Blood Glucose Levels Regulate Pancreatic β-Cell Proliferation during Experimentally-Induced and Spontaneous Autoimmune Diabetes in Mice

Pechhold, Klaus; Koczwara, Kerstin; Zhu, Xiaolong; Harrison, Victor S.; Walker, Greg F.; Lee, Janet; Harlan, David M.

doi:10.1371/journal.pone.0004827

Cited by 33 publications

(31 citation statements)

References 58 publications

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“…We demonstrate that the subsequent phase of hyperglycemia after immune intervention induces islet mass expansion by hypertrophy and hyperplasia of b-cells, emphasizing the role of glucose as an inducer of b-cell proliferation (33)(34)(35). At the same time, the hyperglycemic environment prevents refilling of granular stores and functional recovery.…”

Section: Discussionmentioning

confidence: 86%

Distinct Roles of β-Cell Mass and Function During Type 1 Diabetes Onset and Remission

et al. 2015

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Cure of type 1 diabetes (T1D) by immune intervention at disease onset depends on the restoration of insulin secretion by endogenous b-cells. However, little is known about the potential of b-cell mass and function to recover after autoimmune attack ablation. Using a longitudinal in vivo imaging approach, we show how functional status and mass of b-cells adapt in response to the onset and remission of T1D. We demonstrate that infiltration reduces b-cell mass prior to onset and, together with emerging hyperglycemia, affects b-cell function. After immune intervention, persisting hyperglycemia prevents functional recovery but promotes b-cell mass increase in mouse islets. When blood glucose levels return to normoglycemia b-cell mass expansion stops, and subsequently glucose tolerance recovers in combination with b-cell function. Similar to mouse islets, human islets exhibit cell exhaustion and recovery in response to transient hyperglycemia. However, the effect of hyperglycemia on human islet mass increase is minor and transient. Our data demonstrate a major role of functional exhaustion and recovery of b-cells during T1D onset and remission. Therefore, these findings support early intervention therapy for individuals with T1D.Successful therapy at the onset of type 1 diabetes (T1D) not only requires an effective block of the pathological autoimmune process, but also the restoration of adequate insulin levels. Most promising for optimal glucose control is endogenous b-cell activity, which even at low levels reduces the risk for complications and hypoglycemic events (1). Therefore, preserved b-cell function and mass at diagnosis and their potential to recover after immune intervention are a crucial aspect of T1D therapy. Initially, b-cell mass was suggested to be almost completely destroyed at T1D onset (2,3), which questioned the justification of immune intervention at this late time point (4). However, more recent data demonstrate preserved b-cell mass and function in patients with newly diagnosed (5-7) and long-standing T1D (8,9). These observations raise the question of whether immune intervention at T1D onset will allow functional and morphological recovery of the residual b-cells. Indications of a potential recovery are the so-called "honeymoon phase" observed after initial insulin treatment (10), as well as the reported detection of b-cell proliferation in patients with T1D (11). However, it is unclear if b-cell mass and function have the capability to recover after immune intervention, and their distinct roles in the remission process have not been shown.Here we take advantage of a noninvasive in vivo imaging platform (12,13), and the possibility of successful immune intervention in mouse models of T1D (14), to study functional and morphological changes of b-cells and islets during the onset and remission of T1D. Our results demonstrate substantial morphological and functional b-cell plasticity before and after immune intervention. We furthermore show that b-cell mass and function differentially progress duri...

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Section: Discussionmentioning

confidence: 86%

Distinct Roles of β-Cell Mass and Function During Type 1 Diabetes Onset and Remission

et al. 2015

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“…This phenomenon of a temporary improvement in islet function has been observed previously (6), and there are several studies showing increased cell replication before onset of T1D (7-10). The autoimmune attack with the inflammatory cell response has been suggested to be responsible for this stimulated cell proliferation (7)(8)(9)(10).…”

