Normoglycemic Subjects Research Articles

Association of Three Simple Insulin Resistance Indexes with Prehypertension in Normoglycemic Subjects.

Background: Insulin resistance (IR) is the common pathophysiology of prehypertension and prediabetes. Recognition of IR in one of the two disease states is critical for carrying out preventive strategies of another disease state. This study aimed to explore which simple IR indexes were significantly associated with prehypertension in subjects with normoglycemia. Methods: A total of 108,370 adults without elevated fasting plasma glucose and hypertension were included in this study. The three simple IR indexes [triglycerides to high-density lipoprotein cholesterol ratio, the product of fasting triglycerides and glucose, and metabolic score for IR (METS-IR)] were calculated. Partial correlation was used to analyze the correlation between the three indicators and blood pressure (BP) levels, and logistic regression analysis was used to explore their association with prehypertension. Results: Among the three indicators, only METS-IR had positive correlations with systolic and diastolic blood pressure levels. Furthermore, METS-IR was also significantly associated with prehypertension, irrespective of the categorization of waist circumference (WC). The odds ratios of the highest quartile were 2.223 (95% confidence interval [CI]: 2.044-2.417) in all subjects, 2.022 (95% CI: 1.501-2.725) in elevated WC subgroup, and 1.815 (95% CI: 1.620-2.034) in normal WC subgroup. Conclusions: METS-IR was associated with prehypertension in normoglycemic Chinese subjects, which bypasses the impact of WC and might be valuable for the management of prehypertension and the prevention of prediabetes in different ethnic groups.

Clinical Recognition and Management of Patients with Prediabetes

Objective: Early identification and management of prediabetes is critical to prevent progression to diabetes. We aimed to assess whether prediabetes is appropriately recognized and managed among patients with impaired fasting glucose (IFG). Methods: We carried out an observational study of Olmsted County residents evaluated at the Mayo Clinic between 1999-2017. We randomly selected 108 subjects with biochemical criteria of IFG and 105 normoglycemic subjects. We reviewed their health records at baseline (1999-2004) and during follow up (2005-2017) collecting demographic and clinical data including vitals, diagnoses, laboratory, and medications associated with cardiovascular comorbidities. The main outcome was documentation of any recognition of prediabetes and management recommendations (lifestyle changes and/or medications). Results: At baseline (1999-2004), 26.85% (29/108) of subjects with IFG were recognized as having prediabetes, and of these 75.86% (22/29) received management recommendations with 6.9% (2/29) getting metformin. During follow-up (2005-2017), 26.67% (28/105) of initial cohort of normoglycemic subjects developed incident IFG and of these, 85.71% (24/28) were recognized as having prediabetes, and 58.33% (14/24) received management recommendations. During the entire study period, 62.50% (85/136) were recognized as having prediabetes of which 75.29% (64/85) had documented management recommendations. High body mass index (BMI) (≥35) was associated with increased recognition (odds ratio [OR] 3.66; confidence interval [CI] 1.065, 12.500; P = .0395), and normal BMI (<25) was associated with a lack of recognition (OR 0.146; CI 0.189, 0.966; P = .0413). Conclusion: Despite evidence supporting the efficacy of lifestyle changes and medications in managing prediabetes, this condition is not fully recognized in routine clinical practice. Increased awareness of diagnostic criteria and appropriate management are essential to enhance diabetes prevention. Abbreviations: BMI = body mass index; CI = confidence interval; EHR = electronic health records; FBG = fasting blood glucose; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; OR = odds ratio.

2426-PUB: Circulating WBC, RBC, and Hemoglobin Level in Relation to Metabolic Syndrome and Incident Prediabetes in a Biracial Cohort of Normoglycemic Subjects with Parental Type 2 Diabetes

