Hepatic Insulin Gene Therapy in Insulin-Dependent Diabetes Mellitus

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease resulting in destruction of the pancreatic beta-cells in the islets of Langerhans. Commonly employed treatment of IDDM requires periodic insulin therapy, which is not ideal because of its inability to prevent chronic complications such as nephropathy, neuropathy and retinopathy. Although pancreas or islet transplantation are effective treatments that can reverse metabolic abnormalities and prevent or minimize many of the chronic complications of IDDM, their usefulness is limited as a result of shortage of donor pancreas organs. Gene therapy as a novel field of medicine holds tremendous therapeutic potential for a variety of human diseases including IDDM. This review focuses on the liver-based gene therapy for generation of surrogate pancreatic beta-cells for insulin replacement because of the innate ability of hepatocytes to sense and metabolically respond to changes in glucose levels and their high capacity to synthesize and secrete proteins. Recent advances in the use of gene therapy to prevent or regenerate beta-cells from autoimmune destruction are also discussed.     

老年2型糖尿病患者运动疗法中的护理干预

目的 探讨老年2型糖尿病患者在运动疗法中实施护理干预的效果.方法 将70例老年2型糖尿病患者随机分为干预组和对照组各35例.两组均给予饮食、心理疗法及药物治疗.对照组自行锻炼,干预组对运动疗法中的运动方式、强度、时间、时机等进行护理干预.结果 干预1个月后,干预组空腹血糖、餐后2 h血糖、糖化血红蛋白值显著低于对照组(均P＜0.05);同时干预组血压改善明显(均P＜0.05),血糖水平控制总有效率达80.00%(均P＜0.05).结论 对老年2型糖尿病患者的运动疗法实施护理干预,可使运动安全有效,不但减少了降糖药物的用量,缩短疗程,延缓了并发症的发生和发展,而且提高了患者的生活质量.     

2型糖尿病患者饮食治疗依从性研究

目的了解2型糖尿病患者饮食治疗依从性及其影响因素，为进一步有效开展糖尿病患者饮食教育提供依据。方法对3．49例2型糖尿病患者进行饮食治疗依从性及有关疾病知识、健康信念和自我效能等问卷调查，分析患者饮食治疗依从性的影响因素。结果患者饮食依从性总分8．58±2．44；患者饮食治疗依从性与其年龄、应用技能、健康信念、自我效能呈显著正相关（P〈0．05，P〈0．01）。结论提高患者饮食治疗依从性需重视其实际操作技能训练及健康信念、自我效能的影响作用，同时应特别关注非老年患者的饮食治疗依从性。     

2型糖尿病患者饮食治疗依从性研究

目的 了解2型糖尿病患者饮食治疗依从性及其影响因素,为进一步有效开展糖尿病患者饮食教育提供依据.方法 对349例2型糖尿病患者进行饮食治疗依从性及有关疾病知识、健康信念和自我效能等问卷调查,分析患者饮食治疗依从性的影响因素.结果 患者饮食依从性总分8.58±2.44;患者饮食治疗依从性与其年龄、应用技能、健康信念、自我效能呈显著正相关(P＜0.05,P＜0.01).结论 提高患者饮食治疗依从性需重视其实际操作技能训练及健康信念、自我效能的影响作用,同时应特别关注非老年患者的饮食治疗依从性.     

Amphiregulin as a Novel Target for Breast Cancer Therapy

Amphiregulin, an EGF family growth factor, binds and activates the epidermal growth factor receptor (EGFR or ErbB1). Activation of the EGFR by amphiregulin can occur through autocrine, paracrine and juxtacrine mechanisms. Amphiregulin plays a role in several biological processes including nerve regeneration, blastocyst implantation, and bone formation. Amphiregulin also plays an important role in mammary duct formation as well as the outgrowth and branching of several other human tissues such as the lung, kidney and prostate. This effect is most likely due to the induction of genes involved in invasion and migration such as cytokines and matrix metalloproteases. Clinical studies have suggested that amphiregulin also plays a role in human breast cancer progression and its expression has been associated with aggressive disease. Therefore, amphiregulin may be a novel and effective target for the treatment of breast cancer and could represent an alternative to targeting the EGFR.     

