Carotid Body Resection Prevents Short-Term Spatial Memory Decline in Prediabetic Rats Without Changing Insulin Signaling in the Hippocampus and Prefrontal Cortex.

Individuals who develop type 2 diabetes (T2D) at an early age are at higher risk of developing neurodegenerative disorders such as Alzheimer's and Parkinson's disease. A shared dysfunctional characteristic between T2D and these neurodegenerative disorders is insulin resistance. Recently, it was shown that prediabetes animals and patients exhibited increased carotid body (CB) activity. Moreover, these organs are deeply involved in the development of metabolic diseases, since upon abolishment of their activity via carotid sinus nerve (CSN) resection, several dysmetabolic features of T2D were reverted. Herein, we investigated if CSN resection may also prevent cognitive impairment associated with brain insulin resistance. We explored a diet-induced prediabetes animal model where Wistar rats are kept in a high fat-high sucrose (HFHSu) diet for 20 weeks. We evaluated CSN resection effects on behavioral parameters and on insulin signaling-related proteins levels, in the prefrontal cortex and the hippocampus. HFHSu animals exhibited impaired short-term memory evaluated by the y-maze test. Remarkably, CSN resection prevented the development of this phenotype. HFHSu diet or CSN resection did not promote significant alterations in insulin signaling-associated proteins levels. Our findings suggest that CBs modulation might have a role in preventing short-term spatial memory deficits associated with peripheral dysmetabolic states.

Bile acid, glucose, lipid profile, and liver enzyme changes in prediabetic patients 1 year after sleeve gastrectomy.

BACKGROUND: Few articles have studied individuals with prediabetes after sleeve gastrectomy. Bile acid and lipid levels remain inconsistent in postbariatric patients. The purpose of this study was to explore bile acid, glucose, lipid, and liver enzyme changes in patients with different diabetes statuses who underwent sleeve gastrectomy. The impact of bariatric surgery and its potential benefits for prediabetic patients was also discussed. METHODS: A total of 202 overweight and obese patients who underwent bariatric surgery in our hospital between January 2016 and October 2018 were retrospectively reviewed. Patients were divided into prediabetes (n = 32), nondiabetes (n = 144), and diabetes (n = 26) groups and analysed. Glucose and lipid data were collected from medical records at baseline and at each follow-up visit. RESULT: Significant improvements in body weight, glucose and lipid levels, and liver enzymes (P ≤ 0.05) in prediabetic patients were found throughout the first year postoperatively. Improvement in glycaemic control was first seen one month postoperatively, followed by persistent improvement in the next 12 months. Total bile acid (TBA) decreased, which was associated with ALT improvement in prediabetic patients 1-year post-surgery. There were no significant differences in HbA1c, glucose, or triglycerides (TGs) between prediabetic and T2DM patients or between prediabetic and nondiabetic patients at 12 months post-surgery. CONCLUSION: LSG is highly effective at interfering with glucose and lipid levels as well as total bile acid levels in prediabetic patients in the first year postoperatively. Thus, LSG is indeed an alternative for overweight and obese prediabetic patients.

SCCA-IgM as a Potential Biomarker of Non-Alcoholic Fatty Liver Disease in Patients with Obesity, Prediabetes and Diabetes Undergoing Sleeve Gastrectomy.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has a high prevalence in obesity and its presence should be screened. Laparoscopic sleeve gastrectomy (LSG) is an effective treatment for obesity, but its effects on NAFLD are still to be firmly established. The diagnosis of non-alcoholic steatohepatitis (NASH) is currently performed by liver biopsy, a costly and invasive procedure. Squamous cell carcinoma antigen-IgM (SCCA-IgM) is a biomarker of viral hepatitis to hepatocellular carcinoma development and its role in NAFLD to NASH progression has not yet been investigated. OBJECTIVE: The aim of this study was to evaluate SCCA-IgM as a non-invasive biomarker of NAFLD/NASH in patients with different degrees of metabolic-complicated obesity before and after LSG. METHOD: Fifty-six patients with obesity were studied before and 12 months after LSG; anthropometric, biochemical, clinical, and imaging data were collected. RESULTS: At baseline steatosis was strongly associated with the glycaemic profile (p = 0.016) and was already present in prediabetic patients with obesity (82%). Only 3 patients had an SCCA-IgM level above the normal cut-off. SCCA-IgM titre did not change according to glycaemic profile or steatosis. Metabolic and inflammatory factors and transaminases significantly reduced after LSG-induced weight loss, except for SCCA-IgM. The ALT/AST ratio decreased post-LSG correlated with BMI (r = 0.297, p = 0.031), insulin (r = 0.354, p = 0.014), and triglycerides (r = 0.355, p = 0.009) reduction. CONCLUSIONS: Our results confirm the tight link between NAFLD and metabolic complications, suggesting prediabetes as a new risk factor of steatosis. SCCA-IgM does not seem to have a role in the identification and prognosis of NAFLD.