Objective: We assessed the relationships among blood cell counts, metabolic syndrome (MetS), and prediabetes risk in a biracial cohort of African Americans (AA) and European Americans (EA) with parental type 2 diabetes mellitus (T2DM). Methods: We studied 603 normoglycemic subjects (264 EA, 339 AA), mean (+SD) age 46.14 ± 10.58 y and BMI 31.1 + 7.30 kg/m2. Each subject underwent clinical examination and OGTT. Blood specimens were analyzed for RBC, WBC and differentials, and lipids. MetS markers were identified using NCEP cut-offs for waist, blood pressure, HDL cholesterol and triglyceride (TG) levels. Results: Total WBC count correlated positively with waist circumference (P=&amp;lt;0.001), TG (P=0.018) and fasting plasma glucose (FPG) (P=0.023) and inversely with HDL level (P=0.005), as did segmented neutrophil and monocyte counts. RBC count also correlated positively with waist (P= 0.0002), TG (P= 0.0004), FPG (P=0.035) and WBC count (P=0.0016) and inversely with HDL cholesterol level (P=&amp;lt;0.0001). Hemoglobin (Hb) and hematocrit (Hct), both strongly reflecting RBC count (r=0.75, P=0.0001), mirrored the association with MetS markers seen with RBC. Among 372 subjects followed longitudinally for 5 y, baseline MetS markers, absolute eosinophil and basophil counts, and Hb significantly predicted progression to prediabetes. After adjustment for age and BMI, logistic regression odds ratio [95% CI] for incident prediabetes was 1.37[1.094-1.633], P=0.0045 for MetS; 1.21[1.037-1.405], P=0.015 for Hb; 1.006[1.002-1.011], P=0.0093 for absolute basophil count; and 1.003[1.000-1.005], P=0.0237 for absolute eosinophil count. Conclusions: The known association between cardiometabolic risk and WBC extends to RBC count as well. Moreover, Hb level, eosinophil and basophil counts specifically predict increased risk of prediabetes, probably via proinflammatory and iron-related mechanisms. Disclosure I. Abutineh: None. N.A. Umekwe: None. F. Ariganjoye: None. S. Dagogo-Jack: Board Member; Self; Jana Care Inc. Consultant; Self; Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Sanofi-Aventis. Research Support; Self; AstraZeneca, Novo Nordisk Inc. Stock/Shareholder; Self; Dance Biopharm Holdings Inc. Funding National Institutes of Health

509-P: Utility of Serum Cystatin C in Early Kidney Dysfunction in Prediabetics

Background: Serum cystatin C (sCys C) has been proposed as a marker of kidney function with advantages compared to creatinine. It is unclear whether renal damage begin in prediabetes (PDM), when sCys C could be a promisor marker of early kidney dysfunction. We investigated whether sCys C differed between normoglycemic (NG) and PDM subjects and contributed to the detection of kidney dysfunction. Methods: A cross-sectional analysis of 947 nondiabetic participants (mean age 45.7 years) from the Brazilian Longitudinal Study of Adult Health was performed. sCys C (determined by ELISA) and CKD-EPI eGFR were compared between NG and PDM (fasting plasma glucose: 100-125 mg/dL or 2-hour post-load: 140-199 mg/dL or A1c: 5.7-6.4%). PDM were stratified in 4 groups according to altered sCys C and albumin excretion rate (AER): normal sCys C and AER (G1), abnormal sCys C and normal AER (G2), normal sCys C and abnormal AER (G3) and abnormal sCys C and AER (G4) were compared using ANOVA. Results: PDM subjects (n = 671) had anthropometric and biochemical data higher than NG (n=276), higher sCys C levels [0.67 (0.41-0.95) vs. 0.48 (0.31-0.81), p&amp;lt;0.001] and lower eGFR (96.3±17.4 vs. 100.6±17.1 mL/min/1.73m2, p&amp;lt;0.001). In eGFR categories (60-&amp;lt;90, 90-&amp;lt;125 and ≥125 mL/min/1.73m2), sCys C were always higher in PDM subjects than in NG. Comparing NG individuals, hyperfiltrants had lower sCys C than normofiltrants (p=0.03) but not than mildly reduced eGFR individuals (p=0.12). Considering the PDM groups, eGFR gradually dropped from G1 to G4 (96.8±17.4 vs. 96.2±16.9 vs. 94.0±17.2 vs. 77.2±25.4 mL/min/1.73m2, p-trend = 0.06) and, as expected, mean eGFR in G4 was lower than in G1 (p=0.017). Conclusion: Our data confirmed that sCys C is increased in PDM. Reduced sCys C only in NG hyperfiltrant subjects could suggest an inability of hyperfiltrant PDM to excrete Cys C. No statistical evidence that sCys C could be an early marker of kidney dysfunction in prediabetes was found; prospective studies should address its utility to detect dysfunction before AER elevation. Disclosure J.I.F. Branda: None. B. Almeida: None. S.R.G. Vivolo: None.

