Dose- and Time-Dependent Association of Smoking and Its Cessation with Glycemic Control and Insulin Resistance in Male Patients with Type 2 Diabetes Mellitus: The Fukuoka Diabetes Registry

Objective

Cigarette smoking is an important modifiable risk factor for cardiovascular diseases. However, the effect of smoking and its cessation on glycemic control in diabetic patients has not been fully examined yet. The aim of the present study was to examine the association of smoking status with glycemic level and markers of insulin resistance and secretion in patients with type 2 diabetes mellitus.

Research Design and Methods

A total of 2,490 Japanese male patients with type 2 diabetes mellitus aged ≥20 years were divided according to smoking status, amount of cigarettes smoked and years since quitting. The associations with glycemic level and markers of insulin resistance and secretion were examined cross-sectionally.

Results

HbA_1c levels increased progressively with increases in both number of cigarettes per day and pack-years of cigarette smoking compared with never smokers (P for trend = 0.001 and <0.001, respectively), whereas fasting plasma glucose did not. On the other hand, HbA_1c, but not fasting plasma glucose, decreased linearly with increase in years after smoking cessation (P for trend <0.001). These graded relationships persisted significantly after controlling for the confounders, including total energy intake, current drinking, regular exercise, depressive symptoms, and BMI. In addition, a homeostasis model assessment of insulin resistance and high-sensitivity C-reactive protein also showed similar trends.

Conclusions

Smoking and its cessation showed dose- and time-dependent relationship with glycemic control and insulin resistance in patients with type 2 diabetes mellitus. These findings may highlight the importance of smoking cessation in the clinical management of diabetes mellitus.     

Genetic Variants of TPCN2 Associated with Type 2 Diabetes Risk in the Chinese Population

Objective

The aim of this study was to determine whether TPCN2 genetic variants are associated with type 2 diabetes and to elucidate which variants in TPCN2 confer diabetes susceptibility in the Chinese population.

Research Design and Methods

The sample population included 384 patients with type 2 diabetes and 1468 controls. Anthropometric parameters, glycemic and lipid profiles and insulin resistance were measured. We selected 6 TPCN2 tag single nucleotide polymorphisms (rs35264875, rs267603153, rs267603154, rs3829241, rs1551305, and rs3750965). Genotypes were determined using a Sequenom MassARRAY SNP genotyping system.

Results

Ultimately, we genotyped 3 single nucleotide polymorphisms (rs3750965, rs3829241, and rs1551305) in all individuals. There was a 5.1% higher prevalence of the rs1551305 variant allele in type 2 diabetes individuals (A) compared with wild-type homozygous individuals (G). The AA genotype of rs1551305 was associated with a higher diabetes risk (p<0.05). The distributions of rs3829241 and rs3750965 polymorphisms were not significantly different between the two groups. HOMA-%B of subjects harboring the AA genotype of rs1551305 decreased by 14.87% relative to the GG genotype.

Conclusions

TPCN2 plays a role in metabolic regulation, and the rs1551305 single nucleotide polymorphism is associated with type 2 diabetes risk. Future work will begin to unravel the underlying mechanisms.     

Plasma HMGB-1 Levels in Subjects with Obesity and Type 2 Diabetes: A Cross-Sectional Study in China

Object

To detect the levels of plasma High-Mobility Group Box-1(HMGB1) in Chinese subject with obesity and type 2 diabetes mellitus (T2DM), and to investigate the correlations between plasma HMGB1 concentration and parameters of body fat, insulin resistance (IR) metabolism and inflammation.

Methods

This study recruited 79 normal glucose tolerance (NGT) subjects and 76 newly diagnosed T2DM patients. NGT and T2DM groups were divided into normal weight (NW) and obese (OB)subgroups respectively. Anthropometric parameters such as height, weight, waist circumference, hip circumference and blood pressure were measured. Plasma concentrations of HMGB1, IL-6, fasting plasma glucose (FPG), 2 hours post challenge plasma glucose (2hPG), serum lipid, glycated hemoglobin (HbA_1C) and fasting insulin (FINS) were examined. The homeostasis model assessment (HOMA) was performed to assess IR status.

