Normal Fasting Glucose Levels Research Articles

65-Year-Old Woman With Intermittent Fevers, Lower Extremity Paresthesia, Weight Loss, and Malaise

65-Year-Old Woman With Intermittent Fevers, Lower Extremity Paresthesia, Weight Loss, and Malaise

The type 2 diabetes risk allele of TMEM154-rs6813195 associates with decreased beta cell function in a study of 6,486 Danes.

ObjectivesA trans-ethnic meta-analysis of type 2 diabetes genome-wide association studies has identified seven novel susceptibility variants in or near TMEM154, SSR1/RREB1, FAF1, POU5F1/TCF19, LPP, ARL15 and ABCB9/MPHOSPH9. The aim of our study was to investigate associations between these novel risk variants and type 2 diabetes and pre-diabetic traits in a Danish population-based study with measurements of plasma glucose and serum insulin after an oral glucose tolerance test in order to elaborate on the physiological impact of the variants.MethodsCase-control analyses were performed in up to 5,777 patients with type 2 diabetes and 7,956 individuals with normal fasting glucose levels. Quantitative trait analyses were performed in up to 5,744 Inter99 participants naïve to glucose-lowering medication. Significant associations between TMEM154-rs6813195 and the beta cell measures insulinogenic index and disposition index and between FAF1-rs17106184 and 2-hour serum insulin levels were selected for further investigation in additional Danish studies and results were combined in meta-analyses including up to 6,486 Danes.ResultsWe confirmed associations with type 2 diabetes for five of the seven SNPs (TMEM154-rs6813195, FAF1-rs17106184, POU5F1/TCF19-rs3130501, ARL15-rs702634 and ABCB9/MPHOSPH9-rs4275659). The type 2 diabetes risk C-allele of TMEM154-rs6813195 associated with decreased disposition index (n=5,181, β=-0.042, p=0.012) and insulinogenic index (n=5,181, β=-0.032, p=0.043) in Inter99 and these associations remained significant in meta-analyses including four additional Danish studies (disposition index n=6,486, β=-0.042, p=0.0044; and insulinogenic index n=6,486, β=-0.037, p=0.0094). The type 2 diabetes risk G-allele of FAF1-rs17106184 associated with increased levels of 2-hour serum insulin (n=5,547, β=0.055, p=0.017) in Inter99 and also when combining effects with three additional Danish studies (n=6,260, β=0.062, p=0.0040).ConclusionStudies of type 2 diabetes intermediary traits suggest the diabetogenic impact of the C-allele of TMEM154-rs6813195 is mediated through reduced beta cell function. The impact of the diabetes risk G-allele of FAF1-rs17106184 on increased 2-hour insulin levels is however unexplained.

Impact of PTBP1 rs11085226 on glucose-stimulated insulin release in adult Danes.

BackgroundThe variant rs11085226 (G) within the gene encoding polypyrimidine tract binding protein 1 (PTBP1) was reported to associate with reduced insulin release determined by an oral glucose tolerance test (OGTT) as well as an intravenous glucose tolerance test (IVGTT). The aim of the present study was to validate the association of the rs11085226 G-allele of PTBP1 with previously investigated OGTT- and IVGTT-derived diabetes-related metabolic quantitative phenotypes, to conduct exploratory analyses of additional measures of beta-cell function, and to further investigate a potential association with type 2 diabetes.MethodsPTBP1 rs11085226 was genotyped in 20,911 individuals of Danish Caucasian ethnicity ascertained from 9 study samples. Case control analysis was performed on 5,634 type 2 diabetic patients and 11,319 individuals having a normal fasting glucose level as well as 4,641 glucose tolerant controls, respectively. Quantitative trait analyses were performed in up to 13,605 individuals subjected to an OGTT or blood samples obtained after an overnight fast, as well as in 596 individuals subjected to an IVGTT.ResultsAnalyses of fasting and OGTT-derived quantitative traits did not show any significant associations with the PTBP1 rs11085226 variant. Meta-analysis of IVGTT-derived quantitative traits showed a nominally significant association between the variant and reduced beta-cell responsiveness to glucose (β = −0.1 mmol · kg−1 · min−1; 95% CI: −0.200.20 – −0.024; P = 0.01) assuming a dominant model of inheritance, but failed to replicate a previously reported association with area under the curve (AUC) for insulin. Case control analysis did not show an association of the PTBP1 rs11085226 variant with type 2 diabetes.ConclusionsDespite failure to replicate the previously reported associations of PTBP1 rs11085226 with OGTT- and IVGTT-derived measures of beta-cell function, we did find a nominally significant association with reduced beta-cell responsiveness to glucose during an IVGTT, a trait not previously investigated, leaving the potential influence of this variant in PTBP1 on glucose stimulated insulin release open for further investigation. However, the present study does not support the hypothesis that the variant confers risk of type 2 diabetes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-015-0160-7) contains supplementary material, which is available to authorized users.

