Enhanced synthesis, storage, and secretion of insulin in pancreatic islets derived from obese subjects

Jahr, H; Ratzmann, K P; Beckert, R; Besch, W; Hahn, Hans-Jürgen

doi:10.1016/0026-0495(83)90055-0

Cited by 12 publications

(8 citation statements)

References 29 publications

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“…In this study, IUGR neonatal lambs had enhanced in vitro glucose-stimulated insulin secretion, or β-cell hypersecretion relative to control lambs, which occurs in obese individuals, as well as early in the pathogenesis of type 2 diabetes [61], [62], [63]. Interestingly, exendin-4 treatment of IUGR lambs abolished this in vitro insulin hypersecretion from isolated islets, suggesting some normalisation of intrinsic β-cell function and its determinants.…”

Section: Discussionmentioning

confidence: 52%

Neonatal Exendin-4 Reduces Growth, Fat Deposition and Glucose Tolerance during Treatment in the Intrauterine Growth-Restricted Lamb

et al. 2013

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BackgroundIUGR increases the risk of type 2 diabetes mellitus (T2DM) in later life, due to reduced insulin sensitivity and impaired adaptation of insulin secretion. In IUGR rats, development of T2DM can be prevented by neonatal administration of the GLP-1 analogue exendin-4. We therefore investigated effects of neonatal exendin-4 administration on insulin action and β-cell mass and function in the IUGR neonate in the sheep, a species with a more developed pancreas at birth.MethodsTwin IUGR lambs were injected s.c. daily with vehicle (IUGR+Veh, n = 8) or exendin-4 (1 nmol.kg-1, IUGR+Ex-4, n = 8), and singleton control lambs were injected with vehicle (CON, n = 7), from d 1 to 16 of age. Glucose-stimulated insulin secretion and insulin sensitivity were measured in vivo during treatment (d 12–14). Body composition, β-cell mass and in vitro insulin secretion of isolated pancreatic islets were measured at d 16.Principal FindingsIUGR+Veh did not alter in vivo insulin secretion or insulin sensitivity or β-cell mass, but increased glucose-stimulated insulin secretion in vitro. Exendin-4 treatment of the IUGR lamb impaired glucose tolerance in vivo, reflecting reduced insulin sensitivity, and normalised glucose-stimulated insulin secretion in vitro. Exendin-4 also reduced neonatal growth and visceral fat accumulation in IUGR lambs, known risk factors for later T2DM.ConclusionsNeonatal exendin-4 induces changes in IUGR lambs that might improve later insulin action. Whether these effects of exendin-4 lead to improved insulin action in adult life after IUGR in the sheep, as in the PR rat, requires further investigation.

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Section: Discussionmentioning

confidence: 52%

Neonatal Exendin-4 Reduces Growth, Fat Deposition and Glucose Tolerance during Treatment in the Intrauterine Growth-Restricted Lamb

et al. 2013

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“…Obesity is frequently characterized by a major peripheral hyperinsulinemia, resulting from both higher insulin secretion and reduced insulin clearance, as well as by marked insulin resistance (1)(2)(3). The impaired glucose tolerance seen in severely obese subjects can be explained by the presence of major insulin resistance that cannot be fully compensated for by adequate insulin secretion.…”

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confidence: 99%

Correction of obesity and diabetes in genetically obese mice by leptin gene therapy

Muzzin

Eisensmith²,

Copeland³

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

144

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The ob͞ob mouse is genetically deficient in leptin and exhibits both an obese and a mild non-insulindependent diabetic phenotype. To test the hypothesis that correction of the obese phenotype by leptin gene therapy will lead to the spontaneous correction of the diabetic phenotype, the ob͞ob mouse was treated with a recombinant adenovirus expressing the mouse leptin cDNA. Treatment resulted in dramatic reductions in both food intake and body weight, as well as the normalization of serum insulin levels and glucose tolerance. The subsequent diminishment in serum leptin levels resulted in the rapid resumption of food intake and a gradual gain of body weight, which correlated with the gradual return of hyperinsulinemia and insulin resistance. These results not only demonstrated that the obese and diabetic phenotypes in the adult ob͞ob mice are corrected by leptin gene treatment but also provide confirming evidence that body weight control may be critical in the long-term management of non-insulin-dependent diabetes mellitus in obese patients.

