Hydroxychloroquine improves insulin sensitivity in obese non-diabetic individuals

Introduction

Hydroxychloroquine (HCQ) is a common disease modifying therapy for the treatment of rheumatoid arthritis (RA). Prior research suggests that HCQ may reduce the risk of diabetes mellitus in patients with RA. To investigate the mechanism of this effect, we examined the effect of HCQ on insulin resistance, insulin sensitivity, and pancreatic β-cell secretion of insulin in non-diabetic, obese subjects.

Methods

We recruited 13 obese, non-diabetic subjects without systemic inflammatory conditions for an open-label longitudinal study of HCQ 6.5 mg per kilogram per day for six weeks. Subjects underwent an oral glucose tolerance test at three time points: 0 weeks (pre-treatment with HCQ), 6 weeks (at the end of the HCQ treatment), and 12 weeks (6 weeks post HCQ-treatment). The Matsuda Insulin Sensitivity Index (ISI), HOMA-IR, and HOMA-B were compared across time-points.

Results

The mean age of the cohort was 49 years, 77% females and median body mass index was 36.1 kg/m². After 6 weeks of HCQ therapy, ISI increased from a median (interquartile range) of 4.5 (2.3-7.8) to 8.9 (3.7-11.4) with a p-value of 0.040, and HOMA-IR decreased from a median of 2.1 (1.6-5.4) to 1.8 (1.02-2.1) with a p-value of 0.09. All these variables returned toward baseline at week 12.

Conclusion

HCQ use for 6 weeks in non diabetic obese subjects was associated with a significant increase in ISI and trends toward reduced insulin resistance and insulin secretion. These data suggest that HCQ, a common medication used to treat RA, possesses beneficial effects upon insulin sensitization. Further study of the insulin sensitizing effects of HCQ in patients with RA is warranted.     

Effect of parturition on serum glycerol and non-esterified fatty acids in obese and normal weight women

Serum glycerol and NEFA content variations are examined before and after labor in obese and normal weighing women (35 subjects). Blood glycerol and NEFA are shown to increase before delivery. Glycerol values are shown to drop to normal immediately after delivery, while NEFA values diminish to a lesser extent. Statistical analysis shown that blood glycerol increase could be pregnancy-dependent in both normal weighing and obese women, but that NEFA increase could be pregnancy-dependent in normal weighing women only. Obesity increases blood glycerol and NEFA concentration considerably, thus masking the effects of pregnancy.     

Improvement of metabolic parameters and vascular function by metformin in obese non-diabetic rats

AimsMetformin is an insulin sensitizing agent with beneficial effects in diabetic patients on glycemic levels and in the cardiovascular system. We examined whether the metabolic changes and the vascular dysfunction in monosodium glutamate-induced obese non-diabetic (MSG) rats might be improved by metformin.Main methods16 week-old MSG rats were treated with metformin for 15 days and compared with age-matched untreated MSG and non-obese non-diabetic rats (control). Blood pressure, insulin sensitivity, vascular reactivity and prostanoid release in the perfused mesenteric arteriolar bed as well as nitric oxide production and reactive oxygen species generation in isolated mesenteric arteries were analyzed.Key findings18-week-old MSG rats displayed higher Lee index, fat accumulation, dyslipidemia, insulin resistance and hyperinsulinemia. Metformin treatment improved these alterations. The norepinephrine-induced response, increased in the mesenteric arteriolar bed from MSG rats, was corrected by metformin. Indomethacin corrected the enhanced contractile response in MSG rats but did not affect metformin effects. The sensitivity to acetylcholine, reduced in MSG rats, was also corrected by metformin. Indomethacin corrected the reduced sensitivity to acetylcholine in MSG rats but did not affect metformin effects. The sensitivity to sodium nitroprusside was increased in preparations from metformin-treated rats. Metformin treatment restored both the reduced PGI2/TXA2 ratio and the increased reactive oxygen species generation in preparations from MSG rats.SignificanceMetformin improved the vascular function in MSG rats through reduction in reactive oxygen species generation, modulation of membrane hyperpolarization, correction of the unbalanced prostanoids release and increase in the sensitivity of the smooth muscle to nitric oxide.     