Glucose challenge test (50-g GCT) in detection of glucose metabolism disorders in peritoneal dialysis patients: preliminary study.

Background The aim was to evaluate the clinical utility of the oral glucose tolerance screening test (50-g GCT—glucose challenge test) for the detection of glucose metabolism disorders (GMD) in peritoneal dialysis (PD) patients with normal fasting glucose levels. Methods The 50-g GCT was performed in 20 prevalent patients without history of diabetes before PD treatment onset, who had been on dialysis for a median time of 15.34 months. In addition, other indicators of glucose metabolism were measured: C-peptide, fasting insulin serum concentration, and the glycated hemoglobin level (HbA1c). The patients were prospectively followed for a median time of 25.8 months. Results50-g GCT revealed GMD in 15 studied patients (75 %)—impaired glucose tolerance in 11 patients (55 %) and diabetes mellitus in four patients (20 %). HbA1c and insulin resistance, estimated by homeostasis model assessment, were elevated in two (10 %) and seven (35 %) patients, respectively. In patients with GMD, dietetic and pharmacologic interventions were performed. When the 50-g GCT was repeated at the end of the observation period, 12 (60 %) patients reported GMD, with no case of diabetes.Conclusion50-g GCT appears to be a simple and practical tool for the detection of GMD in PD patients with normal fasting glucose. Timely therapeutic intervention can effectively inhibit the progression of glucose intolerance during PD treatment.

Association between Serum Lipid Profile and Glycated Hemoglobin in Pre-diabetic Individuals

Background: Pre-diabetes is a condition in which the blood glucose level is above normal but below the diagnostic threshold for diabetes mellitus. Impaired lipid profile i.e dyslipidemia is commonly associated with CVD in type 2 diabetes and can also occur in pre-diabetics. Material and Method: The present study was conducted on 50 patients with no sign and symptoms of diabetes mellitus with HbA1c level between 5.7%–6.4%. Pre-diabetic individuals were categorized into 2 groups according to their fasting blood sugar level, FBS?110 mg/dl as normal and for impaired fasting glucose between 110–125 mg/dl. HbA1c was analyzed by high pressure liquid chromatography (Biorad D10). Fasting blood sugar and lipid profile were analyzed on Vitros 250 dry chemistry fully autoanalyzer. Result: There was no significant difference in total cholesterol, triglyceride, HDL-c, VLDL, LDL, TC/HDL and LDL/HDL in patients with normal and impaired fasting glucose level with HbA1c between 5.7%–6.4% Conclusion: Relationship between high risk range of HbA1c (5.7% - 6.4%) and CVD mortality is still not clear. Studies on large population are required to find out whether estimation of lipid profile in pre-diabetic should be used routinely or not in pre-diabetic patients..

Oral administration of soybean peptide Vglycin normalizes fasting glucose and restores impaired pancreatic function in Type 2 diabetic Wistar rats

