Differential volumetry of A,B and D cells in the pancreatic islets of diabetic and nondiabetic subjects.

Saito, Ken; Yaginuma, Nobuhisa; Takahashi, Tohru

doi:10.1620/tjem.129.273

Cited by 129 publications

(78 citation statements)

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“…The present study forms an interesting parallel to the finding of a decreased islet volume in human Type 2 (non-insulin-dependent) diabetes [13,14] and increased islet volume in obese non-diabetic subjects [15]. It may be implied, as proposed previously from these observations [16,17], that Type 2 diabetes develops only in those individuals who have a diminished capacity for islet cell regeneration.…”

Section: Discussionsupporting

confidence: 85%

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

Swenne

Andersson

1984

Diabetologia

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Summary. Proliferation of islet cells may compensate for bothan increased peripheral insulin resistance and islet cell destruction but the capacity for regeneration may be genetically determined. For the latter reason, glucose-stimulated islet cell replication was estimated in both inbred C57BL/6J (BL/6) and C57BL/KsJ (BL/Ks) mice. Islets isolated from both strains were exposed to high concentrations of glucose in vitro or in vivo for a prolonged time period. This was achieved either by culturing the islets free-floating in a high glucose concentration medium for 3 days or implanting the islets intrasplenically in insufficient numbers to cure alloxan-diabetic syngeneic recipients. In both strains high glucose concentration culture was found to increase the autoradiographic labelling index of the islets but the replicatory activity decreased with age. The proliferative rate of the islet cells of the BL/6 mice was about twice as high as that of the BL/Ks mice irrespective of age and glucose concentration. Likewise, the labelling index of intrasplenic BL/6 islets implanted into alloxan-diabetic mice was twice as high as that of the islets implanted into alloxan-diabetic BL/Ks mice. The replicatory activity of the latter islets did not differ statistically from that of islets implanted into non-diabetic control BL/Ks mice. No differences in the rates of proinsulin and total protein biosynthetic rates were observed between high glucose concentration-cultured islets of the two mouse strains. The present resuits indicate that the proliferative response of pancreatic islets to a prolonged glucose stimulation may be genetically determined. This may play a significant role in the development of different diabetic syndromes both in laboratory animals and man.Key words: Inbred mouse strains, alloxan diabetes, islet culture, islet implantation, islet cell replication, autoradiographic labelling index, proinsulin biosynthesis.We have reported that intrasplenic transplantation of syngeneic pancreatic islets isolated from lean mice failed to cure obese hyperglycaemic mice, despite a considerable growth of the grafted islets [1]. In an attempt to elucidate the influence of hyperglycaemia on the growth of these islet grafts, syngeneic islets in numbers insufficient to cure diabetes (approximately 150) were implanted into alloxan-diabetic mice of two different inbred strains, C57BL/6J (BL/6) and C57BL/KsJ (BL/ Ks) [2]. The volume of the islets implanted intrasplenically into alloxan-diabetic BL/Ks mice decreased markedly, whereas that of islets implanted into BL/6 mice was usually unaffected. Some mice of the latter strain, however, became normoglycaemic and indeed, in these particular mice an increase of the volume of the implanted islets was found.The present study was carried out in order to elucidate to what extent a difference in islet cell replicatory activity of these two mouse strains contributes to the fate of intrasplenically implanted islets. For this purpose islets either were exposed to a high glucose environment in v...

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Section: Discussionsupporting

confidence: 85%

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

Swenne

Andersson

1984

Diabetologia

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“…At 3 wk (n = 7) and at 6 wk (n = 4) after pancreatectomy this difference was apparent at 30 min and at 50 min after glucose injection (P < 0.01). Worsening of glucose tolerance was apparent in the 90% group after 6 wk, as depicted by the 50-min determination (6 wk 436±59 vs. 3 wk 342±16 mg/dl, P < 0.01). This abnormality of glucose tolerance has been associated with impaired insulin secretion in previous studies (31).…”

Section: Methodsmentioning

confidence: 88%

“…In noninsulin-dependent diabetes mellitus the deficit of insulin production is less well characterized. Reductions of B cell number (6,7) and of extractable pancreatic insulin (8,9) have been observed at autopsy, although these findings have not been consistent (3)(4)(5) and their functional significance is unknown. Insulin resistance has been shown to be important in increasing the metabolic demands for insulin, but pathogenetic relationships between insulin sensitivity and capacity to produce insulin remain unclear (10).…”

Section: Introductionmentioning

confidence: 99%

“…Despite an appreciation of the importance of insulin production, there has been no adequate quantitative assessment of capacity to produce insulin in humans. In insulin-dependent diabetes mellitus a deficit in insulin production has been established by the loss of endogenous insulin secretion (1,2), and by a paucity of B cells in pancreas at autopsy (3)(4)(5)(6). In noninsulin-dependent diabetes mellitus the deficit of insulin production is less well characterized.…”

Section: Introductionmentioning

confidence: 99%

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Modulation of proinsulin messenger RNA after partial pancreatectomy in rats. Relationships to glucose homeostasis.

Orland¹,

Chyn²,

Permutt³

1985

J. Clin. Invest.

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These studies of partial pancreatectomy assess pancreatic proinsulin messenger RNA (mRNA) levels as an index of in vivo insulin biosynthesis, and show relationships to glucose homeostasis. Rats were subjected to sham operation, 50% pancreatectomy (Px), or 90% Px, and were examined after 1, 3, or 14 wk. Proinsulin mRNA was measured by dot hybridization to complementary DNA. After 50% Px there was a nearly complete adaptation of proinsulin mRNA. After 90% Px a marked increase of proinsulin mRNA occurred, but it was insufficient and it was not maintained with time. The deficit in insulin production is related to development of hyperglycemia.Sham-operated controls showed no worsening of fasting or fed blood glucose or of intraperitoneal glucose tolerance within the period of observation. Total proinsulin mRNA and pancreatic insulin content rose in proportion to body weight. 50% PN produced no change from controls in body weight or blood glucose. The concentration of proinsulin mRNA in the 50% pancreatic remnant paralleled that of controls after 1 and 3 wk, but then increased after 14 wk, such that total proinsulin mRNA approached control levels. This adaptive response was reflected by changes in serum insulin, but not by pancreatic insulin content, which was only 30% of control after 14 wk. Intraperitoneal glucose tolerance was impaired mildly, and did not worsen with time after pancreatectomy.90% Px led to elevated fed blood glucose and reduced serum insulin after 3 wk, and fasting hyperglycemia was seen after 14 wk. Proinsulin mRNA concentration in the 10% pancreatic remnant showed an adaptive increase after 1 and 3 wk, such that total proinsulin mRNA reached 40% of control. After 14 wk, however, remnant proinsulin mRNA concentration was no longer increased; total proinsulin mRNA and pancreatic insulin content were severely reduced. Intraperitoneal glucose tolerance was impaired more dramatically than with the 50% Px animals, and worsened with time after operation.These observations indicate ability to increase proinsulin mRNA levels as an adaptation to pancreatectomy. Insufficiency of this adaptation is associated with the development of hyperglycemia, and the loss of this adaptation correlates with a worsening of glucose tolerance.

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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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Differential volumetry of A,B and D cells in the pancreatic islets of diabetic and nondiabetic subjects.

Cited by 129 publications

References 14 publications

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

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

Modulation of proinsulin messenger RNA after partial pancreatectomy in rats. Relationships to glucose homeostasis.

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

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