Development Of Impaired Glucose Metabolism Research Articles

Calculation of the benchmark duration of shift work associated with the development of impaired glucose metabolism: a 14-year cohort study on 7104 male workers

ObjectivesThe aim of this study was to calculate the benchmark doses (BMD) and their 95% lower confidence boundary (BMDL) for the threshold number of years of shift work associated with...

Tumor necrosis factor- (TNF- ) in glutathione (GSH)-depleted rats. A possible link to impaired glucose metabolism

Rats: treated with the glutathione depleting agent, allyl alcohol (AlAl) (1 mmol/kg) was found to induce a marked increase in serum TNF- 45 minutes post treatment. This increase is suggested to play a critical role in the development of impaired glucose metabolism and glucose intolerance in AlAl-treated rats. Impaired glucose metabolism was evidenced by the significant increase in serum creatinine, urea and blood urea nitrogen accounting for accelerated glycolysis and breakdown of creatinine phosphate. These are the metabolic consequences of the activation of a back up system for the generation of ATP when the primary energy forming pathway is impaired. Meanwhile, the present data show a significant decrease in the serum levels of triglycerides and cholesterol in AlAl-treated rats that was accompanied with a concomitant increase in their liver levels indicating the development of fatty livers in these rats. Due to the strong link between TNF- and the GSH status and to the well established role of TNF- in causing insulin resistance, which is potentiated by fat accumulation in different tissues, it is concluded that the combination of TNF- overproduction, GSH depletion and lipid accumulation in the liver caused by AlAl treatment, cooperate making cells more sensitive to AlAl poisoning, therefore, imposing a potent negative impact on glucose metabolism. Added to the deleterious effects of TNF- , enhanced lipid peroxidation observed in AlAl- treated rats suggests possible alterations in the rates of glucose transport and metabolism which may further contribute to AlAl-induced impairment in glucose metabolism. Conclusion: Finally, the selective effect of TNF- in inhibiting insulin secretion give an additional support to its hypothesized role in initiating glucose intolerance in GSH-depleted rats.

Analysis of Posttransplant Diabetes Mellitus Prevalence in a Population of Kidney Transplant Recipients

Aim The onset of posttransplant diabetes mellitus (PTDM) among kidney recipients is associated with an increased risk of graft failure and death. Minimizing the risk of PTDM is a priority for long-term improvement in survival rates. We sought to evaluate the prevalence of PTDM and impaired fasting glucose (IFG) among a population of kidney transplant recipients to identify the risk factors and to evaluate graft and patient survivals. Methods We analyzed 250 consecutive Caucasian patients who received kidney allografts in our center between May 2000 and December 2005, with a median follow-up of 32 months (range, 1–78 months). Results We observed altered glucose metabolism in 17% of patients; specifically, the prevalences of PTDM and IFG were 12.2% and 4.8%, respectively. Patients who developed PTDM or IFG were overweight (BMI, 26.4 ± 3.4 and 28.1 ± 3.4 kg/m 2, respectively), whereas the normal glucose (NG) group's BMI was 23.8 ± 3.5 kg/m 2 ( P = .002 and P = .004, respectively). Prevalence of acute rejection was higher in the PTDM and IFG patients compared with the NG patients (60.7%, 63.6%, and 32.1%, respectively; P = .006; P < .04), while no difference was observed in terms of graft and patient overall survival. Conclusion In our series of patients, we showed that being overweight represents a major risk factor for the development of PTDM, which results in an increased acute rejection rate. These results confirmed the importance of appropriate weight control among patients undergoing kidney transplantation, which should also be strictly monitored for all risk factors associated with the development of impaired glucose metabolism.

Prevention and management of hyperglycemia after pancreas transplantation

Pancreas transplantation is considered the optimal therapy for patients with insulin-dependent diabetes. Successful pancreas transplantation achieves euglycemia and allows freedom from insulin therapy. Long-term allograft success may be limited by the development of impaired glucose metabolism. The objectives of the present review are to summarize the possible reasons for endocrine pancreatic dysfunction and to focus on its prevention and management and emphasize the role of immunosuppression. The diabetogenic effects of current immunosuppressive agents have been well established. Regimens without corticosteroids and calcineurin-inhibitor minimization or avoidance have been promoted. Recent studies have revisited the pathogenesis of type I and type II diabetes and demonstrated common pathways, including apoptosis induction, for the exhaustion and destruction of the pancreatic islets. The immunosuppressive regimens in pancreatic transplantation should be designed and appropriately modified according to the graft immunological and metabolic conditions. New molecules that are able to preserve islet function and maintain optimal insulin secretion should be considered for pancreas transplant recipients.