Vglycin, a natural 37-residue polypeptide isolated from pea seeds in which six half-cysteine residues are embedded in three pairs of disulfide bonds, is resistant to digestive enzymes and has antidiabetic potential. To investigate the pharmacological activity of Vglycin in vivo and to examine the mechanisms involved, the therapeutic effect of Vglycin in diabetic rats was examined. Diabetes was induced in Wistar rats by high-fat diet and multiple streptozotocin intraperitoneal injections. Diabetic rats were treated daily with Vglycin for 4 weeks. Body weight, food intake, fasting plasma glucose and insulin levels were assayed weekly. Glucose and insulin tolerance tests were conducted on Day 29. Subsequently, levels of p-Akt in the liver and pancreas and cleaved PARP, Pdx-1 and insulin in the pancreas were detected by immunoblotting. The morphology of the pancreas and the insulin expression in the pancreas were analyzed by hematoxylin–eosin staining and immunohistochemistry, respectively. Furthermore, human liver-derived cell lines were used to explore the in vitro effects of Vglycin on insulin sensitivity and glucose uptake. Chronic treatment with Vglycin normalized fasting glucose levels in diabetic rats. The improvement in glucose homeostasis and the increased insulin sensitivity mediated by restored insulin signaling likely contributed to decreased food intake and reduced body weight. Vglycin protected pancreatic cells from damage by streptozotocin. Although insulin synthesis and secretion in impaired β-cell were not significantly elevated, islets morphology was improved in the Vglycin-treated groups. These results suggest that Vglycin could be useful in Type 2 diabetes for restoring impaired insulin signaling, glucose tolerance and pancreatic function.

Abstract 594: Macrophage Proteomics Identifies Mechanistic Links Between Type 2 Diabetes and Atherosclerosis

Obesity and Type 2 Diabetes (T2Ds) are associated with increased risk of atherosclerosis and CHD. However, the mechanism(s) linking these diseases are incompletely understood. Macrophages play essential roles in the pathogenesis of both disorders, suggesting that changes in macrophage biology link obesity/T2D and atherosclerosis. We previously showed that the atherogenic actions of cholesterol-loaded macrophages (foam cells) are an emergent property of a dysregulated sterol responsive protein network secreted by macrophages (MSRN). Thus, we hypothesized that obesity/T2Ds may impact atherogenesis by similarly disrupting the MSRN. To test this hypothesis, we isolated peritoneal macrophages (PMΦ) from C57BL/6 mice fed a chow or obesogenic diet and interrogated their secreted proteomes using mass spectrometry. Based on stringent statistical analysis (FDR<5%), we identified 36 proteins that were differentially expressed in media conditioned by macrophages from obese relative to lean mice. Unsupervised gene set enrichment analysis demonstrated that obesity-induced changes to the PMΦ proteome significantly targeted the MSRN. Importantly, this phenomenon could not be explained by cholesterol accumulation or inflammation, since PMΦ’s from obese mice did not accumulate cholesterol and pro-inflammatory cytokine expression was not induced in PMΦ’s from obese or atherogenic mice. Our previous studies showed that treating hypercholesterolemic Ldlr -/- mice with TZD (insulin sensitizer) could normalize MSRN protein expression in vivo , suggesting that insulin resistance is a key regulator of the network. To test this hypothesis, we placed C57BL/6 mice on an obesogenic diet for 7 weeks and treated the mice with TZD for 2 weeks. TZD therapy had no effect on body weight, but normalized fasting glucose levels. Moreover, PMΦ’s isolated from TZD-treated mice, demonstrated normalized protein expression patterns. Collectively, our studies suggest that insulin resistance in T2Ds reproduces macrophage protein dysfunction observed in atherogenic models, and provides a plausible mechanism by which T2Ds may act to increase risk of atherosclerosis.

Basal insulin glargine and microvascular outcomes in dysglycaemic individuals: results of the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial.

As glycaemia and the incidence of microvascular diabetes complications follow a log-linear relationship, it becomes increasingly difficult to demonstrate a microvascular benefit of glucose-lowering when the HbA1c level is close to normal. The Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial randomised 12,537 people with diabetes, impaired glucose tolerance or impaired fasting glucose to receive standard glycaemic care or standard care with the addition of basal insulin glargine (A21Gly,B31Arg,B32Arg human insulin), targeting a fasting plasma glucose level ≤5.3mmol/l. Microvascular outcomes during a median follow-up of 6.2years were examined in participants whose baseline HbA1c was above or below the median of 6.4% (46.4mmol/mol). Allocation to the insulin glargine group reduced the incidence of the primary microvascular composite outcome of kidney and eye disease in participants whose baseline HbA1c level was ≥6.4% (46.4mmol/mol; HR 0.90 [95% CI 0.81, 0.99]) but not in participants with a lower baseline HbA1c (HR 1.07 [95% CI 0.95, 1.20]; p value for interaction 0.031). In people whose baseline HbA1c level was ≥6.4% (46.4mmol/mol), the median post-randomisation change in HbA1c was -0.65% (interquartile range -0.16, -0.91%) after allocation to insulin glargine and -0.33% (-0.83, 0.13%) after allocation to standard care (median HbA1c difference 0.33%; p < 0.0001). A smaller median difference of 0.22% was noted in people whose baseline HbA1c was <6.4% (p < 0.0001). In patients with dysglycaemia, intervention targeting normal fasting glucose levels reduced HbA1c and attenuated the risk of microvascular outcomes in participants with a baseline HbA1c level ≥6.4% (46.4mmol/mol). A neutral effect was seen in those with a lower baseline HbA1c level. ClinicalTrials.gov NCT00069784.

