Acute effects of valsartan on insulin sensitivity in obese, non-hypertensive subjects with and without type 2 diabetes.

BACKGROUND: Two studies were designed to determine whether a single dose (80 mg) of the angiotensin II receptor blocker (ARB), valsartan, alters insulin sensitivity in obese, non-hypertensive subjects with and without Type 2 diabetes. METHODS: Insulin sensitivity (S(I)), glucose effectiveness (S(G)), and acute insulin response (AIR(0-10 min)) were measured by means of a 3-hour insulin-modified frequently sampled intravenous glucose tolerance test (FSIVGTT) before and after a single dose of valsartan. Study 1: obese, normotensive non-diabetic male subjects (n = 12), mean (SD) age 37.2 +/- 11.2 years, BMI 32.8 +/- 6.8 kg/m (2); Study 2: obese, normotensive Type 2 diabetic patients (n = 12), mean age 55.7 +/- 6.9 years, BMI 35.0 +/- 6.8 kg/m (2)/l. Both studies were randomised, double-blind, placebo-controlled, single-dose crossover group studies involving subjects in two study days, two weeks apart. After fasting samples were taken, a 300 mg/kg iv glucose bolus was injected at 0 min, and 0.05 U/kg iv insulin was given 20 min later. Blood samples for analysis of glucose and insulin were taken throughout the 3-hour study period. RESULTS: Study 1 (non-diabetic subjects) S(I) 2.81 vs. 2.63 x 10 (-4) min (-1) per microU/ml (p = 0.54), S(G) 0.020 vs. 0.020 min (-1) (p = 0.90), AIR(0-10) min 3305 vs. 3450 microU/min/ml (p = 0.71); Study 2 (patients with type 2 diabetes) S(I) 0.59 vs. 0.85 x 10 (-4) min (-1) per microU/ml (p = 0.15), S(G) 0.013 vs. 0.014 min (-1) (p = 0.71), AIR(0-10) min 65 vs. 119 microU/min/ml (p = 0.14), placebo vs. valsartan, respectively. CONCLUSION: In obese, non-hypertensive non-diabetic and Type 2 diabetic subjects a single dose of valsartan does not alter insulin sensitivity.     

Increased proton leak and SOD2 expression in myotubes from obese non-diabetic subjects with a family history of type 2 diabetes

Muscle insulin resistance is linked to oxidative stress and decreased mitochondrial function. However, the exact cause of muscle insulin resistance is still unknown. Since offspring of patients with type 2 diabetes mellitus (T2DM) are susceptible to developing insulin resistance, they are ideal for studying the early development of insulin resistance. By using primary muscle cells derived from obese non-diabetic subjects with (FH +) or without (FH ?) a family history of T2DM, we aimed to better understand the link between mitochondrial function, oxidative stress, and muscle insulin resistance. Insulin-stimulated glucose uptake and glycogen synthesis were normal in FH + myotubes. Resting oxygen consumption rate was not different between groups. However, proton leak was higher in FH + myotubes. This was associated with lower ATP content and decreased mitochondrial membrane potential in FH + myotubes. Surprisingly, mtDNA content was higher in FH + myotubes. Oxidative stress level was not different between FH + and FH ? groups. Reactive oxygen species content was lower in FH + myotubes when differentiated in high glucose/insulin (25 mM/150 pM), which could be due to higher oxidative stress defenses (SOD2 expression and uncoupled respiration). The increased antioxidant defenses and mtDNA content in FH + myotubes suggest the existence of compensatory mechanisms, which may provisionally prevent the development of insulin resistance.     

Genetic and environmental components of family history in type 2 diabetes

Family history of diabetes is a major risk factor for type 2 diabetes (T2D), but whether this association derives from shared genetic or environmental factors is unclear. To address this question, we developed a statistical framework that models four components of variance, including known and unknown genetic and environmental factors, using a liability threshold model. Focusing on parental history, we simulated case–control studies with two first-degree relatives for each individual, assuming 50 % genetic similarity and a range of values of environmental similarity. By comparing the association of parental history with T2D in our simulations to case–control studies of T2D nested in the Nurses’ Health Study and Health Professionals Follow-up Study, we estimate that first-degree relatives have a correlation of 23 % (95 % CI 15–27 %) in their environmental contribution to T2D liability and that this shared environment is responsible for 32 % (95 % CI 24–36 %) of the association between parental history and T2D, with the remainder due to shared genetics. Estimates are robust to varying model parameter values and our framework can be extended to different definitions of family history. In conclusion, we find that the association between parental history and T2D derives from predominately genetic but also environmental effects.     

