Advanced glycation end products serve as ligands for lectin-like oxidized low-density lipoprotein receptor-1(LOX-1): biochemical and binding characterizations assay

Advanced glycation end products (AGEs) are a class of complex heterogeneous compounds which accumulate with age and is known to be involved in the pathogenesis of several diseases from diabetes to atherosclerosis. AGEs serve as ligands for multiple receptors including scavenger receptor (SR-A), CD36, and SR-BIota. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) plays an important role in both atherosclerosis and is found to be an endothelial cell receptor for AGEs. To explore the binding characterization of AGEs to LOX-1, AGEs were prepared by three different reducing sugars (d-glucose, d-fructose, and d-ribose) and the biochemical characterization including, free amino groups, free amine content, fructosamine residues, carbonyl content, fluorescence, and absorbance were determined. The binding activity was determined by FITC labeled AGEs using Chinese hamster ovary-K1 cells stably transfected with human LOX-1 gene. The obtained AGEs showed significant differences in the extent of side chain modifications, carbonyl content, fluorescence, and absorption models. All of the AGEs showed specific and saturable binding to hLOX-1-CHO-K1 cells. Furthermore, dose-dependent binding processes were observed. However, the maximal cellular binding of AGEs differs between the sugars (glucose > ribose > fructose). In addition, oxidized low-density lipoprotein (ox-LDL) could significantly inhibit the binding of AGEs to LOX-1 with different inhibitory efficiency. LOX-1 serves as receptor for AGEs which may give some insight into the role of LOX-1 in the pathogenesis of diabetes and related disorders.     

Advanced glycation end-products and the progress of diabetic vascular complications

Epidemiological studies have confirmed that hyperglycemia is the most important factor in the onset and progress of vascular complications, both in Type 1 and 2 diabetes mellitus. The formation of advanced glycation end-products (AGEs) correlates with glycemic control. The AGE hypothesis proposes that accelerated chemical modification of proteins by glucose during hyperglycemia contributes to the pathogenesis of diabetic complications including nephropathy, retinopathy, neuropathy and atherosclerosis. Recent studies have shown that increased formation of serum AGEs exists in diabetic children and adolescents with or without vascular complications. Furthermore, the presence of diabetic complications in children correlates with elevated serum AGEs. The level of serum AGEs could be considered as a marker of later developments of vascular complications in children with Type 1 and 2 diabetes mellitus. The careful metabolic monitoring of young diabetics together with monitoring of serum AGEs can provide useful information about impending AGE-related diabetic complications. It is becoming clear that anti-AGE strategies may play an important role in the treatment of young and older diabetic patients. Several potential drug candidates such as AGE inhibitors have been reported recently.     

Diabetes enhances lectin-like oxidized LDL receptor-1 (LOX-1) expression in the vascular endothelium: possible role of LOX-1 ligand and AGE

Diabetes mellitus accelerating atherosclerosis was associated with the enhanced glycoxidative modification of lipoproteins. LOX-1, the endothelial oxidized LDL receptor might be involved in the pathogenesis of diabetic atherosclerosis. In this study, we examined the vascular expression of LOX-1 in streptozotocin-induced diabetic rats. We found that LOX-1 was significantly increased in diabetic rat aorta compared with nondiabetic control. Immunohistochemistry revealed that the most distinctive staining of LOX-1 was in the endothelial cells, especially in the bifurcations of artery branches from aorta. In cultured aortic endothelial cells, diabetic rat serum and advanced glycation endproducts-BSA induced LOX-1 expression, while control rat serum along with high glucose did not. Applying a competitive inhibition assay, we found that LOX-1 ligand activity was accumulated in the diabetic rat serum, mainly in VLDL/LDL fractions. In addition, VLDL/LDL prominently increased LOX-1 among all the lipoprotein fractions of diabetic rat serum. In conclusion, diabetes markedly upregulated LOX-1 expression in the aortic endothelial cells. The enhanced glycoxidative modification of lipoproteins may contribute to the underlying mechanisms.     