Effect of Change in Body Weight on Incident Diabetes Mellitus in Patients With Stable Coronary Artery Disease Treated With Atorvastatin (from the Treating to New Targets Study)

Features of the metabolic syndrome are independent risk factors for new-onset diabetes mellitus (NODM) related to statin therapy. Obesity is the predominant underlying risk factor for the metabolic syndrome and diabetes mellitus. This study investigated whether change in body weight may predict NODM in statin-treated patients. A total of 7,595 patients without prevalent diabetes mellitus at baseline from the Treating to New Targets (TNT) study were included in this analysis. They were randomized to atorvastatin 10 or 80 mg/day and monitored for a median of 4.9 years. NODM developed in 659 patients (8.1% in the 10-mg group and 9.2% in the 80-mg group). There was a significant increase in body weight (0.9 kg, p <0.01 in both men and women) over 1 year after randomization. The increase in body weight was greater in patients with NODM than those without NODM (1.6 vs 0.9 kg, p <0.001). The association of change in body weight with NODM risk remained significant after adjusting for confounding factors (hazard ratios 1.33, 1.42, and 1.88 for quartiles 2, 3, and 4 compared with quartile 1, respectively). Similar results were obtained in patients with normal fasting glucose level. In conclusion, 1-year change in body weight is predictive of NODM in patients who underwent statin therapy from the TNT trial. Our study highlights the importance of weight control as a lifestyle measure to prevent statin-related NODM.

Prevalence of insulin resistance and cardiometabolic risk in Korean children and adolescents: A population-based study

AimsWe aimed to establish normal reference values of serum insulin and the homeostasis model assessment of insulin resistance (HOMA-IR). We also aimed to verify HOMA-IR “cut-off values” in predicting cardiometabolic risk among Korean children and adolescents. MethodsData from 2716 Korean subjects (1421 male and 1295 female, aged 10–20 years) were evaluated. Insulin resistance was defined as HOMA-IR >95th percentile. The odds ratios of cardiometabolic risk were assessed based on the state of insulin resistance. ResultsReference values of insulin and HOMA-IR were determined according to sex and age, based on data obtained from normal-weight subjects with normal fasting glucose levels. HOMA-IR values appeared to peak at the age of 14–15 years in male subjects and at the age of 12–13 years in female subjects. The prevalence of insulin resistance in the subjects was 9.8% (male=10.9%, female=8.6%). The prevalence of insulin resistance in normal-weight, overweight, and obese subjects were 4.7%, 25.6%, and 47.1% respectively. Subjects with insulin resistance had a higher prevalence of metabolic syndrome (odds ratios=18.33; 95% confidence interval, 9.62–34.94) and its components, especially hyperglycemia and hypertriglyceridemia. ConclusionWe established reference values of serum insulin and HOMA-IR according to age and sex. Obesity is the most important risk factor for insulin resistance and metabolic syndrome. However, insulin resistance independently increases cardiometabolic risk. This information may be useful for Korean as well as other Asian in planning programs for the prevention of type 2 diabetes.

Prevalence of Prediabetes and Newly Diagnosed Diabetes in Patients with a Transient Ischemic Attack or Stroke