Xenograft of Microencapsulated Sertoli Cells for the Cell Therapy of Type 2 Diabetes Mellitus in Spontaneously Diabetic Nonhuman Primates: Preliminary Data

Insulin resistance in type 2 diabetes mellitus (T2DM) may be due to a chronic inflammation of the visceral adipose tissue (VAT) leading to local and systemic increases in proinflammatory cytokines. Microencapsulated porcine Sertoli cells (MC-pSC), by provision of immunomodulatory and trophic factors, have been successfully used to reduce such inflammation in rodent animal models of type 1 diabetes with no complications or deleterious side effects. Herein, we have begun to investigate this novel and safe therapeutic approach in the spontaneously obese nonhuman primate with spontaneous, insulin-dependent T2DM. After MC-pSC intraperitoneal injection we have evaluated, throughout a 6-month follow-up period, daily ad libitum fed glucose levels, daily exogenous insulin supplementation, biweekly body weight measurements, periodic fasting blood glucose concentrations, glycated hemoglobin (HbA1c) levels, glucose tolerance tests (GTT), and fluorescence-activated cell sorting cytometry (FACS) assessment of peripheral blood mononuclear cells. Very preliminarily, we have observed a slight reduction in fasting (FPG) and mean nonfasting (NF) plasma glucose levels. We found minimal changes, only in 1 animal, in daily exogenous insulin requirements and HbA1c levels. Flow cytometric analysis was associated with decrease in CD8⁺ cells only in 1 recipient with a reduction in mean regulatory T Cells (Treg), whereas interestingly, decrease of B lymphocytes was observed in both animals. These results may suggest that this novel MC-SC–based transplantation protocol might possibly impact the metabolic status of T2DM in higher mammals that are close to humans.     

2型糖尿病患者发生小腿肌间静脉血栓的危险因素分析

目的:探讨2型糖尿病患者发生小腿肌间静脉血栓的危险因素。方法:回顾性分析2013年6月—2019年6月于济南市中医医院内分泌科及滕州市中医医院内分泌科住院治疗的90例2型糖尿病患者的临床资料,根据发生小腿肌间静脉血栓与否分为血栓组(n=30)与对照组(n=60),对比分析两组患者的性别、年龄、体质量指数、糖尿病病程等临床资料,进行单因素分析,组间比较有显著差异的单因素,代入二元Logistic回归分析进行独立危险因素检验。结果:两组患者在年龄、体质量指数、糖尿病病程、合并糖尿病周围神经病变人数、合并活动性溃疡人数、合并冠心病人数、合并高血压人数、吸烟人数、血糖控制方案、白细胞计数、血小板计数、凝血酶原时间、活化部分促凝血酶原激酶时间、纤维蛋白原、D-二聚体、纤维蛋白原降解产物、红细胞沉降率等方面组间比较差异无统计学意义(P0.05);在性别、合并糖尿病周围血管病变人数、糖化血红蛋白水平、超敏C反应蛋白水平差异有统计学意义(P0.05)。Logistic回归显示,糖化血红蛋白高水平、超敏C反应蛋白高水平为2型糖尿病患者发生小腿肌间静脉血栓的独立危险因素。结论:糖化血红蛋白高水平、超敏C反应蛋白高水平为2型糖尿病患者发生小腿肌间静脉血栓的独立危险因素。     

SGLT2 Inhibition: A Novel Prospective Strategy in Treatment of Diabetes Mellitus

The role of the kidney in glucose homeostasis and the potential of the kidney as a therapeutic target in type 2 diabetes is little appreciated. Hyperglycemia is an important pathogenic component in the development of microvascular and macrovascular complications in type 2 diabetes mellitus. Inhibition of renal tubular glucose re-absorption that leads to glycosuria has been proposed as a new mechanism to attain normoglycemia and thus prevent and diminish these complications, thus representing an innovative therapeutic strategy for the treatment of hyperglycemia and/or obesity in patients with type 1 or type 2 diabetes by enhancing glucose and energy loss through the urine. Sodium glucose co-transporter 2 (SGLT2) has a key role in re-absorption of glucose in kidney. Competitive inhibitors of SGLT2 have been discovered and a few of them have also been advanced in clinical trials for the treatment of diabetes.     