Effect of adrenalectomy on in vivo glucose metabolism in insulin resistant Zucker obese rats

Lean (Fa/?) and obese (fa/fa) Zucker rats were adrenalectomized (ADX) in order to assess the contribution of adrenal hormones to insulin resistance of the obese Zucker rat. Glucose utilization was measured using an insulin suppression test. Sham-operated obese rats gained almost twice as much weight as sham-operated lean littermates. However, body weight gain of ADX animals was comparable in both genotypes. It was significantly less than that of the respective sham-operated controls. Body weight differences can be accounted for almost entirely by a marked loss of adipose tissue. Although insulin resistance may be attributable to obesity in part, steroid hormones are thought to be directly antagonistic to insulin for glucose metabolism. Adrenalectomy resulted in a decrease in serum glucose concentrations for both lean and obese Zucker rats compared with their respective sham-operated groups. Serum insulin concentration of lean ADX rats was 23% of sham-operated controls; in obese ADX rats, it was 9% of controls. Elevated levels of steady state serum glucose (SSSG) levels in sham-operated obese rats demonstrate a marked resistance to insulin induced glucose uptake compared with sham-operated lean animals. Adrenalectomy caused a marked improvement in insulin sensitivity of obese rats. The hyperglycemic SSSG levels of the obese rats were reduced 2.5 times by ADX. These results indicate that insulin resistance of Zucker obese rats can be ameliorated by ADX, suggesting adrenal hormones contribute to insulin resistance in these animals.     

Effect of omega-3 fatty acids on haemostatic functions in urocortin-treated obese rats

Urocortin 1 (UCN1) decreases food intake. We investigated the effects of UCN1 and omega-3 fatty acids (FA) on metabolic and coagulation parameters in high fat diet (HFD)-fed rats. Fifty male Sprague Dawley rats were divided into five groups; control, HFD, HFD with omega-3 FA, HFD with UCN1, and HFD with UCN1 and omega-3 FA. Food intake, body weight (BW), body mass index (BMI), Lee index, glucose, insulin, HOMA-IR, triglycerides, cholesterol, low (LDL) and high (HDL) density lipoproteins, fibrinogen, plasminogen activator inhibitor 1 (PAI-1), fibrin degradation product (FDP), clotting time, bleeding time, prothrombin time (PT), activated partial thromboplastin time (aPTT), and platelet aggregation were measured. Food intake, BW, BMI, Lee index, glucose, insulin, HOMA-IR, triglycerides, cholesterol, LDL, fibrinogen, platelet aggregation, PAI-1, and FDP increased while bleeding and clotting times, PT, and aPTT decreased in HFD rats. UCN1 decreased food intake, BW, BMI, Lee index, bleeding and clotting times, PT, and aPTT and increased fibrinogen, PAI-1, FDP, and platelet aggregation in HFD rats. Omega-3 FA decreased food intake, BW, BMI, Lee index, platelet aggregation, glucose, insulin, HOMA-IR, triglycerides, and increased HDL and bleeding time in HFD rats. We concluded that UCN1 worsens the hypercoagulable state in HFD rats while omega-3 FA improve the insulin resistance and decrease the platelet aggregation in those rats.     

Effect of the pattern of elevated free fatty acids on insulin sensitivity and insulin secretion in healthy humans.

In order to investigate whether the pattern of elevated free fatty acids (FFAs) has any effect on insulin sensitivity and insulin secretion in humans, we produced 2 distinct serum FFA patterns (PT 1 and 2) by infusing 6 healthy volunteers with 2 different lipid emulsions plus heparin for 24 hours. A hyperglycemic clamp (approx. 8 mM, 140 min) was performed before and 5 and 24 hours after both lipid infusions to determine insulin sensitivity and insulin secretion simultaneously. Total FFAs had increased comparably by 24 hours (2020+/-268 microM in PT 1) and (1812+/-154 microM in PT 2, p =0.24). Serum PT 1 contained 66% saturated FFAs plus monoenes and 34% polyenes, while PT 2 contained 80% saturated FFAs plus monoenes and 20% polyenes. Thus, the ratio of polyunsaturated to saturated plus monoenes was about 0.5 in PT 1 vs. 0.25 in PT 2. In PT 1, the insulin sensitivity index (ISI) decreased by 20 +/- 7% and 27 +/- 10% from basal after 5 and 24 hours, respectively. In PT 2, the ISI decreased significantly more after 5 (41+/-7%, p = 0.008) and 24 hours (52+/-6%, p = 0.005). In contrast, different phases of insulin secretion did not change during the lipid infusion and did not vary between the two FFA profiles. In conclusion, these findings provide preliminary evidence that the composition of elevated serum FFAs influenced insulin sensitivity in humans. The FFA pattern low in polyunsaturated FFAs reduced insulin sensitivity more than the pattern high in polyunsaturated FFAs. In contrast, no effect on insulin secretion was observed.     