Soluble RAGE in type 2 diabetes: association with oxidative stress

Advanced glycation end products (AGEs) contribute to diabetic vascular complications by engaging the AGE receptor (RAGE). A soluble RAGE form (sRAGE) acts as a decoy domain receptor, thus decreasing AGE cellular binding. A cross-sectional comparison of sRAGE, asymmetric dimethylarginine (ADMA) plasma levels (index of endothelial dysfunction), and urinary 8-iso-prostaglandin (PG)F(2alpha) (marker of oxidative stress) was performed between 86 diabetic patients and 43 controls. Plasma sRAGE levels were significantly lower and ADMA levels were significantly higher in diabetic patients as compared to controls (P<0.0001). HbA1c and urinary 8-iso-PGF(2alpha) were correlated inversely with sRAGE and directly with ADMA. On multivariate analysis HbA1c was independently related to sRAGE levels in diabetic patients. Twenty-four of 86 patients with newly diagnosed diabetes and 12 patients in poor metabolic control were reevaluated after treatment with a hypoglycemic agent or insulin, respectively. Improvement in metabolic control by oral agents or insulin resulted in a significant increase in sRAGE and decrease in ADMA levels (P<0.0001). Thus, poor glycemic control reduces sRAGE levels, in association with enhanced oxidative stress and endothelial dysfunction in diabetes. These abnormalities are susceptible to modulation by improvement in metabolic control.     

Elevated soluble lectin-like oxidized LDL receptor-1 (sLOX-1) levels in obese postmenopausal women

We investigated the association between soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) levels and obesity in older women. Fifty-one postmenopausal women (10 lean, 22 overweight, and 19 obese) were included in this small retrospective analysis. Plasma sLOX-1 levels were measured using a chemiluminescent enzyme-linked immunoassay. Plasma levels of sLOX-1 were significantly higher in obese women (55.33 +/- 4.49 pg/ml) compared to lean (30.91 +/- 6.19 pg/ml, P = 0.002) and overweight women (38.31 +/- 4.18 pg/ml, P = 0.017). Plasma sLOX-1 levels were positively associated with body weight, BMI, total body fat, and trunk fat. The relationship between sLOX-1 and BMI was attenuated after adjustment for age, hormone replacement therapy, and body fat. In conclusion, obese women have higher sLOX-1 levels, which may reflect increased LOX-1 expression in adipose tissue.     

Membrane Cholesterol Modulates LOX-1 Shedding in Endothelial Cells

The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a scavenger receptor responsible for ox-LDL recognition, binding and internalization, which is up-regulated during atherogenesis. Its activation triggers endothelium dysfunction and induces inflammation. A soluble form of LOX-1 has been identified in the human blood and its presence considered a biomarker of cardiovascular diseases. We recently showed that cholesterol-lowering drugs inhibit ox-LDL binding and internalization, rescuing the ox-LDL induced apoptotic phenotype in primary endothelial cells. Here we have investigated the molecular bases of human LOX-1 shedding by metalloproteinases and the role of cell membrane cholesterol on the regulation of this event by modulating its level with MβCD and statins. We report that membrane cholesterol affects the release of different forms of LOX-1 in cells transiently and stably expressing human LOX-1 and in a human endothelial cell line (EA.hy926). In particular, our data show that i) cholesterol depletion triggers the release of LOX-1 in exosomes as a full-length transmembrane isoform and as a truncated ectodomain soluble fragment (sLOX-1); ii) endothelial cells secrete a soluble metalloproteinase which induces LOX-1 ectodomain shedding and iii) long term statins treatment enhances sLOX-1 proteolytic shedding.     

Impaired Increase of Plasma Abscisic Acid in Response to Oral Glucose Load in Type 2 Diabetes and in Gestational Diabetes

The plant hormone abscisic acid (ABA) is present and active in humans, regulating glucose homeostasis. In normal glucose tolerant (NGT) human subjects, plasma ABA (ABAp) increases 5-fold after an oral glucose load. The aim of this study was to assess the effect of an oral glucose load on ABAp in type 2 diabetes (T2D) subjects. We chose two sub-groups of patients who underwent an oral glucose load for diagnostic purposes: i) 9 treatment-naive T2D subjects, and ii) 9 pregnant women with gestational diabetes (GDM), who underwent the glucose load before and 8–12 weeks after childbirth. Each group was compared with matched NGT controls. The increase of ABAp in response to glucose was found to be abrogated in T2D patients compared to NGT controls. A similar result was observed in the women with GDM compared to pregnant NGT controls; 8–12 weeks after childbirth, however, fasting ABAp and ABAp response to glucose were restored to normal in the GDM subjects, along with glucose tolerance. We also retrospectively compared fasting ABAp before and after bilio-pancreatic diversion (BPD) in obese, but not diabetic subjects, and in obese T2D patients, in which BPD resulted in the resolution of diabetes. Compared to pre-BPD values, basal ABAp significantly increased 1 month after BPD in T2D as well as in NGT subjects, in parallel with a reduction of fasting plasma glucose. These results indicate an impaired hyperglycemia-induced ABAp increase in T2D and in GDM and suggest a beneficial effect of elevated ABAp on glycemic control.     