294-LB: Transcriptome-Wide Signals Converge Upon Mitochondrial Function in Developmental Stages of Type 2 Diabetes in Human Skeletal Muscle

Skeletal muscle is a major contributor to overall glucose homeostasis in the body and together with the liver is chiefly responsible for the whole-body insulin sensitivity. However, few studies have investigated the transcriptional signature of insulin resistance in skeletal muscles, at different stages of T2D development. Thus, the aim of this study was to identify the transcriptional signature of dysregulated glucose metabolism in skeletal muscle in humans by profiling the transcriptome with next-generation sequencing (NGS). We selected 40 sedentary males, aged 40-65 years, with BMI 26-33 kg/m2, diagnosed into three groups: 18 normoglycemics, 14 prediabetics and 8 subjects with type 2 diabetes. mRNA was extracted from biopsied Vastus lateralis muscles and sequenced with Illumina HiSeq 4000.Comparing normoglycemic and diabetic subjects revealed 4404 significantly differentially expressed (DE) genes, which represents around 30% of all mapped genes in studied samples. For the comparison between type 2 diabetics and prediabetics, the number of DE genes was 4055 genes. Interestingly we found no significantly DE genes between normoglycemics and prediabetics. KEGG enrichment analysis revealed that DE pathways between diabetics vs. nondiabetics were enriched for pathways related to oxidative phosphorylation, thermogenesis, nonalcoholic fatty liver disease and neurological diseases, which share the same underlying mechanism: mitochondrial dysfunction.These results indicate that skeletal muscle contributes most to overt T2D, with a possible indication that the liver contributes most to early stages the disease development. Differences observed between type 2 diabetics and the two remaining groups, occurring primarily in oxidative phosphorylation and electron transport chain pathways suggests that mitochondrial dysfunction plays the predominant role in the pathogenesis of T2D. Disclosure L. Szczerbinski: None. M. Niemira: None. K. Szczerbinski: None. U. Puchta: None. E. Siewiec: None. A. Citko: None. J. Zapolska: None. M. Taylor: None. S. Larsen: None. M. Gorska: None. A. Kretowski: None.

Association of serum fibulin-1, lipid profile and C-reactive protein in normoglycemic subjects

Association of serum fibulin-1, lipid profile and C-reactive protein in normoglycemic subjects

Reduced insulin sensitivity in young, normoglycaemic subjects alters microvascular tissue oxygenation during postocclusive reactive hyperaemia.

What is the central question of the study? Are measures of reduced insulin sensitivity in young, normoglycaemic subjects correlated with near-infrared spectroscopy-derived microvascular responsiveness [tissue oxygen saturation reperfusion rate (STO2 upslope)] during postocclusive reactive hyperaemia? What is the main finding and its importance? A sevenfold range of hepatic insulin sensitivity is significantly correlated (r=0.44, P=0.02) with STO2 upslope after transient tissue ischaemia. Near-infrared spectroscopy may be an important tool for determining altered microvascular function before onset of hyperglycaemia. Identification of pre-type2 diabetes much earlier than with the present clinical criteria is important for pre-emptive measures against microvascular deterioration. Near-infrared spectroscopy (NIRS) measurement of postocclusive reactive hyperaemia (PORH) tissue oxygen saturation reperfusion rate [STO2 upslope (as a percentage per minute)] has recently been correlated with the percentage of flow-mediated dilatation (%FMD). Cardiovascular disease is associated with impairments in %FMD. Reduced insulin sensitivity may negatively affect the vascular system for many years before prediabetes/type2 diabetes states. The aim of this study was to determine whether static and dynamic STO2 parameters during PORH are correlated with reduced insulin sensitivity in young, normoglycaemic subjects. Glucose and insulin were measured during an oral glucose tolerance test in 18- to 26-year-old, healthy subjects (11men and 11 women), and STO2 was measured during PORH of antebrachial muscle. Hepatic (ISIHOMA ) and whole-body (ISICOMP ) insulin sensitivities were calculated. The STO2 upslope was negatively correlated with minimal STO2 (r=-0.5, P=0.01). The change of STO2 from minimum to baseline (ΔSTO2 ) was significantly negatively correlated with fasting insulin (r=-0.5, P=0.01) and a positively correlated with ISIHOMA (r=0.65, P=0.001). The minimum STO2 was significantly negatively correlated with ISIHOMA , and STO2 upslope was significantly positively correlated with ISIHOMA (r=0.44, P=0.02). The minimum STO2 (a measure of O2 extraction while the cuff was inflated), ΔSTO2 (a measure of the amount of reperfusion) and STO2 upslope (a measure of responsiveness of the microcirculation to ischaemia) were all positively correlated with ISIHOMA , one of the longest-used measures of insulin sensitivity. The NIRS-derived STO2 might be a useful tool for assessing how levels of reduced insulin sensitivity in young, normoglycaemic adults affect the microvasculature.

