Biodritin microencapsulated human islets of Langerhans and their potential for type 1 diabetes mellitus therapy

BACKGROUND: Microencapsulation of pancreatic islets with polymeric compounds constitutes an attractive alternative therapy for type 1 diabetes mellitus. The major limiting factor is the availability of a biocompatible and mechanically stable polymer. We investigated the potential of Biodritin, a novel polymer constituted of alginate and chondroitin sulfate, for islet microencapsulation. METHODS: Biodritin microcapsules were obtained using an air jet droplet generator and gelated with barium or calcium chloride. Microencapsulated rat insulinoma RINm5F cells were tested for viability using the [3-(4,5-dimetyl-thiazol-2-yl)-2,5-diphenyl-tetrazoliumbromide] [MTT] colorimetric assay. Microencapsulated rat pancreatic islets were coincubated with macrophages derived from mouse peritoneal liquid to assess the immunomodulatory potential of the microcapsules, using quantitative real time-PCR (qPCR). Biodritin biocompatibility was demonstrated by subcutaneous injection of empty microcapsules into immunocompetent Wistar rats. Insulin secretion by microencapsulated human pancreatic islets was evaluated using an electrochemoluminescent assay. Microencapsulated human islets transplanted into chemically induced diabetic mice were monitored for reversal of hyperglycemia. RESULTS: The metabolic activity of microencapsulated RINm5F cells persisted for at least 15 days. Interleukin-1beta expression by macrophages was observed during coculture with islets microencapsulated with Biodritin-CaCl2, but not with Biodritin-BaCl2. No statistical difference in glucose-stimulated insulin secretion was observed between nonencapsulated and microencapsulated islets. Upon microencapsulated islet transplantation, the blood glucose level of diabetic mice normalized; they remained euglycemic for at least 60 days, displaying normal oral glucose tolerance tests. CONCLUSION: This study demonstrated that Biodritin can be used for islet microencapsulation and reversal of diabetes; however, further investigations are required to assess its potential for long-term transplantation.     

Optimized parameters for microencapsulation of pancreatic islet cells: an in vitro study clueing on islet graft immunoprotection in type 1 diabetes mellitus

Alginate (AG)-based microcapsules may provide a selective permeable and biocompatible physical barrier to prevent islet graft (TX)-directed immune destruction. However, extent of the achieved immunoprotection will continue to be variable and unpredictable until the role of the individual mechanisms involved with TX-related inflammatory cell and immune reactivity are clarified. Macrophages (M) are believed to play a pivotal role in controlling the host/TX interaction and its consequences. We then have studied the effects of isolated rat M and their secretory products on allogeneic islets enveloped in variably sized and configured microcapsules, within in vitro mixed islet-M cocultures. In particular, we aimed to determine the sequence of immune or not immune specific cascade of early events that derive from such on interaction. One of the specific aims was to assess whether the membrane's physical intactness and conversely its even minimal rupture, along with the microcapsules' size (i.e., large vs. small) would significantly impact M reactivity and, thereby, the encapsulated islet viability and function. Special care was taken to evaluate extent of the elicited reactivity by meticulously monitoring cytokine, N2 derivative, and other proinflammatory protein curve profiles during the early M activation process. The study has preliminarily shown that, for equally formulated microcapsules, the capsular size and membrane's morphologic thoroughness are key to prevent M reactivity and possibly avoid the intracapsular islet cell damage. While elucidation of pathways involved with the encapsulated islet TX-directed host's responsiveness actually is in progress, it has clearly emerged that microcapsules should comply with well-defined physical properties and formulation specifications in order to obviate the primum movens of the inflammatory reaction process.     