Alterations in the growth hormone-insulin-like growth factor axis in insulin dependent diabetes mellitus.

The growth hormone (GH)-insulin-like growth factor (IGF) axis and insulin are major anabolic effectors in promoting weight gain and linear growth. These two anabolic systems are interlinked at many levels, thus abnormalities in one of these systems effect the other causing disordered metabolic homeostasis. Insufficient portal insulinization in insulin dependent diabetes mellitus (IDDM) results in hepatic GH resistance and increased production of IGF-binding proteins-1 (IGFBP-1) and IGFBP-2. GH resistance is reflected by decreased hepatic IGF-I production. In addition, changes in other GH-dependent proteins are also observed in IDDM. Increased proteolysis of IGFBP-3 results in reduction of intact IGFBP-3. Serum ALS levels are also slightly diminished in untreated diabetic patients. Hepatic resistance to GH is, at least in part, caused by diminished GH receptors as reflected by diminished circulating GHBP levels. In addition, there is also evidence from experimental and human studies suggesting post-receptor defect(s) in GH action. As a result of these changes, circulating total and free IGF-I levels are decreased during insulinopenia. Lack of negative feed-back effect of IGF-I on GH secretion causes GH hypersecretion which increases hyperglycemia by decreasing sensitivity to insulin. GH hypersecretion in poorly controlled diabetic patients may play a role in the pathogenesis of diabetic vascular complications. Most of these abnormalities in the GH-IGF axis in diabetes are reversed by effective insulinization of the patient. Addition of IGF-I treatment to insulin in adolescents with IDDM allows correction of GH hypersecretion, improves insulin sensitivity and glycemic control, and decreases insulin requirements. The effect of IGF-I treatment on diabetic complications has yet to be seen.     

Plasma protein advanced glycation end products, carboxymethyl cysteine, and carboxyethyl cysteine, are elevated and related to nephropathy in patients with diabetes

In Diabetes Mellitus (DM), glucose and the aldehydes glyoxal and methylglyoxal modify free amino groups of lysine and arginine of proteins forming advanced glycation end products (AGEs). Elevated levels of these AGEs are implicated in diabetic complications including nephropathy. Our objective was to measure carboxymethyl cysteine (CMC) and carboxyethyl cysteine (CEC), AGEs formed by modification of free cysteine sulfhydryl groups of proteins by these aldehydes, in plasma proteins of patients with diabetes, and investigate their association with the albumin creatinine ratio (ACR, urine albumin (mg)/creatinine (mmol)), an indicator of nephropathy. Blood was collected from forty-two patients with type 1 and 2 diabetes (18–36 years) and eighteen individuals without diabetes (17–35 years). A liquid chromatography-mass spectrophotometric method was developed to measure plasma protein CMC and CEC levels. Values for ACR and hemoglobin A1C (HbA1C) were obtained. Mean plasma CMC (μg/l) and CEC (μg/l) were significantly higher in DM (55.73 ± 29.43, 521.47 ± 239.13, respectively) compared to controls (24.25 ± 10.26, 262.85 ± 132.02, respectively). In patients with diabetes CMC and CEC were positively correlated with ACR, as was HbA1C. Further, CMC or CEC in combination with HbA1C were better predictors of nephropathy than any one of these variables alone. These results suggest that glucose, glyoxal, and methylglyoxal may all be involved in the etiology of diabetic nephropathy.     

