HYPERGLYCEMIA AS A PREDICTOR OF OUTCOME IN PAEDIATRIC SEVERE TRAUMATIC BRAIN INJURY PATIENTS UNDERWENT SURGERY: A SINGLE CENTER EXPERIENCE FROM EASTERN INDONESIA FROM 2017-2022.

OBJECTIVE: The aim: Traumatic Brain Injury (TBI) remains a significant health burden worldwide. This study aimed to describe, determine and recommendation concerning the impact of hyperglycemia on pediatric TBI. PATIENTS AND METHODS: Materials and methods: Paediatric trauma patients with severe TBI event were identified and admitted to our Dr. Soetomo General Hospital, Surabaya, the regional Trauma Center of East Java, Indonesia between calendar year of 2017 and 2022. Our institutions trauma database was utilized to select the patient included in this study. Patients with GCS ≤ 8 who underwent neurosurgical interventions were included to the study. Neurosurgical interventions are craniotomy for clot evacuation and decompressive craniectomy. We excluded patients with GCS > 8 and/or treated with conservative therapy (no surgery needed). Data collected for analysis as independent variables included patient age, admission GCS score and admission serum glucose score, mechanism of injury, type of intracranial lesion and type of surgery. Outcome of the patients included was examined at discharge which sub-grouped by Glasgow Outcomes Scale (GOS) score. Independent variables were entered into the logistic model in a stepwise fashion with a significant cutoff of p< 0,05. RESULTS: Results: Patients with worse neurological outcomes (GOS score 1-2) had a mean serum glucose value of over 200 mg/dL. Patients who died (GOS score of 1) had higher mean admission glucose values (226.44 ± 62,00) than the patients who had survived with a GOS score of 3 (139.80 ± 10.87), 4 (87), or 5 (134). Patients who resulted in a vegetative state (GOS score of 2) had higher mean admission serum glucose values than patients who were discharged with a GOS score of 5 (205.14 ± 36.17 vs. 134; p = 0.003). CONCLUSION: Conclusions: Hyperglycaemia in pediatric TBI patients that underwent neurosurgical intervention is associated with worse outcomes, even mortality. We believe that prospective evaluation of glucose normalization in the context of acute management of pediatric head injuries is both appropriate and necessary for the next study.

Insulin resistance in bariatric surgery.

PURPOSE OF REVIEW: To give an updated review on the underlying mechanisms and clinical effects of improved glucose control after bariatric surgery. RECENT FINDINGS: The basic principles of the mechanism for the metabolic effects of bariatric surgery can be categorized into calorie restriction, deviation of nutrients, and reduced amounts of adipose tissue. Recent findings suggest the importance of early changes following deviation of nutrients to more distal parts of the small bowel resulting in altered release of gastrointestinal hormones, altered gut microbiota, and weight-reduction. In the long-term, loss of adipose tissue results in reduced inflammation and improved insulin sensitivity. From a clinical perspective these changes are associated with remission of diabetes in patients with morbid obesity and type 2 diabetes, prevention of diabetes in patients with insulin resistance without overt type 2 diabetes and prevention of both microvascular and macrovascular complications for all patients with morbid obesity. SUMMARY: At present, bariatric surgery remains the most effective treatment option to improve glucose control and long-term complications associated with hyperglycemia in patients with obesity.Although the mechanisms behind these metabolic effects remain only partially understood, further knowledge on these complex mechanisms may help identifying durable treatment options for morbid obesity and important metabolic comorbidities.

Islet Transplantation in Children.