Transplantation of macroencapsulated human islets within the bioartificial pancreas βAir to patients with type 1 diabetes mellitus

Macroencapsulation devices provide the dual possibility of immunoprotecting transplanted cells while also being retrievable, the latter bearing importance for safety in future trials with stem cell–derived cells. However, macroencapsulation entails a problem with oxygen supply to the encapsulated cells. The βAir device solves this with an incorporated refillable oxygen tank. This phase 1 study evaluated the safety and efficacy of implanting the βAir device containing allogeneic human pancreatic islets into patients with type 1 diabetes. Four patients were transplanted with 1‐2 βAir devices, each containing 155 000‐180 000 islet equivalents (ie, 1800‐4600 islet equivalents per kg body weight), and monitored for 3‐6 months, followed by the recovery of devices. Implantation of the βAir device was safe and successfully prevented immunization and rejection of the transplanted tissue. However, although beta cells survived in the device, only minute levels of circulating C‐peptide were observed with no impact on metabolic control. Fibrotic tissue with immune cells was formed in capsule surroundings. Recovered devices displayed a blunted glucose‐stimulated insulin response, and amyloid formation in the endocrine tissue. We conclude that the βAir device is safe and can support survival of allogeneic islets for several months, although the function of the transplanted cells was limited (Clinicaltrials.gov: NCT02064309).     

Bone mineral density in patients with type 1 diabetes mellitus

Although osteopenia is often reported as a complication of type 1 diabetes mellitus, its frequency and severity remain unclear, and studies of bone mineral density in type 1 diabetics have yielded conflicting results. We measured bone mineral density at the lumbar spine and femoral neck in 88 Spanish adults with type 1 diabetes mellitus responsible for moderately severe complications. Mean age (+/- SD) was 28.9 +/- 8.8 years, and mean disease duration was 11.2 +/- 6.4 years. As compared to normal Spanish adults, bone mineral density was decreased in the patients at the lumbar spine (Z-score, -0.32 +/- 1.08; P < 0.001) but not at the femoral neck (Z-score, -0.21 +/- 1.03; P non-significant). The magnitude of bone loss in the diabetics was small (T-score, -0.38 +/- 1.13 at the lumbar spine and -0.37 +/- 1.08 at the femoral neck). Only three patients met WHO criteria for osteoporosis at one or both measurement sites. Patients with retinopathy (n = 37) had lower lumbar spine bone mineral density values than patients without retinopathy; however, this difference was no longer present after adjustment for age and disease duration. Bone mineral density values were similar in patients with (n = 13) and without microalbuminuria. Our findings suggest that bone loss is not a major problem in younger type 1 diabetics with short disease durations and no severe diabetic complications.     

Cochlear changes in patients with type 1 diabetes mellitus.

OBJECTIVE: To evaluate the effects of diabetes on cochlear elements in human beings. STUDY DESIGN AND SETTING: Twenty-six temporal bones (mean age, 37.5 years) with type 1 diabetes and 30 age-matched controls were examined by light microscopy. We compared the findings of cochlear vessels, hair cells, spiral ganglion cells, and cochlear lateral walls. RESULTS: In diabetics, the walls of vessels of the basilar membrane (P < 0.001) and vessels of the stria vascularis were (P < 0.01) significantly thicker in all turns and loss of outer hair cells (OHCs) was significantly greater in the lower basal turn (P < 0.01). Atrophy of the stria vascularis in all turns (P < 0.0001) and loss of spiral ligament cells in upper turns (P < 0.01) were significantly higher than controls. No significant difference was obtained in the number of spiral ganglion cells between groups. CONCLUSION: This study suggests that type 1 diabetes mellitus can cause cochlear microangiopathy and subsequently degeneration of cochlear lateral walls and OHCs.     