Antioxidant icariside II combined with insulin restores erectile function in streptozotocin‐induced type 1 diabetic rats

Erectile dysfunction (ED) worsens in patients with diabetes mellitus (DM) despite good control of blood glucose level with insulin. Recent studies imply that diabetic vascular stresses (e.g. oxidative stress) persist in spite of glucose normalization, which is defined as metabolic memory. Studies suggest that the interaction between advanced glycation end products (AGEs) and their receptor (RAGE) mediates the development of metabolic memory. To investigate the effects of the antioxidant icariside II plus insulin on erectile function in streptozotocin (STZ)‐ induced type 1 diabetic rats. Fifty 8‐week‐old Sprague‐Dawley rats were randomly distributed into five groups: normal control, diabetic, insulin‐treated diabetic, icariside II‐treated diabetic, and insulin plus icariside II‐treated diabetic. Diabetes was induced by a single intraperitoneal injection of STZ. Eight weeks after induction of diabetes, icariside II was administered by gastric lavage once a day (5 mg/kg) for 6 weeks; and 2–6 units of intermediate‐acting insulin were given to maintain normal glycemia for 6 weeks. The main outcome measures were the ratio of intracavernous pressure (ICP) to mean arterial pressure (MAP); histology of penile endothelial cells and smooth muscle cells; neural nitric oxide synthase, AGEs and RAGE expression; malondialdehyde concentration; superoxide dismutase activity; and apoptosis index. Diabetic rats demonstrated a significantly lower ICP/MAP ratio, reduced penile endothelial cells, reduced smooth muscle cells, increased AGEs and RAGE, and increased apoptosis. Insulin and icariside II monotherapy partially restored erectile function and histological changes. However, the combination therapy group showed significantly better erectile parameters, cytological components and biochemistry, similar to those in the normal control group. These results suggest that, although insulin can effectively control glycemic levels, it does not completely alter the pathological changes in erectile tissues. Better efficacy could be expected with tight glycemic control plus the antioxidant icariside II. The proposed combination therapy might have the potential to eliminate metabolic memory by down‐regulating the AGEs‐RAGE‐oxidative stress axis.     

Inhibition of LOX-1 by statins may relate to upregulation of eNOS.

LOX-1, a receptor for oxidized low-density lipoprotein (ox-LDL), plays a critical role in endothelial dysfunction and atherosclerosis; both of these conditions are associated with diminished expression of constitutive endothelial nitric oxide synthase (eNOS). Recent studies show that HMG CoA reductase inhibitors (statins) exert cardioprotective effect. We examined the role of LOX-1 in eNOS expression and modulation of this relationship by two different statins, simvastatin and atorvastatin in human coronary artery endothelial cells (HCAECs). Ox-LDL (40 microg/ml) upregulated the expression of LOX-1; simultaneously, there was a reduction in eNOS expression. Pretreatment of HCAECs with simvastatin or atorvastatin (1 and 10 microM) reduced ox-LDL-induced upregulation of LOX-1 and downregulation of eNOS (both P < 0.05). High concentration of statins (10 microM) was more potent than the low concentration (1 microM) (P < 0.05). Both statins also attenuated ox-LDL-mediated activation of MAP kinase. These observations indicate that statins attenuate the effect of ox-LDL on eNOS expression. Inhibitory effect on LOX-1 and subsequently MAP kinase activity provides a potential mechanism of beneficial effects of statins beyond lowering cholesterol.     

Advanced glycation end-products and advanced oxidation protein products in patients with diabetes mellitus

Accelerated glycoxidation takes part in the development of diabetic complications. We determined advanced glycation end-products (AGEs) and advanced oxidation protein products (AOPP) in the sera of 52 patients with diabetes mellitus (DM) - 18 with DM Type 1 and 34 with DM Type 2 and examined their relationship to the compensation of the disease. AGEs were estimated spectrofluorimetrically (350 nm/440 nm) whereas AOPP were determined spectro-photometrically (340 nm). AGEs were elevated only in DM Type 2 (DM2 5.11+/-1.15 x 10(3) AU/g vs controls 4.08+/-0.71 x 10(3) AU/g, p<0.001, vs DM1 4.14+/-0.86 x 10(3) AU/g, p<0.005, DM1 vs controls were not significant). AOPP were elevated significantly in both types of DM with higher levels in DM Type 2 (DM2 157.50+/-75.15 micromol/l vs healthy subjects 79.80+/-23.72 micromol/l, p<0.001, vs DM1 97.50+/-30.91 micromol/l, p<0.005, DM1 vs controls p<0.05). There was a tight correlation between AGEs and AOPP in both types of DM (DM1 r=0.75, DM2 r=0.47 (p<0.05)) and both AGEs and AOPP correlated with triglycerides. In DM Type 1 only, AGEs correlated with HbA1c r=0.47 (p<0.05) and with blood glucose. Slight but not significant differences in AGEs and AOPP levels were observed in patients with or without diabetic complications. Oxidative stress is increased in both types of DM, more in Type 2 where it contributes to the formation of glycoxidation products.     