Visceral Fatness and Insulin Sensitivity in Women With a Previous History of Gestational Diabetes Mellitus

The purpose of this study was to investigate the insulin sensitivity and visceral fatness in women with previous gestational diabetes mellitus (GDM), who are prone to develop type 2 diabetes. A 75-g oral glucose tolerance test (OGTT) performed 1 year postpartum identified 21 GAD(-) women with previous GDM and impaired glucose tolerance (GDM-IGT). Sixty age- and BMI-matched women with normal glucose tolerance (GDM-NGT) were selected by 1:3 matching to the GDM-IGT group. Another 18 women with normal glucose metabolism during a previous pregnancy and no family history of diabetes were recruited as the normal control group. Age and BMI matching was performed using a range of +/-1.0 years and +/-1.0 kg/m(2), respectively. Total body fat was measured by tetrapolar bioelectrical impedance, and visceral fat was determined using a single cut of a computed tomography scan. Insulin sensitivity was determined by the minimal model technique using the frequently sampled intravenous glucose tolerance test. One year postpartum, visceral fat was greater in the GDM-IGT group than in the age- and BMI-matched GDM-NGT or normal control groups. The insulin sensitivity index was lower in the GDM-IGT group than in the GDM-NGT or normal control groups. beta-Cell function, as measured by the acute insulin response to glucose, was also lower in GDM-IGT. High body fat content, especially visceral fat content, and a low insulin response to glucose seem to contribute simultaneously to the development of impaired glucose metabolism in Korean women with previous GDM.

Tumor necrosis factor‐(TNF‐α ) in glutathione (GSH)‐depleted rats. A possible link to impaired glucose metabolism

Rat treatment with the glutathione depleting agent, allyl alcohol (AlAl)(1 mmol/kg) was found to induce a marked increase in serum TNF-α 45 minutes post treatment. This increase is suggested to play a critical role in the development of impaired glucose metabolism and glucose intolerance in AlAl-treated rats. Impaired glucose metabolism was evidenced by the significant increase in serum creatinine, urea and blood urea nitrogen accounting for accelerated glycolysis and breakdown of creatinine phosphate. These are the metabolic consequences of the activation of a back up system for the generation of ATP when the primary energy forming pathway is impaired. Meanwhile, the present data show a significant decrease in the serum levels of triglycerides and cholesterol in AlAl-treated rats that was accompanied with a concomitant increase in their liver levels indicating the development of fatty livers in these rats. Due to the strong link between TNF-α and the GSH status and to the well established role of TNF-α in causing insulin resistance, which is potentiated by fat accumulation in different tissues, it is concluded that the combination of TNF-α verproduction, GSH depletion and lipid accumulation in the liver caused by AlAl treatment, cooperate making cells more sensitive to AlAl poisoning, therefore, imposing a potent negative impact on glucose metabolism. Added to the deleterious effects of TNF-α, enhanced lipid peroxidation observed in AlAl-treated rats suggests possible alterations in the rates of glucose transport and metabolism which may further contribute to AlAl-induced impairment in glucose metabolism. Finally, the selective effect of TNF-α in inhibiting insulin secretion give an additional support to its hypothesized role in initiating glucose intolerance in GSH-depleted rats.

Role of premature leptin surge in obesity resulting from intrauterine undernutrition

Intrauterine undernutrition is closely associated with obesity related to detrimental metabolic sequelae in adulthood. We report a mouse model in which offspring with fetal undernutrition (UN offspring), when fed a high-fat diet (HFD), develop pronounced weight gain and adiposity. In the neonatal period, UN offspring exhibited a premature onset of neonatal leptin surge compared to offspring with intrauterine normal nutrition (NN offspring). Unexpectedly, premature leptin surge generated in NN offspring by exogenous leptin administration led to accelerated weight gain with an HFD. Both UN offspring and neonatally leptin-treated NN offspring exhibited an impaired response to acute peripheral leptin administration on a regular chow diet (RCD) with impaired leptin transport to the brain as well as an increased density of hypothalamic nerve terminals. The present study suggests that the premature leptin surge alters energy regulation by the hypothalamus and contributes to "developmental origins of health and disease."