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“…Obesity is a complex disorder and often leads to peripheral hyperinsulinemia, hyperglycemia, and insulin resistance (1)(2)(3). Obesity is also a major risk factor for hypertension and cardiovascular disease (3).…”

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confidence: 99%

Long-term correction of obesity and diabetes in genetically obese mice by a single intramuscular injection of recombinant adeno-associated virus encoding mouse leptin

Murphy¹,

Zhou²,

Giese³

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

119

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The ob͞ob mouse is genetically deficient in leptin and exhibits a phenotype that includes obesity and non-insulin-dependent diabetes melitus. This phenotype closely resembles the morbid obesity seen in humans. In this study, we demonstrate that a single intramuscular injection of a recombinant adeno-associated virus (AAV) vector encoding mouse leptin (rAAV-leptin) in ob͞ob mice leads to prevention of obesity and diabetes. The treated animals show normalization of metabolic abnormalities including hyperglycemia, insulin resistance, impaired glucose tolerance, and lethargy. The effects of a single injection have lasted through the 6-month course of the study. At all time points measured the circulating levels of leptin in the serum were similar to age-matched control C57 mice. These results demonstrate that maintenance of normal levels of leptin (2-5 ng͞ml) in the circulation can prevent both the onset of obesity and associated non-insulin-dependent diabetes. Thus a single injection of a rAAV vector expressing a therapeutic gene can lead to complete and long-term correction of a genetic disorder. Our study demonstrates the long-term correction of a disease caused by a genetic defect and proves the feasibility of using rAAV-based vectors for the treatment of chronic disorders like obesity.Obesity is a complex disorder and often leads to peripheral hyperinsulinemia, hyperglycemia, and insulin resistance (1-3). Obesity is also a major risk factor for hypertension and cardiovascular disease (3). It is clear that there are multiple pathways that control the complex balance of caloric intake and expenditure. The intake of calories is controlled by molecules that include leptin, leptin receptor, melanin concentrating hormone, the melanocortin 4 receptor, urocortin, and neuropeptide Y and its type 5 receptor (4). In rodents several genes responsible for obesity, including obese (ob), fat ( fa), agouti (ay), and diabetes (db) have been identified in genetically obese models (3, 5-7). Recently, the human and mouse ob genes have been cloned, and the secreted gene product, termed leptin, has been characterized (3,(8)(9)(10)(11).In ob͞ob mice, mutation in the ob gene leads to a marked increase in food consumption that results in an increase in adipose tissue mass and a syndrome that resembles morbid obesity in humans (9). Abnormalities include hypothermia, lethargy, hyperglycemia, glucose intolerance, and hyperinsulinemia resembling non-insulin-dependent diabetes melitus in humans. Leptin, a 16-kDa secreted protein, is produced exclusively in the adipose tissue and is thought to act mainly on the hypothalamus, although leptin receptors are also present in peripheral tissues (3,(12)(13)(14). Leptin has been shown to mediate its effect via the appetite-stimulating peptide, neuropeptide Y (15). In ob͞ob mice repeated administration of recombinant leptin reduces food intake, increases energy expenditure and leads to loss of body weight and fat mass (8-11). These effects require continuous administration of the recombinant ...

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Enhanced synthesis, storage, and secretion of insulin in pancreatic islets derived from obese subjects

Cited by 12 publications

References 29 publications

Neonatal Exendin-4 Reduces Growth, Fat Deposition and Glucose Tolerance during Treatment in the Intrauterine Growth-Restricted Lamb

Neonatal Exendin-4 Reduces Growth, Fat Deposition and Glucose Tolerance during Treatment in the Intrauterine Growth-Restricted Lamb

Correction of obesity and diabetes in genetically obese mice by leptin gene therapy

Long-term correction of obesity and diabetes in genetically obese mice by a single intramuscular injection of recombinant adeno-associated virus encoding mouse leptin

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