Results

Plasma HMGB1 levels were higher in T2DM group than that in NGT group. The concentrations of serum HMGB1 were also higher in subjects with OB than those in subjects with NW both in NGT and T2DM groups. Plasma levels of HMGB1 were positively correlated with waist hip ratio (WHR), blood pressure, FPG, FINS, HOMA-IR, TG, IL-6 and negatively correlated with HOMA-βand high-density lipoprotein-cholesterol (HDL-c) independent of age, gender and BMI. Plasma levels of HMGB1 were significantly correlated with diabetes in fully adjusted models.

Conclusion

Plasma HMGB1 levels were increased in Chinese subjects with pure T2DM, which might be caused by IR. Serum HMGB1 participated in the pathological process of obesity and T2DM via its proinflammatory effect.     

Both Fasting and Glucose-Stimulated Proinsulin Levels Predict Hyperglycemia and Incident Type 2 Diabetes: A Population-Based Study of 9,396 Finnish Men

Background

Hyperproinsulinemia is an indicator of β-cell dysfunction, and fasting proinsulin levels are elevated in patients with hyperglycemia. It is not known whether proinsulin levels after a glucose load are better predictors of hyperglycemia and type 2 diabetes than fasting proinsulin.

Methods

Participants were 9,396 Finnish men (mean±SD, age 57.3±7.1 years, BMI 27.0±4.0 kg/m²) of the population-based METabolic Syndrome In Men Study who were non-diabetic at the recruitment, and who participated in a 6-year follow-up study. Proinsulin and insulin levels were measured in the fasting state and 30 and 120 min after an oral glucose load. Area under the curve (AUC) and proinsulin to insulin ratios were calculated.

Results

Fasting proinsulin, proinsulin at 30 min and proinsulin AUC during the first 30 min of an oral glucose tolerance test significantly predicted both the worsening of hyperglycemia and type 2 diabetes after adjustment for confounding factors. Further adjustment for insulin sensitivity (Matsuda index) or insulin secretion (Disposition index) weakened these associations. Insulin sensitivity had a major impact on these associations.

Conclusion

Our results suggest that proinsulin in the fasting state and after an oral glucose load similarly predict the worsening of hyperglycemia and conversion to type 2 diabetes.     

A cross-sectional characterization of insulin resistance by phenotype and insulin clamp in East Asian Americans with type 1 and type 2 diabetes

Objective

Classic features of type 1 and type 2 diabetes may not apply in Asian Americans, due to shared absence of common HLA DR-DQ genotype, low prevalence of positive anti-islet antibodies and low BMI in both types of diabetes. Our objective was to characterize diabetic phenotypes in Asian Americans by clamp and clinical features.

Materials/Methods

This was a cross-sectional study conducted in a referral center. Thirty East young Asian American adult volunteers (27.6±5.5 years) with type 1, type 2 diabetes or controls underwent hyperinsulinemic euglycemic clamp to assess insulin resistance and DEXA to assess adiposity.

Results

Gender, BMI, waist/hip ratio, leptin, LDL, anti-GAD, anti-IA2 antibodies and C-reactive protein were similar among three groups. Serum C-peptide, adiponectin, free fatty acid, HDL concentrations and truncal fat by DEXA, were different between diabetic groups. Glucose disposal rate by clamp was lowest in type 2 diabetes, followed by type 1 diabetes and controls (5.43±2.70, 7.62±2.59, 8.61±2.37 mg/min/kg, respectively, p = 0.001). Free fatty acid concentration universally plummeted during steady state of the clamp procedure regardless of diabetes types in all three groups. Adipocyte fatty acid binding protein in the entire cohort (r = −0.625, p = 0.04) and controls (r = −0.869, p = 0.046) correlated best with insulin resistance, independent of BMI.

Conclusions

Type 2 diabetes in Asian Americans was associated with insulin resistance despite having low BMI as type 1 diabetes, suggesting a potential role for targeting insulin resistance apart from weight loss. Adipocyte fatty acid binding protein, strongly associated with insulin resistance, independent of adiposity in the young Asian American population, may potentially serve as a biomarker to identify at-risk individuals. Larger studies are needed to confirm this finding.     

