Innate immunity, insulin resistance and type 2 diabetes.

Recent evidence has disclosed previously unrecognized links among insulin resistance, obesity, circulating immune markers, immunogenetic susceptibility, macrophage function and chronic infection. Genetic variations leading to altered production or function of circulating innate immune proteins, cellular pattern-recognition receptors and inflammatory cytokines have been linked with insulin resistance, type 2 diabetes, obesity and atherosclerosis. Cellular innate immune associations with obesity and insulin resistance include increased white blood cell count and adipose tissue macrophage numbers. The innate immune response is modulated possibly by both predisposition (genetic or fetal programming), perhaps owing to evolutionary pressures caused by acute infections at the population level (pandemics), and chronic low exposure to environmental products or infectious agents. The common characteristics shared among innate immunity activation, obesity and insulin resistance are summarized.     

PPARS, insulin resistance and type 2 diabetes

It is clear that the PPAR receptors are exciting targets for therapeutic compounds likely to impact on insulin sensitivity, lipid and glucose homeostasis and vascular disease. The PPARgamma receptor agonists rosiglitazone and pioglitazone are very useful additions to the treatment options for type 2 diabetes. Currently they have limited licences, particularly in Europe, and hopefully as further clinical trial data becomes available these will be extended. Clinical outcome studies are important to ensure that the surrogate effects on glucose and other parameters translate into improved outcomes. There is exciting potential for these agents with the possibility of a combination of effects not only on glucose and lipid homeostasis but also on coagulation and thrombosis, blood pressure and microalbuminuria, which are likely to impact on vascular disease. If the current lack of evidence of serious hepatic toxicity persists they have an advantage over metformin in terms of tolerability and can be used in patients with impaired renal function. In addition to potential effects on diabetic outcome it will be of tremendous interest to determine whether these compounds, which improve insulin sensitivity and beta-cell function, will impact on the natural history of the disease. From what is known of the PPAR receptor systems it is likely that compounds acting as agonists or partial agonists for these receptors will have differing effects and it is possible to envisage the tailoring of compounds to enhance wanted effects and diminish unwanted effects, particularly fluid retention and weight gain. The future certainly looks exciting in this area.     

Magnesium deficiency and insulin resistance in patients with type 2 diabetes mellitus

Magnesium is a predominantly intracellular ion, and it is a cofactor in more than 300 enzymatic reactions, like tyrosinokinase activity. Its deficiency may increase insulin resistance, especially in patients with metabolic syndrome or type 2 diabetes. This study evaluated in 27 patients with poorly controlled type 2 diabetes if there was correlation between intracellular magnesium levels, laboratorial indexes of insulin resistance and glycemic control. Decreased serum and intracellular magnesium depletion were found in 75% and 30.8% of patients, respectively. A negative correlation between intracellular magnesium levels (ICMg) and BMI and HbA1 was found. The homeostasis model assessment for insulin resistance (HOMA-IR) was higher than 3.0 in 59.2% of patients and there was a tendency to negative correlation with ICMg levels, although without statistical significance. Despite the small number of patients, this study shows that magnesium deficiency is frequent in patients with diabetes and its correlation with insulin resistance should be more studied.     

Relation among left ventricular mass, insulin resistance, and hemodynamic parameters in type 2 diabetes.

Increased left ventricular mass (LVM) is an independent cardiovascular risk marker, which often occurs independently of arterial blood pressure in type 2 diabetes. To investigate the factors related to the disproportionate increase in LVM in type 2 diabetes, we conducted a cross-sectional study. We studied 40 male type 2 diabetic patients aged 36 to 70 years with controlled blood pressure. Magnetic resonance imaging was used to measure LVM accurately. Radial arterial waveforms were recorded non-invasively by applanation tonometry to assess the hemodynamic status, radial augmentation index (AI) and time from forward peak to reflection peak (TPP). Glycemic control status and insulin resistance were evaluated by plasma HbA1c and homeostasis model assessment (HOMA) score, respectively. E/E', an echocardiographic parameter for left ventricular (LV) diastolic function, was also analyzed by echocardiography. Univariate analyses showed that HbA1c and TPP had trends toward a positive correlation with LVM indexed for body surface area (LVMI), whereas AI did not. When patients' age, heart rate, and systolic blood pressure were simultaneously included in the linear regression model, the TPP and HOMA score were independently related to LVMI (p<0.05 for each variable). Increased LVMI was accompanied with impaired LV diastolic function assessed by E/E'. In conclusion, the TPP and HOMA score were associated with a modest but clinically relevant increase in LVM in type 2 diabetes independently of arterial blood pressure. Pulse wave analysis may reveal hemodynamic alterations that affect LVM but that cannot be identified using a sphygmomanometer.     