尿微量白蛋白检测在社区糖尿病患者管理中的临床意义

目的：观察尿微量白蛋白在糖尿病患者中的改变情况,探讨提高社区糖尿病肾病早期诊断检出率的方法。方法：选择社区2型糖尿病患者73例,根据空腹血糖控制情况及糖尿病病程时长分别分组,比较不同组间患者尿微量白蛋白水平及阳性病例检出率,同时进行相关性分析。结果：MAIb在不同血糖控制情况患者中,血糖水平与MAIb数值、阳性检出率具有正相关性（P〈0．05）;血糖控制良好患者与其他血糖控制情况患者相比,差异具有（高度）统计学意义（P〈0．01;P〈0．05）;MAIb在不同病程患者中,病程时间与MAIb数值、阳性检出率具有正相关性（P〈0．05）;≤5年组患者与5～10年组和≥10年组相比,差异具有（高度）统计学意义（P〈0．01;P〈0．05）。结论：尿微量白蛋白（MAIb）W作为早期糖尿病肾病检测的重要指标,能够提示肾脏病变的发展,定期检查能够提高早期糖尿病肾病的检出率。     

Propionyl-L-carnitine effects on postischemic recovery of heart function and substrate oxidation in the diabetic rat

Previous studies have shown that propionyl-L-carnitine (PLC) can exert cardiac antiischemic effects in models of diabetes. In the nonischemic diabetic rat heart, PLC improves ventricular function secondary to stimulation in the oxidation of glucose and palmitate. Whether this increase in the oxidation of these substrates can explain the beneficial effects of PLC in the ischemic reperfused diabetic rat heart has yet to be determined. Diabetes was induced in male Sprague-Dawley rats by an intravenous injection of streptozotocin (60 mg/kg). Treatment was initiated by supplementing the drinking water with propionyl-L-carnitine at the concentration of 1 g/L. After a 6-week treatment period, exogenous substrate oxidation and recovery of mechanical function following ischemia were determined in isolated working hearts. In aerobically perfused diabetic hearts, compared with those of controls, rates of glucose oxidation were lower, but those of palmitate oxidation were similar. Diabetes was also characterized by a pronounced decrease in heart function. Following treatment with by propionyl-L-carnitine, however, there was a marked increase in rates at which glucose and palmitate were oxidized by diabetic hearts and a significant improvement in heart performance. Postischemic recovery of function in diabetic hearts was also improved with PLC. This improvement in contractile function was accompanied by an increase in both glucose and palmitate oxidation. Our findings show that postischemic diabetic rat heart can be improved following chronic PLC treatment. This beneficial effect of propionyl-L-carnitine can be explained, in part, by an improvement in the oxidation of glucose and palmitate.     

Monitoring of early and advanced glycation in relation to the occurrence of microvascular complications in children and adolescents with type 1 diabetes mellitus

The authors aimed to evaluate if the monitoring of serum advanced glycation end-products (s-AGEs) could help to predict a development of diabetic complications. Clinical and biochemical parameters including fructosamine (FAM), glycated hemoglobin (HbA1c) and serum AGEs were investigated in children and adolescents with 1 type diabetes with (+DC) and without (-DC) complications. FAM levels (in mmol/l) were significantly elevated in +DC diabetic group compared to -DC one (3.043+/-0.459 vs. 2.614+/-0.430; p<0.001) or to controls (3.043+/-0.459 vs. 1.620+/-0.340; p<0.001) as well as in -DC compared to controls (2.614+/-0.430 vs. 1.620+/-0.340; p<0.001). HbA1c (in %) were significantly elevated in +DC diabetic group compared to -DC one (10.48+/-1.83 vs. 8.41+/-1.19; p<0.001) or to controls (10.48+/-1.83 vs. 5.0+/-0.38, p<0.001) and also in -DC compared to controls (8.41+/-1.19 vs. 5.0+/-0.38; p<0.001). Serum AGEs levels (in A. U.) were significantly higher in +DC group than in -DC (73.0+/-14.09 vs. 65.8+/-9.05; p<0.05) and in group +DC than in controls (73.0+/-14.09 vs. 60.17+/-13.78; p<0.05), whereas there was no difference between -DC and controls. FAM correlated with HbA1c in both diabetic groups (+DC: r=0.374; p<0.05; -DC: r=0.719; p<0.001), but not in controls. Serum AGEs were correlated with HbA1c (r=0.478; p=0.003) in +DC, but not in -DC or controls. Enhanced serum AGEs levels show that they could be not only an attendant phenomenon of microangiopathies, but also a predictor of their development.     