PPARgamma2 Pro12Ala polymorphism in relation to free fatty acids concentration and composition in lean healthy Czech individuals with and without family history of diabetes type 2

Free fatty acids (FFAs) are natural ligands of the PPARgamma2 receptor. FFA plasma concentration and composition may represent one of the factors accounting for high heterogeneity of conclusions concerning the effect of the Pro12Ala on BMI, insulin sensitivity or diabetes type 2 (DM2) susceptibility. Our objective was to investigate the relation and possible interactions between the Pro12Ala polymorphism and FFA status, metabolic markers, and body composition in 324 lean nondiabetic subjects (M/F: 99/225; age 32+/-11 years; BMI 23.9+/-4.0 kg/m(2)) with and without family history of DM2. Family history of DM2 was associated with lower % PUFA and slightly higher % MUFA. The presence of Pro12Ala polymorphism was not associated with fasting plasma FFA concentration or composition, anthropometric or metabolic markers of glucose and lipid metabolism in tested population. However, the interaction of carriership status with FFA levels influenced the basal glucose levels, insulin sensitivity and disposition indices, triglycerides, HDL-cholesterol and leptin levels, especially in women. The metabolic effects of 12Ala carriership were influenced by FFA levels - the beneficial role of 12Ala was seen only in the presence of low concentration of plasma FFA. Surprisingly, a high PUFA/SFA ratio was associated with lower insulin sensitivity, the protective effect of 12Ala allele was apparent in subjects with family history of DM2. On the basis of our findings and published data we recommend the genotyping of diabetic patients for Pro12Ala polymorphism of the PPARgamma2 gene before treatment with thiazolidinediones and education of subjects regarding diet and physical activity, which modulate metabolic outcomes.     

Effects on insulin secretion and insulin action of a 48-h reduction of plasma free fatty acids with acipimox in nondiabetic subjects genetically predisposed to type 2 diabetes

Elevated plasma FFA cause beta-cell lipotoxicity and impair insulin secretion in nondiabetic subjects predisposed to type 2 diabetes mellitus [T2DM; i.e., with a strong family history of T2DM (FH+)] but not in nondiabetic subjects without a family history of T2DM. To determine whether lowering plasma FFA with acipimox, an antilipolytic nicotinic acid derivative, may enhance insulin secretion, nine FH+ volunteers were admitted twice and received in random order either acipimox or placebo (double-blind) for 48 h. Plasma glucose/insulin/C-peptide concentrations were measured from 0800 to 2400. On day 3, insulin secretion rates (ISRs) were assessed during a +125 mg/dl hyperglycemic clamp. Acipimox reduced 48-h plasma FFA by 36% (P < 0.001) and increased the plasma C-peptide relative to the plasma glucose concentration or DeltaC-peptide/Deltaglucose AUC (+177%, P = 0.02), an index of improved beta-cell function. Acipimox improved insulin sensitivity (M/I) 26.1 +/- 5% (P < 0.04). First- (+19 +/- 6%, P = 0.1) and second-phase (+31 +/- 6%, P = 0.05) ISRs during the hyperglycemic clamp also improved. This was particularly evident when examined relative to the prevailing insulin resistance [1/(M/I)], as both first- and second-phase ISR markedly increased by 29 +/- 7 (P < 0.05) and 41 +/- 8% (P = 0.02). There was an inverse correlation between fasting FFA and first-phase ISR (r2 = 0.31, P < 0.02) and acute (2-4 min) glucose-induced insulin release after acipimox (r2 =0.52, P < 0.04). In this proof-of-concept study in FH+ individuals predisposed to T2DM, a 48-h reduction of plasma FFA improves day-long meal and glucose-stimulated insulin secretion. These results provide additional evidence for the important role that plasma FFA play regarding insulin secretion in FH+ subjects predisposed to T2DM.     