Section: Discussionmentioning

confidence: 99%

Lowering apolipoprotein CIII delays onset of type 1 diabetes

Holmberg

Refai

Höög

et al. 2011

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

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Serum levels of apolipoprotein CIII (apoCIII) are increased in type 1 diabetic patients, and when β cells are exposed to these diabetic sera, apoptosis occurs, an effect abolished by an antibody against apoCIII. We have investigated the BB rat, an animal model that develops a human-like type 1 diabetes, and found that apoCIII was also increased in sera from prediabetic rats. This increase in apoCIII promoted β-cell death. The endogenous levels of apoCIII were reduced by treating prediabetic animals with an antisense against this apolipoprotein, resulting in a significantly delayed onset of diabetes. ApoCIII thus serves as a diabetogenic factor, and intervention with this apolipoprotein in the prediabetic state can arrest disease progression. These findings suggest apoCIII as a target for the treatment of type 1 diabetes.W e have previously shown that there is a group of patients with type 1 diabetes (T1D) whose sera induce an increased activity of voltage-gated Ca 2+ channels in pancreatic β cells, resulting in increased cytoplasmic free Ca 2+ concentration ([Ca 2+ ] i ) and apoptosis (1). T1D serum was found to contain increased concentrations of apolipoprotein CIII (apoCIII), and we could later demonstrate that this serum factor was responsible for the [Ca 2+ ] i increase and β-cell death in vitro (2). Consequently, the effects of both T1D serum and apoCIII on [Ca 2+ ] i and β-cell death are abolished when β cells are coincubated with an antibody against apoCIII (2).To clarify the extent to which apoCIII is also involved in β-cell death in vivo, we have used the animal model diabetes-prone BB rat (DPBB), which spontaneously, at around the age of 60 d, develops T1D that resembles the human form of the disease (3, 4). Diabetes-resistant BB rats (DRBB) were developed from selective breeding from diabetes-prone (DP) forebears and were used as controls (5).This model gives an opportunity to study the impact of prediabetic interventions to prevent or delay onset of the disease. In this study, three prediabetic age groups (40, 50, and 60 d) were investigated both in vitro and in vivo, and we could demonstrate that lowering the endogenous levels of apoCIII by antisense treatment markedly delayed onset of diabetes. ResultsMorphological and Immunohistochemical Characterization. Qualitative morphological analysis showed that pancreas taken from prediabetic rats at the age of 40 d had a lower number of insulincontaining cells than the age-matched controls. The shape of the islets was round to oval with an intact thin layer of collagen around the islets. No inflammation was seen (Fig. 1A). At the age of 50 d, the number of insulin-containing cells did not differ compared with islets from control rats. Islet shape and border did not differ from control rats. No inflammation was seen (Fig. 1B). At 60 d of age, there was a clear decrease in the number of insulin-positive cells. The shape of the islet was irregular, and in some islets, exocrine cells were found. There was no distinct border between the islets and the surroun...

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“…CamkIV is also expressed by pancreatic beta cells [24], but its roles in beta cells have not been fully defined. Earlier reports that glucose and GLP-1 receptor agonists regulate beta cell mass through CREBand IRS2-dependent inhibition of apoptosis and stimulation of proliferation [17,18,21,26,[38][39][40][41] led us to examine the role of the CaMK IV -CREB cascade in the regulation of Irs2 expression by beta cells.…”

Section: Discussionmentioning

confidence: 99%

Calcium/calmodulin-dependent kinase IV controls glucose-induced Irs2 expression in mouse beta cells via activation of cAMP response element-binding protein

et al. 2011

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Aims/hypothesis Irs2, which is upregulated by glucose, is important for beta cell plasticity. Cyclic AMP response element-binding protein (CREB) stimulates beta cell Irs2 expression and is a major calcium/calmodulin-dependent kinase (CaMK) IV target in neurons. We therefore hypothesised that CaMK IV mediates glucose-induced Irs2 expression in beta cells via CREB activation. Methods The functions of CaMK IV and CREB were investigated in MIN6 beta cells and mouse islets using the CaMK inhibitor KN62, the calcium chelator bapta-(AM) and the voltage-dependent calcium channel inhibitor nifedipine. Small interfering RNAs were used to silence endogenous CaMK IV production and expression vectors to overproduce constitutively active and dominant negative forms of CaMK IV and CREB. Irs1 and Irs2 expression were determined by quantitative PCR and Western blotting, and the role of CREB was also investigated by assessing its phosphorylation on serine 133.

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Blood Glucose Levels Regulate Pancreatic β-Cell Proliferation during Experimentally-Induced and Spontaneous Autoimmune Diabetes in Mice

Cited by 33 publications

References 58 publications

Distinct Roles of β-Cell Mass and Function During Type 1 Diabetes Onset and Remission

Distinct Roles of β-Cell Mass and Function During Type 1 Diabetes Onset and Remission

Lowering apolipoprotein CIII delays onset of type 1 diabetes

Calcium/calmodulin-dependent kinase IV controls glucose-induced Irs2 expression in mouse beta cells via activation of cAMP response element-binding protein

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