Outcomes of pancreas transplants for patients with type 2 diabetes mellitus

BACKGROUND: The objective of this study was to examine how effectively pancreas transplants provide long-term glucose control in patients with type 2 diabetes mellitus (DM). We used guidelines from the American Diabetes Association (ADA) and the World Health Organization (WHO) to appropriately classify recipients with type 2 DM (vs. type 1 DM). RESULTS: From 1994 through 2002, a total of 17 patients with type 2 DM underwent a pancreas transplant at our center. Mean recipient age was 52.5 yr. The mean age at diabetes onset was 35.7 yr; mean duration, 16.8 yr. Most recipients had one or more secondary complications related to their diabetes: retinopathy (94%), neuropathy (76%), or nephropathy (65%). At the time of their transplant, three (18%) were on oral hypoglycemic agents alone and 14 (82%) were on insulin therapy. Of the 17 transplants, seven (41%) were a simultaneous pancreas-kidney transplant (SPK); four (24%), pancreas after kidney transplant (PAK); and six (35%), pancreas transplant alone (PTA). One recipient died during the perioperative period because of aspiration. The other 16 recipients became euglycemic post-transplant and had a functional graft at 1 yr post-transplant (patient and graft survival rates, 94%). Now, with a mean follow-up of 4.3 yr post-transplant, the patient survival rate is 71%. The four additional deaths were because of sepsis (n = 2), suicide (n = 1), and unknown cause (n = 1). All four of these recipients were insulin-independent at the time of death, although one was on an oral hypoglycemic agent. Of the 12 recipients currently alive, 11 remain euglycemic without requiring insulin therapy or oral hypoglycemic agents; one began insulin therapy 1.2 yr post-transplant (current daily dose, 60 units). CONCLUSION: These findings suggest that pancreas transplants can provide excellent glucose control in recipients with type 2 DM. All 16 (94%) of our recipients whose transplant was technically successful were rendered euglycemic. Long-term results were comparable with those seen in transplant recipients with type 1 DM.     

2型糖尿病患者有效持续运动时间的研究

目的探讨在明确糖尿病患者个体运动强度下,确定有效持续运动时间及运动方案对2型糖尿病患者糖、脂代谢的影响。方法将70例2型糖尿病患者按入院时间分为观察组和对照组各35例。观察组根据最少运动时间制定有效运动方案,对照组患者采用常规运动方法。比较两组患者空腹血糖、血脂、平均运动时间变化。结果经过4周、5周、6周锻炼后,两组空腹血糖及血脂均呈好转趋势,但两组比较,差异无统计学意义(均P0.05);观察组平均每次运动时间明显短于对照组(P0.01)。结论以最少持续运动时间的运动处方进行运动能获得与长时间锻炼同样的运动效果,有效控制2型糖尿病患者血糖水平,维持血脂稳定。     

Glomerular hemodynamics and the renin-angiotensin system in patients with type 1 diabetes mellitus

BACKGROUND: Many studies have reported that blocking the renin-angiotensin-system (RAS) with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker in the patient with diabetes mellitus leads to an increase in renal plasma flow (RPF), no change in glomerular filtration rate (GFR), and a fall in filtration fraction. This constellation is generally attributed to predominant efferent arteriolar dilation. METHODS: This study examined the renal hemodynamic response to blocking the RAS with both captopril and candesartan on separate days in 31 patients with type 1 diabetes mellitus. RESULTS: There was a wide range of changes in RPF and GFR in response to the two agents, each administered at the top of its dose-response range. The RPF response to the two agents was strongly concordant (r = 0.65; P < 0.001), as was the GFR response (r = 0.81; P < 0.001). Moreover, there was a strong correlation between the RPF response and the change in GFR with each agent (r = 0.83 and 0.66; P < 0.01). A significant rise in RPF was followed by a rise in GFR. The RPF dependency of GFR in the type 1 diabetics suggests strongly that glomerular filtration equilibrium exists in the glomeruli of the diabetic kidney: Simple notions of local control based on afferent:efferent arteriolar resistance ratios are too simplistic. CONCLUSION: Our data suggest that the intrarenal RAS is activated in over 80% of patients with type 1 diabetes mellitus. Abundant evidence suggests that this activation predisposes to diabetic nephropathy.     

Urinary glycosaminoglycan and proteoglycan excretion in normoalbuminuric patients with type 1 diabetes mellitus