Beta-cell dysfunctions and insulin resistance in subjects with increased risk for type 2 diabetes mellitus

The aim of this study was to test if a beta-cell defect is associated to deterioration of glucose tolerance early during the natural history of the type 2 diabetes mellitus . In 41 overweight women, with macrosomic infants in their antecedent deliveries, measures of insulin response and insulin sensitivity were derived from a short (45 min) iv glucose test. The early (EIR) and the late (LIR) phase insulin responses and the insulin sensitivity index (Si) were calculated. According the response to 75 g oral glucose test the subjects were divided into two groups: Imparired glucose tolerance (IGT;n = 12), and normal glucose tolerance (NGT; n = 29). EIR was reduced in IGT group (14.9 ± 3.6 vs 37.0 ± 4.0; p< 0.002). Glucose tolerance during oral glucose tolerance test (OGTT), correlated inversly to EIR (r=-0.45; n=41; p< 0.01). A strong correlation of EIR to LIR (r=0.88; n = 41; p< 0.001) but no correlation between glucose tolerance and Si was found.     

Association of insertion/deletion polymorphism of alpha-adrenoceptor gene in essential hypertension with or without type 2 diabetes mellitus in Malaysian subjects

An insertion/deletion (I/D) polymorphism of Alpha2B-Adrenoceptor (ADRA2B) gene located on chromosome 2 has been studied extensively in related to cardiovascular diseases. The main aim of the present study was to examine the potential association of D allele frequency of I/D polymorphism of ADRA2B gene in Malaysian essential hypertensive subjects with or without type 2 diabetes mellitus (T2DM). This study includes 70 hypertensive subjects without T2DM, 65 hypertensive subjects with T2DM and 75 healthy volunteers as control subjects. Genotyping of I/D polymorphism was performed by conventional PCR method. There was significant difference found in age, body mass index, systolic/diastolic blood pressure and high density lipoprotein cholesterol level between the case and control subjects. DD genotypic frequency of I/D polymorphism was significantly higher in hypertensive subjects (42.84% vs. 29.33%; P-=0.029) and in hypertensive with T2DM subjects (46.15% vs. 29.33%; P=0.046) than control group. D allele frequency was higher in hypertensive group (67.41%) than control subjects (52.67%). However, no significant difference was found between the three genotypes of I/D polymorphism of ADRA2B gene and the clinical characteristics of the subjects. The result obtained in this study show D allele of ADRA2B gene was associated with essential hypertension with or without T2DM in Malaysian subjects.     

Functional state of hypothalamic signaling systems in rats with type 2 diabetes mellitus treated with intranasal insulin

Intranasal insulin (II) administration is widely used in the last years to treat Alzheimer’s disease and other cognitive disorders. Meanwhile, it is almost not used to treat type 2 diabetes mellitus (DM2), mainly due to insufficiently studied molecular mechanisms of its effect on the hormonal and metabolic status of the organism. The effect of II on activity of the hypothalamic signaling systems playing a key role in central regulation of energy metabolism is also poorly studied. The aim of this work was to study the effect of 5-week II treatment of male rats with the neonatal model of DM2 (0.48 ME/rat) both on the metabolic parameters and functional activity of the hypothalamic signaling systems. II treatment of diabetic rats (DI group) was shown to normalize the blood glucose level and restore glucose tolerance and utilization. In the hypothalamus of the DI group, the regulatory effects of agonists of the type 4 melanocortin receptor (MC4R), type 2 dopamine receptor (D2-DAR) and serotonin 1B receptor (S1BR) on adenylyl cyclase (AC) activity, reduced under DM2, were found to be restored; moreover, the inhibitory effect of S1BR agonists became even stronger as compared to control. In the DI group, the restoration of AC hormonal regulation was associated with a considerable increase in expression of the genes encoding S1BR and MC4R. Besides, the attenuation of the AC-stimulating effect of D2-DAR agonists against the background of decreasing expression of the Drd1 gene was found to promote the enhancement of the negative effect of dopamine on AC activity. II treatment did not have a considerable effect on expression of the genes encoding the insulin receptor and insulin receptor substrate-2, which was slightly reduced in the hypothalamus of diabetic rats. Thus, II treatment of rats with the neonatal model of DM2 partially restores the hypothalamic AC signaling pathways regulated by melanocortin, serotonin and dopamine, demonstrating thereby one of the mechanisms of the positive influence of II on energy metabolism and insulin sensitivity in peripheral tissues.     