Beneficial effects of taurine on serum lipids in overweight or obese non-diabetic subjects

Summary. Taurine has beneficial effects on lipid metabolism in experimental animals fed with high-cholesterol or high fat diets. Whether taurine benefits lipid metabolism in humans has rarely been investigated. The aim of this study was to evaluate the effects of taurine on serum lipids in overweight or obese young adults. Thirty college students (age: 20.3±1.7 years) with a body mass index (BMI) 25.0kg/m², and with no evidence of diabetes mellitus were selected and assigned to either the taurine group (n=15) or the placebo group (n=15) by double-blind randomization. Taurine 3g/day or placebo was taken orally for 7 weeks. Triacylglycerol (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and plasma glucose were measured before and after supplementation. The atherogenic index (AI) was calculated as (TC–HDL-C)/HDL-C. There were no differences in any baseline parameter between the two groups. Taurine supplementation decreased TG and AI significantly. Body weight also reduced significantly in the taurine group. These results suggest that taurine produces a beneficial effect on lipid metabolism and may have an important role in cardiovascular disease prevention in overweight or obese subjects.     

Mobilization of fatty acids in genetically obese rats

The mobilization of fatty acids has been studied in genetically obese rats of the Zucker strain and in control obese animals with bilateral destructive lesions in the hypothalamus. The body weight and size of adipose cells did not differ significantly between the genetically obese rats and the obese controls. Weight loss in control and genetically obese rats was identical during a 1 month fast. The release of glycerol and the rise in free fatty acids in adipose tissue incubated in vitro were similar in tissue from genetic and hypothalamic obese rats. Epinephrine, theophylline, and dibutyryl cyclic adenosine monophosphate all augmented lipolysis, and the effects were usually greater in the tissues from genetically obese rats.     

Eating disorder symptomatology in normal-weight vs. obese individuals with binge eating disorder

Although normal-weight individuals comprise a substantial minority of the binge eating disorder (BED) population, little is known about their clinical presentation. This study sought to investigate the nature and severity of eating disturbances in normal-weight adults with BED. We compared 281 normal-weight (n = 86) and obese (n = 195) treatment-seeking adults with BED (mean age = 31.0; s.d. = 10.8) on a range of current and past eating disorder symptoms using ANOVA and χ(2) analyses. After controlling for age and sex, normal-weight participants reported more frequent use of a range of healthy and unhealthy weight control behaviors compared to their obese peers, including eating fewer meals and snacks per day; exercising and skipping meals more frequently in the past month; and avoiding certain foods for weight control. They also endorsed more frequent attempts at dieting in the past year, and feeling more frequently distressed about their binge eating, at a trend level. There were no group differences in binge eating frequency in the past month, age at onset of binge eating, overvaluation of shape/weight, or likelihood of having used certain weight control behaviors (e.g., vomiting, laxative use) or having sought treatment for an eating disorder in the past. Based on our findings, normal-weight individuals appear to be a behaviorally distinct subset of the BED population with significantly greater usage of both healthy and unhealthy weight control behaviors compared to their obese peers. These results refute the notion that distress and impairment in BED are simply a result of comorbid obesity.     

Effect of long- and medium-chain fatty acids on insulin secretion from pieces of rat pancreas.

The effect of fatty acids on insulin secretion in vitro was investigated. Pieces of pancreas from fed rats were incubated for 15 or 90 min at low (0.6 mg/ml) and high (3.0 mg/ml) glucose concentrations with and without either sodium octanoate or sodium oleate. A highly significant difference in insulin secretion between low and high glucose concentrations indicated viability and responsiveness of the incubated tissue. No statistically significant effect of octanoate or oleate on insulin secretion was found at either low or high glucose concentration. Thus, no support was found for the concept that medium- and long-chain free fatty acids are insulin secretagogues.     

Enzymatic microdetermination of serum free fatty acids.