Cardiovascular risk reduction over time in patients with diabetes or pre-diabetes undergoing bariatric surgery: data from a single-center retrospective observational study.

BACKGROUND: Bariatric surgery is effective in remission of obesity comorbidities. This study was aimed at comparing CVD risk between morbidly obese patients with type 2 diabetes and pre-diabetes before and after bariatric surgery as well as assessing comorbidities. METHODS: This is a retrospective observational study with 105 patients with type 2 diabetes (DMbaseline) and prediabetes (preDMbaseline) who underwent Roux-en-Y gastric bypass. Data were collected preoperative and then at 3,6,12,18,24,36,48, and 60 months after surgery. Anthropometric, cardiovascular and glycemic parameters were assessed. CVD risk was calculated using the Framingham Risk Score. RESULTS: Prior to surgery, 48 patients had type 2 diabetes, while 57 had pre-diabetes. Mean age was 48 (9.2) and mean BMI was 52 (7.4). 26.1% of patients had a high CVD risk. CVD risk decreased in patients with type 2 diabetes and prediabetes at month 12 after surgery compared to the baseline risk (p < 0.001). BMI, body fat percentage, fasting plasma glucose, HbA1c, c-peptide, HOMA-IR, LDL-c, systolic blood pressure, and diastolic blood pressure decreased during the first year after surgery. From the 12th month until the 60th, they showed a flat trend, or a very mild increase in some cases. 3.2% of patients maintained high CVD risk at 60 months. Type 2 diabetes remission was 92%. No patient of the preDMbaseline group developed type 2 diabetes. CONCLUSION: Bariatric surgery reduces CVD risk in type 2 diabetes and pre-diabetes. Given that patients with type 2 diabetes benefit the most, more studies are necessary to consider pre-diabetes as a criterion for metabolic surgery in patients with BMI ≥ 35 kg/m2.

A 5-Year Follow-Up Study of Laparoscopic Sleeve Gastrectomy Among Morbidly Obese Adolescents: Does It Improve Body Image and Prevent and Treat Diabetes?

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is widely used, and it is important to examine its physiologic and psychological efficacy among adolescents. We assessed LSG's efficacy for weight loss, its short- and long-term effects on resolving and improving obesity-related comorbidities, and its psychological outcomes among morbidly obese adolescents. METHODS: We retrospectively analyzed the medical records of 91 morbidly obese adolescents in Qatar who underwent LSG (2011-2014), with 1- and 5-year follow-ups. RESULTS: The mean preoperative weight and body mass index (BMI) were 132.5 ± 25.3 kg and 48 ± 7.5 kg/m2, respectively. Postoperatively, mean weight and BMI decreased to 101 ± 22 kg and 36.4 ± 7.2 kg/m2, respectively. At 1 year, the mean excess weight loss (%EWL), percent total weight loss (%TWL), and percent BMI loss (%BMIL) were 49.48 ± 25.8, 23.1 ± 11.9, and 23.16 ± 11.8%, respectively. At 5 years, %EWL, %TWL, and %BML were 78 ± 12, 35.8 ± 11.5, and 36 ± 12%, respectively. No patients developed postoperative leaks, and three patients had endoscopic dilatation due to stenosis. Overall, 64% of obstructive sleep apnea patients were cured, all prediabetic patients had total remission, and 50% of the diabetic patients were cured. The overall mean HBA1c level was 6 mmol/L, which significantly decreased to 5.1 mmol/L postoperatively (P = 0.0001). At 5 years, there was no relapse of diabetes, and 75% of the diabetic adolescents had complete remission. The only patient with hypertension showed complete resolution with laparoscopic sleeve gastrectomy. Postoperatively, overall body image satisfaction significantly improved (P = 0.0001). CONCLUSION: LSG significantly ameliorated short- and long-term obesity-related comorbidities and body image dissatisfaction among Qatari adolescents.

