) and inbred strains of mice (11-13). Indeed, Hummel et al. (9) and Coleman and Hummel (14) have shown that when mutations in leptin found in the ob/ob mouse are bred into different backgrounds, there is a difference in the severity of obesity and diabetes. A more recent strategy to define the role of genetic alterations and candidate genes for type 2 diabetes has been the creation of transgenic and knockout mice with alterations in insulin action (15) and in insulin secretion (16). Whereas knockout and transgenic mice often show diabetic or insulin-resistant phenotypes, by their very nature, the development of knockout mice leads to progeny that are born with a mixed genetic background and provide a unique tool for evaluation of the impact of background genes on phenotype (17,18).We have reported the creation and characterization of mice double h...

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Section: Discussioncontrasting

confidence: 53%

Impact of Genetic Background on Development of Hyperinsulinemia and Diabetes in Insulin Receptor/Insulin Receptor Substrate-1 Double Heterozygous Mice

et al. 2003

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“…Effect of genetic background on alterations in ␤-cell mass in MCH-KO mice. Genetic background plays a significant role in modulating ␤-cell replication, mass, and function (28,29,36). To examine whether mice lacking MCH and bred on different genetic backgrounds display alterations in ␤-cell mass, we examined wild-type and KO mice backcrossed to C57Bl/6 (B6) and 129Sv (129) strains-two common inbred strains used in the study of diet-induced obesity (28,29).…”

Section: Resultsmentioning

confidence: 99%

Melanin Concentrating Hormone Is a Novel Regulator of Islet Function and Growth

et al. 2007

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Melanin concentrating hormone (MCH) is a hypothalamic neuropeptide known to play a critical role in energy balance. We have previously reported that overexpression of MCH is associated with mild obesity. In addition, mice have substantial hyperinsulinemia and islet hyperplasia that is out of proportion with their degree of obesity. In this study, we further explored the role of MCH in the endocrine pancreas. Both MCH and MCHR1 are expressed in mouse and human islets and in clonal ␤-cell lines as assessed using quantitative real-time PCR and immunohistochemistry. Mice lacking MCH (MCH-KO) on either a C57Bl/6 or 129Sv genetic background showed a significant reduction in ␤-cell mass and complemented our earlier observation of increased ␤-cell mass in MCH-overexpressing mice. Furthermore, the compensatory islet hyperplasia secondary to a high-fat diet, which was evident in wild-type controls, was attenuated in MCH-KO. Interestingly, MCH enhanced insulin secretion in human and mouse islets and rodent ␤-cell lines in a dose-dependent manner. Real-time PCR analyses of islet RNA derived from MCH-KO revealed altered expression of islet-enriched genes such as glucagon, forkhead homeobox A2, hepatocyte nuclear factor (HNF)4␣, and HNF1␣. Together, these data provide novel evidence for an autocrine role for MCH in the regulation of ␤-cell mass dynamics and in islet secretory function and suggest that MCH is part of a hypothalamic-islet (pancreatic) axis. Diabetes 56:311-319, 2007 S everal neuropeptides that act in the central nervous system to regulate feeding behavior and energy homeostasis are also expressed in the enteric system as part of a potential hypothalamic-pancreatic axis (1). While some of these neuropeptides have an effect on exocrine pancreatic function, their effects on endocrine secretion are not fully understood. Thus, ghrelin, neuropeptide Y, galanin, orexins A and B, leptin, and the agouti gene product are neuropeptides that act in the hypothalamus to regulate feeding behavior and have also been reported to modulate islet function and/or growth (2-11). Melanin concentrating hormone (MCH) is another hypothalamic peptide that is known to regulate energy balance. A previous study reported that mice overexpressing MCH have islet hyperplasia, suggesting that MCH may also play a role in islet growth. However, the potential role of MCH and its receptors in the endocrine pancreas and a potential role of MCH in islet biology have not been explored.MCH is expressed in the lateral hypothalamus and zona incerta and has been shown to be important for feeding and energy homeostasis in rodents (12,13). MCH expression in the hypothalamus is upregulated by fasting and suppressed by leptin injection (13-15). Intracerebroventricular injections of MCH acutely stimulate feeding behavior (16). Mice lacking the prohormone are lean and hypophagic, whereas mice overexpressing MCH are obese (17,18). In rodents, MCH acts via a high-affinity G-proteincoupled receptor, designated MCH receptor (MCHR)1. In humans and primates, a second ...

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“…In the context of restricted beta-cell mass as a very early hallmark in the sequence of events leading to overt diabetes in the GK model, it now becomes necessary to pay more attention to the role of altered beta-cell neogenesis and/or beta-cell replication. Available information on rodents suggests that limitations of the size of the proliferative beta-cell compartment determine whether compensatory growth will be successful [45,46]. As this capacity depends among others on genetic factors, it is conceivable that several genes among the set causing diabetes in the GK rat [47] are responsible for impaired beta-cell growth.…”

Section: Discussionmentioning

confidence: 99%

Impaired development of pancreatic beta-cell mass is a primary event during the progression to diabetes in the GK rat

et al. 1997

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Established non-insulin-dependent diabetes mellitus (NIDDM) is associated with profound insulin secretory defects that occur together with insulin resistance. The basis for the insulin secretory defects is unknown and is difficult to study in human subjects because it is not possible to identify prospectively those subjects in whom glucose control will deteriorate. The fact that total beta-cell mass is decreased in NIDDM patients compared to weight-matched control subjects [1] offers strong support for the notion that insulin production may become insufficient if beta-cell growth is deficient. The contribution of decreased beta-cell mass to deficient insulin secretion Diabetologia (1997) 40: 916-925 Impaired development of pancreatic beta-cell mass is a primary event during the progression to diabetes in the GK rat

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Effect of genetic background on the capacity for islet cell replication in mice

Cited by 82 publications

References 14 publications

Impact of Genetic Background on Development of Hyperinsulinemia and Diabetes in Insulin Receptor/Insulin Receptor Substrate-1 Double Heterozygous Mice

Impact of Genetic Background on Development of Hyperinsulinemia and Diabetes in Insulin Receptor/Insulin Receptor Substrate-1 Double Heterozygous Mice

Melanin Concentrating Hormone Is a Novel Regulator of Islet Function and Growth

Impaired development of pancreatic beta-cell mass is a primary event during the progression to diabetes in the GK rat

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