The reproducibility of the plasma response to a physiological dose of zinc in healthy subjects

Zinc absorption may be estimated by measuring the area under the plasma zinc curve following the ingestion of a zinc supplement. The aim of this study is to determine the reproducibility of such a response when a small dose of zinc is administered to healthy volunteers. Five female subjects were asked to consume 4.5 mg elemental zinc, and blood samples were obtained at 30 min intervals for 5 h. The experiment was repeated in the same volunteers 12–16 d later. The area under the plasma zinc curve was 30% lower after the second zinc tolerance test compared with the first (11.0 vs 15.8 μmol/1 h). This difference could not be explained by differences in the fasting plasma zinc levels (12.9 μmol/L Experiment one, 15.1 μmol/L Experiment 2) nor was it related to technical or clinical parameters. The area under the curve after 5 h was strongly correlated with the response after 4 h. Hence we conclude that a small dose of zinc can be used to determine zinc absorption and a shorter experimental period may be used. However, trials must be designed to take into account the sequence variability in the response.     

Cost-effectiveness of self-monitoring of blood glucose in patients with type 2 diabetes mellitus managed without insulin

Background

The benefits of self-monitoring blood glucose levels are unclear in patients with type 2 diabetes mellitus who do not use insulin, but there are considerable costs. We sought to determine the cost effectiveness of self-monitoring for patients with type 2 diabetes not using insulin.

Methods

We performed an incremental cost-effectiveness analysis of the self-monitoring of blood glucose in adults with type 2 diabetes not taking insulin. We used the United Kingdom Prospective Diabetes Study (UKPDS) model to forecast diabetes-related complications, corresponding quality-adjusted life years and costs. Clinical data were obtained from a systematic review comparing self-monitoring with no self-monitoring. Costs and utility decrements were derived from published sources. We performed sensitivity analyses to examine the robustness of the results.

Results

Based on a clinically modest reduction in hemoglobin A_1C of 0.25% (95% confidence interval 0.15–0.36) estimated from the systematic review, the UKPDS model predicted that self-monitoring performed 7 or more times per week reduced the lifetime incidence of diabetes-related complications compared with no self-monitoring, albeit at a higher cost (incremental cost per quality-adjusted life year $113 643). The results were largely unchanged in the sensitivity analysis, although the incremental cost per quality-adjusted life year fell within widely cited cost-effectiveness thresholds when testing frequency or the price per test strip was substantially reduced from the current levels.

Interpretation

For most patients with type 2 diabetes not using insulin, use of blood glucose test strips for frequent self-monitoring (≥ 7 times per week) is unlikely to represent efficient use of finite health care resources, although periodic testing (e.g., 1 or 2 times per week) may be cost-effective. Reduced test strip price would likely also improve cost-effectiveness.Self-monitoring of blood glucose in patients with diabetes who use insulin may contribute to improved glycemic control and reduced hypoglycemia by allowing for self-adjustments in insulin dose to be made based on meter readings.¹ Self-monitoring may also allow for appropriate changes in diet and physical activity to be made. However, the benefits of self-monitoring of blood glucose for patients not using insulin are less clear. Hypoglycemia is less frequent in this population² and is confined mainly to those taking secretagogues. The degree to which patients can adjust the dose of oral antidiabetes drugs in response to readings is limited.Nevertheless, self-monitoring of blood glucose is routinely recommended for patients who are not using insulin.¹ This results in major investments in this technology by patients and payers.³ In 2006, $250 million was spent on blood glucose test strips in 8 publicly funded drugs plans in Newfoundland and Labrador, Nova Scotia, Quebec, Ontario, Manitoba, Saskatchewan and British Columbia, while over $120 million was spent in privately funded drug plans in Canada.⁴ In some publicly funded drug plans in Canada, blood glucose test strips are among the top 5 classes in terms of total expenditure,⁵ with costs exceeding those for all oral antidiabetes drugs combined.^4,6 It is estimated that more than 50% of the total expenditure on blood glucose test strips is for patients with type 2 diabetes who are not using insulin.³ Costs related to test strips are expected to rise steadily^5,7 because of the increasing prevalence of type 2 diabetes.⁸Decisions about the prescribing and reimbursement of blood glucose test strips require consideration of information about the costs and clinical benefits.^9,10 As part of a larger initiative to determine the optimal use of this technology, we sought to determine the cost-effectiveness of self-monitoring of blood glucose for patients with type 2 diabetes who do not use insulin, based on data from our systematic review¹¹ of the available clinical evidence.     