Analysis of Inflammatory Gene Expression Profile of Peripheral Blood Leukocytes in Type 2 Diabetes

ABSTRACTThe pathophysiology of type 2 diabetes (T2DM) is associated with perturbation of innate immune response. Several studies indicated alteration of pro-inflammatory and anti-inflammatory cytokines, chemokines and other mediators of innate immune response in T2DM. This study was designed to perform quantitative PCR-based expression profiling of genes involved in inflammation (i.e. CASP1, CASP5, CCL5, CXC11, CCR5, NF-Κb, IL-4, PPARG and PGC1α) in peripheral blood leukocytes of T2DM patients. The T2DM patients are often prescribed with metformin and insulin while metformin has also been reported to possess anti-inflammatory activity. To address the question whether metformin exerts any effect on inflammatory mediators in bloodstream, human subjects in this study were divided into four groups on the basis of medication they were taking during last 6 month. These groups included NT-T2DM (T2DM patients not taking medication, n = 34), Met-T2DM (T2DM patients taking metformin, n = 33), INS-T2DM (T2DM patients taking insulin, n = 15) and NGT (normoglycemic subjects, n = 34) groups. Differential expression of gene transcripts at a cutoff of fourfold was considered significant. In the NT-T2DM group, transcripts of inflammation-related genes (i.e. CASP1, CASP5, CCL5, CCR5 and NF-kB) were up-regulated while transcripts of PPARG and PGC1α genes were down-regulated compared to NGT group. On the other hand, down-regulation of CASP1, CASP5, CCL5, CCR5 and NF-kB transcripts was evident in Met-T2DM and INS-T2DM groups when compared to the NT-T2DM group. The Met-T2DM group and INS-T2DM group showed a significant difference in the transcript level of CASP1 and CCL5 which are more down-regulated in the Met-T2DM group compared to INS-T2DM group. These findings indicated that (a) in T2DM, expression of inflammation-related genes is up-regulated and (b) anti-inflammatory activity of metformin appears to be independent of its anti-hyperglycemic activity.

Identification of AnnexinA1 as an Endogenous Regulator of RhoA, and Its Role in the Pathophysiology and Experimental Therapy of Type-2 Diabetes.

Annexin A1 (ANXA1) is an endogenously produced anti-inflammatory protein, which plays an important role in the pathophysiology of diseases associated with chronic inflammation. We demonstrate that patients with type-2 diabetes have increased plasma levels of ANXA1 when compared to normoglycemic subjects. Plasma ANXA1 positively correlated with fatty liver index and elevated plasma cholesterol in patients with type-2 diabetes, suggesting a link between aberrant lipid handling, and ANXA1. Using a murine model of high fat diet (HFD)-induced insulin resistance, we then investigated (a) the role of endogenous ANXA1 in the pathophysiology of HFD-induced insulin resistance using ANXA1−/− mice, and (b) the potential use of hrANXA1 as a new therapeutic approach for experimental diabetes and its microvascular complications. We demonstrate that: (1) ANXA1−/− mice fed a HFD have a more severe diabetic phenotype (e.g., more severe dyslipidemia, insulin resistance, hepatosteatosis, and proteinuria) compared to WT mice fed a HFD; (2) treatment of WT-mice fed a HFD with hrANXA1 attenuated the development of insulin resistance, hepatosteatosis and proteinuria. We demonstrate here for the first time that ANXA1−/− mice have constitutively activated RhoA. Interestingly, diabetic mice, which have reduced tissue expression of ANXA1, also have activated RhoA. Treatment of HFD-mice with hrANXA1 restored tissue levels of ANXA1 and inhibited RhoA activity, which, in turn, resulted in restoration of the activities of Akt, GSK-3β and endothelial nitric oxide synthase (eNOS) secondary to re-sensitization of IRS-1 signaling. We further demonstrate in human hepatocytes that ANXA1 protects against excessive mitochondrial proton leak by activating FPR2 under hyperglycaemic conditions. In summary, our data suggest that (a) ANXA1 is a key regulator of RhoA activity, which restores IRS-1 signal transduction and (b) recombinant human ANXA1 may represent a novel candidate for the treatment of T2D and/or its complications.

