Human clinical trials in type 1 diabetes (T1D) patients using mesenchymal stem cells (MSC) are presently underway without prior validation in a mouse model for the disease. In response to this void, we characterized bone marrow-derived murine MSC for their ability to modulate immune responses in the context of T1D, as represented in NOD mice. In comparison to NOD mice, BALB/c-MSC mice were found to express higher levels of the negative costimulatory molecule PD-L1 and to promote a shift toward Th2-like responses in treated NOD mice. In addition, transfer of MSC from resistant strains (i.e., nonobese resistant mice or BALB/c), but not from NOD mice, delayed the onset of diabetes when administered to prediabetic NOD mice. The number of BALB/c-MSC trafficking to the pancreatic lymph nodes of NOD mice was higher than in NOD mice provided autologous NOD-MSC. Administration of BALB/c-MSC temporarily resulted in reversal of hyperglycemia in 90% of NOD mice (p = 0.002). Transfer of autologous NOD-MSC imparted no such therapeutic benefit. We also noted soft tissue and visceral tumors in NOD-MSC-treated mice, which were uniquely observed in this setting (i.e., no tumors were present with BALB/c- or nonobese resistant mice-MSC transfer). The importance of this observation remains to be explored in humans, as inbred mice such as NOD may be more susceptible to tumor formation. These data provide important preclinical data supporting the basis for further development of allogeneic MSC-based therapies for T1D and, potentially, for other autoimmune disorders.
-Cell dysfunction is an important factor in the development of hyperglycemia of type-2 diabetes mellitus, and pancreatic islet amyloidosis (IA) has been postulated to be one of the main contributors to impaired insulin secretion. The aim of this study was to evaluate the correlation of IA with metabolic parameters and its effect on islets of Langerhans remodeling and relative endocrine-cell volume in baboons. We sequenced the amylin peptide, determined the fibrillogenic propensities, and evaluated pancreatic histology, clinical and biochemical characteristics, and endocrine cell proliferation and apoptosis in 150 baboons with different metabolic status. Amylin sequence in the baboon was 92% similar to humans and showed superimposable fibrillogenic propensities. IA severity correlated with fasting plasma glucose (FPG) (r ؍ 0.662, P < 0.001) and HbA1c (r ؍ 0.726, P < 0.001), as well as with free fatty acid, glucagon values, decreased homeostasis model assessment (HOMA) insulin resistance, and HOMA-B. IA severity was associated with a decreased relative -cell volume, and increased relative ␣-cell volume and hyperglucagonemia. These results strongly support the concept that IA and -cell apoptosis in concert with ␣-cell proliferation and hypertrophy are key determinants of islets of Langerhans ''dysfunctional remodeling'' and hyperglycemia in the baboon, a nonhuman primate model of type-2 diabetes mellitus. The most important determinants of IA were age and FPG (R 2 ؍ 0.519, P < 0.0001), and different FPG levels were sensitive and specific to predict IA severity. Finally, a predictive model for islet amyloid severity was generated with age and FPG as required variables.amyloid deposits ͉ non-human primates ͉ insulin resistance ͉ islet of Langerhans ͉ type-2 diabetes mellitus T ype-2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance in liver, muscle, and adipose tissue, as well as progressive -cell dysfunction leading to hyperglycemia (1-3). Hyperglycemia and islet amyloidosis (IA) have been implicated in the progressive loss of  cells in T2DM (4, 5). The prevalence of IA has been reported to range from 40 to 90% in T2DM individuals, and from 7% to 33% in nondiabetic controls (6 -11). Islet amyloid pancreatic polypeptide (IAPP) is the major constituent of pancreatic amyloid deposits (12, 13). In humans, monkeys, and cats, but not in mice and rats, IAPP has an amyloidogenic-promoting region, which resides within amino acids 20 to 29. Abnormalities in IAPP processing and secretion have been proposed as important contributors to the formation of IA (14 -17). Of note, IA and -cell apoptosis have been observed in normal human islets transplanted into diabetic nude mice, as well as in the liver of type-1 diabetic patients transplanted with human islets (18,19).IA can cause -cell death by occupying extracellular space, thereby impairing nutrients and oxygen uptake. In addition, small IAPP oligomers can form nonselective ion-permeable membrane pores, leading to increased...
Glutamate is the major excitatory neurotransmitter of the central nervous system (CNS) and may induce cytotoxicity through persistent activation of glutamate receptors and oxidative stress. Its extracellular concentration is maintained at physiological concentrations by high affinity glutamate transporters of the solute carrier 1 family (SLC1). Glutamate is also present in islet of Langerhans where it is secreted by the ␣-cells and acts as a signaling molecule to modulate hormone secretion. Whether glutamate plays a role in islet cell viability is presently unknown. We demonstrate that chronic exposure to glutamate exerts a cytotoxic effect in clonal -cell lines and human islet -cells but not in ␣-cells. In human islets, glutamate-induced -cell cytotoxicity was associated with increased oxidative stress and led to apoptosis and autophagy. We also provide evidence that the key regulator of extracellular islet glutamate concentration is the glial glutamate transporter 1 (GLT1). GLT1 localizes to the plasma membrane of -cells, modulates hormone secretion, and prevents glutamate-induced cytotoxicity as shown by the fact that its down-regulation induced -cell death, whereas GLT1 up-regulation promoted -cell survival. In conclusion, the present study identifies GLT1 as a new player in glutamate homeostasis and signaling in the islet of Langerhans and demonstrates that -cells critically depend on its activity to control extracellular glutamate levels and cellular integrity.