Effects of Goshajinkigan on insulin resistance in patients with type 2 diabetes

We investigated the effects of Goshajinkigan (GJG), a Chinese herbal medicine, on insulin sensitivity in patients with type 2 diabetes using the homeostasis model assessment of insulin resistance (HOMA-R) and the euglycemic insulin clamp procedure. Daily oral administration of GJG (7.5 g/day) was performed for 1 month in 71 type 2 diabetes patients: the GJG treatment group. HOMA-Rs were calculated before and after 1 month of GJG treatment and compared with those of 44 controls who were matched in terms of sex, age, body mass index (BMI) and HbA1c levels with the experimental group. In 64 patients out of the GJG treatment group, HOMA-R was calculated 1 month after discontinuation of treatment. In addition, euglycemic clamp was conducted in eight patients before and after the GJG treatment. HOMA-R was 4.78+/-0.37 (means+/-S.E.) before GJG treatment and significantly decreased to 4.02+/-0.25 after GJG treatment (P=0.019). No significant change was observed in the control group. HOMA-R returned to the pre-treatment level (P=0.018) 1 month after GJG treatment discontinuation. Glucose infusion rates and metabolic clearance rates determined by the high-dose euglycemic clamp increased after 1 month of GJG treatment (from 9.6+/-1.1 to 11.1+/-0.7 mg/kg/min, P=0.045 and from 7.9+/-0.8 to 9.1+/-0.8 ml/kg/min, P=0.046, respectively). These results indicate that GJG administration might be useful for improving insulin resistance in patients with type 2 diabetes.     

Disease burden of urinary tract infections among type 2 diabetes mellitus patients in the U.S.

AimsType 2 diabetes is a reported risk factor for more frequent and severe urinary tract infections (UTI). We sought to quantify the annual healthcare cost burden of UTI in type 2 diabetic patients.MethodsAdult patients diagnosed with type 2 diabetes were identified in MarketScan administrative claims data. UTI occurrence and costs were assessed during a 1-year period. We examined UTI-related visit and antibiotic costs among patients diagnosed with UTI, comparing those with versus without a history of UTI in the previous year (prevalent vs. incident UTI cases). We estimated the total incremental cost of UTI by comparing all-cause healthcare costs in patients with versus without UTI, using propensity score-matched samples.ResultsWithin the year, 8.2% (6,014/73,151) of subjects had ≥ 1 UTI, of whom 33.8% had a history of UTI. UTI-related costs among prevalent versus incident cases were, respectively, $603 versus $447 (p = 0.033) for outpatient services, $1,607 versus $1,819 (p = NS) for hospitalizations, and $61 versus $35 (p < 0.0001) for antibiotics. UTI was associated with a total all-cause incremental cost of $7,045 (95% CI: 4,130, 13,051) per patient with UTI per year.ConclusionsUTI is common and may impose a substantial direct medical cost burden among patients with type 2 diabetes.     

Comparison of demographic factors and cardiovascular risk factor control among U.S. adults with type 2 diabetes by insulin treatment classification

AimsData on glucose and cardiovascular disease (CVD) risk factor control among persons with type 2 diabetes mellitus (DM) according to insulin treatment status are lacking. We examined DM control, risk factors, and comorbidities among U.S. persons according to insulin treatment status.MethodsIn the U.S. National Health and Nutrition Examination Surveys 2003–2006, we examined in 10,637 adults aged ≥ 30 with type 2 DM the extent of control of A1c, LDL-C, HDL-C, triglycerides, and blood pressure (BP) and composite goal attainment by insulin use status.Results6.6% (n = 889, projected to 14.3 million) had type 2 DM; of these, 22.9% were insulin users and 57.2% were treated only by other diabetes medications. Overall, 58.2% had an A1c < 7% (53 mmol/mol) (insulin users 33.1%, non-insulin treated 66.1%, and 77.9% of those not on medication, p < 0.0001). Overall, 44.2% were at a BP goal of < 130/80 mmHg, 43.8% had an LDL-C < 100 mg/dl (2.6 mmol/L), and 13.9% a BMI < 25 kg/m². Only 10.2% were simultaneously at A1c, LDL, and BP goals (5.4% of those on insulin).ConclusionsU.S. adults with type 2 DM, especially those treated with insulin remain inadequately controlled for A1c and CVD risk factors and have a high prevalence of comorbidities.     