Effect of insulin therapy on plasma leptin and body weight in patients with type 2 diabetes.

AIMS: This study set out to define relationships between changes in plasma leptin and changes in body weight, plasma insulin and blood glucose control during a 12-month crossover study of once-daily Ultratard or twice-daily Insulatard insulin. PATIENTS AND METHODS: Fasting plasma leptin and insulin were measured during a multicentre cross-over study involving 60 subjects with type 2 diabetes (fasting glucose > 8 mM). After a 2-month run-in, there were two 6-month periods of treatment with Insulatard or Ultratard insulin. RESULTS: Mean plasma leptin increased significantly in both groups after insulin therapy was instigated (12.8 +/- 8.1 to 22.9 +/- 13.1 ng/ml in the Insulatard group; 12.1 +/- 7.2 to 19.2 +/- 12.3 ng/ml in the Ultratard group). Weight also increased significantly in both groups (82.4 +/- 14.3 kg to 88.8 +/- 14.3 kg and 82.2 +/- 15.3 kg to 85.3 +/- 15.2 kg respectively). The increase in plasma leptin correlated well with the increase in weight (R = 0.416, p = 0.001), and this correlation continued after the crossover point. Plasma leptin correlated with BMI throughout the study (R = 0.540, p = 0.000). CONCLUSION: The sustained rise in body weight despite a substantial increase in plasma leptin suggests that either resistance to the hypothalamic action of leptin develops when insulin therapy is begun in type 2 diabetes, or that resetting of the set point for body weight occurs such that a larger body mass is tolerated for a given level of plasma leptin.     

Acute lowering of circulating fatty acids improves insulin secretion in a subset of type 2 diabetes subjects

We tested the effects of acute perturbations of elevated fatty acids (FA) on insulin secretion in type 2 diabetes. Twenty-one type 2 diabetes subjects with hypertriglyceridemia (triacylglycerol >2.2 mmol/l) and 10 age-matched nondiabetic subjects participated. Glucose-stimulated insulin secretion was monitored during hyperglycemic clamps for 120 min. An infusion of Intralipid and heparin was added during minutes 60-120. In one of two tests, the subjects ingested 250 mg of Acipimox 60 min before the hyperglycemic clamp. A third test (also with Acipimox) was performed in 17 of the diabetic subjects after 3 days of a low-fat diet. Acipimox lowered FA levels and enhanced insulin sensitivity in nondiabetic and diabetic subjects alike. Acipimox administration failed to affect insulin secretion rates in nondiabetic subjects and in the group of diabetic subjects as a whole. However, in the diabetic subjects, Acipimox increased integrated insulin secretion rates during minutes 60-120 in the 50% having the lowest levels of hemoglobin A(1c) (379 +/- 34 vs. 326 +/- 30 pmol x kg(-1) x min(-1) without Acipimox, P < 0.05). A 3-day dietary intervention diminished energy from fat from 39 to 23% without affecting FA levels and without improving the insulin response during clamps. Elevated FA levels may tonically inhibit stimulated insulin secretion in a subset of type 2 diabetic subjects.     

Effect of IGF-I on FFA and glucose metabolism in control and type 2 diabetic subjects