Adolescents with Type 1 Diabetes – The Impact of Gender,Age, and Health-Related Functioning on Eating Disorder Psychopathology

Objective

To investigate correlates of eating disorder psychopathology in adolescent males and females with type 1 diabetes.

Method

A total of 105 adolescents with type 1 diabetes (42% males), aged 12–20 years, were recruited from the Norwegian Childhood Diabetes Registry in this population-based study. All participants were interviewed with the Child Eating Disorder Examination. Additionally, the Brief Illness Perception Questionnaire, the Adolescent Coping Orientation for Problem Experiences and the Beliefs about Medicines Questionnaire were administered to assess health-related functioning. Clinical data were obtained from the Norwegian Childhood Diabetes Registry.

Results

Significant gender differences were demonstrated in the pattern of correlates of eating disorder pathology. Among females, eating disorder psychopathology was significantly associated with body mass index adjusted for age and gender, age, insulin restriction, coping, illness perceptions, and perceptions of insulin concern. In a regression model, age, illness perceptions, and insulin restriction remained significantly associated with eating disorder psychopathology, explaining 48% of the variance. None of the variables were associated with eating disorder psychopathology among males.

Discussion

Greater clinical awareness of illness perceptions, attitudes toward insulin, and insulin restriction may potentially decrease the risk of developing eating disorders among female adolescents with type 1 diabetes, and the subsequent increased morbidity and mortality associated with comorbid type 1 diabetes and eating disorders.     

IGF2BP2 Alternative Variants Associated with Glutamic Acid Decarboxylase Antibodies Negative Diabetes in Malaysian Subjects

Background

The association of Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) common variants (rs4402960 and rs1470579) with type 2 diabetes (T2D) has been performed in different populations. The aim of this study was to evaluate the association of alternative variants of IGF2BP2; rs6777038, rs16860234 and rs7651090 with glutamic acid decarboxylase antibodies (GADA) negative diabetes in Malaysian Subjects.

Methods/Principal Findings

IGF2BP2; rs6777038, rs16860234 and rs7651090 single nucleotide polymorphisms (SNPs) were genotyped in 1107 GADA negative diabetic patients and 620 control subjects of Asian from Malaysia. The additive genetic model adjusted for age, race, gender and BMI showed that alternative variants; rs6777038, rs16860234 and rs7651090 of IGF2BP2 associated with GADA negative diabetes (OR = 1.21; 1.36; 1.35, P = 0.03; 0.0004; 0.0002, respectively). In addition, the CCG haplotype and diplotype CCG-TCG increased the risk of diabetes (OR = 1.51, P = 0.01; OR = 2.36, P = 0.009, respectively).

Conclusions/Significance

IGF2BP2 alternative variants were associated with GADA negative diabetes. The IGF2BP2 haplotypes and diplotypes increased the risk of diabetes in Malaysian subject.     

Red Blood Cell Fatty Acids and Incident Diabetes Mellitus in the Women’s Health Initiative Memory Study

Context

The relations between dietary and/or circulating levels of fatty acids and the development of type 2 diabetes is unclear. Protective associations with the marine omega-3 fatty acids and linoleic acid, and with a marker of fatty acid desaturase activity delta-5 desaturase (D5D ratio) have been reported, as have adverse relations with saturated fatty acids and D6D ratio.

Objective

To determine the associations between red blood cell (RBC) fatty acid distributions and incident type 2 diabetes.

Design

Prospective observational cohort study nested in the Women’s Health Initiative Memory Study.

Setting

General population.

Subjects

Postmenopausal women.

Main Outcome Measures

Self-reported incident type 2 diabetes.

Results

There were 703 new cases of type 2 diabetes over 11 years of follow up among 6379 postmenopausal women. In the fully adjusted models, baseline RBC D5D ratio was inversely associated with incident type 2 diabetes [Hazard Ratio (HR) 0.88, 95% confidence interval (CI) 0.81–0.95) per 1 SD increase. Similarly, baseline RBC D6D ratio and palmitic acid were directly associated with incident type 2 diabetes (HR 1.14, 95% CI 1.04–1.25; and HR 1.24, 95% CI 1.14–1.35, respectively). None of these relations were materially altered by excluding incident cases in the first two years of follow-up. There were no significant relations with eicosapentaenoic, docosahexaenoic or linoleic acids.