Innate immunity, insulin resistance and type 2 diabetes

In this edition of ‘Then and now’ the initial studies by J.C. Pickup and colleagues supporting the hypothesis that type 2 diabetes is caused by activated innate immunity, published in Diabetologia in 1997 (40:1286–1292), are discussed. These initial findings led to research that has uncovered links between insulin resistance, obesity, circulating immune markers, immunogenetic susceptibility, macrophage function and chronic infection. Genetic variations leading to the altered production or function of circulating innate immune proteins, cellular pattern recognition receptors and inflammatory cytokines are linked to obesity, insulin resistance and type 2 diabetes. Components of the innate immune system in the muscle, bone, liver and adipose tissue, as well as macrophages, have been revealed to play a role in systemic insulin action. Evolutionary pressures, such as acute infections at the population level (pandemics) and chronic low exposure to environmental products or infectious agents, may have contributed to increased susceptibility and to the current increase in the prevalence of insulin resistance and type 2 diabetes.     

Factors associated with antidepressant use among low-income racially and ethnically diverse patients with type 2 diabetes

ObjectiveDepression is common in patients with type 2 diabetes and associated with poor diabetes-related outcomes. We evaluated the factors associated with antidepressant use in a low-income, racially and ethnically diverse sample of patients with type 2 diabetes.Research design and methodsWe performed a cross-sectional study of baseline data from participants in a cluster randomized trial evaluating a health literacy intervention for diabetes care in safety net clinics. Depressive symptoms were measured by the Center for Epidemiological Studies Depression Scale (CES-D); antidepressant use was abstracted from medication lists. Multivariable mixed effects logistic regression was used to evaluate the relationship between antidepressant use and race/ethnicity adjusting for depressive symptoms, age, gender, income, and health literacy.ResultsOf 403 participants, 58% were non-Hispanic White, 18% were non-Hispanic Black, and 24% were Hispanic. Median age was 51 years old; 60% were female, 52% of participants had a positive screen for depression, and 18% were on antidepressants. Black and Hispanic participants were significantly less likely to be on an antidepressant compared with white participants, adjusted odds ratios 0.31(95% CI: 0.12 to 0.80) and 0.26 (95% CI: 0.10 to 0.74), respectively.ConclusionsIn this vulnerable population with type 2 diabetes, we found a high prevalence of depressive symptoms, and a small proportion of participants were on an antidepressant. Black and Hispanic participants were significantly less likely to be treated with an antidepressant. Our findings suggest depression may be inadequately treated in low-income, uninsured patients with type 2 diabetes, especially racial and ethnic minorities.     

Microalbuminuria, cardiovascular autonomic dysfunction, and insulin resistance in patients with type 2 diabetes mellitus

Urinary albumin excretion/microalbuminuria and cardiovascular autonomic dysfunction are associated with high mortality in type 2 diabetic patients. We tested the hypothesis that the presence of microalbuminuria would correlate with cardiovascular autonomic dysfunction and insulin resistance in type 2 diabetic patients. The study group consisted of 15 Japanese patients with type 2 diabetes and microalbuminuria (age: 56 +/- 10 years, mean +/- SD). The control group consisted of 19 age-matched patients with normalbuminuria (56 +/- 7 years). Cardiovascular autonomic function was assessed by baroreflex sensitivity (BRS), heart rate variability, plasma norepinephrine concentration, and cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphy. BRS was lower in the microalbuminuria group than in the normalbuminuria group (P < .05). Early and delayed 123I-MIBG myocardial uptake values were lower (P < .05 and P < .005, respectively) and the percent washout rate of 123I-MIBG was higher (P < .0005) in the microalbuminuria group than in the normalbuminuria group. Fasting plasma glucose (P < .05) and insulin concentrations (P < .05), and the homeostasis model assessment (HOMA) index (P < .01) were higher in the microalbuminuria group than in the normalbuminuria group. Multiple regression analysis showed that urinary albumin excretion was independently predicted by the myocardial uptake of 123I-MIBG at delayed phase, fasting plasma insulin concentration, and the HOMA index. Our results indicate that the presence of microalbuminuria in our Japanese patients with type 2 diabetes is characterized by depressed cardiovascular autonomic function and insulin resistance, and that the myocardial uptake of 123I-MIBG at delayed phase, fasting plasma insulin, and HOMA index are independent predictors of urinary albumin excretion.     