Jugular Venous Bulb Oxygen Saturation in Patients with Preexisting Diabetes Mellitus or Stroke during Normothermic Cardiopulmonary Bypass

Background: The authors hypothesized that patients with cerebrovascular abnormalities or metabolic disorders may experience abnormality in cerebral circulation more frequently than patients without these risks. The current study attempted to assess jugular venous bulb oxygen saturation (SjvO2) in patients with preexisting diabetes mellitus or stroke undergoing normothermic cardiopulmonary bypass.

Methods: Thirty-nine patients undergoing elective coronary artery bypass graft surgery were studied, including 19 age-matched control patients, 10 diabetic patients, and 9 patients with preexisting stroke A 4.0-French fiberoptic oximetry oxygen saturation catheter was inserted into the right jugular bulb to continuously monitor internal SjvO2. Hemodynamic parameters and arterial and jugular venous blood gases were measured at seven time points: (1) after the induction of anesthesia and before the start of surgery, (2) just after the beginning of cardiopulmonary bypass, (3) 20 min after the beginning of bypass, (4) 40 min after the beginning of bypass, (5) 60 min after the beginning of bypass, (6) just after the cessation of bypass, and (7) at the end of the operation.

Results: No significant differences were seen in mean arterial pressure, arterial carbon dioxide tension (PaCO2), or hemoglobin concentration among the three groups during the study. The SjvO2 value did not differ among the three groups after anesthesia induction and before surgery, just after the beginning of cardiopulmonary bypass, 60 min after the beginning of bypass, just after the end of bypass, or at the end of the operation. Significant differences between the control group and the diabetic and stroke groups were observed, however, at 20 min and 40 min after the beginning of bypass (at 20 min: control group 62.2 +/- 6.8%, diabetes group 48.4 +/- 5.1%, stroke group 45.9 +/- 6.3%; at 40 min: control group 62.6 +/- 5.2%, diabetes group 47.1 +/- 5.2%, stroke group 48.8 +/- 4.1% [values expressed as the mean +/- SD];P < 0.05). Also, values in the diabetes and stroke groups were decreased at 20 min and 40 min after the beginning of bypass compared with before the start of surgery.     

Analysis of the Factors Related to a Decrease in Jugular Venous Oxygen Saturation in Patients with Diabetes Mellitus During Normothermic Cardiopulmonary Bypass

Purpose We sought to examine what factors, including cerebrovascular carbon dioxide (CO₂) reactivity, are related to a decrease in internal jugular venous oxygen saturation (SjvO₂) during normothermic cardiopulmonary bypass (CPB) in patients with diabetes mellitus.Methods Twenty-three diabetic patients scheduled to undergo elective coronary artery bypass grafting were studied. As a control, 27 age-matched control patients without diabetes mellitus were also examined. After the induction of anesthesia, a fiberoptic oximetry oxygen saturation catheter was inserted into the right jugular bulb to continuously monitor SjvO₂. Arterial and jugular venous blood gases were measured during CPB. The cerebrovascular CO₂ reactivity was measured after the induction of anesthesia and before the start of surgery using a 2.5-MHz pulsed transcranial Doppler probe.Results The SjvO₂ values in the diabetic group were lower than those in the control group at the initiation of CPB and at 20, 40, and 60 min after the start of CPB. The values for pre- and post-CO₂ reactivity in the control group did not significantly differ (pre-CPB: 4.8% ± 2.3% mmHg⁻¹; post-CPB: 5.9% ± 4.4% mmHg⁻¹). In contrast, the values for CO₂ reactivity were lower post CPB than pre-CPB in the diabetic group (Pre-CPB: 6.3% ± 2.9% mmHg⁻¹; post-CPB: 4.7% ± 2.6% mmHg⁻¹; P < 0.05). In the diabetic group, glycosylated hemoglobin A1c (HbA1c) is considered to be a factor related to a decrease in SjvO₂ during CPB.Conclusions Cerebrovascular CO₂ reactivity in diabetic patients decreased after the cessation of CPB but not in the control patients. In addition, HbA1c is also thought to be a factor related to a decrease in SjvO₂ in diabetic patients.     