Resolution of type 2 diabetes and prediabetes following laparoscopic sleeve gastrectomy: medium term results.

PURPOSE: To determine the impact of Laparoscopic Sleeve Gastrectomy (LSG) on the resolution of type 2 diabetes (T2DM) and Prediabetes (PDM) in obese patients, as well as potential improvements in other comorbidities. MATERIAL AND METHODS: Observational retrospective study. We studied all patients with T2DM (n= 36) or PDM (n= 44) who underwent LSG in our hospital between years 2009 and 2012. PDM was defined as having at least 2 values of HbA1c between 5.7 and 6.4%. Follow-up period was 1-4 years (mean 17.5 months). T2DM remission criteria were fasting plasma glucose (FPG).

Objetivos: Evaluar la efectividad de la gastroplastia tubular laparoscópica (GTL) en la resolución de la diabetes tipo 2 (DM2), de la prediabetes (PDM) y de otras comorbilidades en pacientes obesos. Material y métodos: Estudio observacional retrospectivo. Se incluyeron a los pacientes con DM2 (n= 36) o PDM (n= 44) que fueron sometidos a GTL en nuestro hospital entre 2009 y 2012. Se consideró criterio de PDM presentar HbA1c entre 5.7-6.4% en al menos dos ocasiones. Periodo de seguimiento entre 1-4 años (media 17.5 meses). Como criterio de resolución de la DM2 se consideró presentar HbA1c.

Differential outcomes in prediabetic vs. overtly diabetic NOD mice nonmyeloablatively conditioned with costimulatory blockade.

OBJECTIVE: Autoimmune diabetes can be reversed with mixed chimerism. However, the myelotoxic agents currently required to establish chimerism have prevented the translation of this approach to the clinic. Here, we investigated whether multimodal costimulatory blockade would enhance chimerism and promote islet allograft tolerance in spontaneously diabetic nonobese diabetic (NOD) mice. MATERIALS AND METHODS: Prediabetic and spontaneously diabetic NOD mice were preconditioned with anti-CD8 monoclonal antibody before conditioning with 500 cGy total body irradiation and transplantation with 30 × 10(6) B10.BR bone marrow cells. Overtly diabetic animals were conditioned similarly and transplanted with 300 to 400 B10.BR islets. After irradiation, both groups of recipients were treated with anti-CD154, anti-OX40L, and anti-inducible T-cell costimulatory monoclonal antibodies. Urine, blood glucose levels, and chimerism were monitored. RESULTS: Conditioning of NOD mice with costimulatory blockade significantly enhanced engraftment, with 61% of mice engrafting at 1 month. Eleven of 12 chimeric animals with engraftment at 1 month remained diabetes-free over a 12-month follow-up, whereas nonchimeric animals progressed to diabetes. In contrast, similar conditioning prolonged islet allograft survival in only 2 of 11 overtly diabetic NOD recipients. Chimerism levels in the 9 islet rejector animals were 0%. CONCLUSIONS: Although nonmyeloablative conditioning reversed the autoimmune process in prediabetic NOD mice, the same regimen was significantly less effective in establishing chimerism and reversing autoimmune diabetes in spontaneously diabetic NOD mice.

Low levels of allogeneic but not syngeneic hematopoietic chimerism reverse autoimmune insulitis in prediabetic NOD mice.