Anti-inflammatory effects of empagliflozin in patients with type 2 diabetes and insulin resistance

Background

Inflammation might be a pathological mediator of cardiovascular events in patients with type 2 diabetes and high cardiovascular risk.

Methods

We investigated whether empagliflozin (EMPA) exerts anti-inflammatory effects that are reflected in decreased high-sensitivity C-reactive protein (hsCRP) values. Patients were allocated to receive a placebo (n?=?51) or EMPA (n?=?51) as an add-on treatment. Fasting blood samples were collected before and every 3 months after this intervention for 1 year.

Results

Empagliflozin tended to elicit reductions in BMI, HbA1c, aspartate aminotransferase, alanine aminotransferase (ALT), and gamma-glutamyl transpeptidase compared with the placebo, but the differences did not reach statistical significance. Levels of LDL-cholesterol, HDL-cholesterol, and triglycerides were unaltered, significantly increased, and decreased, respectively, by EMPA, but the differences were not statistically significant compared with the placebo. Empagliflozin for 12 months notably reduced the homeostatic model assessment of insulin resistance (HOMA-IR), remnant-like particle cholesterol (RLP-C), and hsCRP by 43%, 52% and 54%, respectively. The time courses of these reductions significantly differed from those of the placebo. Systolic and diastolic blood pressure were also significantly reduced by EMPA compared with the placebo. We applied multiple linear regression analysis to determine which factors were associated with changes in hsCRP induced by EMPA. The results revealed that alterations in hsCRP values (log [hsCRP at 12 months] minus log [hsCRP at month 0]) were significantly associated with changes in HOMA-IR, RLP-C, systolic blood pressure, HDL-C and ALT.

Conclusion

Empagliflozin decreased hs-CRP and lowered levels of remnant related lipoproteins probably via ameliorating insulin resistance. The cardiovascular benefits conferred by EMPA might be driven at least partly by anti-inflammatory effects, and this mechanism might cooperate with other EMPA-induced changes including reduced blood pressure, to achieve the degree of cardioprotection revealed by the EMPA-REG OUTCOME trial.Trial registration UMIN Clinical Registry (UMIN000021552). Registered 21 March 2016, https://upload.umin.ac.jp/UMIN000021552

     

Counseling patients with type 2 diabetes and insulin resistance in the outpatient setting

Insulin resistance is a major health concern. Besides being a leading risk factor for type 2 diabetes, it is also associated with hypertension, dyslipidemia, obesity, and cardiovascular disease. Making lifestyle changes can reduce insulin resistance and help prevent the onset of diabetes. For those with type 2 diabetes, treatment with insulin-sensitizing drugs, such as the TZDs and biguanides, can improve glycemic control and prevent some of the adverse consequences of the disease. Adherence to both lifestyle and medication regimens is very important and should be actively supported by all members of the healthcare team. Diabetes educators, including pharmacists, can increase awareness of the underlying pathophysiology and clinical implications of insulin resistance. Diabetes educators also play a vital role in counseling patients with type 2 diabetes on strategies that reduce their risk of hyperglycemic complications and in providing support, education, and guidance. By understanding the disease and its management, diabetes educators can contribute to improved outcomes and help to reduce the impact of this worldwide epidemic.     

Postprandial hypertriglyceridemia and insulin resistance in normoglycemic first-degree relatives of patients with type 2 diabetes.

BACKGROUND: Impaired ability to eliminate lipids in the postprandial state is an atherogenic trait associated with insulin resistance. OBJECTIVE: To assess insulin sensitivity and postprandial triglyceride metabolism in prediabetic persons. DESIGN: Cross-sectional study. SETTING: Sahlgrenska University Hospital, G?teborg, Sweden. PARTICIPANTS: 13 healthy, normotriglyceridemic men with two first-degree relatives with type 2 diabetes and 13 carefully matched controls without known diabetes heredity. MEASUREMENTS: Oral glucose tolerance test, insulin sensitivity (euglycemic clamp technique), and fasting and postprandial triglyceride levels after a mixed meal. RESULTS: Relatives of persons with type 2 diabetes were insulin resistant but had normal glucose tolerance. They exhibited postprandial hypertriglyceridemia; the 6-hour triglyceride incremental area under the curve was 50% higher than that of the control group (P = 0.037). CONCLUSIONS: These healthy male first-degree relatives of patients with type 2 diabetes are insulin resistant and exhibit postprandial lipid intolerance despite having normal fasting triglyceride levels. These characteristics, which occur in the absence of glucose intolerance, are associated with an increased risk for macroangiopathy.     