Management of Hyperglycaemia After Pancreas Transplantation

Pancreas transplantation is considered the optimal therapy for patients with diabetes mellitus who reach end-stage renal disease. Despite achievement of euglycaemia after this procedure, the progression to impaired pancreatic function and metabolic exhaustion still represents one of the major concerns that increase the risk of graft loss. This paper reviews the possible mechanisms that can induce post-transplant hyperglycaemia, including those related to immunosuppression and those non-related, and the new strategies available for minimising or preventing this complication. Different aetiologies can induce pancreatic dysfunction. Technical complications, acute pancreatitis and delayed graft function, mostly related to impaired insulin secretion, are considered the early causes for abnormal glucose control. In general, acute rejection does not affect the endocrine portion of the pancreas graft because islet destruction occurs later than the inflammation of the exocrine components. Hyperinsulinaemia and insulin resistance represent the main concern for the progression of blood glucose intolerance. The anastomotic techniques of the exocrine portion of the pancreas and the immunosuppressive regimens are of critical importance for the development of impaired glucose metabolism. Hyperinsulinaemia, as a result of the fact that systemic-enteric or systemic-bladder drainages reducing the hepatic clearance of insulin, has led to the introduction of more physiological techniques using portal drainage of the endocrine secretions. Experimental and clinical data have shown that many of the current immunosuppressants account, to a large degree, for the increased risk of the development of post-transplant hyperglycaemia. The most common maintenance regimen in pancreatic transplantation still consists of triple therapy with a combination of corticosteroids, calcineurin inhibitors (either ciclosporin [cyclosporine] or tacrolimus), and mycophenolate mofetil (MMF).The diabetogenic effects of corticosteroids and calcineurin inhibitors have resulted in the need for protocols able to minimise their use. Recent studies have shown the safety and efficacy of steroid-sparing or -free regimens. Sirolimus has shown powerful immunosuppressive potency in absence of nephrotoxicity and diabetogenicity. Multicentre and single-centre reports have demonstrated that both calcineurin inhibitor withdrawal and avoidance were possible when sirolimus was used in a concentration-controlled fashion, with low-dose corticosteroids and MMF. Although the experience with sirolimus in pancreatic transplantation is still limited, the results are promising. Patients affected by diabetic gastroparesis seem to better tolerate a regimen with sirolimus and low-dose tacrolimus than one with tacrolimus in combination with MMF.For successful, long-term results of pancreatic transplantation, it is crucial to combine donor selection, technical aspects, modified anastomotic techniques and new therapeutic approaches designed to minimise the metabolic and non-metabolic adverse effects of the immunosuppressive regimens.

Is there a link between impaired glucose metabolism and protein kinase C activity in the diabetic heart?

The activity of the beta isoform of protein kinase C (PKC beta) is reduced in the diabetic heart. Since this isozyme has been implicated in insulin action, we tested the hypothesis that PKC beta contributes to the development of impaired glucose metabolism by the noninsulin-dependent diabetic heart. Exposure of the diabetic heart to buffer containing the protein kinase C activator, phorbol myristate acetate, increased PKC beta activity in the membrane. Associated with the improvement in PKC beta activity was a biphasic change in glucose metabolism. The initial phase was characterized by a breakdown in glycogen stores, a stimulation in glucose oxidation and a decrease in endogenous fatty acid oxidation. This was followed by a second phase in which the uptake of glucose was modestly stimulated. Nonetheless, since the phorbol ester did not overcome the diabetes-linked defect in pyruvate dehydrogenase, the increase in glycolytic flux was not associated with a rise in glucose oxidation. Consequently, nearly 50% of the triose units were diverted into lactate and pyruvate production and the generation of ATP from glucose was restricted. Since insulin promotes not only glucose uptake, but also glycogen synthesis and glucose oxidation, the phorbol ester and insulin effects are very different. Thus, the data do not support a role for PKC beta in the development of glucose metabolic defects in the hearts of noninsulin-dependent diabetic rats.

The relationship between first-phase insulin secretion and glucose metabolism.

A possible pathogenetic link between absence of first-phase insulin secretion and development of impaired glucose metabolism has been suggested by the results of several cross-sectional studies. First-phase insulin secretion measured during a +7 mmol/l hyperglycemic glucose clamp correlated with total glucose disposal during the clamp (r = 0.65, p < 0.001, N = 59). To examine whether restoration of first-phase insulin secretion improves peripheral glucose uptake in subjects with impaired glucose utilization, seven insulin-resistant subjects (age 54 (38-62) years: BMI 29.3 (21.7-35.8); fasting plasma glucose 5.5 (4.8-7.2) mmol/l; fasting insulin 57 (37-105) pmol/l with impaired first-phase (148 (29-587) vs controls 485 (326-1086) pmol/l x 10 min; p < 0.05) and normal second-phase (1604 (777-4480) vs controls (1799 (763-2771) pmol/l x 110 min) insulin secretion were restudied. The impaired first-phase insulin secretion was restored by an iv insulin bolus at the start of the hyperglycemic clamp. Substrate oxidation rates and hepatic glucose production were determined by indirect calorimetry and [3-3H]glucose infusion. Total glucose uptake was impaired in the insulin-resistant subjects with impaired first-phase insulin secretion compared to controls (18.8 (13.2-22.2) vs 34.8 (24.3-62.1) mumol.kg-1 x min-1; p < 0.01). Restoration of first-phase insulin secretion (1467 (746-2440) pmol/l x 10 min) did not affect glucose uptake (20.2 (9.9-23.8) mumol.kg-1.min-1), with no difference in oxidative and non-oxidative glucose metabolism between the experiments. Second-phase insulin secretion was similar during both experiments.(ABSTRACT TRUNCATED AT 250 WORDS)