Background: Patients with a transient ischemic attack (TIA) or stroke and prediabetes or newly diagnosed diabetes are at high risk of recurrent stroke or cardiovascular events. This underlines the importance of accurate screening for impaired glucose metabolism in clinical practice. Fasting plasma glucose levels are currently the most commonly measured glycemic parameter to detect prediabetes or diabetes, even if 2-hour postload glucose and glycosylated hemoglobin levels can be used as well. We assessed the prevalence of prediabetes and newly diagnosed diabetes with different screening methods, including fasting plasma glucose, 2-hour postload glucose and glycosylated hemoglobin levels in consecutive patients with recent TIA, ischemic stroke or intracerebral hemorrhage admitted to the stroke unit or visiting the specialized TIA outpatient clinic in the Erasmus Medical Center, Rotterdam, The Netherlands. Methods: We measured fasting plasma glucose, 2-hour postload glucose and glycosylated hemoglobin levels in 269 patients with a TIA, 374 with ischemic stroke and 57 with intracerebral hemorrhage, all without a history of diabetes mellitus. Prediabetes was defined as fasting plasma glucose levels of 5.6-6.9 mmol/l and/or 2-hour postload glucose levels of 7.8-11.0 mmol/l and/or glycosylated hemoglobin levels of 5.7-6.4%. Newly diagnosed diabetes was defined as fasting plasma glucose levels of ≥7.0 mmol/l and/or 2-hour postload levels of ≥11.1 mmol/l and/or glycosylated hemoglobin levels of ≥6.5%. The diagnosis was based on a one-time measurement. Results: Based on fasting plasma glucose, 2-hour postload glucose and glycosylated hemoglobin levels combined, 365 patients (52%) were identified as prediabetics and 188 (27%) as having newly diagnosed diabetes. Patients with intracerebral hemorrhage had more often newly diagnosed diabetes compared with patients with an ischemic stroke or a TIA [27 (47%) and 161 (25%), respectively; p < 0.001]; the prevalence of prediabetes was similar. Newly diagnosed diabetes was identified more frequently by 2-hour postload glucose levels (n = 162; 23%) than by fasting plasma glucose (n = 49; 7%) or glycosylated hemoglobin levels (n = 36; 5%). About one third of the patients with normal fasting glucose levels has impaired glucose tolerance or elevated glycosylated hemoglobin levels. Conclusions: Prediabetes and newly diagnosed diabetes are highly prevalent in patients with a TIA or stroke. The majority of these patients would not have been identified by fasting plasma glucose levels alone. Both 2-hour postload glucose and glycosylated hemoglobin levels identify more patients with a disturbed glucose metabolism.

Diabetes mellitus in patients with thalassemia major

Diabetes mellitus is a major endocrinopathy for patients with thalassemia major. Although diabetes mellitus is multifactorial, iron loading is its primary cause and its management poses a clinical challenge. Detecting the pre-diabetes stage is critical because clinical diabetes can potentially be reversed or prevented. Patients with thalassemia major who received regular blood transfusion therapy from 1994 to 2010 were evaluated for the incidence of diabetes mellitus and glucose dysregulation. The association between patients' clinical, biochemical, and image parameters was also evaluated. The patients with diabetes were significantly older, had higher ferritin levels, a smaller pancreas volume, and lower cardiac T2* magnetic resonance imaging (MRI) values than the patients without diabetes. The pancreas T2* MRI values were higher in the patients without diabetes, but the difference was not statistically significant. The liver iron concentration did not differ between the patients with and without diabetes. The prevalence of hepatitis C infection and hypogonadism was also higher in the patients with diabetes. In the patients without diabetes, the cardiac T2* MRI values were higher in patients with normal fasting glucose levels (P = 0.03), and the homeostasis model assessment of insulin resistance level was associated with hepatitis C infection (P = 0.024, r = 0.32) and hypogonadism (P = 0.034, r = 0.301). Fasting glucose and insulin levels were appropriate screening tools for evaluating glucose dysregulation and complemented the MRI findings. The cardiac T2* and pancreas volumes were significant predictors of diabetes.

The Prevalence of Glucose Intolerance in Japanese Schizophrenic Patients With a Normal Fasting Glucose Level

The prevalence of diabetes in patients with schizophrenia is 2- to 3-fold higher than in the general population. Glucose abnormalities were detected in 11.9% of Japanese schizophrenic patients in a recent cross-sectional study that included fasting glucose monitoring. However, detailed studies of glucose intolerance using the glucose tolerance test have been limited in Japanese patients with schizophrenia. We investigated the prevalence of abnormal glucose tolerance after glucose loading among Japanese inpatients with schizophrenia, with normal fasting glucose levels. A total of 258 inpatients with schizophrenia participated in this study after giving their written informed consent. A 75-g oral glucose tolerance test was conducted in the morning after a 12-hour overnight fast. Among patients with normal fasting glucose, 81.3% had normal glucose tolerance, 17.3% had impaired glucose tolerance, and 1.3% were diagnosed with diabetes. This study showed that the frequency of impaired glucose tolerance in patients with schizophrenia with normal fasting glucose levels might be higher than in the general population. Careful monitoring and screening of patients with schizophrenia for abnormal glucose metabolism might therefore be necessary.