Mitochondrial dysfunction,insulin resistance,and type 2 diabetes mellitus

Insulin resistance is a characteristic feature of type 2 diabetes mellitus, obesity, and the metabolic syndrome. Increased intracellular fat content in skeletal muscle and liver associated with insulin resistance has led to the hypothesis that a mitochondrial defect in substrate oxidation exists in disorders of insulin resistance. In vivo measurements of metabolic fluxes through the tricarboxylic acid and oxidative phosphorylation with magnetic resonance spectroscopy have demonstrated multiple defects in mitochondrial function in skeletal muscle. A decrease in mitochondrial density and mitochondrial copy number has been reported in insulin-resistant individuals. However, these findings have not been a consistent observation in all studies. Similarly, an intrinsic functional defect in mitochondrial adenosine triphosphate production synthesis has been reported in some but not all studies. This review summarizes evidence that implicates a defect in mitochondrial oxidative phosphorylation and its relationship to insulin resistance in common metabolic diseases characterized by impaired insulin action.     

Myokines in insulin resistance and type 2 diabetes

Skeletal muscle represents the largest organ of the body in non-obese individuals and is now considered to be an active endocrine organ releasing a host of so-called myokines. These myokines are part of a complex network that mediates communication between muscle, the liver, adipose tissue, the brain and other organs. Recent data suggest that myokines regulated by muscle contraction may play a key role in mediating the health-promoting effects of regular physical activity. Although hundreds of myokines have recently been described in proteomic studies, we currently have a rather limited knowledge of the specific role these myokines play in the prevention of insulin resistance, inflammation and associated metabolic dysfunction. Several myokines are known to have both local and endocrine functions, but in many cases the contribution of physical activity to the systemic level of these molecules remains as yet unexplored. Very recently, novel myokines such as irisin, which is thought to induce a white to brown shift in adipocytes, have gained considerable interest as potential therapeutic targets. In this review, we summarise the most recent findings on the role of myokines in the regulation of substrate metabolism and insulin sensitivity. We further explore the role of myokines in the regulation of inflammation and provide a critical assessment of irisin and other myokines regarding their potential as therapeutic targets.     

2型糖尿病患者血清鸢尾素水平与胰岛素抵抗的相关性

目的 探讨血清鸢尾素（irisin）水平与胰岛素抵抗是否存在相关性.方法 选取2013年6月至2014年1月在浙江大学医学院附属第一医院内分泌科2型糖尿病（T2DM）住院患者82例（男48例,女34例）为T2DM组,同期体检中心健康体检者62名（男33名,女29名）为对照组（NC组）.所有受试者均接受体格检查、生化指标和血清irisin水平检测,T2DM组加测空腹胰岛素（FINS）、餐后血糖.采用Studentt检验、Pearson相关分析和多元线性回归进行统计学分析.结果 T2DM组血清irisin浓度明显低于NC组[（1.5±0.6）比（2.6±0.6）ng/L,t=-10.233,P＜0.05];且经Pearson相关分析,T2DM组血清irisin浓度与腰臀比（WHR）、餐后2h血糖、稳态模型胰岛素抵抗指数（HOMA-IR）呈负相关（r=-0.603、-0.295、-0.22,均P＜0.05）;与病程、性别、年龄、是否吸烟、是否存在并发症、是否存在合并症、体质指数（BMI）、收缩压、舒张压、空腹血糖（FBG）、糖化血红蛋白（HbA1c）、FINS、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、总胆固醇（TC）、甘油三酯（TG）、动脉粥样硬化指数（AI）无明显相关性（均P＞0.05）;进一步用多元线性回归分析发现,在排除性别、年龄、血压、并发症、合并症后,血清irisin水平与WHR呈显著负相关,WHR是血清irisin水平独立的负性影响因子（标准化回归系数=-3.995,P＜0.05）.结论 T2DM患者血清irisin水平较正常人减低,并与胰岛素抵抗的发生发展有关.