BACKGROUND: Diabetic nephropathy may be related to an abnormal metabolism of glycosaminoglycans (GAG) in the glomerular basement membrane (GBM). The first manifestation of nephropathy is microalbuminuria, whose appearance indicates a loss of GBM selectivity. The present study evaluated whether GAG excretion becomes abnormal in parallel with microalbuminuria, and whether such abnormalities are also present in normoalbuminuric diabetic patients. METHODS: We measured urinary GAG excretion in 60 patients with type 1 (insulin-dependent) diabetes mellitus and in 22 healthy subjects. GAG were isolated from 24-h urine using ion-exchange chromatography on DEAE Sephacel. GAG composition was determined by cellulose acetate electrophoresis and expressed as percentages by densitometric scanning of Alcian Blue stained strips. RESULTS: On subgrouping for albuminuric status and glyco-metabolic control, we found high urinary GAG concentrations in all except the normoalbuminuric patients with good glyco-metabolic control. The urinary GAG electrophoretic pattern showed alterations in chondroitin sulphate (CS) and heparan sulphate (HS) relative contents. A higher frequency of low sulphated chondroitin sulphate-proteoglycan (LSC-PG) was observed in all patients, including those with normoalbuminuria and good glyco-metabolic control. CONCLUSIONS: This urinary pattern may be indicative of an abnormal GBM metabolism. Since GAG play an important role in GBM permeability, these anomalies might consequently represent a first step towards selective changes of GBM in type 1 diabetes mellitus.     

Pancreas islet transplantation in patients with type 1 diabetes mellitus after kidney transplantation

Diabetic patients with end-stage renal disease have a high mortality rate. A combined kidney-pancreas transplant is associated with greater life expectancy. Pancreas islet transplantation is an alternative involving a lower degree of morbidity. We present two patients, of 41 and 37 years of age, with a long history of diabetes mellitus (C-peptide negative), both with a previous kidney transplant, who had been treated with 22 and 28 U of insulin/d, respectively. Both patients had frequent episodes of unawareness hypoglycemia. Pancreatic islets were infused to a total of 7809 and 19,180 IE/kg, respectively. Basal posttransplant C peptide levels were 2.9 and 1.3 ng/mL. After the implant, one patient required occasional doses of insulin, and the other patient more than 50% reduced dose. After the first implant neither patient had any episodes of unawareness hypoglycemia. HbA1c at 4 months were 6.2% and 6.9%. There were no transplant-related complications.     

微重力培养的新鲜和冻存胰岛联合移植治疗1型糖尿病

目的经微重力培养的新鲜和冻存胰岛联合移植提高1型糖尿病的治疗效果。方法将分离纯化的大鼠胰岛分为（1）体外实验组：实验组1．1：冻存的胰岛经微重力培养；实验组2．1：冻存的胰岛在普通培养基中培养；对照组1：新鲜大鼠胰岛经微重力培养。观察胰岛收获率和体外胰岛素分泌情况。（2）胰岛移植组：即将新鲜和冻存的胰岛经微重力或普通培养7d后分别移植入受体鼠体内，观察移植效果。结果经微重力培养的各组胰岛收获率、DNA含量和胰岛素含量高于普通组。普通培养组在培养后期胰岛素分泌明显下降，并且胰岛素刺激指数明显低于经微重力培养组（P〈0．05）。移植经过微重力培养的500 IEQ新鲜胰岛和1500 IEQ冻存胰岛在移植后1周内可达100％纠正糖尿病，全部受体维持正常血糖耐受曲线一直到观察结束。结论采用细胞内低温保存液（HTS）结合细胞冻存液（DMSO）对大鼠胰岛进行冻存前后经微重力培养可以明显提高胰岛冻存质量，是目前胰岛冻存的最佳选择。使经微重力培养的新鲜和冻存胰岛联合移植一次治愈糖尿病成为可能，并有效的节约了胰岛资源，提高了移植效果。     

1型糖尿病成年患者长期自我管理体验的质性研究

目的 了解1型糖尿病成年患者5年后自我管理的体验.方法 采用质性研究法,深度访谈10例1型糖尿病成年患者患病5年后糖尿病自我管理体验.结果 提炼出饮食困扰长期存在,并发症感知不一致,内心煎熬,客观指标监测懈怠,治疗技术认知不足,体育锻炼认同不一致6个主题.结论 1型糖尿病成年患者长期自我管理过程中,尚存在饮食管理、知识技能更新等困难,需进一步探寻完善护理干预方案.     

Effects of smoking on renal function in patients with type 1 and type 2 diabetes mellitus.