PURPOSE OF REVIEW: Transplantation of the islets of Langerhans or the pancreas aims to restore blood sugar control. We review both forms of transplantation in children. RECENT FINDINGS: Allogenic islet transplantation typically in to the liver via the portal vein may be a potential alternative to pancreas transplantation in the future. Autologous islet transplantation after total pancreatectomy is effective for debilitating symptoms of recurrent and chronic pancreatitis. Chronic pancreatitis in children is most often related to genetic mutations but is otherwise similar to adults with eventual exocrine and endocrine failure. Removal of the pancreas ameliorates pain, and islet transplantation preserves endocrine function to the extent allowed by the damage sustained by the pancreas from chronic inflammation. Despite the complexity of the operative procedure, the outcome of total pancreatectomy and autologous islet transplantation in children has been excellent including quality of life.

Risk Factors of Intraoperative Dysglycemia in Elderly Surgical Patients.

BACKGROUNDː Dysglycemia is associated with adverse outcome including increased morbidity and mortality in surgical patients. Acute insulin resistance due to the surgical stress response is seen as a major cause of so-called stress hyperglycemia. However, understanding of factors determining blood glucose (BG) during surgery is limited. Therefore, we investigated risk factors contributing to intraoperative dysglycemia. METHODSː In this subgroup investigation of the BIOCOG study, we analyzed 87 patients of ≥ 65 years with tight intraoperative BG measurement every 20 min during elective surgery. Dysglycemia was defined as at least one intraoperative BG measurement outside the recommended target range of 80-150 mg/dL. Additionally, all postoperative BG measurements in the ICU were obtained. Multivariable logistic regression analysis adjusted for age, sex, American Society of Anesthesiologists (ASA) status, diabetes, type and duration of surgery, minimum Hemoglobin (Hb) and mean intraoperative norepinephrine use was performed to identify risk factors of intraoperative dysglycemia. RESULTSː 46 (52.9%) out of 87 patients developed intraoperative dysglycemia. 31.8% of all intraoperative BG measurements were detected outside the target range. Diabetes [OR 9.263 (95% CI 2.492, 34.433); p=0.001] and duration of surgery [OR 1.005 (1.000, 1.010); p=0.036] were independently associated with the development of intraoperative dysglycemia. Patients who experienced intraoperative dysglycemia had significantly elevated postoperative mean (p<0.001) and maximum BG levels (p=0.001). Length of ICU (p=0.007) as well as hospital stay (p=0.012) were longer in patients with dysglycemia. CONCLUSIONSː Diabetes and duration of surgery were confirmed as independent risk factors for intraoperative dysglycemia, which was associated with adverse outcome. These patients, therefore, might require intensified glycemic control. Increased awareness and management of intraoperative dysglycemia is warranted.

DISORDERS OF CARBOHYDRATE METABOLISM IN PATIENTS WITH GASTRIC CANCER.

Object study carbohydrate metabolism state in patient with GC during the surgical treatment period, and the detection of factors that influence these kind of disorders. The results of investigations of 270 patients with GC were analyzed. The rest of patients were males - 193 (71.48%). 239 patients underwent different surgical involvements. The state of carbohydrate metabolism was evaluated based on the study of the level of glucose in blood serum and urine at various stages of surgical treatment. The results of carbohydrate metabolism in 270 patients with gastric cancer in the perioperative period are analyzed. Factors that have an effect on the changes in glucose and insulin levels in the blood and its appearance in the urine before the specific treatment, as well as at various periods of staying patients in the surgical department, was the duration of the anamnesis, advanced stages of the oncological process, complicated clinical course of the underlying disease.. It was established that surgical intervention itself, its extension, and also postoperative period have a direct negative effect on the disorders in carbohydrate metabolism. In 65.3% of cases operations were accompanied by hyperglycemia, and in 25.9% of cases glucosuria was detected. The duration of a surgical operation for more than two hours lead to an almost twofold increase in the incidence of cases of hyperglycemia, and tripled increase in glucosuria. Intensive correction of blood glucose level along with enteral feeding led to a decrease in levels of hyperglycemia and glucosuria. Complicated postoperative period did not lead to an increase in the incidence of carbohydrate metabolism disorders, but had an effect on the longer retention of elevated levels of glucose in the blood and urine.