Comparison of normal fasting and one-hour glucose levels as predictors of future diabetes during a 34-year follow-up

Introduction. Early identification of those at risk of developing type 2 diabetes (T2DM) is essential. We examined how normoglycemic levels of fasting blood glucose (FBG) and 1-hour glucose predict the development of diabetes among men initially at low risk.Methods. In the Helsinki Businessmen Study (men born in 1919– 1934), 1,145 men had normal FBG (< 5.0 mmol/L) in 1974, and 1-hour glucose values available. Multivariate, adjusted models were used to investigate how fasting and 1-hour glucose at baseline related to new-onset diabetes during a follow-up of 34 years.Results. The median FBG and 1-hour glucose values at baseline were 4.4 and 6.6 mmol/L, respectively. During follow-up, 108 men developed diabetes. The risk of incident diabetes was doubled for the highest quintile of FBG (fully adjusted relative risk (RR) 2.22, 95% confidence interval (CI) 1.10–4.50), and quadrupled for that of 1-hour glucose (RR 4.23, 95% CI 2.49–7.17). FBG could not separate the risk for those with higher levels of glucose in the range < 5.0 mmol/L, whereas 1-hour glucose discriminated the risk better at higher values.Conclusions. Higher values in the normoglycemic range for both fasting and 1-hour glucose predicted long-term incidence of diabetes in healthy middle-aged men.

Nondiabetic patients with either subclinical Cushing's or nonfunctional adrenal incidentalomas have lower insulin sensitivity than healthy controls: Clinical implications

ObjectiveThe aim of this study was to estimate insulin sensitivity (IS) in nondiabetic patients with adrenal incidentalomas (AI): nonfunctional adrenal incidentalomas (NAI) and patients with AI and subclinical Cushing's syndrome (SCS). MethodsBased on the inclusion criteria (normal fasting glucose levels, no previous history of impaired fasting glucose and/or diabetes, and no medications or concomitant relevant diseases) and the exclusion criteria (pheochromocytoma, overt hypercortisolism, hyperaldosteronism, adrenal carcinoma, metastasis of extra-adrenal tumors, extra-adrenal malignancies), 142 subjects were drawn from a series of patients with AI. The subjects were age-, sex- and body mass index (BMI)-matched: 70 with NAI (50 women and 20 men), 37 with AI and SCS (31 women and 6 men) and 35 healthy control (HC) subjects (30 women and 5 men).The oral glucose tolerance test (OGTT) and several indices of insulin sensitivity (IS) were used: homeostasis model assessment (HOMA), quantitative insulin sensitivity check index (QUICKI), triglycerides and glucose index (TyG), index of whole-body insulin sensitivity (ISI-composite) and glucose to insulin ratio (G/I). ResultsThere was a significant difference in IS between subjects with NAI and HC (HOMA, p=0.049; QUICKI, p=0.036; TyG, p=0.002; ISI-composite, p=0.024) and subjects with SCS and HC (AUC insulin, p=0.01; HOMA, p=0.003; QUICKI, p=0.042; TyG, p=0.008; ISI-composite, p=0.002). There was no difference in the tested indices of IS between subjects with NAI and SCS (p>0.05). However, subjects with SCS had a significantly higher prevalence of impaired glucose tolerance and higher area under the curve for glucose than subjects with NAI (p=0.0174). The linear regression analysis showed that 1mg-DST cannot be used as a predictor of HOMA (R2=0.004, F=0.407, p=0.525). Significant relationship was found between 1mg-DST and ISI-composite (R2=0.042, F=4.981, p=0.028) but this relationship was weak and standard error of estimate was high. The linear regression model also showed that ACTH cannot be used as a predictor of HOMA (R2=0.001, F=0.005, p=0.943) or ISI-composite (R2=0.015, F=1.819, p=0.187). ConclusionsInsulin resistance is a major cardiovascular risk factor; therefore, the assessment of IS in patients with AI, even nonfunctional, has a valuable place in the endocrine workup of these patients.