Conclusions

Whether altered fatty acid desaturase activities or palmitic acid levels are causally related to the development of type 2 diabetes cannot be determined from this study, but our findings suggest that proportions of certain fatty acids in RBC membranes are associated with risk for type 2 diabetes.     

Use of Autoantigen-Loaded Phosphatidylserine-Liposomes to Arrest Autoimmunity in Type 1 Diabetes

Introduction

The development of new therapies to induce self-tolerance has been an important medical health challenge in type 1 diabetes. An ideal immunotherapy should inhibit the autoimmune attack, avoid systemic side effects and allow β-cell regeneration. Based on the immunomodulatory effects of apoptosis, we hypothesized that apoptotic mimicry can help to restore tolerance lost in autoimmune diabetes.

Objective

To generate a synthetic antigen-specific immunotherapy based on apoptosis features to specifically reestablish tolerance to β-cells in type 1 diabetes.

Methods

A central event on the surface of apoptotic cells is the exposure of phosphatidylserine, which provides the main signal for efferocytosis. Therefore, phosphatidylserine-liposomes loaded with insulin peptides were generated to simulate apoptotic cells recognition by antigen presenting cells. The effect of antigen-specific phosphatidylserine-liposomes in the reestablishment of peripheral tolerance was assessed in NOD mice, the spontaneous model of autoimmune diabetes. MHC class II-peptide tetramers were used to analyze the T cell specific response after treatment with phosphatidylserine-liposomes loaded with peptides.

Results

We have shown that phosphatidylserine-liposomes loaded with insulin peptides induce tolerogenic dendritic cells and impair autoreactive T cell proliferation. When administered to NOD mice, liposome signal was detected in the pancreas and draining lymph nodes. This immunotherapy arrests the autoimmune aggression, reduces the severity of insulitis and prevents type 1 diabetes by apoptotic mimicry. MHC class II tetramer analysis showed that peptide-loaded phosphatidylserine-liposomes expand antigen-specific CD4⁺ T cells in vivo. The administration of phosphatidylserine-free liposomes emphasizes the importance of phosphatidylserine in the modulation of antigen-specific CD4⁺ T cell expansion.

Conclusions

We conclude that this innovative immunotherapy based on the use of liposomes constitutes a promising strategy for autoimmune diseases.     

Mechanisms Regulating Insulin Response to Intragastric Glucose in Lean and Non-Diabetic Obese Subjects: A Randomized,Double-Blind,Parallel-Group Trial

Background/Objectives

The changes in blood glucose concentrations that result from an oral glucose challenge are dependent on the rate of gastric emptying, the rate of glucose absorption and the rate of insulin-driven metabolism that include the incretins, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). The rate of insulin-driven metabolism is clearly altered in obese subjects, but it is controversial which of these factors is predominant. We aimed to quantify gastric emptying, plasma insulin, C-peptide, glucagon and glucose responses, as well as incretin hormone secretions in obese subjects and healthy controls during increasing glucose loads.

Subjects/Methods

The study was conducted as a randomized, double-blind, parallel-group trial in a hospital research unit. A total of 12 normal weight (6 men and 6 women) and 12 non-diabetic obese (BMI > 30, 6 men and 6 women) participants took part in the study. Subjects received intragastric loads of 10 g, 25 g and 75 g glucose dissolved in 300 ml tap water.

Results

Main outcome measures were plasma GLP-1 and GIP, plasma glucagon, glucose, insulin, C-peptide and gastric emptying. The primary findings are: i) insulin resistance (P < 0.001) and hyperinsulinemia (P < 0.001); ii) decreased insulin disposal (P < 0.001); iii) trend for reduced GLP-1 responses at 75 g glucose; and iv) increased fasting glucagon levels (P < 0.001) in obese subjects.