Hyperglycemia in Stroke Impairs Polarization of Monocytes/Macrophages to a Protective Noninflammatory Cell Type.

UNLABELLED: Hyperglycemia is common in patients with acute stroke, even in those without preexisting diabetes, and denotes a bad outcome. However, the mechanisms underlying the detrimental effects of hyperglycemia are largely unclear. In a mouse model of ischemic stroke, we found that hyperglycemia increased the infarct volume and decreased the number of protective noninflammatory monocytes/macrophages in the ischemic brain. Ablation of peripheral monocytes blocked the detrimental effect of hyperglycemia, suggesting that monocytes are required. In hyperglycemic mice, α-dicarbonyl glucose metabolites, the precursors for advanced glycation end products, were significantly elevated in plasma and ischemic brain tissue. The receptor of advanced glycation end products, AGER (previously known as RAGE), interfered with polarization of macrophages to a noninflammatory phenotype. When Ager was deleted, hyperglycemia did not aggravate ischemic brain damage any longer. Independently of AGER, methylglyoxal reduced the release of endothelial CSF-1 (M-CSF), which stimulates polarization of macrophages to a noninflammatory phenotype in the microenvironment of the ischemic brain. In summary, our study identified α-dicarbonyls and AGER as mediators by which hyperglycemia lowers the number of protective noninflammatory macrophages and consequently increases ischemic brain damage. Modulating the metabolism of α-dicarbonyls or blocking AGER may improve the treatment of stroke patients with hyperglycemia. SIGNIFICANCE STATEMENT: Although glucose is the main energy substrate of the brain, hyperglycemia aggravates ischemic brain damage in acute stroke. So far, clinical trials have indicated that insulin treatment provides no solution to this common clinical problem. This study shows, in an experimental stroke model, that hyperglycemia interferes with the polarization of monocytes/macrophages to a protective cell type. Key players are α-dicarbonyls and the receptor for advanced glycation end products (AGER). Deletion of AGER normalized monocyte/macrophage polarization and reversed the detrimental effects of hyperglycemia, suggesting new avenues to treat stroke patients.

Diabetes Mellitus and Hyperglycemia and the Risk of Aseptic Loosening in Total Joint Arthroplasty.

BACKGROUND: It is unknown to what extent diabetes mellitus modifies the long-term risk of aseptic loosening in total hip arthroplasty (THA) and total knee arthroplasty (TKA). We examined the association between diabetes mellitus, perioperative hyperglycemia, and the likelihood of revisions for aseptic loosening. METHODS: We studied 16,085 primary THA and TKA procedures performed at a large tertiary care hospital between 2002 and 2009. All blood glucose values around the time of surgery (within 1 week) were retrieved. Subsequent revision surgeries and the reasons for revision were ascertained through the institutional joint registry. Multivariate Cox models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for aseptic loosening associated with diabetes mellitus and hyperglycemia adjusting for age, gender, body mass index, and surgery type. RESULTS: A total of 2911 (18%) surgeries had a diagnosis of diabetes mellitus at the time of surgery. Glucose testing was performed at least once in 7055 (44%) procedures within ±1 week of surgery. Although diabetic patients did not experience a higher risk of revision for aseptic loosening (HR, 0.87; 95% CI, 0.55-1.38), higher preoperative glucose values on the day before surgery were significantly associated with both the overall risk of revisions (HR, 2.80; 95% CI, 1.00-7.85) and revisions for aseptic loosening (HR, 4.95; 95% CI, 1.26-19.54). CONCLUSION: High preoperative hyperglycemia is a potential risk factor for aseptic loosening in THA and TKA.

Perioperative Management of Patients with Diabetes and Hyperglycemia Undergoing Elective Surgery.