FTY720 preserved islet β‐cell mass by inhibiting apoptosis and increasing survival of β‐cells in db/db mice

FTY720, an analogue of sphingosine-1-phosphate, has shown potential in the treatment of several autoimmune diseases, such as multiple sclerosis, type 1 diabetes and systemic lupus erythematosus. It prevents development or cure of autoimmune diabetes in animal models. Recently, we reported that FTY720 also prevents development of diabetes in db/db mice by β-cell regeneration in vivo. This study investigated the effect of FTY720 on apoptosis in β-cells in db/db mice treated with FTY720 16 weeks. Six week old female db/db mice were divided into control and FTY720 groups. FTY720 (10 mg/kg) was orally administrated daily. Body weights and fasting glucose levels were measured once a week after overnight fasting. After 16 weeks of treatment, oral glucose and insulin tolerance tests were performed, serum insulin levels and insulin contents in pancreas were determined, and then all mice were subjected to physiological and histological analyses. FTY720-treated mice showed normal fasting glucose levels, improved glucose tolerance with normal insulin sensitivity and restored β-cell function to produce and secret insulin. Pancreas histology revealed that FTY720 prevented islet damage and preserved β-cell mass by inhibiting apoptosis and increasing β-cell survival in pancreatic islets. We concluded that early intervention with FTY720 in db/db mice can prevent development of diabetes through preserving β-cell mass by inhibiting apoptosis and increasing survival of islet β-cells.

Excessive Insulin Secretion in Japanese Schizophrenic Patients Treated With Antipsychotics Despite Normal Fasting Glucose Levels

The development of impaired glucose tolerance induced by antipsychotics (APs) is of concern as a serious adverse effect of psychiatric drug therapy. However, the mechanism by which APs cause dysfunction of the glucose-insulin response is not fully understood. Recent studies have shown that patients treated with APs for schizophrenia were more likely to exhibit impaired glucose tolerance after a glucose load compared with healthy control subjects, even if fasting glucose levels were within the reference range. To explain these findings, we hypothesized that insulin secretion is increased in schizophrenic patients treated with AP, even those normal fasting glucose (NFG) levels. Therefore, oral glucose tolerance tests were conducted in 159 Japanese inpatients with AP-treated schizophrenia and in 90 healthy subjects without schizophrenia. Plasma glucose and serum insulin concentrations were measured before (0 minute) and at 30, 60, 90, and 120 minutes after the oral glucose load. Although insulin levels at 0 minute were similar in both groups of subjects, insulin levels were significantly higher in the patients treated with AP at all times after the glucose load than in the healthy subjects. In analyses of NFG subjects, insulin levels were significantly higher in the patients treated with AP compared with the healthy subjects at all times after glucose loading. Overall, we found that insulin secretion in response to a glucose load was significantly higher in the patients treated with AP, irrespective of NFG. These results suggest that APs affect the glucose-insulin response, which may lead to subclinical insulin resistance before the onset of overt glucose intolerance.

Impact of eating rate on obesity and cardiovascular risk factors according to glucose tolerance status: the Fukuoka Diabetes Registry and the Hisayama Study

Medical nutrition therapy plays a critical role in the prevention and treatment of type 2 diabetes. However, appropriate measures of eating behaviours, such as eating rate, have not yet been clearly established. The aim of the present study was to examine the associations among eating rate, obesity and cardiovascular risk factors. A total of 7,275 Japanese individuals aged ≥40 years who had normal fasting glucose levels, impaired fasting glucose or diabetes were divided into four groups according to self-reported eating rate: slow, medium, relatively fast and very fast. The associations between eating rate and various cardiovascular risk factors were investigated cross-sectionally. The proportions of participants who were obese or who had elevated waist circumference levels increased progressively with increases in eating rate (p for trend <0.001), regardless of glucose tolerance status. These associations remained significant after adjustment for potential confounders, namely, age, sex, total energy intake, dietary fibre intake, current smoking, current drinking and regular exercise (p for trend <0.001). Blood pressure and lipid levels also tended to increase in association with eating rate. HbA(1c) rose significantly as eating rate increased, even after multivariate adjustment, including BMI, in diabetic patients on insulin therapy (p = 0.02), whereas fasting plasma glucose did not increase significantly. Our findings suggest that eating rate is associated with obesity and other cardiovascular risk factors and therefore may be a modifiable risk factor in the management of cardiovascular risk factors and diabetes.