An Odyssey of Islet Transplantation for Therapy of Type 1 Diabetes

Canadian surgical contributions to the field of islet transplantation have a rich heritage and a promising future. In this article, some seminal Canadian contributions to this field are reviewed, including contributions at the basic research laboratory and translational applications to bedside therapy of type 1 diabetes.     

Congenic Mesenchymal Stem Cell Therapy Reverses Hyperglycemia in Experimental Type 1 Diabetes

OBJECTIVE

A number of clinical trials are underway to test whether mesenchymal stem cells (MSCs) are effective in treating various diseases, including type 1 diabetes. Although this cell therapy holds great promise, the optimal source of MSCs has yet to be determined with respect to major histocompatibility complex matching. Here, we examine this question by testing the ability of congenic MSCs, obtained from the NOR mouse strain, to reverse recent-onset type 1 diabetes in NOD mice, as well as determine the immunomodulatory effects of NOR MSCs in vivo.

RESEARCH DESIGN AND METHODS

NOR MSCs were evaluated with regard to their in vitro immunomodulatory function in the context of autoreactive T-cell proliferation and dendritic cell (DC) generation. The in vivo effect of NOR MSC therapy on reversal of recent-onset hyperglycemia and on immunogenic cell subsets in NOD mice was also examined.

RESULTS

NOR MSCs were shown to suppress diabetogenic T-cell proliferation via PD-L1 and to suppress generation of myeloid/inflammatory DCs predominantly through an IL-6-dependent mechanism. NOR MSC treatment of experimental type 1 diabetes resulted in long-term reversal of hyperglycemia, and therapy was shown to alter diabetogenic cytokine profile, to diminish T-cell effector frequency in the pancreatic lymph nodes, to alter antigen-presenting cell frequencies, and to augment the frequency of the plasmacytoid subset of DCs.

CONCLUSIONS

These studies demonstrate the inimitable benefit of congenic MSC therapy in reversing experimental type 1 diabetes. These data should benefit future clinical trials using MSCs as treatment for type 1 diabetes.Mesenchymal stem cell (MSC) therapy has in recent years emerged as a promising treatment modality for diseases with immune etiology, particularly given the increasing appreciation for the morbidity associated with immunosuppression. MSCs have been demonstrated to exhibit profound immunomodulatory effects in vitro and in vivo, and these immunomodulatory capabilities have been shown to be exerted through both direct contact and production of soluble markers (1–4). Moreover, upregulation of B7-H1/PD-L1 by IFN-γ has been shown to play a central role in the immunosuppressive properties of MSCs via direct contact with activated T-cells (5,6). In vitro studies have also demonstrated the ability of MSCs to regulate the function of T-cell effector pathways through promotion of regulatory dendritic cell (DC) generation, due to MSC-modulated alteration of DC cytokine profiles as evidenced by increased production of regulatory cytokines such as IL-10 and reduction of inflammatory cytokines including IFN-γ, IL-12, and TNF-α, thereby inducing a more anti-inflammatory or tolerant DC phenotype (7,8). These immunomodulatory effects as well as an extensive capacity for in vitro expansion of MSCs have prompted the launch of numerous clinical trials (1). MSC therapy has yielded promising results in the treatment of graft versus host disease (GVHD) as well as in the resolution of Crohn''s disease-associated fistulas, in stabilization of refractory progressive multiple sclerosis, and in reversal of multiorgan dysfunction in patients with systemic lupus erythematosus (9–12). However, although the therapeutic value of MSCs for attenuating the autoimmune disorder type 1 diabetes has logical potential, MSC treatment of this particular disease remains largely unexplored. Trials using MSC therapy in patients with type 1 diabetes are underway, yet these efforts have been initiated in the near absence of preclinical data. In this regard, we and others have recently demonstrated delayed onset of experimental type 1 diabetes as well as reversal of recent-onset diabetes in response to allogeneic MSC therapy, whereas in our study administration of autologous diabetic MSCs showed no beneficial effect (13,14). Our previous work also indicated that congenic NOR MSCs imparted the greatest benefit in preventing type 1 diabetes. The NOR/LtJ strain, while resistant to insulitis due to the protective Idd alleles (15), shares the diabetogenic H2^g7 complex with the NOD/LtJ strain. NOR mice are 85% homologous to spontaneously diabetic NOD mice and are thus somewhat analogous to nondiabetic siblings of type 1 diabetic patients. Here, we sought to further examine the therapeutic efficacy of NOR MSCs on reversal of recent-onset diabetes and to elucidate the mechanisms by which NOR MSCs may act to ameliorate diabetes pathogenesis.     