Diabetes mellitus (DM) and hyperglycemia are associated with increased surgical morbidity and mortality. Hyperglycemia is a determinant of risk of surgical complications and should be addressed across the continuum of surgical care. While data support the need to address hyperglycemia in patients with DM in the ambulatory setting prior to surgery and in the inpatient setting, data are less certain about hyperglycemia occurring during the perioperative period-that part of the process occurring on the day of surgery itself. The definition of "perioperative" varies in the literature. This paper proposes a standardized definition for the perioperative period as spanning the time of patient admission to the preoperative area through discharge from the recovery area. Available information about the impact of perioperative hyperglycemia on surgical outcomes within the framework of that definition is summarized, and the authors' approach to standardizing perioperative care for patients with DM is outlined, including the special case of patients receiving insulin pump therapy. The discussion is limited to adult ambulatory non-obstetric patients undergoing elective surgical procedures under general anesthesia.

The impact of glycaemic variability on the surgical patient.

PURPOSE OF REVIEW: Diabetes is the most prevalent long-term metabolic condition and its incidence continues to increase unabated. Patients with diabetes are overrepresented in the surgical population. It has been well recognized that poor perioperative diabetes control is associated with poor surgical outcomes. The outcomes are worst for those people who were not recognized as having hyperglycaemia. RECENT FINDINGS: Recent work has shown that preoperative recognition of diabetes and good communication between the clinical teams at all stages of the patient pathway help to minimize the potential for errors, and improve glycaemic control. The stages of the patient journey start in primary care and end when the patient goes home. The early involvement of the diabetes specialist team is important if the glycated haemoglobin is more than 8.5%, and advice sought if the preoperative assessment team is not familiar with the drug regimens. To date the glycaemic targets for the perioperative period have remained uncertain, but recently a consensus is being reached to ensure glucose levels remain between 108 and180 mg/dl (6.0 and 10.0 mmol/l). There have been a number of ways to achieve these - primarily by manipulating the patients' usual diabetes medications, to also allow day of surgery admission. SUMMARY: glycaemic control remains an important consideration in the surgical patient.

Behavioral Modification of Intraoperative Hyperglycemia Management with a Novel Real-time Audiovisual Monitor.

BACKGROUND: Hyperglycemia, defined as blood glucose (BG) levels above 200 mg/dl (11.1 mM), is associated with increased postoperative morbidity. Yet, the treatment standard for intraoperative glycemic control is poorly defined for noncardiac surgery. Little is known of the interindividual treatment variability or methods to modify intraoperative glycemic management behaviors. AlertWatch (AlertWatch, USA) is a novel audiovisual alert system that serves as a secondary patient monitor for use in operating rooms. The authors evaluated the influence of use of AlertWatch on intraoperative glycemic management behavior. METHODS: AlertWatch displays historical patient data (risk factors and laboratory results) from multiple networked information systems, combined with the patient's live physiologic data. The authors extracted intraoperative data for 19 months to evaluate the relationship between AlertWatch usage and initiation of insulin treatment for hyperglycemia. Outcome associations were adjusted for physical status, case duration, procedural complexity, emergent procedure, fasting BG value, home insulin therapy, patient age, and primary anesthetist. RESULTS: Overall, 2,341 patients had documented intraoperative hyperglycemia. Use of AlertWatch (791 of 2,341; 33.5%) was associated with 55% increase in insulin treatment (496 of 791 [62.7%] with and 817 of 1,550 [52.7%] without AlertWatch; adjusted odds ratio [95% CI], 1.55 [1.23 to 1.95]; P < 0.001) and 44% increase in BG recheck after insulin administration (407 of 791 [51.5%] with AlertWatch and 655 of 1,550 [42.3%] in controls; adjusted odds ratio [95% CI], 1.44 [1.14 to 1.81]; P = 0.002). CONCLUSION: AlertWatch is associated with a significant increase in desirable intraoperative glycemic management behavior and may help achieve tighter intraoperative glycemic control.

