β-Cell Deficit and Increased β-Cell Apoptosis in Humans With Type 2 Diabetes

Butler, Alexandra E.; Janson, Juliette; Bonner-Weir, Susan; Ritzel, Robert; Rizza, Robert A.; Butler, Peter C.

doi:10.2337/diabetes.52.1.102

Cited by 3,621 publications

(3,304 citation statements)

References 59 publications

(69 reference statements)

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“…Beta cell replication in adult human pancreas is rare (∼1 positive cell in 20 islets, corresponding to a frequency of ∼0.001%) [7,10,[13][14][15]. However, the present report reveals a more than 100-fold increased frequency (0.69% Ki67-positive beta cells) in an 89-year-old man with recentonset type 1 diabetes.…”

Section: Discussioncontrasting

confidence: 63%

“…Despite the marked increase in beta cell replication, the number of beta cells was decreased to ∼20-30% of normal in this case [10,11]. The mechanism subserving this was presumably the increased beta cell apoptosis, now confirmed in freshly fixed pancreas tissue.…”

Section: Discussionmentioning

confidence: 56%

“…2 and 3). The average number of CD4- The fractional beta cell area in the tumour-free pancreas sections of the patients was 0.54±0.2% of the total pancreatic area, corresponding to a deficit of ∼70-80% in fractional beta cell area compared with lean non-diabetic individuals [10,11]. Again, there was a large degree of heterogeneity between different pancreas blocks (range 0.014-1.12%).…”

Section: Resultsmentioning

confidence: 92%

“…The physical examination was normal except for patches of vitiligo on his chest. Thyroid function tests revealed a mildly elevated concentration of thyroid-stimulating hormone (5.07 μIU/ml; normal range 0.46-4.68 μIU/ml), normal free T4 (13.4 10.8% (normal range 4.4-5.9%), glucosuria 4+ on urinalysis, and high titres of islet autoantibodies (GAD 65 antibodies, 65 U/ml; normal range <0.5 U/ml; ICA-512, 49 U/ml; normal range <1 U/ml). The plasma C-peptide measured when the plasma glucose was 12.7 mmol/l was undetectable (limit of detection 0.5 ng/ml [1.5 nmol/l], reference range at normal fasting glucose 0.36-1.52 nmol/l [1.1-4.6 ng/ml]).…”

Section: Case Historymentioning

confidence: 99%

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Direct evidence of attempted beta cell regeneration in an 89-year-old patient with recent-onset type 1 diabetes

Meier¹,

Lin

Butler³

et al. 2006

Diabetologia

169

113

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Aims/hypothesis We investigated whether there was evidence of attempted beta cell regeneration in the pancreas obtained from a patient with recent-onset type 1 diabetes, and if so by what mechanism this occurred. Subjects, materials and methods We examined pancreas tissue from a lean 89-year-old patient (BMI 18.0 kg/m 2 ) with recent-onset type 1 diabetes who had had a distal pancreatectomy to remove a low-grade pancreatic intraepithelial neoplasia. Results In the tumour-free tissue, the fractional beta cell area was 0.54±0.2% of pancreas area (about one-third of that in non-diabetic humans). CD3-positive T lymphocytes and macrophages had infiltrated the majority of the islets. Subclassification of the T cell population revealed a predominance of CD8-positive cells over CD4-positive cells. Beta cell apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling [TUNEL] staining) was greatly increased, consistent with ongoing immune-mediated beta cell destruction. There was also a marked increase (more than ∼100-fold) in the frequency of beta cell replication (0.69±0.15% Ki67-positive beta cells) in all blocks examined. Conclusions/interpretationThe present report provides direct evidence of attempted beta cell regeneration through the mechanism of beta cell replication in a case of newly diagnosed type 1 diabetes, and affirms that beta cell apoptosis is an important mechanism for beta cell loss in type 1 diabetes.

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Section: Discussioncontrasting

confidence: 63%

Section: Discussionmentioning

confidence: 56%

Section: Resultsmentioning

confidence: 92%

Section: Case Historymentioning

confidence: 99%

See 2 more Smart Citations

Direct evidence of attempted beta cell regeneration in an 89-year-old patient with recent-onset type 1 diabetes

Meier¹,

Lin

Butler³

et al. 2006

Diabetologia

169

113

View full text Add to dashboard Cite

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“…In addition to reduced insulin action and beta cell function, a reduction in beta cell mass is also thought to be a key factor in type 2 diabetes [10,15]; however, the extent to which this is involved in the development of the disease remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

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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