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

Abstract

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...

Longitudinal three-dimensional visualisation of autoimmune diabetes by functional optical coherence imaging

“…As illustrated in Fig. 3 and as suggested in a previous report [29], transplanted islets were found to be functional and secreting insulin after ACE transplantation. The anatomical organisation of the transplanted islets was intact, with beta cells scattered between alpha and delta cells and distributed over the entire islet volume (Fig 3a).…”

Alterations in β-Cell Calcium Dynamics and Efficacy Outweigh Islet Mass Adaptation in Compensation of Insulin Resistance and Prediabetes Onset

“…For this purpose, we correlated systemic glucose homeostasis with longitudinal in vivo imaging of transplanted islets of Langerhans during diet-induced obesity. Although we cannot exclude potential effects of the different local environment on intraocular islets, our own data and previous studies suggest that the behavior of islets in the anterior chamber of the eye closely resembles that of endogenous pancreatic islets (26,28,(33)(34)(35).…”

“…Prediabetes was defined as significantly increased 2-h blood glucose values at unchanged nonfasting blood glucose levels. Islet isolation and transplantation to the anterior chamber of the eye were performed as previously described (25)(26)(27)(28). Transplanted islets were allowed to engraft fully for at least 4 weeks before the start of any in vivo experiments.…”

“…Transplanted islets were allowed to engraft fully for at least 4 weeks before the start of any in vivo experiments. In vivo imaging was performed as previously described (26). Briefly, islet recipients were intubated and anesthetized by 2% isoflurane in 100% oxygen.…”

Label-free fast 3D coherent imaging reveals pancreatic islet micro-vascularization and dynamic blood flow

“…These endpoint measurements prevent the assessment of the full blood flow dynamics and alterations in identical islets during diabetes progression. In vivo imaging of the vascularization of islets has been achieved through intravital fluorescence microscopy either in the native pancreas [4,17,18], in grafted islets in the anterior chamber of the eye [19][20][21][22][23][24] or in striated muscle by using a dorsal skin-fold window [25][26][27][28]. However, fluorescent microscopy requires both genetically modified mice expressing fluorescent proteins to detect specific cellular populations and the injection of labelled dextran or labelled red blood cells to image the vascularization and quantify blood flow.…”