Bariatric surgery and microvascular complications of type 2 diabetes mellitus.

Metabolic dysregulation is the defining characteristic of type 2 diabetes mellitus (T2DM) and can give rise to microvascular complications, specifically retinopathy, nephropathy and neuropathy. Pharmacological targeting of risk factors for microvascular complications can yield therapeutic gains, particularly in relation to retinopathy and nephropathy. Bariatric surgery is superior to intensified pharmacotherapy in relation to glycaemic control and can remediate dyslipidaemia and hypertension. Consequently, evidence of the effect of bariatric surgery on microvascular complications is now emerging in the literature. Examination of the recent published evidence base (covering the period 2011-2014) on the effects of bariatric surgery on microvascular complications reveals further evidence supportive of the efficacy of bariatric surgery in preventing the incidence and progression of albuminuria and arresting renal functional decline. Data on retinopathy are more ambivalent potentially representing the potential in some cases for a degree of surgery associated reactive hypoglycaemia to detract from the benefits of amelioration of hyperglycaemia. A significant gap in the literature remains in relation to the effects of surgery on diabetic neuropathy. Overall, there is a pressing need for prospective randomised controlled trials examining long-term microvascular outcomes following bariatric surgery in patients with T2DM.

Nano-scale encapsulation enhances allograft survival and function of islets transplanted in a mouse model of diabetes.

AIMS/HYPOTHESIS: The success of islet transplantation as a treatment for type 1 diabetes is currently hampered by post-transplantation loss of functional islets through adverse immune and non-immune reactions. We aimed to test whether early islet loss can be limited and transplant survival improved by the application of conformal nano-coating layers to islets. METHODS: Our novel coating protocol used alternate layers of phosphorylcholine-derived polysaccharides (chitosan or chondroitin-4-sulphate) and alginate as coating materials, with the binding based on electrostatic complexation. The in vitro function of encapsulated mouse islets was studied by analysing islet secretory function and cell viability. The in vivo function was evaluated using syngeneic and allogeneic transplantation in the streptozotocin-induced mouse model of diabetes. RESULTS: Nano-scale encapsulated islets retained appropriate islet secretory function in vitro and were less susceptible to complement- and cytokine-induced apoptosis than non-encapsulated control islets. In in vivo experiments using a syngeneic mouse transplantation model, no deleterious responses to the coatings were observed in host animals, and the encapsulated islet grafts were effective in reversing hyperglycaemia. Allo-transplantation of the nano-coated islets resulted in preserved islet function post-implantation in five of seven mice throughout the 1 month monitoring period. CONCLUSIONS/INTERPRETATION: Nano-scale encapsulation offers localised immune protection for implanted islets, and may be able to limit early allograft loss and extend survival of transplanted islets. This versatile coating scheme has the potential to be integrated with tolerance induction mechanisms, thereby achieving long-term success in islet transplantation.

Antioxidant effect of enamel matrix derivative for early phase of periodontal tissue regeneration in diabetes.

BACKGROUND: Diabetes involves metabolic disorders in various tissues via hyperglycemia-induced oxidative stress. This study aimed to investigate the antioxidative effect of enamel matrix derivative (EMD) on periodontal regeneration in diabetes. METHODS: Twenty-two rats were equally divided into streptozotocin (STZ)-induced diabetes or control group. Two months after induction of hyperglycemia, systemic oxidative stress was measured using urinary 8-hydroxy-2'-deoxyguanosine. EMD or saline was applied into the intrabony defects created in the bilateral maxillary molar. mRNA expressions of inflammatory and oxidative stress markers were quantified (n = 6). Histometric analyses and immunohistochemistry of superoxide dismutase-1 (SOD-1) were performed 7 days postoperatively (n = 5). For in vitro experiments, the bone marrow-derived mesenchymal stem cells were isolated from rat femur and cultured in a high glucose (HG) or control medium. Reactive oxygen species (ROS) measurement and alizarin red staining were performed with/without EMD. RESULTS: Systemic oxidative stress was significantly higher in the diabetic group. The connective tissue attachment and cementum formation were significantly increased at EMD-treated sites in both diabetic and non-diabetic groups. The expression of nicotinamide adenine dinucleotide phosphate oxidase two and four was significantly lower at EMD-treated sites than at EMD-untreated sites in both diabetic and non-diabetic rats. Immunohistochemistry showed significantly higher SOD-1 expression at the EMD-treated site. In vitro, HG culture had significantly higher ROS production compared with control, which was downregulated by EMD. EMD treatment significantly recovered the impaired calcification in HG. CONCLUSION: EMD promoted early-phase wound healing and periodontal tissue regeneration in the surgically created bony defect of STZ-induced diabetic rat by suppressing hyperglycemia-induced oxidative stress.

