Measurements of Insulin Secretory Capacity and Glucose Tolerance to Predict Pancreatic β-Cell Mass In Vivo in the Nicotinamide/Streptozotocin Göttingen Minipig, a Model of Moderate Insulin Deficiency and Diabetes

Larsen, Marianne O.; Rolin, Bidda; Wilken, Michael; Carr, Richard D.; Gotfredsen, Carsten F.

doi:10.2337/diabetes.52.1.118

Cited by 54 publications

(56 citation statements)

References 41 publications

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“…In agreement with previous reports, a reduction in beta cell mass of around 70% resulted in mild fasting hyperglycaemia and post-prandial hyperglycaemia in the present study [19,20]. The in vivo insulin secretory response to an MMTT after NIA+STZ was delayed rather than reduced, indicating that the remaining beta cells compensate for the reduced mass by secreting more insulin during a physiological stimulus.…”

Section: Discussionsupporting

confidence: 93%

“…The in vivo insulin secretory response to an MMTT after NIA+STZ was delayed rather than reduced, indicating that the remaining beta cells compensate for the reduced mass by secreting more insulin during a physiological stimulus. However, when applying more extensive stimulation with a combination of glucose and arginine, the insulin response in this model has been shown to be clearly related to beta cell mass [20]. This difference could indicate that, during more extensive stimulation of insulin secretion (such as intravenous glucose plus arginine), beta cells in NIA+STZ animals are not able to compensate for the reduced beta cell mass.…”

Section: Discussionmentioning

confidence: 79%

“…The nicotinamide (NIA)-streptozotocin (STZ) Göttingen minipig is a model of moderate insulin deficiency and hyperglycaemia due to a primary reduction in beta cell mass [19]. In this model, beta cell function in vivo has previously been demonstrated to be closely related to beta cell mass [20]. Furthermore, an isolated perfused pancreas preparation has been developed in this species [21,22,23].…”

Section: Introductionmentioning

confidence: 99%

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Reduction of beta cell mass: partial insulin secretory compensation from the residual beta cell population in the nicotinamide?streptozotocin G�ttingen minipig after oral glucose in vivo and in the perfused pancreas

et al. 2004

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Aims/hypothesis. A progressive loss of beta cell function and mass are important contributory factors in the development and progression of type 2 diabetes. The aim of this study was to evaluate the effects of a primary reduction in beta cell mass on beta cell function in vivo and in the perfused pancreas and to relate these characteristics to beta cell mass. Methods. The beta cell mass of six Göttingen minipigs was reduced chemically (using 67 mg/kg nicotinamide and 125 mg/kg streptozotocin). Six untreated minipigs were kept as control animals. Insulin responses were evaluated in vivo using the mixed meal tolerance test (2 g/kg oral glucose) and in the isolated perfused pancreata from the same animals by stimulation with glucose, glucagon-like peptide-1 or arginine. Results. Beta cell mass was reduced in the beta-cellreduced animals compared with the control minipigs (182±76 vs 464±156 mg, p<0.01). AUC glucose was increased in the beta-cell-reduced animals (1383±385 vs 853±113 mmol·l −1 ·min in control minipigs, p<0.01), as was the insulin response to oral glucose per unit of beta cell mass (123±84 vs 56±24 pmol·l -1 ·min·mg -1 , p<0.05). Total in vitro insulin secretion was increased per unit of beta cell mass in nicotinamide + streptozotocin pancreata compared to controls (83.7±45.9 vs 34.6±14.4 nmol/mg beta cells, p<0.05) with responses to glucose and glucagon-like peptide-1 showing a partial compensation for reduced beta cell mass, whereas no compensation was seen in response to arginine. Conclusions/interpretation. A primary reduction in beta cell mass impairs glucose tolerance and leads to a compensatory increase in insulin secretion from the remaining beta cells after oral glucose in vivo, which is even more apparent in the perfused pancreas. It remains to be determined whether this compensation can be maintained in the long term.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

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Reduction of beta cell mass: partial insulin secretory compensation from the residual beta cell population in the nicotinamide?streptozotocin G�ttingen minipig after oral glucose in vivo and in the perfused pancreas

et al. 2004

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“…Conversely, the parameters reflecting basal (fasting insulinaemia) or stimulated (maximal insulinaemia and AIR) insulin secretion were significantly correlated with the outcome of islet isolation. Interestingly, the two measures of stimulated insulin secretion, both of which have previously been shown to be highly correlated with pancreatic islet mass in the minipig [12] and in islet graft recipients [13], were highly predictive of the islet isolation yield in our model. These results confirm, for the first time in a large mammal, that the donor's endocrine mass is a major determinant of islet isolation outcome.…”