BACKGROUND: Smoking increases the risk of end-stage renal failure in patients with primary renal disease. Whether and to what extent smoking affects the kidneys in diabetic patients with normal renal function and variable degrees of proteinuria has not been fully studied. METHODS: We followed 185 patients with type 1 or 2 diabetes mellitus and with or without signs of overt renal disease for at least 3 years, median 5.1 (3-6.8) years. Each patient had a baseline visit and at least four follow-up visits (average 4.8+/-0.3). Cases were patients who were smoking (n = 44) at the time the survey was started. Controls were patients who had never smoked (n = 141). Glomerular filtration rate (GFR) was estimated using the MDRD formula. Multiple logistic regression was used to correct for confounding factors. RESULTS: At baseline, smokers were younger (47+/-14 vs 54+/-16 years, P < 0.01), and had a lower GFR (95+/-26 ml/min) than non-smokers (107+/-33 ml/min, P < 0.05). Mean GFR remained constant during follow-up in non-smokers (106+/-31 ml/min), but decreased significantly in smokers (83+/-22 ml/min, P < 0.0001), and this relationship persisted when adjusted for retinopathy, glycaemic control, age, body habitus, ACE-inhibitor treatment, blood pressure control or severity of proteinuria. The effect of smoking on GFR decline was stronger in patients with type 1 diabetes or male gender. CONCLUSIONS: Cigarette smoking causes a decrease in GFR in diabetic patients with normal or near-normal renal function, independent of confounding factors including severity of proteinuria. The latter finding suggests a mechanism independent of glomerular damage.     

微囊化猪胰岛肝动脉内移植治疗犬Ⅰ型糖尿病

目的　观察放射介入方法行微囊化猪胰岛细胞肝动脉肝内移植的可行性及有效性。方法　采用放射介入技术经股动脉穿刺将微囊猪胰岛经肝动脉植入糖尿病模型犬肝内 ,术后监测空腹血糖、C肽、胰岛素用量变化 ,行肝功能、肝脏组织病理学检查。结果　移植后糖尿病犬血清C肽水平升高 2～ 6倍 ,胰岛素用量逐步减少 ,3只犬停用胰岛素并维持空腹血糖正常 ;移植后肝转氨酶一过性升高 ,2周后降至正常。结论　经肝动脉肝内微囊猪胰岛素异种移植治疗移植Ⅰ型糖尿病犬安全、可行。     

2型糖尿病患者合并非糖尿病性肾损害的临床病理分析

目的：了解2型糖尿病合并非糖尿病性肾损害的临床病理特点。方法：总结分析29例2型糖尿病合并非糖尿病肾损害的临床资料、病理改变及治疗反应。结果：2型糖尿病或糖尿病肾病可以合并多种非糖尿病肾损害,以各种类型的原发性及继发性肾小球疾病为主。原发性肾小球疾病常见病理类型有轻度系膜增生性肾小球肾炎、膜性肾病、IgA肾病和微小病变。这些患者具有以下不同于典型糖尿病肾病的特点：（1）糖尿病病程短于5年;（2）大量蛋白尿或肾功能不全时血压正常;（3）急性肾功能衰竭;（4）血尿明显。大部分肾病水平蛋白尿患者经糖皮质激素或糖皮质激素联合细胞毒类药物治疗后可完全缓解.结论：（1）2型糖尿病合并肾损害不等于糖尿病肾病;（2）2型糖尿病可以合并各种非糖尿病性肾损害;（3）当2型糖尿病伴肾脏受累者具有上述不符合糖尿病肾病特征时,应尽早行肾活检明确诊断;（4）在充分考虑患者 的临床特点、病理改变、严格控制血糖及血压的情况下,糖皮质激素或糖皮质激素联合细胞毒类药物治疗是安全有效的,可以改变患者的预后。     

1型糖尿病患者心理健康状况及其干预的研究进展

从1型糖尿病的定义、常见的各种心理状况等方面总结1型糖尿病患者在心理方面存在的问题及其影响因素;综述1型糖尿病患者的心理护理措施以及存在的问题,为1型糖尿病患者的心理护理提供参考。