The relative efficiencies of allogeneic and syngeneic bone marrow transplantation and the threshold levels of donor chimerism required to control autoimmune insulitis were evaluated in prediabetic NOD mice. Male and female NOD mice were conditioned by radiation and grafted with bone marrow cells from allogeneic and syngeneic sex-mismatched donors. Establishment of full allogeneic chimerism in peripheral blood reversed insulitis and restored glucose tolerance despite persistence of residual host immune cells. By contrast, sublethal total body irradiation (with or without syngeneic transplant) reduced the incidence and delayed the onset of diabetes. The latter pattern was also seen in mice that rejected the bone marrow allografts. Low levels of stable allogeneic hematopoietic chimerism (>1%) were sufficient to prevent the evolution of diabetes following allogeneic transplantation. The data indicate that immunomodulation attained at low levels of allogeneic, but not syngeneic, hematopoietic chimerism is effective in resolution of islet inflammation at even relatively late stages in the evolution of the prediabetic state in a preclinical model. However, our data question the efficacy and rationale behind syngeneic (autologous-like) immuno-hematopoietic reconstitution in type 1 diabetes.

Insulin glargine improves glycaemic control after coronary surgery in patients with diabetes or pre-diabetes.

OBJECTIVES: Determine if pre-emptive daily insulin glargine surpasses regular insulin when needed for glycaemic control after cardiac surgery. DESIGN: Prospective, randomized study of 43 patients (scheduled for coronary artery bypass grafting) with preoperatively diagnosed diabetes (DM) or pre-DM. Lantus group received insulin glargine daily from start of surgery while Actrapid group received regular insulin (sliding scale) when needed (plasma glucose (P-glu)>10 mmol/l). Primary endpoint was percent of pre- and post-prandial P-glu values within Target Intervals: Pre-prandial P-glu: 4.5-7 mmol/l; post-prandial P-glu: 4.5-9 mmol/l. Study period 1-4 days after surgery. Tissue glucose was also measured continuously. RESULTS: More than twice as many P-glu values were within Target Interval for Lantus patients as compared with Actrapid patients (p<0.001). One of 504 timed measurements was <4 mmol/l. Area under the curve for glucose>7 mmol/l was reduced by 61% by Lantus (p<0.001). CONCLUSION: The routine protocol with pre-emptive glargine insulin studied here provides a major improvement in glycaemic control with a minimal incidence of hypoglycaemia and without an excessive increase in nursing burden.

Effect of FK506 and anti-CD4 therapy on fetal pig pancreas xenografts and host lymphoid cells in nod/Lt, CBA, and BALB/c mice.

Varying doses of FK506, and a cell-depleting anti-CD4 monoclonal antibody, GK1.5, were tested as either monotherapy or in combination for their effect on the survival of renal subcapsular xenografts of organ-cultured fetal pig pancreas in three strains of mice. Subcutaneous injections of FK506 at 4.0 mg/kg/day for 28 d prevented graft rejection to day 35 posttransplantation (i.e., 7 days after cessation of treatment in NOD/Lt, and CBA mice) while BALB/c mice had intact grafts at 28 days. Lower doses were less effective and immunosuppression was less effective in NOD mice than in the other strains. Even 2.0 mg/kg/day of FK506 prevented rejection in CBA mice until day 35, but not in NOD/Lt mice. GK1.5 alone did not prevent rejection in NOD/Lt mice but when a low dose of FK506 (2.0 mg/day) was added, the grafts were present, essentially intact, at 35 days. There were no obvious toxic effects of FK506 in NOD/Lt and CBA mice. With FK506 treatment there was no significant difference in absolute numbers of total leucocytes or lymphocytes in peripheral blood and spleen, but there was a decrease in thymus cellularity. Flow cytometric analysis of lymphocyte subsets in blood and spleen also showed no significant differences, but in the thymus the percentage of immature CD4/CD8 "double positive" cells increased while the more mature CD3"high", and CD4 or CD8 "single-positive" cells decreased. Thus, prolonged discordant xenograft survival in mice is possible and the use of two agents that act on different parts of the immune system allows a reduction in the dose of FK506 to safe levels.