Conclusions

It seems that, rather than changes in incretin secretion, fasting hyperglucagonemia and consequent hyperglycemia play a role in reduced disposal of insulin, contributing to hyperinsulinemia and insulin resistance.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01875575","term_id":"NCT01875575"}}NCT01875575     

Serum Level of Soluble Receptor for Advanced Glycation End Products Is Associated with A Disintegrin And Metalloproteinase 10 in Type 1 Diabetes

Background

The receptor for advanced glycation end products (RAGE) is involved in the pathogenesis of diabetic complications, and soluble forms of the receptor (sRAGE) can counteract the detrimental action of the full-length receptor by acting as decoy. Soluble RAGE is produced by alternative splicing [endogenous secretory RAGE (esRAGE)] and/or by proteolytic cleavage of the membrane-bound receptor. We have investigated the role of A Disintegrin And Metalloproteinase 10 (ADAM10) in the ectodomain shedding of RAGE.

Methods

Constitutive and insulin-induced shedding of RAGE in THP-1 macrophages by ADAM10 was evaluated using an ADAM10-specific metalloproteinase inhibitor. Serum ADAM10 level was measured in type 1 diabetes and control subjects, and the association with serum soluble RAGE was determined. Serum total sRAGE and esRAGE were assayed by ELISA and the difference between total sRAGE and esRAGE gave an estimated measure of soluble RAGE formed by cleavage (cRAGE).

Results

RAGE shedding (constitutive and insulin-induced) was significantly reduced after inhibition of ADAM10 in macrophages, and insulin stimulated ADAM10 expression and activity. Diabetic subjects have higher serum total sRAGE and esRAGE (p<0.01) than controls, and serum ADAM10 was also increased (p<0.01). Serum ADAM10 correlated with serum cRAGE in type 1 diabetes (r = 0.40, p<0.01) and in controls (r = 0.31. p<0.01) but no correlations were seen with esRAGE. The association remained significant after adjusting for age, gender, BMI, smoking status and HbA1c.

Conclusion

Our data suggested that ADAM10 contributed to the shedding of RAGE. Serum ADAM10 level was increased in type 1 diabetes and was a significant determinant of circulating cRAGE.     

Prevalence and Incidence of Hypoglycaemia in 532,542 People with Type 2 Diabetes on Oral Therapies and Insulin: A Systematic Review and Meta-Analysis of Population Based Studies

Objective

To collate and evaluate the current literature reporting the prevalence and incidence of hypoglycaemia in population based studies of type 2 diabetes.

Research Design and Methods

Medline, Embase and Cochrane were searched up to February 2014 to identify population based studies reporting the proportion of people with type 2 diabetes experiencing hypoglycaemia or rate of events experienced. Two reviewers independently screened studies for eligibility and extracted data for included studies. Random effects meta-analyses were carried out to calculate the prevalence and incidence of hypoglycaemia.

Results

46 studies (n = 532,542) met the inclusion criteria. Prevalence of hypoglycaemia was 45% (95%CI 0.34,0.57) for mild/moderate and 6% (95%CI, 0.05,0.07) for severe. Incidence of hypoglycaemic episodes per person-year for mild/moderate and for severe was 19 (95%CI 0.00, 51.08) and 0.80 (95%CI 0.00,2.15), respectively. Hypoglycaemia was prevalent amongst those on insulin; for mild/moderate episodes the prevalence was 50% and incidence 23 events per person-year, and for severe episodes the prevalence was 21% and incidence 1 event per person-year. For treatment regimes that included a sulphonylurea, mild/moderate prevalence was 30% and incidence 2 events per person-year, and severe prevalence was 5% and incidence 0.01 events per person-year. A similar prevalence of 5% was found for treatment regimes that did not include sulphonylureas.

Conclusions

Current evidence shows hypoglycaemia is considerably prevalent amongst people with type 2 diabetes, particularly for those on insulin, yet still fairly common for other treatment regimens. This highlights the subsequent need for educational interventions and individualisation of therapies to reduce the risk of hypoglycaemia.     

Patterns of Circulating Fibroblast Growth Factor 21 in Subjects with and without Type 2 Diabetes

Background

Fibroblast growth factor 21 (FGF21) exerts wide-range effects on carbohydrate and lipid metabolism. However, its perturbation in type 2 diabetes mellitus (T2DM) remains elusive. Besides, previous human studies in T2DM simply investigated fasting or stimulated levels of FGF21. The current study sought to evaluate the temporal changes of circulating FGF21 in subjects with and without T2DM.