Influence of glutathione S-transferase polymorphisms on type-2 diabetes mellitus risk

Glutathione S-transferase (GST) protects cells against oxidative stress. We evaluated the effect of genetic polymorphisms of the GST gene family on the risk of developing type-2 diabetes mellitus and on glycemic control. We also investigated the effects of smoking combined with these polymorphisms on type-2 diabetes mellitus risk. We enrolled 100 type-2 diabetes mellitus patients and 100 healthy controls matched for age, gender and origin, from the Sinai area of Egypt. Fasting serum glucose, HbA(1c) and lipid profiles were determined. Two polymorphisms were identified by multiplex PCR within the GST genes: GSTM1 and GSTT1. The proportion of the GSTT1- and GSTM1-null genotypes was significantly greater in diabetic patients when compared to controls. Patients carrying both null polymorphisms had a 3.17-fold increased risk of having type-2 diabetes mellitus compared to those with normal genotypes of these two genes (P = 0.009). Additionally, patients with the GSTT1-null genotype had higher levels of triglycerides and very low-density lipoprotein cholesterol compared to those with the GSTT1-present genotype. On the other hand, patients with the GSTM1- null genotype had significantly higher levels of HbA(1c) and significantly higher diastolic blood pressure compared to those with the GSTM1- present genotype. The interaction between these genotypes and smoking status was not significant. These results give evidence that the GSTT1- and GSTM1-null genotypes, alone or combined, are associated with increased risk of type-2 diabetes mellitus, regardless of smoking status. Only the GSTM1-null genotype had an effect on glycemic control.     

The Insulin Tolerance Test in Morbidly Obese Patients Undergoing Bariatric Surgery

Objective: To assess the effect of massive weight loss in relation to insulin resistance and its correlation to changes in glycemic homeostasis and lipid profile in severely obese patients. Research Methods and Procedures: A prospective clinical intervention study was carried out with 31 morbidly obese women (body mass index: 54.2 ± 8.8 kg/m²) divided into three groups according to their glucose tolerance test: 14 normal, 8 impaired glucose tolerance, and 9 type 2 diabetes. All subjects underwent an insulin tolerance test with intravenous bolus of 0.1 U insulin/kg body weight before silastic ring vertical gastroplasty Roux‐en‐Y gastric bypass surgery, and again at 2, 4, 6, and 12 months postoperatively. Fasting plasma glucose, hemoglobin A1c, and lipid profile were also evaluated. Results: A reduction of 68 ± 15% in initial excess body weight was evident within 1 year. Along with weight loss, the following statistically significant changes were found: an increase in the insulin‐sensitivity index (Kitt) and a decrease in fasting plasma glucose and hemoglobin A1c, most notably in the type 2 diabetes group. An overall improvement in lipid profile was observed in all three groups. Discussion: Bariatric surgery was an effective therapeutic approach for these obese patients because it reduced both weight and insulin resistance, along with improving metabolic parameters. Significant correlations were found between insulin resistance and metabolic improvements. Weight loss after bariatric surgery induced an improvement in metabolic fitness, related to the reduction in insulin resistance over a range of glucose tolerance statuses from normal to diabetic.     