Influence of the Gly1057Asp variant of the insulin receptor substrate 2 (IRS2) on insulin resistance and relationship with epicardial fat thickness in the elderly

Insulin receptor substrate 2 (IRS2) plays a crucial role in the regulation of insulin signaling. Several polymorphisms of the gene encoding IRS2 have been identified. The variant causing Gly1057Asp substitution is relatively frequent in humans and its impact on insulin sensitivity seems to be dependent on age and body weight. The aim of our study was to evaluate the relationships between Gly1057Asp variant and insulin sensitivity assessed by HOMA, and adiposity evaluated by measurement of epicardial fat (EpiF) thickness in the elderly. We studied 87 subjects, 42 men and 45 women, mean age±SD: 74.23±7.24years. In the subjects carrying the Gly1057Asp variant of the IRS2 gene we found higher HOMA index values (3.40±1.14 vs. 2.21±1.25, p<0.001) and increased epicardial adipose tissue (11.77±1.65 vs. 10.43±1.93mm, p<0.001) compared to wild type subjects. Univariate linear regression analyses evidenced that HOMA index was correlated with BMI (beta=0.152, p<0.001), fasting plasma glucose (beta=0.018, p=0.002), LDL cholesterol (beta=0.008, p=0.024), total cholesterol (beta=0.007, p=0.039), weight (beta=0.054, p<0.001), presence of Gly1057Asp variant (beta=1.185, p<0.001) and EpiF thickness (beta=0.540, p<0.001). In multivariate analysis HOMA index was still associated with the presence of the Gly1057Asp variant of the IRS-2 gene (beta=0.568, p=0.002) and with EpiF thickness (beta=0.414, p<0.001). Furthermore, a statistically significant positive correlation between EpiF thickness and HOMA was found (r=0.773, p<0.001) and this was not different between wild type control subjects and carriers of Gly1057Asp variant of the IRS2 gene (p=0.718). Similar results were obtained in comparing subjects with normal fasting glucose levels. In conclusion, in our elderly subjects the presence of the allelic variant Gly1057Asp of IRS2 gene was associated to the degree of insulin resistance assessed by HOMA index and with EpiF thickness, independently from the extent of obesity, suggesting its contribution to global cardiometabolic risk.

Adrenomedullin is Up-regulated in Patients With Pancreatic Cancer and Causes Insulin Resistance in β Cells and Mice

New-onset diabetes in patients with pancreatic cancer is likely to be a paraneoplastic phenomenon caused by tumor-secreted products. We aimed to identify the diabetogenic secretory product(s) of pancreatic cancer. Using microarray analysis, we identified adrenomedullin as a potential mediator of diabetes in patients with pancreatic cancer. Adrenomedullin was up-regulated in pancreatic cancer cell lines, in which supernatants reduced insulin signaling in beta cell lines. We performed quantitative reverse-transcriptase polymerase chain reaction and immunohistochemistry on human pancreatic cancer and healthy pancreatic tissues (controls) to determine expression of adrenomedullin messenger RNA and protein, respectively. We studied the effects of adrenomedullin on insulin secretion by beta cell lines and whole islets from mice and on glucose tolerance in pancreatic xenografts in mice. We measured plasma levels of adrenomedullin in patients with pancreatic cancer, patients with type 2 diabetes mellitus, and individuals with normal fasting glucose levels (controls). Levels of adrenomedullin messenger RNA and protein were increased in human pancreatic cancer samples compared with controls. Adrenomedullin and conditioned media from pancreatic cell lines inhibited glucose-stimulated insulin secretion from beta cell lines and islets isolated from mice; the effects of conditioned media from pancreatic cancer cells were reduced by small hairpin RNA-mediated knockdown of adrenomedullin. Conversely, overexpression of adrenomedullin in mice with pancreatic cancer led to glucose intolerance. Mean plasma levels of adrenomedullin (femtomoles per liter) were higher in patients with pancreatic cancer compared with patients with diabetes or controls. Levels of adrenomedullin were higher in patients with pancreatic cancer who developed diabetes compared those who did not. Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in β cells and mice.