Imaging changes in the pancreas can provide valuable information about the status of islet beta-cell function in different pancreatic diseases, such as diabetes, pancreatitis, pancreatic cancer, fatty pancreas, and insulinoma. While imaging cannot directly measure beta-cell function; it can be used as a marker of disease progression and a tool to guide therapeutic interventions. As imaging technologies continue to advance, they will likely play an increasingly important role in diagnosing, monitoring, and managing diabetes.

In type 1 diabetes (T1D), immune-cell infiltration into islets of Langerhans (insulitis) and β-cell decline occur years before diabetes presents. There is a lack of validated clinical approaches for detecting insulitis and β-cell decline, to diagnose eventual diabetes and monitor the efficacy of therapeutic interventions. We previously determined that contrast-enhanced ultrasound measurements of pancreas perfusion dynamics predict disease progression in T1D pre-clinical models. Here, we test whether these measurements predict therapeutic prevention of T1D. We performed destruction-reperfusion measurements with size-isolated microbubbles in non-obese diabetic (NOD)-severe combined immunodeficiency (SCID) mice receiving an adoptive transfer of diabetogenic splenocytes. Mice received vehicle control or the following treatments: (i) anti-CD3 to block T-cell activation; (ii) anti-CD4 to deplete CD4+ T cells; (iii) verapamil to reduce β-cell apoptosis; or (iv) tauroursodeoxycholic acid (TUDCA) to reduce β-cell endoplasmic reticulum stress. We compared measurements of pancreas perfusion dynamics with subsequent progression to diabetes. Anti-CD3, anti-CD4, and verapamil delayed diabetes development. Blood flow dynamics was significantly altered in treated mice with delayed/absent diabetes development compared with untreated mice. Conversely, blood flow dynamics in treated mice with unchanged diabetes development was similar to that in untreated mice. Thus, measurement of pancreas perfusion dynamics predicts the successful prevention of diabetes. This strategy may provide a clinically deployable predictive marker for therapeutic prevention in asymptomatic T1D.

Translational medicine, experimental medicine and experimental animal models, in particular mice and rats, represent a multidisciplinary field that has made it possible to achieve, in the last decades, important scientific progress. In this review, we have summarized the most frequently used imaging animal models, such as ultrasound (US), micro-CT, MRI and the optical imaging methods, and their main implications in diagnostic and therapeutic fields, with a particular focus on diabetes mellitus, a multifactorial disease extremely widespread among the general population.

Type 1 diabetes (T1D) results from immune infiltration and destruction of insulin-producing β cells within the pancreatic islets of Langerhans (insulitis). Early diagnosis during presymptomatic T1D would allow for therapeutic intervention prior to substantial β-cell loss at onset. There are limited methods to track the progression of insulitis and β-cell mass decline. During insulitis, the islet microvasculature increases permeability, such that submicron-sized particles can extravasate and accumulate within the islet microenvironment. Ultrasound is a widely deployable and cost-effective clinical imaging modality. However, conventional microbubble contrast agents are restricted to the vasculature. Submicron nanodroplet (ND) phase-change agents can be vaporized into micron-sized bubbles, serving as a microbubble precursor. We tested whether NDs extravasate into the immune-infiltrated islet microenvironment. We performed ultrasound contrast-imaging following ND infusion in nonobese diabetic (NOD) mice and NOD;Rag1ko controls and tracked diabetes development. We measured the biodistribution of fluorescently labeled NDs, with histological analysis of insulitis. Ultrasound contrast signal was elevated in the pancreas of 10-wk-old NOD mice following ND infusion and vaporization but was absent in both the noninfiltrated kidney of NOD mice and the pancreas of Rag1ko controls. High-contrast elevation also correlated with rapid diabetes onset. Elevated contrast was also observed as early as 4 wk, prior to mouse insulin autoantibody detection. In the pancreata of NOD mice, infiltrated islets and nearby exocrine tissue were selectively labeled with fluorescent NDs. Thus, contrast ultrasound imaging with ND phase-change agents can detect insulitis prior to diabetes onset. This will be important for monitoring disease progression, to guide and assess preventative therapeutic interventions for T1D.