Pancreaticoduodenectomy model demonstrates a fundamental role of dysfunctional ß cells in predicting diabetes.

BACKGROUNDThe appearance of hyperglycemia is due to insulin resistance, functional deficits in the secretion of insulin, and a reduction of ß cell mass. There is a long-standing debate as to the relative contribution of these factors to clinically manifesting ß cell dysfunction. The aim of this study was to verify the acute effect of one of these factors, the reduction of ß cell mass, on the subsequent development of hyperglycemia.METHODSTo pursue this aim, nondiabetic patients, scheduled for identical pancreaticoduodenectomy surgery, underwent oral glucose tolerance tests (OGTT) and hyperglycemic clamp (HC) procedures, followed by arginine stimulation before and after surgery. Based on postsurgery OGTT, subjects were divided into 3 groups depending on glucose tolerance: normal glucose tolerance (post-NGT), impaired glucose tolerance (post-IGT), or having diabetes mellitus (post-DM).RESULTSAt baseline, the 3 groups showed similar fasting glucose and insulin levels; however, examining the various parameters, we found that reduced first-phase insulin secretion, reduced glucose sensitivity, and rate sensitivity were predictors of eventual postsurgery development of IGT and diabetes.CONCLUSIONDespite comparable functional mass and fasting glucose and insulin levels at baseline and the very same 50% mass reduction, only reduced first-phase insulin secretion and glucose sensitivity predicted the appearance of hyperglycemia. These functional alterations could be pivotal to the pathogenesis of type 2 diabetes (T2DM).TRIAL REGISTRATIONClinicalTrials.gov NCT02175459.FUNDINGUniversità Cattolica del Sacro Cuore; Italian Ministry of Education, University and Research; European Foundation for the Study of Diabetes.

Impact of poor glycemic control upon clinical outcomes after radical prostatectomy in localized prostate cancer.

To evaluate the clinical impact of preoperative glycemic status upon oncological and functional outcomes after radical prostatectomy in patients with localized prostate cancer, we analyzed the data of 2664 subjects who underwent radical prostatectomy with preoperative measurement of hemoglobin A1c within 6 months before surgery. The possible association between high hemoglobin A1c (≥ 6.5 ng/dL) and oncological/functional outcomes was evaluated. Among all subjects, 449 (16.9%) were categorized as the high hemoglobin A1c group and 2215 (83.1%) as the low hemoglobin A1c group. High hemoglobin A1c was associated with worse pathological outcomes including extra-capsular extension (HR 1.277, 95% CI 1.000-1.630, p = 0.050) and positive surgical margin (HR 1.302, 95% CI 1.012-1.674, p = 0.040) in multi-variate regression tests. Kaplan-Meier analysis showed statistically shorter biochemical recurrence-free survival in the high hemoglobin A1c group (p < 0.001), and subsequent multivariate Cox proportional analyses revealed that high hemoglobin A1c is an independent predictor for shorter BCR-free survival (HR 1.135, 95% CI 1.016-1.267, p = 0.024). Moreover, the high hemoglobin A1c group showed a significantly longer incontinence-free survival than the low hemoglobin A1c group (p = 0.001), and high preoperative hemoglobin A1c was also an independent predictor for longer incontinence-free survival in multivariate Cox analyses (HR 0.929, 95% CI 0.879-0.981, p = 0.008). The high preoperative hemoglobin A1c level was independently associated with worse oncological outcomes and also with inferior recovery of urinary continence after radical prostatectomy.