A reliable, simple, and rapid enzymatic method is described for the microdetermination of serum free fatty acids. The principle of the method is based on the activation of free fatty acids by a bacterial acyl-CoA synthetase (EC 6.2.1.3). The reaction is followed as production of AMP using the myokinase-pyruvate kinase-lactate dehydrogenase system as an indicator reaction. Results on the determination using human and rabbit sera showed a close correlation with the chemical colorimetric method.     

Effect of zinc supplementation on serum leptin levels and insulin resistance of obese women

Leptin is thought to be a lipostatic signal that contributes to body weight regulation. Zinc might play an important role in appetite regulation and its administration stimulates leptin production. However, there are few reports in the literature on its role on leptin levels in the obese population. The present work assesses the effect of zinc supplementation on serum leptin levels in insulin resistance (IR). A prospective double-blind, randomized, clinical, placebo-controlled study was conducted. Fifty-six normal glucose-tolerant obese women (age: 25-45 yr, body mass index [BMI] = 36.2 +/- 2.3 kg/m2) were randomized for treatment with 30 mg zinc daily for 4 wk. Baseline values of both groups were similar for age, BMI, caloric intake, insulin concentration, insulin resistance, and zinc concentration in diet, plasma, urine, and erythrocytes. Insulin and leptin were measured by radioimmunoassay and IR was estimated by the homeostasis model assessment (HOMA). The determinations of zinc in plasma, erythrocytes, and 24- h urine were performed by using atomic absorption spectrophotometry. After 4 wk, BMI, fasting glucose, and zinc concentration in plasma and erythrocyte did not change in either group, although zinc concentration in the urine increased from 385.9 +/- 259.3 to 470.2 +/- 241.2 +/- microg/24 h in the group with zinc supplementation (p < 0.05). Insulin did not change in the placebo group, whereas there was a significant decrease of this hormone in the supplemented group. HOMA also decreased from 5.8 +/- 2.6 to 4.3 +/- 1.7 (p < 0.05) in the zinc-supplemented group but did not change in the placebo group. Leptin did not change in the placebo group. In the zinc group, leptin was 23.6 +/- 12.3 microg/L and did not change. More human data from a unique population of obese individuals with documented insulin resistance would be useful in guiding future studies on zinc supplementation (with higher doses or longer intervals) or different measures.     

Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals

Obese adipose tissue is characterized by infiltration of macrophages. We and others recently showed that a specific subset of macrophages is recruited to obese adipose and muscle tissue. This subset expresses CD11c and produces high levels of proinflammatory cytokines that are linked to the development of obesity-associated insulin resistance. Here, we used a conditional cell ablation system, based on transgenic expression of the diphtheria toxin receptor under the control of the CD11c promoter, to study the effects of depletion of CD11c+ cells in obese mouse models. Our results show that CD11c+ cell depletion results in rapid normalization of insulin sensitivity. Furthermore, CD11c+ cell ablation leads to a marked decrease in inflammatory markers, both locally and systemically, as reflected by gene expression and protein levels. Together, these results indicate that these CD11c+ cells are a potential therapeutic target for treatment of obesity-related insulin resistance and type II diabetes.     

Biomarker potential of C-peptide for screening of insulin resistance in diabetic and non-diabetic individuals

Insulin resistance is a hallmark feature of type-2 diabetes mellitus (T2DM). We determined the homeostatic model assessment insulin resistance (HOMA-IR) and evaluated its association with C-peptide, insulin, fasting blood glucose (FBG) and glycated hemoglobin (HbA1c) in T2DM patients and non-diabetic subjects. This study comprised a total of 47 T2DM patients and 38 non-diabetic controls. Venous blood samples from all the subjects were collected and sera were analyzed for FBG, HbA1c, insulin and C-peptide using an autoanalyzer. HOMA-IR was calculated using the following equation: HOMA-IR?=?fasting insulin (µU/ml)?×?fasting glucose (mmol/L)/22.5. There was a significant increase in the levels of FBG and HbA1c in diabetic patients. Although the levels of C-peptide and insulin did not differ significantly between the two groups, a significant increase in HOMA-IR was observed in T2DM patients. Both insulin and C-peptide were significantly correlated with HOMA-IR. In conclusion, C-peptide may serve as a simple and convenient predictor of HOMA-IR.