In type1 diabetes (T1D) autoreactive T-cells infiltrate the islets of Langerhans, depleting insulin-secreting β-cells (insulitis). Insulitis arises during an asymptomatic phase, prior to clinical diagnosis of T1D. Methods to diagnose insulitis and β-cell mass changes during this asymptomatic phase are limited, precluding early therapeutic intervention. During T1D the islet microvasculature increases permeability, allowing nanoparticles to access the microenvironment. Contrast enhanced ultrasound (CEUS) uses shell-stabilized gas bubbles to provide acoustic backscatter in vasculature. Here, we report that sub-micron sized 'nanobubble' ultrasound contrast agents can be used to measure increased islet microvasculature permeability and indicate asymptomatic T1D. Through CEUS and histological analysis, pre-clinical models of T1D show accumulation of nanobubbles specifically within pancreatic islets, correlating with insulitis. Importantly, accumulation is detected early in disease progression and decreases with successful therapeutic intervention. Thus, sub-micron sized nanobubble ultrasound contrast agents provide a predicative marker for disease progression and therapeutic reversal early in asymptomatic T1D.

Diabetes is a chronic non-communicable disease affecting over 400 million people worldwide. Diabetic patients are at a high risk of various complications, such as cardiovascular, renal, and other diseases. The pathogenesis of diabetes (both type 1 and type 2 diabetes) is associated with a functional impairment of pancreatic β-cells. Consequently, most efforts to manage and prevent diabetes have focused on preserving β-cells and their function. Advances in imaging techniques, such as magnetic resonance imaging, magnetic resonance spectroscopy, positron emission tomography, and single-photon-emission computed tomography, have enabled noninvasive and quantitative detection and characterization of the population and function of β-cells in vivo. These advantages aid in defining and monitoring the progress of diabetes and determining the efficacy of anti-diabetic therapies. Beyond β-cell targeting, molecular imaging of biomarkers associated with the development of diabetes, e.g., lymphocyte infiltration, insulitis, and metabolic changes, may also be a promising strategy for early detection of diabetes, monitoring its progression, and occurrence of complications, as well as facilitating exploration of new therapeutic interventions. Moreover, molecular imaging of glucose uptake, production and excretion in specified tissues is critical for understanding the pathogenesis of diabetes. In the current review, we summarize and discuss recent advances in noninvasive imaging technologies for imaging of biomarkers beyond β-cells for early diagnosis of diabetes, investigation of glucose metabolism, and precise diagnosis and monitoring of diabetic complications for better management of diabetic patients.

To examine pancreatic volume (PV) changes among patients with different duration of type 2 diabetes and whether pancreatic atrophy was associated with loss of insulin secretory capacity.

This cross-sectional study (203 patients with type 2 diabetes, 93 controls without diabetes) was conducted from January 2016 to December 2017. Patients with type 2 diabetes were divided into 3 groups: recently diagnosed (duration ≤ 2 years), midterm (duration 3-9 years), and long term (duration ≥ 10 years). All the patients were scanned with upper abdominal computerized tomography; PV was then calculated by an experienced technician. Absolute insulin deficiency was defined as fasting C - peptide < 0.9 ng/mL.

Compared with PV (cm³) in the controls, the mean PV was similar in patients with recently diagnosed type 2 diabetes (68.8 versus 71.0, P = 0.56) but significantly reduced in patients with midterm (68.8 versus 60.8, P < 0.05) and long-term (68.8 versus 53.1, P < 0.001) type 2 diabetes. A similar trend was observed for the PV index (PV adjusted for body surface area and body mass index). Furthermore, rates of pancreatic atrophy and absolute insulin deficiency increased with duration of diabetes. Multiple logistic regression analysis indicated that pancreatic atrophy was associated with higher likelihood of absolute insulin deficiency (odds ratio = 4.47, 95%confidence interval = 1.45-13.8).

PV was reduced in those with midterm and long-term type 2 diabetes compared to individuals without type 2 diabetes. Overall, pancreatic atrophy was associated with the loss of insulin secretory capacity in patients with type 2 diabetes.

In type 1 diabetes (T1D), immune-cell infiltration into the islets of Langerhans (insulitis) and β-cell decline occurs many years before diabetes clinically presents. Non-invasively detecting insulitis and β-cell decline would allow the diagnosis of eventual diabetes, and provide a means to monitor therapeutic intervention. However, there is a lack of validated clinical approaches for specifically and non-invasively imaging disease progression leading to T1D. Islets have a denser microvasculature that reorganizes during diabetes. Here we apply contrast-enhanced ultrasound measurements of pancreatic blood-flow dynamics to non-invasively and predictively assess disease progression in T1D pre-clinical models. STZ-treated mice, NOD mice, and adoptive-transfer mice demonstrate altered islet blood-flow dynamics prior to diabetes onset, consistent with islet microvasculature reorganization. These assessments predict both time to diabetes onset and future responders to antiCD4-mediated disease prevention. Thus contrast-enhanced ultrasound measurements of pancreas blood-flow dynamics may provide a clinically deployable predictive marker for disease progression in pre-symptomatic T1D and therapeutic reversal.