Effect of diabetes on BMD and TBS values as determinants of bone health in the elderly: Bushehr Elderly Health program

Considering the aging population associated with higher osteoporotic fracture risk, high prevalence of diabetes and its effect on bone health along with lack of information on bone quality using common methods (BMD) the aim of present study was to determine the association between trabecular bone score (TBS) and diabetes in an elderly population participating in Bushehr Elderly Health (BEH) program. This cross-sectional study was performed on data collected during the BEH Program, stage II. Anthropometric indices were measured based on NHANES III protocol. Diabetes and pre-diabetes were defined according to ADA Guideline 2018. Bone density was measured using DXA method (DXA, Discovery WI, Hologic Inc., USA). A software installed on the same device (TBS iNsight® software) was applied to assess TBS values. Variables related to bone health were compared based on their glycemic status (participants with diabetes, participants with prediabetes, and normoglycemic) using analysis of variance. Univariate and multivariate linear and logistic regression models were used to determine the association between TBS values and bone density in different glycemic states. The data of 2263 participant aged 60years and over were analyzed. Mean TBS values were significantly different between participants with diabetes, participants with prediabetes, and normoglycemic groups (P = 0.004;, however, P trend was not significant (0.400)). Mean BMD values at femoral neck and lumbar spine were significantly higher in diabetics compared with those diagnosed with pre-diabetes; the latter also had higher bone density compared with normoglycemic individuals (both P ANOVA test and P trends for means were < 0.01]. In univariate linear regression model, TBS values were negatively associated with pre-diabetes (β = -0.070; P < 0.001) but not with diabetes (β = -0.002, P = 0.915). This significant relationship disappeared when the results were adjusted for BMI. In fully adjusted multivariate logistic regression models, odds ratio linking pre-diabetes and diabetes with spinal osteoporosis was 0.861 (CI 95% 0.670-1.105) and 0.525 (CI 95% 0.392-0.701), respectively. As for femoral osteoporosis, odds ratio was 0.615 (CI 95% 0.407-0.928) and 0.968 (CI 95% 0.629-1.489), correspondingly. Moreover, for cumulative osteoporosis, the odds were 0.843 (CI 95% 0.676-1.106) and 0.551 (CI 95% 0.415-0.732), respectively. Our findings suggest that subjects with pre-diabetes and diabetes have higher bone mineral density than normoglycemic subjects; the quality of bone, however, was not different between them. The discordance between BMD and TBS values in participants with diabetes suggest that although these patients have higher BMD values, their quality of bone microarchitecture may not be better than normoglycemic subjects.

Adiponectin-leptin Ratio is a Functional Biomarker of Adipose Tissue Inflammation

Obesity favors the development of cardiometabolic alterations such as type 2 diabetes (T2D) and the metabolic syndrome (MS). Obesity and the MS are distinguished by an increase in circulating leptin concentrations, in parallel to a drop in the levels of adiponectin. Consequently, the Adpn/Lep ratio has been suggested as a maker of dysfunctional adipose tissue. We aimed to investigate in humans (n = 292) the reliability of the Adpn/Lep ratio as a biomarker of adipose tissue dysfunction. We considered that an Adpn/Lep ratio of ≥1.0 can be considered normal, a ratio of ≥0.5 <1.0 suggests moderate-medium increased risk, and a ratio of <0.5 indicates a severe increase in cardiometabolic risk. Using these cut-offs, 5%, 54% and 48% of the lean, normoglycemic and without-MS subjects, respectively, fall within the group with an Adpn/Lep ratio below 0.5; while 89%, 86% and 90% of the obese, with T2D and with MS patients fall within the same group (p < 0.001). A significant negative correlation (r = −0.21, p = 0.005) between the Adpn/Lep ratio and serum amyloid A (SAA) concentrations, a marker of adipose tissue dysfunction, was found. We concluded that the Adpn/Lep ratio is a good indicator of a dysfunctional adipose tissue that may be a useful estimator of obesity- and MS-associated cardiometabolic risk, allowing the identification of a higher number of subjects at risk.

Association of transcription factor 7-like 2 (TCF7L2) gene polymorphism with type 2 diabetes mellitus in Chinese Korean ethnicity population.

Presently, data on the type 2 diabetes mellitus (T2DM) in Chinese Korean ethnicity are very scarce. This study aimed to explore the relationship between the transcription factor 7-like 2 (TCF7L2) and T2DM in Chinese Korean ethnicity population. This case-control study involved 43 T2DM Chinese Korean ethnicity patients (T2DM group) and 43 healthy Chinese Korean ethnicity normoglycemic subjects as controls (Control group). All included participants aged from 40 to 75 years old. Clinical and biological data were collected to determine the phenotypic traits. The restriction fragment length polymorphism-polymerase chain reaction was used to analyze the TCF7L2 by genotyping for rs7903146 (C/T). Spectrophotometer with Chronolab kits was used to conduct the biochemical analyses. TCF7L2 was associated with T2DM in the Chinese Korean ethnicity population (P < .01 for alleles, and P < .05 for genotypes). Significant differences were found 2 groups regarding the T allele (37.2% T2DM patients vs 15.1% healthy subjects, P < .01), and G allele (62.8% T2DM patients vs 84.9% healthy subjects, P < .01). The risk genotypes were GG (83.7% T2DM patients, vs 44.2% healthy control, P < .01), GT (4.7% T2DM patients, vs 20.9% healthy control, P = .04), and TT (11.6% T2DM patients, vs 34.9% healthy control, P = .01). The results of this study demonstrated that TCF7L2 is associated with T2DM in the Chinese Korean ethnicity population, which is an important risk factor for T2DM in this population.