Methods

Ten patients with T2DM and 16 normal controls (NC) were recruited. Participants were categorized as obese (BMI≥25 kg/m²) or lean (BMI<25 kg/m²). Blood samples were drawn every 30 min within 7 hours (8 a.m.-3 p.m.). Serum FGF21, blood glucose, insulin, free fatty acids (FFAs) and adiponectin were measured in all subjects.

Results

The peak levels of FGF21 were observed in the fasting state (8 a.m.) both in T2DM and NC groups (267.35 ±158.72 ng/L vs. 178.93±121.37 ng/L, P = 0.096). FGF21 AUC did not differ significantly between the two groups (T2DM: 949.4±471.47 ng/L; NC: 883.13±561.40 ng/L, P = 0.770). Obese subjects had higher FGF21 levels than lean ones in patients either with or without T2DM. The pattern of FFAs closely resembled that of FGF21. Correlation analysis showed that temporal levels of FGF21 were significantly related to FFAs (r = 0.749, P = 0.002),but not blood glucose, insulin or adiponectin (all P> 0.05).

Conclusions

These findings suggest that the pattern of circulating FGF21 does not differ significantly between T2DM and NC,although T2DM patients showed a trend toward higher fasting FGF21 than healthy subjects. The pattern of circulating FFAs is significantly associated with that of FGF21.     

Adipocyte Hypertrophy,Inflammation and Fibrosis Characterize Subcutaneous Adipose Tissue of Healthy,Non-Obese Subjects Predisposed to Type 2 Diabetes

Background

The adipose tissue is important for development of insulin resistance and type 2 diabetes and adipose tissue dysfunction has been proposed as an underlying cause. In the present study we investigated presence of adipocyte hypertrophy, and gene expression pattern of adipose tissue dysfunction in the subcutaneous adipose tissue of healthy, non-obese subjects predisposed to type 2 diabetes compared to matched control subjects with no known genetic predisposition for type 2 diabetes.

Method

Seventeen healthy and non-obese subjects with known genetic predisposition for type 2 diabetes (first-degree relatives, FDRs) and 17 control subjects were recruited. The groups were matched for gender and BMI and had similar age. Glucose tolerance was determined by an oral glucose tolerance test and insulin sensitivity was calculated using HOMA-index. Blood samples were collected and subcutaneous abdominal adipose tissue biopsies obtained for gene expression analysis and adipocyte cell size measurement.

Results

Our findings show that, in spite of similar age, BMI and percent body fat, FDRs displayed adipocyte hypertrophy, as well as higher waist/hip ratio, fasting insulin levels, HOMA-IR and serum triglycerides. Adipocyte hypertrophy in the FDR group, but not among controls, was associated with measures of impaired insulin sensitivity. The adipocyte hypertrophy was accompanied by increased inflammation and Wnt-signal activation. In addition, signs of tissue remodeling and fibrosis were observed indicating presence of early alterations associated with adipose tissue dysfunction in the FDRs.

Conclusion

Genetic predisposition for type 2 diabetes is associated with impaired insulin sensitivity, adipocyte hypertrophy and other markers of adipose tissue dysfunction. A dysregulated subcutaneous adipose tissue may be a major susceptibility factor for later development of type 2 diabetes.     

Elevated Serum Levels of Mannose-Binding Lectin and Diabetic Nephropathy in Type 2 Diabetes

Objective

Inflammation and complement activation initiated by mannose-binding lectin (MBL) may be implicated in the pathogenesis of diabetic vascular complications. We investigated serum MBL levels in type 2 diabetes with diabetic nephropathy (DN) and with persistent normoalbuminuria.

Method

Serum MBL levels were determined in 242 type 2 diabetes with overt nephropathy and 242 type 2 diabetes with persistent normoalbuminuria matched for age, sex, and duration of diabetes, as well as in 100 healthy control subjects. The prediction value of MBL was compared with HbA1c, Hs-CRP and with other known predictors. Multivariate analyses were performed using logistic regression models.