The effects of insulin-like growth factor I (IGF-I) and insulin on free fatty acid (FFA) and glucose metabolism were compared in eight control and eight type 2 diabetic subjects, who received a two-step euglycemic hyperinsulinemic (0.25 and 0.5 mU x kg(-1) x min(-1)) clamp and a two-step euglycemic IGF-I (26 and 52 pmol x kg(-1) x min(-1)) clamp with [3-(3)H]glucose, [1-(14)C]palmitate, and indirect calorimetry. The insulin and IGF-I infusion rates were chosen to augment glucose disposal (R(d)) to a similar extent in control subjects. In type 2 diabetic subjects, stimulation of R(d) (second clamp step) in response to both insulin and IGF-I was reduced by approximately 40-50% compared with control subjects. In control subjects, insulin was more effective than IGF-I in suppressing endogenous glucose production (EGP) during both clamp steps. In type 2 diabetic subjects, insulin-mediated suppression of EGP was impaired, whereas EGP suppression by IGF-I was similar to that of controls. In both control and diabetic subjects, IGF-I-mediated suppression of plasma FFA concentration and inhibition of FFA turnover were markedly impaired compared with insulin (P < 0.01-0.001). During the second IGF-I clamp step, suppression of plasma FFA concentration and FFA turnover was impaired in diabetic vs. control subjects (P < 0.05-0.01). CONCLUSIONS: 1) IGF-I is less effective than insulin in suppressing EGP and FFA turnover; 2) insulin-resistant type 2 diabetic subjects also exhibit IGF-I resistance in skeletal muscle. However, suppression of EGP by IGF-I is not impaired in diabetic individuals, indicating normal hepatic sensitivity to IGF-I.     

Alterations of plasma inflammatory biomarkers in the healthy and chronic obstructive pulmonary disease patients with or without acute exacerbation

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of mortally and morbidity, associated with acute exacerbations (AECOPD) resulted from smoking, infection or air pollution. Systemic inflammation has been considered as one of major pathophysiologic alterations in AECOPD. The present study aimed at developing disease-specific biomarker evaluation by integrating proteomic profiles of inflammatory mediators in AECOPD with clinical and biological informatics. Plasma samples from 18 subjects including healthy people or patients with stable COPD or AECOPD were collected to measure 507 inflammatory mediators using antibody microarray. Clinical informatics was achieved by a Digital Evaluation Score System (DESS) for assessing severity of patients. 20 mediators were significantly different between 3 groups (p<0.05), of which, Cerberus 1, Growth Hormone R, IL-1F6, IL-17B R, IL-17D, IL-19, Lymphotoxin beta, MMP-10, Thrombopoietin and TLR4 were correlated with DESS scores (p<0.05). There was a down-regulation of systemic inflammatory responses in AECOPD. The integration of proteomic profile with clinical informatics as part of clinical bioinformatics is important to screen disease-specific and disease-staged biomarkers. This article is part of a Special Issue entitled: Proteomics: The clinical link.     

Myocardial insulin resistance associated with chronic hypertriglyceridemia and increased FFA levels in Type 2 diabetic patients

We evaluated the influence of chronic hypertriglyceridemia and endothelial dysfunction on myocardial glucose uptake (MGU) in Type 2 diabetic patients without coronary heart disease. Patients were divided into two groups according to fasting triglyceride (TG) levels: 5.4 +/- 1.1 and 1.5 +/- 0.3 mmol/l for high- and normal-TG groups, respectively. Five subjects were assigned to the high-TG group and 11 to the normal-TG group. Age, gender, body mass index, systolic and diastolic blood pressure, glucose, insulin, HbA1c, cholesterol, and HDL cholesterol were similar in the two groups, whereas free fatty acid (FFA) levels were higher in the high-TG group basally and at the end of the clamp. Furthermore, five healthy subjects were subjected to the same protocol and used as the control group. MGU was assessed by using 18F-labeled 2-fluoro-2-deoxy-D-glucose under hyperglycemic-hyperinsulinemic conditions. Basal endothelin-1 and nitric oxide levels were significantly higher in the high-TG group than in the normal-TG and control groups, and cGMP and maximal postischemic vasodilation were significantly decreased in the high-TG group compared with the normal-TG and control groups. However, significant alterations were found in the same parameters in the normal-TG group compared with the control group. By the end of the hyperglycemic clamp, in the high-TG group, MGU was approximately 40 and 65% of that in the normal-TG and control groups. MGU negatively correlated with TG, FFA, and endothelin-1, whereas a positive correlation was found with cGMP and maximal postischemic vasodilation. In conclusion, increased TG and FFA levels are risks, in addition to Type 2 diabetes mellitus, for myocardial insulin resistance, endothelial dysfunction, and alteration of nitric oxide/cGMP levels.     