Intensive Insulin Therapy and Bone Mineral Density in Type 1 Diabetes Mellitus: A Prospective Study

To determine the effect of metabolic control on bone mineral density (BMD) in type 1 diabetes mellitus (type 1 DM), we studied BMD (by dual-energy X-ray energy absorptiometry) and bone remodeling parameters in 62 patients with type 1 DM both before and 7 years after commencement of intensive insulin therapy. Overall outcomes after the 7-year treatment included the stabilization of BMD at all sites, as well as a significant decrease in tartrate-resistant acid phosphatase (TRAP) (4.302 ± 2.62 vs 2.65 ± 0.97 IU/l; p = 0.0001) and increase in intact parathyroid hormone (PTHi) (28.05 ± 15.7 vs 39.78 ± 22.41 ng/l; p = 0.005). Presence of diabetic retinopathy (RTP) versus its absence (non-RTP) was associated with lower BMD in femoral neck (FN) (0.831 ± 0.142 vs 0.756 ± 0.153 mg/cm²; p = 0.03) and Ward’s triangle (WT) (0.736 ± 0.165 vs 0.632 ± 0.172 mg/cm²; p = 0.03), and with a lower T-score in FN (–0.93 ± 1.34 vs –1.70 ± 1.46; p = 0.04) and WT (–0.72 ± 1.42 vs –1.540 ± 1.55; p = 0.04) and Z-score in FN (–0.591 ± 1.23 vs –1.132 ± 1.46; p = 0.01). The percentage of patients with osteopenia or osteoporosis in the RTP group was significantly higher than in the non-RTP group (72% vs 53%, p = 0.05; RR= 3.2) and the glycosylated hemoglobin (HbA1c) levels of the RTP group were also higher (8.53 ± 1.6% vs 7.1 ± 1.1%; p = 0.05). The improvement in metabolic control, increase in body mass index and decrease in resorption parameters could contribute to the stabilization of bone mass in type 1 DM but the presence of retinopathy is a critical factor in the progression of diabetic osteopenia. Received: 4 June 1999 / Accepted: 16 November 1999     

Endometriosis in a Spigelian Hernia Sac: An Unexpected Finding

Describes the existence of endometrioma in a spigelian hernia sac. Spigelian Hernia is a rare ventral hernia, presenting difficulties in diagnosis and carrying a high incarceration and obstruction risk. Endometriomas occur due to implantation of endometrial cells into a surgical wound, most often after a cesarean delivery. A 37-year-old woman presented to our department with persistent abdominal pain, exacerbating during menses, and vomiting for 2 days. Physical examination revealed a mass-like lesion in the border between the left-upper and left-lower quadrant. Ultrasound examination was inconclusive and a computed tomography scan of the abdomen revealed an abdominal wall mass. During surgery, a spigelian hernia was found 5 to 7 cm above a previous cesarean incision. Tissue like “chocolate cysts” was present at the hernia sac. Hernia was repaired while tissue was excised and sent for histological examination that confirmed the diagnosis. Spigelian hernia is a hernia presenting difficulties in diagnosis and treatment. Endometrioma in a spigelian hernia sac is a rare diagnosis, confirmed only histologically. Clinical suspicion can be posed only through symptoms and thorough investigation.Key words: Spigelian hernia, Endometriosis, Cesarean sectionSpigelian hernia (SH) is a rare ventral hernia occurring through semiluminar line and carrying a high incarceration risk. Endometrioma is implantation of endometrial tissue. Authors present a rare case of symptomatic endometriomas discovered within a spigelian hernia sac.