Section: Discussionmentioning

confidence: 84%

Acute insulin response of donors is correlated with pancreatic islet isolation outcome in the pig

et al. 2005

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Aims/hypothesis: Unpredictability of islet isolation outcome remains a frustrating and costly issue in the clinical implementation of islet transplantation. The aim of this experimental study was to test the hypothesis that the donor's insulin secretory reserve, an in vivo surrogate of functional pancreatic mass, is correlated with the outcome of islet isolation. Methods: Insulin secretory reserve was evaluated in 28 healthy adult minipigs prior to pancreatectomy and islet isolation. Blood glucose and insulinaemia were measured before and 1, 3, 5, 10, 15, 30, 60 and 90 min after glucose infusion. Following total pancreatectomy, islet isolation was performed according to Ricordi's semi-automated method, and the total number of islets obtained was determined. Fasting blood glucose, insulinaemia, acute insulin response (AIR), maximal insulinaemia and the glucose decay constant (K G ) were calculated, and possible associations with the outcome of islet isolation were assessed. Results: AIR and maximal insulinaemia after glucose injection were correlated with the outcome of islet isolation (p<0.01). Mean values for AIR and maximal insulinaemia were significantly different between animals in which islet isolation was successful (n=11) vs those in which it was unsuccessful (n=17) (77.6±13.7 μU/ml vs 42.3±7.8 μU/ml, p<0.05; 144.7± 21.6 μU/ml vs 71.9±10.4 μU/ml, p<0.05, respectively). Conclusions/interpretation: This study suggests that the donor's pancreatic endocrine mass, as estimated by AIR, is a major determinant of the outcome of islet isolation in large mammals. Our results may explain the frustrating variability of human islet isolation outcome and could lead to a new approach for optimising the selection of brain-dead and/or living pancreas donors.

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“…Although the amount of insulin/ C-peptide secreted after a glucose or meal challenge gives insight into insulin secretory capacity (4,9), these only indirectly reflect beta-cell mass and do not determine whether this mass is increasing or declining. For example, glucose homeostasis is unaffected until beta-cell mass is reduced to less than half its original value, presumably because of a large functional reserve capacity, and overt diabetes develops only when beta-cell mass is greatly reduced (10)(11)(12). Morphometric analysis of histological sections (13) requires removal of the pancreas to quantify beta-cell mass.…”

mentioning

confidence: 99%

Multimodal image coregistration and inducible selective cell ablation to evaluate imaging ligands

Virostko

Henske

Vinet

et al. 2011

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

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We combined multimodal imaging (bioluminescence, X-ray computed tomography, and PET), tomographic reconstruction of bioluminescent sources, and two unique, complementary models to evaluate three previously synthesized PET radiotracers thought to target pancreatic beta cells. The three radiotracers {[ 18 F]fluoropropyl-(+)-dihydrotetrabenazine ([ 18 F]FP-DTBZ), [ 18 F](+)-2-oxiranyl-3-isobutyl-9-(3-fluoropropoxy)-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinoline ( 18 F-AV-266), and (2S,3R, 11bR)-9-(3-fluoropropoxy)-2-(hydroxymethyl)-3-isobutyl-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol ( 18 F-AV-300)} bind vesicular monoamine transporter 2. Tomographic reconstruction of the bioluminescent signal in mice expressing luciferase only in pancreatic beta cells was used to delineate the pancreas and was coregistered with PET and X-ray computed tomography images. This strategy enabled unambiguous identification of the pancreas on PET images, permitting accurate quantification of the pancreatic PET signal. We show here that, after conditional, specific, and rapid mouse beta-cell ablation, beta-cell loss was detected by bioluminescence imaging but not by PET imaging, given that the pancreatic signal provided by three PET radiotracers was not altered. To determine whether these ligands bound human beta cells in vivo, we imaged mice transplanted with luciferase-expressing human islets. The human islets were imaged by bioluminescence but not with the PET ligands, indicating that these vesicular monoamine transporter 2-directed ligands did not specifically bind beta cells. These data demonstrate the utility of coregistered multimodal imaging as a platform for evaluation and validation of candidate ligands for imaging islets.diabetes | insulin | molecular imaging | pancreatic islet | bioluminescence tomography

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Measurements of Insulin Secretory Capacity and Glucose Tolerance to Predict Pancreatic β-Cell Mass In Vivo in the Nicotinamide/Streptozotocin Göttingen Minipig, a Model of Moderate Insulin Deficiency and Diabetes

Cited by 54 publications

References 41 publications

Reduction of beta cell mass: partial insulin secretory compensation from the residual beta cell population in the nicotinamide?streptozotocin G�ttingen minipig after oral glucose in vivo and in the perfused pancreas

Reduction of beta cell mass: partial insulin secretory compensation from the residual beta cell population in the nicotinamide?streptozotocin G�ttingen minipig after oral glucose in vivo and in the perfused pancreas

Acute insulin response of donors is correlated with pancreatic islet isolation outcome in the pig

Multimodal image coregistration and inducible selective cell ablation to evaluate imaging ligands

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