MicroRNA 144 impairs insulin signaling by inhibiting the expression of insulin receptor substrate 1 in type 2 diabetes mellitus

Background

Dysregulation of microRNA (miRNA) expression in various tissues and body fluids has been demonstrated to be associated with several diseases, including Type 2 Diabetes mellitus (T2D). Here, we compare miRNA expression profiles in different tissues (pancreas, liver, adipose and skeletal muscle) as well as in blood samples from T2D rat model and highlight the potential of circulating miRNAs as biomarkers of T2D. In parallel, we have examined the expression profiles of miRNAs in blood samples from Impaired Fasting Glucose (IFG) and T2D male patients.

Methodology/Principal Findings

Employing miRNA microarray and stem-loop real-time RT-PCR, we identify four novel miRNAs, miR-144, miR-146a, miR-150 and miR-182 in addition to four previously reported diabetes-related miRNAs, miR-192, miR-29a, miR-30d and miR-320a, as potential signature miRNAs that distinguished IFG and T2D. Of these microRNAs, miR-144 that promotes erythropoiesis has been found to be highly up-regulated. Increased circulating level of miR-144 has been found to correlate with down-regulation of its predicted target, insulin receptor substrate 1 (IRS1) at both mRNA and protein levels. We could also experimentally demonstrate that IRS1 is indeed the target of miR-144.

Conclusion

We demonstrate that peripheral blood microRNAs can be developed as unique biomarkers that are reflective and predictive of metabolic health and disorder. We have also identified signature miRNAs which could possibly explain the pathogenesis of T2D and the significance of miR-144 in insulin signaling.     

Switching from premixed insulin to glargine-based insulin regimen improves glycaemic control in patients with type 1 or type 2 diabetes: a retrospective primary care-based analysis

Background

Inflammation contributes to cardiovascular complications in type 2 diabetes, which are often characterized by microvascular alterations. We investigated whether myeloid-related protein 8/14 complex (MRP8/14) secreted by transmigrating monocytes and granulocytes may represent a biomarker for microvascular alterations in patients with type 2 diabetes and nephropathy.

Methods

MRP8/14 was measured in 43 patients with type 2 diabetes and nephropathy. Additionally, the inflammatory markers Interleukin-6 (IL-6), Tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) were quantified. To detect microvascular alterations proteinuria and retinal vessel caliber were used as classical and novel marker, respectively. Proteinuria was quantified by protein-creatinine ratio (PCR); retinal vessel caliber was quantified after retina photography on digitalized retina pictures.

Results

MRP8/14 was positively associated with inflammation (r = 0.57), proteinuria (r = 0.40) and retinal arterial caliber (r = 0.48). Type 2 diabetic patients with MRP8/14 values above the median of 5.8 μg/ml demonstrated higher proteinuria and larger retinal artery caliber than patients with MRP8/14 values below the median (logPCR: -0.51 ± 0.52 versus -0.96 ± 0.46, P < 0.01; retinal artery lumen (μm): 178.3 ± 14.1 versus 162.7 ± 14.9 P < 0.01). Both groups did not differ with regard to metabolic factors and blood pressure. MRP8/14 was an independent predictor of retinal artery caliber in multivariate stepwise regression analysis (β = 0.607) and was positively associated with IL-6 (r = 0.57, P < 0.001) and TNF-α (r = 0.36, P < 0.05).

Conclusion

MRP8/14 – a marker for transendothelial migration – describes not only the state of inflammation in diabetic nephropathy, but additionally the degree of microvascular alterations in the glomerular and retinal bed. Therefore, MRP8/14 may be a potentially selective novel biomarker for microcirculatory defects in diabetic nephropathy.     

Optimal initiation of insulin in type 2 diabetes

Treatment goals for glycemic control in patients with type 2 diabetes are often not achieved or are difficult to maintain as the disease progresses. Too often, insulin therapy is either delayed or is suboptimal. We discuss how the introduction of new insulin analogs may help overcome some of the barriers to insulin use. If combination therapy with oral agents does not achieve glycemic control, the addition of a once-daily intermediate- or long-acting insulin is a simple and highly effective strategy for initiating insulin. If glycemic control is still not achieved, a short- or rapid-acting insulin may be needed prior to meals (basal-prandial approach). A patient's baseline glycosylated hemoglobin (A1C) can guide whether glycemic control can be achieved with basal insulin or will require basal-prandial replacement. In addition to A1C, a patient's age, lifestyle, competence, personal preferences, and comorbidities can be used to help determine the choice of insulin therapy.