The in vivo performance of bioartificial pancreas in bone marrow cavity: a case report of a spontaneous diabetic feline.

Recent studies reported that bone marrow cavity offers a widely distributed and well-vascularized microenvironment which is a considerable implantation site for bioartificial pancreas (BAP). In this study, the in vivo performance of BAPs in bone marrow was further demonstrated in a spontaneous diabetes animal. Mouse insulinoma cells encapsulating in agarose gel were enclosed in a calcium phosphate cement chamber to create a BAP. Ten BAPs were implanted into the femur bone marrow cavity of a diabetic feline. The preprandial blood glucose level, 2 h glucose curve, serum C-peptide level and physiological conditions of the recipient were recorded perioperatively. Results showed that the cat still suffered from hyperglycemia postoperatively. However, the physiological conditions of feline were improved with an increase of serum C-peptide level. The peak point of 2 h glucose curve decreased from 400 to 165-290 mg/dl. The efficiency of exogenous insulin extended from 2 to 10-14 h postoperatively which reveals that the implanted BAPs had partial function. This case report revealed that BAPs implanted in the bone marrow cavity for the spontaneous diabetic is effective. The implanted BAPs provided therapeutic benefit despite sustained hyperglycemia. Further study shall be considered to improve the outcomes of BAPs transplantation.

[Hepatic tissue regeneration after electrothermocoagulation in experimental pathology of local blood circulation].

The regeneration processes course in the liver, occurring after its wedge resection performance using electrothermoadhesion method, were studied on two simulating models: the stress model of atherosclerosis and experimental hyperglycemia. The dynamics of morphological changes in the liver observed have had witnessed a tendency preservation towards formation of elastic linear cicatrix of collagen and a full-fledged morphofunctional restoration of liver after the operation. Peculiarities of the restoration processes course were connected with the disorder severity.

Skeletal myoblast transplantation for attenuation of hyperglycaemia, hyperinsulinaemia and glucose intolerance in a mouse model of type 2 diabetes mellitus.

AIMS/HYPOTHESIS: We aimed to demonstrate the feasibility and efficacy of intra-muscular transplantation of human skeletal myoblasts (hSkMs) for attenuation of hyperglycaemia and improvement of insulin sensitivity using a mouse model of type 2 diabetes mellitus. METHODS: KK Cg-Ay/J mice, aged 12 to 14 weeks, underwent an initial intraperitoneal glucose tolerance test (GTT) and were divided into the following groups: KK control group, basal medium (M199) only; KK myoblast group, with hSkM transplantation; KK fibroblast group, with human fibroblast transplantation. Non-diabetic C57BL mice were used as an additional normal control and also had hSkM transplantation. Cells were transplanted intra-muscularly into the skeletal muscles of the mice. All animals were treated with ciclosporin for 6 weeks only. HbA(1c) and fasting GTT, as well as serum adiponectin, cholesterol, insulin and triacylglycerol were studied. RESULTS: Immunohistochemistry studies showed extensive survival of the transplanted hSkMs in the skeletal muscles at 12 weeks, with nuclei of the hSkMs integrated into the host muscle fibres. Repeat GTT showed a significant decrease in glucose concentrations in the KK myoblast group compared with the KK control and KK fibroblast groups. The KK myoblast group also had reduced mean HbA(1c), cholesterol, insulin and triacylglycerol, and increased adiponectin compared with the KK control and KK fibroblast groups. C57BL mice showed no change in glucose homeostasis after hSkM transplant. CONCLUSIONS/INTERPRETATION: Human skeletal myoblast transplantation attenuated hyperglycaemia and hyperinsulinaemia and improved glucose tolerance in the KK mouse. This novel approach of improving muscle insulin resistance may be a potential alternative treatment for type 2 diabetes mellitus.