Insulin resistance, reduced β-cell mass, and hyperglucagonemia are consistent features in type 2 diabetes mellitus (T2DM). We used pancreas and islets from humans with T2DM to examine the regulation of insulin signaling and cell-cycle control of islet cells. We observed reduced β-cell mass and increased α-cell mass in the Type 2 diabetic pancreas. Confocal microscopy, real-time PCR and western blotting analyses revealed increased expression of PCNA and down-regulation of p27-Kip1 and altered expression of insulin receptors, insulin receptor substrate-2 and phosphorylated BAD. To investigate the mechanisms underlying these findings, we examined a mouse model of insulin resistance in β-cells – which also exhibits reduced β-cell mass, the β-cell-specific insulin receptor knockout (βIRKO). Freshly isolated islets and β-cell lines derived from βIRKO mice exhibited poor cell-cycle progression, nuclear restriction of FoxO1 and reduced expression of cell-cycle proteins favoring growth arrest. Re-expression of insulin receptors in βIRKO β-cells reversed the defects and promoted cell cycle progression and proliferation implying a role for insulin-signaling in β-cell growth. These data provide evidence that human β- and α-cells can enter the cell-cycle, but proliferation of β-cells in T2DM fails due to G1-to-S phase arrest secondary to defective insulin signaling. Activation of insulin signaling, FoxO1 and proteins in β-cell-cycle progression are attractive therapeutic targets to enhance β-cell regeneration in the treatment of T2DM.
OBJECTIVE -Diabetes, hypertension, infections, and nephrotoxicity of certain immunosuppressive drugs (i.e., calcineurin inhibitors) can reduce functional survival of the kidney graft. Our aim was to evaluate survival, hypertrophy, and vascular function of the kidney graft in end-stage renal disease (ESRD) type 1 diabetic patients after transplant. RESEARCH DESIGN AND METHODS -The study population consisted of 234 ESRD type 1 diabetic patients who underwent kidney-pancreas (KP; 166 patients), successful kidney-islet (KI-s; 24 patients), and kidney (KD; 44 patients) transplant. Kidney size, graft survival, vascular function, and microalbuminuria were evaluated prospectively yearly for 6 years. Sixty-eight protocol kidney biopsies were performed routinely between 1993 and 1998 cross-sectionally (3.2 Ϯ 0.3 years from kidney transplant).RESULTS -The KP and KI-s groups had better cumulative kidney graft survival at 6 years than did the KD group (KP: 73%; KI-s: 86%; KD: 42%, P Ͻ 0.01). The KP group but not the KI-s/KD groups showed a persistent kidney graft hypertrophy up to 6 years of follow-up. A significant increase in creatinine levels from baseline to year 6 was evident in the KD group (1.58 Ϯ 0.08 to 2.78 Ϯ 0.44 mg/dl, P Ͻ 0.05) but not in the KP/KI-s groups. The KP/KI-s groups only showed a reduction of renal resistance index from baseline to year 6 (KP at baseline: 0.74 Ϯ 0.01 to 0.68 Ϯ 0.01%, P Ͻ 0.01; KI-s at baseline: 0.72 Ϯ 0.02 to 0.69 Ϯ 0.02%, P Ͻ 0.05). At year 6, an increase from baseline in urinary albumin excretion was observed only in the KD group (31.4 Ϯ 9.0 to 82.9 Ϯ 33.6 mg/l, P Ͻ 0.05). Preliminary data suggested that graft nitric oxide (NO) expression was higher in the KP/KI-s groups than in the KD group (data not shown).CONCLUSIONS -In ESRD type 1 diabetic patients, KP and KI-s compared with KD resulted in enhanced kidney graft survival, hypertrophy, and vascular function. Diabetes Care 28:1303-1310, 2005N ephropathy is one of the most common and most serious complications in type 1 diabetes (1,2). Glomerular hyperfiltration is the first feature of renal involvement and can be observed soon after diabetes onset, accompanied by a loss of renal functional reserve (3). Microalbuminuria appears later, as do morphological changes such as thickening of the glomerular basement membrane and mesangial expansion (4).Nephrosclerosis or glomerulosclerosis of the transplanted kidney in end-stage renal disease (ESRD) type 1 diabetic kidney transplant patients may result from the interaction of diabetes, hypertension, obesity, smoking, and dyslipidemia and from nephrotoxicity of certain immunosuppressive drugs (calcineurin inhibitors but not only) (5-6), leading to a reduction in the intrarenal vascular surface area and an increase in vascular resistance (7-10).Pancreas and islet transplantation can confer insulin independence in type 1 diabetic transplant patients, thus preventing the progression to diabetic nephropathy, improving graft survival, and ameliorating diabetic macro-/microangiopathy (6,(11)(12)(1...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.