Increased pancreatic echogenicity and severity on US: Association with glycemic progression and incident diabetes

Purpose To investigate the relationship of increased pancreatic echogenicity (IPE) on US with the risk of glycemic progression and incident diabetes. Methods This retrospective study was approved by the institutional review board, with waiver of informed consent. Consecutive individuals who had undergone abdominal ultrasonography as part of a health examination at a tertiary hospital between January 2010 and June 2010 were included. IPE was defined as increased echogenicity of the pancreas compared with that of the left lobe of liver or renal cortex. IPE subdivided into mild, moderate, and severe degree comparing to the retroperitoneal fat echogenicity. Glycemic progression was defined as the development of new prediabetes or diabetes in normoglycemic subjects or as new diabetes in prediabetic subjects during the follow up period (median, 86.8 months; interquartile range, 84.1–90.6 months). The occurrence of incident diabetes, defined as a new diagnosis of diabetes during follow-up, was also analyzed. Results A total of 596 subjects were included in the follow-up analysis. Mean age of the 596 subjects was 48.6 years ± 11.5, and 55.4 % (n = 330) were female. The prevalence of IPE was 63.8 % (380/596). Mild, moderate, and severe IPE groups were 32.4%, 22.7%, and 8.7%, respectively. During the follow-up, 79 (13.3%) of the 596 subjects developed glycemic progression and new diabetes. Only presence of IPE was not associated with glycemic progression (P = 0.401). However, IPE more than moderate degree revealed significant associated with glycemic progression (hazard ratio, 1.38; 95% confidence interval: 1.920 – 8.300; P = 0.002). Conclusion Only presence of increased pancreatic echogenicity is not a risk factor of glycemic progression. IPE more than moderate degree is associated with impaired glycemic parameters and higher risk of glycemic progression and incident diabetes.

Effects of dietary fat on insulin secretion in subjects with the metabolic syndrome

Objective Impaired insulin secretion and action contribute to the development of type 2 diabetes. Dietary fat modification may improve insulin sensitivity, whereas the effect on insulin secretion is unclear. We investigated the effect of dietary fat modification on insulin secretion in subjects with the metabolic syndrome. Design In a 12-week pan-European parallel, randomized controlled dietary intervention trial (LIPGENE), 486 subjects were assigned to four isoenergetic diets: high-fat diets rich in saturated fat (HSFA) or monounsaturated fat (HMUFA) or low-fat, high-complex carbohydrate diets with (LFHCC n-3) or without (LFHCC control) 1.2 g/day of n-3 PUFA supplementation. Insulin secretion was estimated as acute insulin response to glucose (AIRg) and disposition index (DI), modeled from an intravenous glucose tolerance test. Results There were no overall effect of the dietary intervention on AIRg and DI in the total cohort, in neither the high-fat nor LFHCC groups. We observed significant diet*fasting glucose category interactions for AIRg (P = 0.021) and DI (P = 0.001) in the high-fat groups. In subjects with normal fasting glucose and preserved first phase insulin secretion, the HMUFA diet increased, whereas the HSFA diet reduced AIRg (P = 0.015) and DI (P = 0.010). Conclusions The effects of dietary fat modification on insulin secretion were minor, and only evident in normoglycemic subjects. In this case, the HMUFA diet improved AIRg and DI, as compared to the HSFA diet.

MiR-20b, miR-296, and Let-7f Expression in Human Adipose Tissue is Related to Obesity and Type 2 Diabetes.