Bioinformatic analysis of peripheral blood RNA-sequencing sensitively detects the cause of late graft loss following overt hyperglycemia in pig-to-nonhuman primate islet xenotransplantation.

Clinical islet transplantation has recently been a promising treatment option for intractable type 1 diabetes patients. Although early graft loss has been well studied and controlled, the mechanisms of late graft loss largely remains obscure. Since long-term islet graft survival had not been achieved in islet xenotransplantation, it has been impossible to explore the mechanism of late islet graft loss. Fortunately, recent advances where consistent long-term survival (≥6 months) of adult porcine islet grafts was achieved in five independent, diabetic nonhuman primates (NHPs) enabled us to investigate on the late graft loss. Regardless of the conventional immune monitoring methods applied in the post-transplant period, the initiation of late graft loss could rarely be detected before the overt graft loss observed via uncontrolled blood glucose level. Thus, we retrospectively analyzed the gene expression profiles in 2 rhesus monkey recipients using peripheral blood RNA-sequencing (RNA-seq) data to find out the potential cause(s) of late graft loss. Bioinformatic analyses showed that highly relevant immunological pathways were activated in the animal which experienced late graft failure. Further connectivity analyses revealed that the activation of T cell signaling pathways was the most prominent, suggesting that T cell-mediated graft rejection could be the cause of the late-phase islet loss. Indeed, the porcine islets in the biopsied monkey liver samples were heavily infiltrated with CD3+ T cells. Furthermore, hypothesis test using a computational experiment reinforced our conclusion. Taken together, we suggest that bioinformatics analyses with peripheral blood RNA-seq could unveil the cause of insidious late islet graft loss.

Risk Factors for Relapse of Hyperglycemia after Laparoscopic Roux-en-Y Gastric Bypass in T2DM Obese Patients: a 5-Year Follow-Up of 24 Cases.

OBJECTIVES: To explore the risk factors for relapse of hyperglycemia in obese patients with type II diabetes mellitus (T2DM) who received laparoscopic Roux-en-Y gastric bypass (LRYGB) surgery. METHODS: A retrospective analysis was performed on all obese patients with T2DM who underwent a LRYGB during the period 2011-2013. Demographics, preoperative body mass index (BMI), preoperative glycated hemoglobin A1c (HbA1c), adherence to lifestyle intervention, preoperative medication of insulin, and the time interval between surgery and diagnosis of T2DM were investigated and compared. RESULTS: A total of 24 patients were included in our study. The median age was 45.5 years, the median BMI was 29.9 kg/m2, and the median HbA1c was 7.9%. Out of 24 patients, 54.2% (13/24) experienced a relapse of hyperglycemia. The 1-year, 3-year, and 5-year relapse rates were 4.2%, 12.5%, and 50.0%, respectively. The preoperative HbA1c level, C-peptide (2 h) level, and C-peptide (3 h) level were identified as independent variables for the relapse of hyperglycemia (8.11 ± 0.48 vs 7.72 ± 0.37 kg/m2, p = 0.036; 4.35 ± 1.46 vs 7.13 ± 4.10 ng/ml, p = 0.032; 3.76 ± 0.61 vs 5.99 ± 3.39 ng/ml, p = 0.029). Lifestyle intervention could reduce the hyperglycemia relapse rate (66.7 vs 41.7%) after LRYGB surgery. CONCLUSIONS: The preoperative HbA1c level and C-peptide level at surgery have an important significance in predicting the relapse of hyperglycemia after LRYGB surgery; lifestyle intervention is crucial for these patients.