Results

The serum MBL levels were significantly higher in diabetes with DN as compared to with persistent normoalbuminuria (P<0.0001). Multivariate logistic regression analysis adjusted for common factors showed that serum MBL levels≥2950ug/L was an independent indictor of DN (OR=7.55; 95%CI: 3.44–19.04). Based on the ROC curve, the optimal cutoff value of serum MBL levels as an indicator for diagnosis of DN was projected to be 2950ug/L, which yielded a sensitivity of 77.2 % and a specificity of 80.8%, with the area under the curve at 0.809 (95%CI, 0.769—0.848).

Conclusion

Our findings suggested that MBL may be involved in the pathogenesis of DN in type 2 diabetes, and that determination of MBL status might be used to identify patients at increased risk of developing nephropathy complications.     

A Randomized,Double-Blind,Placebo-Controlled Trial of Adjunctive Metformin Therapy in Overweight/Obese Youth with Type 1 Diabetes

Context

Insulin resistance has been proposed as one of the causes of poor glycemic control in overweight/obese youth with type 1 diabetes (T1D). However, the role of adjunctive metformin, an insulin sensitizer, on glycemic control in these patients is unclear.

Objective

To compare the effect of metformin vs. placebo on hemoglobin A1c (HbA1c), total daily dose (TDD) of insulin, and other parameters in overweight/obese youth with T1D.

Hypothesis

Adjunctive metformin therapy will improve glycemic control in overweight/obese youth with T1D.

Design, Setting, and Participants

A 9-mo randomized, double-blind, placebo controlled trial of metformin and placebo in 28 subjects (13m/15f) of ages 10-20years (y), with HbA1c >8% (64 mmol/mol), BMI >85%, and T1D > 12 months was conducted at a university outpatient facility. The metformin group consisted of 15 subjects (8 m/ 7f), of age 15.0 ± 2.5 y; while the control group was made up of 13 subjects (5m/ 8f), of age 14.5 ± 3.1y. All participants employed a self-directed treat-to-target insulin regimen based on a titration algorithm of (-2)-0-(+2) units to adjust their long-acting insulin dose every 3rd day from -3 mo through +9 mo to maintain fasting plasma glucose (FPG) between 90–120 mg/dL (5.0–6.7 mmol/L). Pubertal maturation was determined by Tanner stage.

Results

Over the course of the 9 months of observation, the between-treatment differences in HbA1c of 0.4% (9.85% [8.82 to 10.88] for placebo versus 9.46% [8.47 to 10.46] for metformin) was not significant (p = 0.903). There were non-significant reduction in fasting plasma glucose (189.4 mg/dL [133.2 to 245.6] for placebo versus 170.5 mg/dL [114.3 to 226.7] for metformin), (p = 0.927); total daily dose (TDD) of short-acting insulin per kg body weight/day(p = 0.936); and the TDD of long-acting insulin per kg body weight per day (1.15 units/kg/day [0.89 to 1.41] for placebo versus 0.90 units/kg/day [0.64 to 1.16] for metformin) (p = 0.221). There was no difference in the occurrence of hypoglycemia between the groups.

Conclusions

This 9-month RCT of adjunctive metformin therapy in overweight and obese youth with T1D resulted in a 0.4% lower HbA1c value in the metformin group compared to the placebo group.

Trial Registration

ClinicalTrial.gov NCT01334125     

Corneal Confocal Microscopy Detects Neuropathy in Patients with Type 1 Diabetes without Retinopathy or Microalbuminuria

Objective

Corneal innervation is increasingly used as a surrogate marker of human diabetic peripheral neuropathy (DPN) however its temporal relationship with the other microvascular complications of diabetes is not fully established. In this cross-sectional, observational study we aimed to assess whether neuropathy occurred in patients with type 1 diabetes, without retinopathy or microalbuminuria.

Materials and Methods

All participants underwent detailed assessment of peripheral neuropathy [neuropathy disability score (NDS), vibration perception threshold (VPT), peroneal motor nerve conduction velocity (PMNCV), sural sensory nerve conduction velocity (SSNCV) and in vivo corneal confocal microscopy (IVCCM)], retinopathy (digital fundus photography) and albuminuria status [albumin: creatinine ratio (ACR)].