This study aimed to analyze the potential association of different microRNA (miRNA) molecules with both type 2 diabetes (T2D) and obesity and determine their target genes. Quantitative PCR was used to analyze the miR-20b, miR-296, and Let-7f levels in human visceral and subcutaneous adipose tissues (ATs) in relation to obesity and T2D, miRTarBase 4.0 was used for validation of target genes, and the Protein Analysis Through Evolutionary Relationships (PANTHER) Classification System and the Database for Annotation, Visualization and Integrated Discovery (DAVID) were used to annotate the biological processes of the predicted targets. In AT, miR-20b, miR-296, and Let-7f levels were significantly different between normoglycemic subjects and those with T2D. In visceral adipose tissue, miRNA levels were higher in normoglycemic/obesity samples than in T2D/obesity samples. miR-20b-miR-296 and Let-7f target genes that showed significant differences in both ATs in relation to obesity and T2D were CDKN1A, CX3CL1, HIF1A, PPP2R1B, STAT3, and VEGFA. These genes are known to be principally involved in the vascular endothelial growth factor (VEGF) and WNT pathways. This study provides experimental evidence of the possible correlation between AT miR-20b-miR-296-Let-7f with obesity and T2D, which might involve vascular endothelial growth factor and WNT-dependent pathways that are regulated by six different genes, suggesting a novel signaling pathway that could be important for understanding the mechanisms underlying the AT dysfunction associated with obesity and T2D.

Comparison of the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in normoglycemic and hyperglycemic subjects.

ABSTRACTObjective:To compare the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as possible parameters of systemic inflammation in hyperglycemic and normoglycemic subjects.Methods:A retrospective, cross-sectional study of data collected from patients tested for fasting blood glucose, glycated hemoglobin (HbA1c) and blood count on the same day, between July and December 2016. Patients were divided into hyperglycemic and normoglycemic, and matched by age and sex. The data were analyzed using Epi Info™, version 7.2.1.0, for the Windows® platform.Results:We enrolled 278 subjects, 139 hyperglycemic and 139 normoglycemic. The absolute number of leukocytes and neutrophils was higher in the Hyperglycemic Group (p=0.006 and p=0.004, respectively). There was no difference in the neutrophil-to-lymphocyte ratio between the Hyperglycemic Group and the Normoglycemic Group (2.1 versus 2.0; p=0.264), and both neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios showed no differences between those with HbA1c ≥7% (n=127, p=0.778) and those with HbA1c <7% (n=12, p=0.490). In contrast, the platelet-to-lymphocyte ratio was lower in the Hyperglycemic Group (117.8 versus 129.6; p=0.007).Conclusion:Hyperglycemic subjects had a neutrophil-to-lymphocyte ratio similar to that of normoglycemic subjects, but had a lower platelet-to-lymphocyte ratio. Future prospective studies will be useful to determine the importance and prognostic value of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in the hyperglycemic state.

Higher levels of thioredoxin interacting protein (TXNIP) in patients with prediabetes compared to obese normoglycemic subjects

BackgroundThioredoxin interacting protein (TXNIP) is one of the mediators of oxidative stress induced beta-cell glucotoxisity. TXNIP might play a key role in impaired glucose homeostasis preceding overt T2DM. The aim of the present study was to compare TXNIP levels between patients with prediabetes and obese normoglycemic controls and to evaluate the link between TXNIP and metabolic risk factors. Patients and methodsIn the present study we included 79 patients with mean age 50.3 ± 10.6 years, divided into two age and BMI matched groups –control group with obesity without glycemic disturbances (NGT) (n = 40) and prediabetes (n = 39). ResultsWe found significantly higher levels of TXNIP in patients with prediabetes compared to normoglycemic obese controls (54.2 ± 69.9 vs. 23.9 ± 47.1 pg/ml; p = 0.03). The levels of TXNIP gradually increased from normal glucose tolerance trough IFG/IGT only to IFG + IGT (27,1; 44.0; 49.9 and 95.7 pg/ml respectively; p = 0.025 between NGT and IFG + IGT). TXNIP levels correlated weakly only with fasting blood glucose (r = 0.235; p = 0.04) but not with glucose during OGTT or the markers of insulin resistance. ConclusionsThe levels of TXNIP are higher in patients with prediabetes compared to normoglycemic controls as they increase gradually from NGT trough IFG/IGT only to IFG + IGT.

Hemoglobin A1c Levels Are Slightly but Significantly Lower in Normoglycemic Subjects With the Hemoglobin E Phenotype.

