Project description:This dataset consists of single-cell RNA-seq (10X) data from disperesed pancreatic islets of healthy and STZ induced diabetic mice. STZ (Sigma) was injected intraperitoneally in 8-week old male C57BLJ/6 mice at 50 mg/kg for five consecutive days. Islets were isolated from healthy mice and STZ diabetic mice after 100 days of either vehicle or drug treatment.
Project description:Gastric bypass surgery (GBP) emerging as a powerful tool for treatment of obesity has been applied for remission of diabetes. However, the GBP global molecular effects on diabetes remission independent of weight loss remain largely unknown. We profiled plasma metabolites and proteins of 10 normoglycemic obese (NO) and 9 diabetic obese (DO) patients at 1-week, 3-months and 1-year stages after Roux-en-Y gastric bypass (RYGB) as well pre-RYGB stage, by which 146 proteins and 128 metabolites were detected from both NO and DO groups at all four stages. By analyzing a set of bi-molecular associations among the corresponding network of the subjects with our newly developed computational method, we defined the representing physiological states (called the edge-states, in contrast to the traditional node-states) and the related molecular networks of NO and DO patients, respectively. The PCA results and hubnetworks of NO subjects were significantly different from those of DO patients; particularly, the hub-network rearrangement of both groups differentially went through after RYGB. In conclusion, by developing network-based systems signatures rather than relying on individual molecules, we for the first time reveal that RYGB generates a unique recovering-path for diabetes remission independent of weight loss.
Project description:In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the hypothalamus was recently identified as a key target for this effect. To investigate how FGF1 action in this brain area achieves this effect, we combined single-nucleeus RNA sequencing (RNA-seq) with single-cell and traditional RNA-seq to identify >70,000 single-cell transcriptomes from the hypothalamus of diabetic Lepob/ob mice obtained on Days 1, 5 and 42 after icv injection of either FGF1 or vehicle. In addition to robust transcriptomics effects on Agrp neurons, which persisted through Day 42, rapid inhibition of Agrp neurons by FGF1 was shown by both electrophysiology and cFos studies. This effect is predicted to increase hypothalamic melanocortin signaling, and we show that FGF1-induced diabetes remission is melanocortin-dependent, as it was prevented by either genetic or pharmacological blockade of central melanocortin receptors. Combined with dramatic transcriptional and morphological changes induced by icv FGF1 injection in tanycytes, astrocytes and oligodendrocytes, including increased cellular contacts between astrocytes and Agrp neurons, these findings implicate glial-neuron interactions as mediators of the sustained remission of diabetes induced by the hypothalamic action of FGF1 action.
Project description:Type 1 diabetes is a progressive autoimmune disease with unknown etiology. Although the destruction of β-cells is recognized as an irreversible process, many type 1 diabetes patients experience the partial remission stage characterized by spontaneous and transient recovery of β-cell function. However, a comprehensive understanding of immune disturbances in the progression of type 1 diabetes as well as the immunological mechanisms responsible for the partial remission stage remains to be elucidated.
Project description:In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the hypothalamus was recently identified as a key target for this effect. To investigate how FGF1 action in this brain area achieves this effect, we combined single-nucleeus RNA sequencing (RNA-seq) with single-cell and traditional RNA-seq to identify >70,000 single-cell transcriptomes from the hypothalamus of diabetic Lepob/ob mice obtained on Days 1, 5 and 42 after icv injection of either FGF1 or vehicle. In addition to robust transcriptomics effects on Agrp neurons, which persisted through Day 42, rapid inhibition of Agrp neurons by FGF1 was shown by both electrophysiology and cFos studies. This effect is predicted to increase hypothalamic melanocortin signaling, and we show that FGF1-induced diabetes remission is melanocortin-dependent, as it was prevented by either genetic or pharmacological blockade of central melanocortin receptors. Combined with dramatic transcriptional and morphological changes induced by icv FGF1 injection in tanycytes, astrocytes and oligodendrocytes, including increased cellular contacts between astrocytes and Agrp neurons, these findings implicate glial-neuron interactions as mediators of the sustained remission of diabetes induced by the hypothalamic action of FGF1 action.
Project description:The capacity of the brain to elicit sustained remission of hyperglycemia in rodent models of type 2 diabetes (T2D) following intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) is well established. Here, we show that icv FGF1 injection induces signaling by extracellular signal-regulated kinases 1 and 2 (ERK1/2), members of the mitogen-activated protein kinase (MAPK) family in the hypothalamus, and that this activation persists for at least 24h. Further, we show that in diabetic Lepob/ob mice, this prolonged response is required for the sustained antidiabetic action of FGF1, since it is abolished by sustained (but not acute) pharmacologic blockade of hypothalamic MAPK/ERK signaling. We also demonstrate that FGF1 R50E, a FGF1 mutant that activates FGF receptors but induces only transient hypothalamic MAPK/ERK signaling, elicits transient but not sustained glucose lowering. These data implicate sustained hypothalamic MAPK/ERK signaling in the mechanism underlying diabetes remission induced by icv FGF1.
Project description:peripheral blood samples of two leukemia patients in remission were profiled by single cell RNA sequencing approximately 1 year after receiving WT1 specific transgenic T cell therapy, at a time when patients were in clinical remission
Project description:Partial remission (PR) occurs in only half of patients with new-onset type 1 diabetes (T1D) and correspond to a transient period characterized by low daily insulin needs, low glycemic fluctuations and increased endogenous insulin secretion. While identification of newly-onset T1D patients with significant residual beta-cell function may foster patient-specific interventions, reliable predictive biomarkers of PR occurrence currently lack. We analyzed the plasma of children with new-onset T1D to identify biomarkers present at diagnosis that predicted PR at 3 months post-diagnosis. We first performed an extensive shotgun proteomic analysis using Liquid Chromatography-Tandem-Mass-Spectrometry (LCMS/MS) on the plasma of 16 children with new-onset T1D and quantified nearly 1500 unique proteins with 98 significantly correlating with Insulin-Dose Adjusted glycated hemoglobin A1c score (IDAA1C). We next applied a series of both qualitative and statistical filters that yielded to the selection of 26 protein candidates that were associated to pathophysiological mechanisms related to T1D. Finally, we translationally validated several of the candidates using single-shot targeted proteomic (PRM method) on raw plasma. Taken together, we identified plasmatic biomarkers present at diagnosis that may predict the occurrence of PR in a single mass-spectrometry run. We believe that the identification of new predictive biomarkers of PR and β-cell function is key to stratify patients with new-onset T1D for β-cell preservation therapies