Duration of Type I Diabetes Affects Glucagon and Glucose Responses to Insulin-Induced Hypoglycemia

The glucagon response to hypoglycemia, which fulfills a primary role toward restoring the plasma glucose level, is blunted or absent in most patients with type I diabetes. To identify predictive factors for this abnormality and for the capability of glycemic counterregulation, we investigated the relationship between the duration of diabetes and glucagon and glucose responses to insulin-induced hypoglycemia. In 18 type I diabetic patients with 1 through 28 years of disease who had no detectable autonomic neuropathy, individual glucagon increments after insulin hypoglycemia were inversely correlated with the duration of disease (r = -.53, P < .025). Patients with disease for ten or fewer years showed a glucagon rise that was lower than in controls but significantly higher than in patients with a duration of more than ten years. The plasma glucose rise after the nadir correlated with peak glucagon increments (r = .60, P < .01); eight of the nine patients with glycemic increments comparable to normals had had diabetes for ten years or less. Thus, having diabetes for more than ten years implied that not only were glucagon responses to insulin hypoglycemia severely compromised but also that the abrupt restoration of plasma glucose levels was impaired. These findings should be taken into account when establishing goals and modalities for tight metabolic control.     

Non-Diabetic Hyperglycemia Exacerbates Disease Severity in Mycobacterium tuberculosis Infected Guinea Pigs

Hyperglycemia, the diagnostic feature of diabetes also occurs in non-diabetics associated with chronic inflammation and systemic insulin resistance. Since the increased risk of active TB in diabetics has been linked to the severity and duration of hyperglycemia, we investigated what effect diet-induced hyperglycemia had on the severity of Mycobacterium tuberculosis (Mtb) infection in non-diabetic guinea pigs. Post-prandial hyperglycemia was induced in guinea pigs on normal chow by feeding a 40% sucrose solution daily or water as a carrier control. Sucrose feeding was initiated on the day of aerosol exposure to the H37Rv strain of Mtb and continued for 30 or 60 days of infection. Despite more severe hyperglycemia in sucrose-fed animals on day 30, there was no significant difference in lung bacterial or lesion burden until day 60. However the higher spleen and lymph node bacterial and lesion burden at day 30 indicated earlier and more severe extrapulmonary TB in sucrose-fed animals. In both sucrose- and water-fed animals, serum free fatty acids, important mediators of insulin resistance, were increased by day 30 and remained elevated until day 60 of infection. Hyperglycemia mediated by Mtb infection resulted in accumulation of advanced glycation end products (AGEs) in lung granulomas, which was exacerbated by sucrose feeding. However, tissue and serum AGEs were elevated in both sucrose and water-fed guinea pigs by day 60. These data indicate that Mtb infection alone induces insulin resistance and chronic hyperglycemia, which is exacerbated by sucrose feeding. Moreover, Mtb infection alone resulted in the accumulation tissue and serum AGEs, which are also central to the pathogenesis of diabetes and diabetic complications. The exacerbation of insulin resistance and hyperglycemia by Mtb infection alone may explain why TB is more severe in diabetics with poorly controlled hyperglycemia compared to non-diabetics and patients with properly controlled blood glucose levels.     

Early Identification of Individuals with Poorly Controlled Diabetes Undergoing Elective Surgery: Improving A1c Testing in the Preoperative Period

ObjectiveTo describe a process improvement strategy that increased the identification of individuals with poorly controlled diabetes (glycated hemoglobin [A1C] ≥ 8%) undergoing elective surgery at a major academic medical center and increased their access to specialist care.MethodsAn algorithm was developed to ensure A1C measurements were obtained as per the American Association of Clinical Endocrinologists/American Diabetes Association (AACE/ADA) guidelines. The diabetes management team worked collaboratively with anesthesiologists, surgeons, and preoperative nurse practitioners to improve the glycemic control of patients with an A1C ≥ 8%.ResultsBefore implementing the program, A1C testing was recorded in 854 out of 2,335 (37%) patients with diabetes seen in the preoperative clinic from January 1, 2011 to December 31, 2012. The program was instituted in February 2013. From February 2013 to February 2014, A1C testing occurred in 1,236 out of 1,334 (93%) patients with diabetes. After excluding those scheduled for same day surgery, 228 patients were considered high risk with A1C ≥ 8%, and 175 were available for endocrine preoperative consultation. The program led to significant blood glucose level improvements on the day of surgery.ConclusionA process improvement strategy to evaluate and treat diabetes in the preoperative period of elective surgery patients was implemented by a multidisciplinary team (endocrinologists, nurse practitioners, anesthesiologists, and surgeons) and resulted in a substantial improvements in obtaining A1C tests, access to specialist diabetes care, and glycemic control on the day of surgery. The impact of improved glycemic control on hospital and surgical outcomes needs further evaluation. (Endocr Pract. 2015;21:231-236)