Hb mutations can alter the structure, behavior, stability, or quantity of the globin chain produced. Some Hb variants shorten the erythrocyte life span, resulting in physiologically lower hemoglobin A1c (HbA1c) levels. The hemoglobin E (HbE) phenotype involves a single-nucleotide polymorphism that reduces β-globin chain synthesis. We compared the HbA1c levels of subjects with normal Hb (HbAA; N=131) and HbE (N=148) phenotypes, examining potential hematological and biochemical factors contributing to differences in HbA1c levels. All had normal fasting plasma glucose (<5.6 mmol/L), AST, ALT, and creatinine levels. Mean±SD HbA1c levels differed between HbAA and HbE subjects: 5.5±0.3% and 5.3±0.3% (P<0.001) according to an immunoassay, and 5.5±0.3% and 5.3±0.3% (P<0.001) according to cation-exchange HPLC, respectively. In multiple logistic regression, only mean corpuscular volume (P<0.001) contributed to the difference in HbA1c levels between groups. Although a 0.2% difference in HbA1c is relatively small and unlikely to alter clinical decisions, epidemiologically, this can lead to misclassification of a significant proportion of the population, especially since the threshold of non-diabetes HbA1c (≤5.6%) falls very close to the HbA1c median of the general population.

Association of serum bilirubin, selected iron status indicators and body composition in non-obese, normoglycemic subjects

Background: Recently cardiometabolic risk reduction has been observed in patients with slightly elevated bilirubin concentration, as well as increased risk in subjects with excessive iron reserves. The aim of this study was to evaluate the relationship between overweight and/or abdominal obesity, serum bilirubin and selected iron status indicators levels in non-obese subjects. Methods: The study group consisted of 80 healthy, non-obese subjects aged 25–40 years. In all subjects total and direct bilirubin (T-BIL, D-BIL), iron (Fe), transferrin (TRSF), ferritin (FERR) and hepcidin (HEPC) measurements were performed. Anthropometric parameters (BMI, waist circumference, WHR) were measured and body composition (% of body fat, muscles and level of visceral fat) was evaluated using body segment analyzer. Results: Men showed significantly higher values of waist circumference, WHR, muscle mass, visceral fat level and FERR and HEPC concentrations, compared to women. Lower concentrations of T-BIL, D-BIL and higher concentration of FERR, HEPC occurred in the overweight group. In all subjects and in the overweight group T-BIL, D-BIL showed negative correlations with BMI, waist circumference, fat mass and visceral fat level, while for FERR, HEPC those correlations were positive. Overweight subjects had an approximately 4-fold higher incidence of low T-BIL, D-BIL levels (p &lt; 0,001), as well as nearly 2-fold higher incidence of high transferrin level (p = 0,02). Conclusions: Overweight subjects have lower bilirubin levels and higher levels of factors potentially contributing to increased oxidative stress, for example ferritin and hepcidin. Serum bilirubin, ferritin and hepcidin concentration are related to body composition indicators, particullary fat mass and visceral fat level.

Periodontal complications of hyperglycemia/diabetes mellitus: Epidemiologic complexity and clinical challenge.

This report provides a comprehensive overview of the adverse effects of hyperglycemia on the periodontium. It combines data from literature reviews of original data from two large, population-based epidemiologic studies with comprehensive periodontal health assessment. Emphasis is placed on the exploration of hitherto sparsely reported effects of prediabetes and poorly controlled (uncontrolled) diabetes, in contrast to the umbrella term "diabetes." This stems from the realization that it is not simply having a diagnosis of diabetes that may adversely affect periodontal health. Rather, it is the level (severity) of hyperglycemia that is the determining factor, not the case definition of the diagnosis of diabetes or the type of diabetes in question. Importantly, based on existing evidence this paper also attempts to estimate the improvements in periodontal probing depth and clinical attachment level that can be expected upon successful nonsurgical periodontal treatment in people with chronic periodontitis, with and without diabetes, respectively. This exploration includes the implentation of new systematic reviews and meta-analyses that allow comparison of such intervention outcomes between hyperglycemic and normoglycemic subjects. Based on both existing literature and original analyses of population-based studies, we try to answer questions such as: Is there a glycated hemoglobin concentration threshold for periodontitis risk? Does short-term periodontal probing depth reduction and clinical attachment level gain after scaling and root planing depend on glycemic control in type 2 diabetes? Are short-term scaling and root planing outcomes in people with hyperglycemia/diabetes inferior to those in people without diabetes? Do periodontitis patients with diabetes benefit more from the use of adjuvant antibiotics with nonsurgical periodontal treatment than people without diabetes? Does hyperglycemia lead to greater tooth loss in patients in long-term post-periodontal treatment maintenance programs? Throughout this review, we compare our new findings with previous data and report whether the results of these new analyses corroborate, or are in discord with, similar scientific reports in the literature. We also explore the potential role of dental health-care professionals in helping patients control the risk factors that are identical for periodontitis and diabetes. Finally, we suggest various topics that still need exploration in future research.