Results

53 patients with Type 1 diabetes with (n=37) and without retinopathy (n=16) were compared to control subjects (n=27). SSNCV, corneal nerve fibre (CNFD) and branch (CNBD) density and length (CNFL) were reduced significantly (p<0.001) in diabetic patients without retinopathy compared to control subjects. Furthermore, CNFD, CNBD and CNFL were also significantly (p<0.001) reduced in diabetic patients without microalbuminuria (n=39), compared to control subjects. Greater neuropathic severity was associated with established retinopathy and microalbuminuria.

Conclusions

IVCCM detects early small fibre damage in the absence of retinopathy or microalbuminuria in patients with Type 1 diabetes.     

Evidence in Obese Children: Contribution of Hyperlipidemia,Obesity-Inflammation,and Insulin Sensitivity

Background

Evidence shows a high incidence of insulin resistance, inflammation and dyslipidemia in adult obesity. The aim of this study was to assess the relevance of inflammatory markers, circulating lipids, and insulin sensitivity in overweight/obese children.

Methods

We enrolled 45 male children (aged 6 to 13 years, lean control = 16, obese = 19, overweight = 10) in this study. The plasma total cholesterol, HDL cholesterol, triglyceride, glucose and insulin levels, the circulating levels of inflammatory factors, such as TNF-α, IL-6, and MCP-1, and the high-sensitive CRP level were determined using quantitative colorimetric sandwich ELISA kits.

Results

Compared with the lean control subjects, the obese subjects had obvious insulin resistance, abnormal lipid profiles, and low-grade inflammation. The overweight subjects only exhibited significant insulin resistance and low-grade inflammation. Both TNF-α and leptin levels were higher in the overweight/obese subjects. A concurrent correlation analysis showed that body mass index (BMI) percentile and fasting insulin were positively correlated with insulin resistance, lipid profiles, and inflammatory markers but negatively correlated with adiponectin. A factor analysis identified three domains that explained 74.08% of the total variance among the obese children (factor 1: lipid, 46.05%; factor 2: obesity-inflammation, 15.38%; factor 3: insulin sensitivity domains, 12.65%).

Conclusions

Our findings suggest that lipid, obesity-inflammation, and insulin sensitivity domains predominantly exist among obese children. These factors might be applied to predict the outcomes of cardiovascular diseases in the future.     

The Effect of Comorbidity on Glycemic Control and Systolic Blood Pressure in Type 2 Diabetes: A Cohort Study with 5 Year Follow-Up in Primary Care

Aims

To explore the longitudinal effect of chronic comorbid diseases on glycemic control (HbA₁C) and systolic blood pressure (SBP) in type 2 diabetes patients.

Methods

In a representative primary care cohort of patients with newly diagnosed type 2 diabetes in The Netherlands (n = 610), we tested differences in the five year trend of HbA₁C and SBP according to comorbidity profiles. In a mixed model analysis technique we corrected for relevant covariates. Influence of comorbidity (a chronic disease already present when diabetes was diagnosed) was tested as total number of comorbid diseases, and as presence of specific disease groups, i.e. cardiovascular, mental, and musculoskeletal disease, malignancies, and COPD. In subgroup effect analyses we tested if potential differences were modified by age, sex, socioeconomic status, and BMI.

Results

The number of comorbid diseases significantly influenced the SBP trend, with highest values after five years for diabetes patients without comorbidity (p = 0.005). The number of diseases did not influence the HbA₁C trend (p = 0.075). Comorbid musculoskeletal disease resulted in lower HbA₁C at the time of diabetes diagnosis, but in higher values after five years (p = 0.044). Patients with cardiovascular diseases had sustained elevated levels of SBP (p = 0.014). Effect modification by socioeconomic status was observed in some comorbidity subgroups.

Conclusions

Presence of comorbidity in type 2 diabetes patients affected the long-term course of HbA₁C and SBP in this primary care cohort. Numbers and types of comorbidity showed differential effects: not the simple sum of diseases, but specific types of comorbid disease had a negative influence on long-term diabetes control parameters. The complex interactions between comorbidity, diabetes control and effect modifiers require further investigation and may help to personalize treatment goals.