Discovering New Challenges in the Pharmacological and Non-Pharmacological Management of Insulin Resistance.

Background: Obstructive sleep apnea (OSA) is a prevalent condition that is associated with significant comorbidities, including obesity, hypertension, cardiovascular disease, and insulin resistance. Continuous positive airway pressure (CPAP) is an effective treatment for OSA. The effect of CPAP on glucose metabolism in patients with OSA has been controversial. This study evaluates the impact of CPAP on patients with OSA and type 2 diabetes mellitus (T2DM) or prediabetes. Materials and Methods: PubMed, Ovid Medline, and EMBASE were searched for original English language studies performed on or after 2003. Subjects were aged > 18 years, were diagnosed with OSA via polysomnography, and had either T2DM or prediabetes according to laboratory evaluation. Results: Of the 22 articles that met the selection criteria, 17 studies (77%) showed that a prolonged use of CPAP produced significant changes in glucose metabolism of patients who had T2DM and prediabetes. These changes were observed in studies measuring glycosylated hemoglobin (HbA1c), postprandial or nocturnal glucose, and insulin sensitivity or resistance. Of the 17 studies, 4 showed improvement in HbA1c levels or increased insulin sensitivity only after long-term use of CPAP for ≥ 3 months. Conclusion: This literature review shows that CPAP improves not only hypoxia while restoring normal breathing during sleep, but also glucose metabolism in patients with OSA and T2DM or prediabetes. A few studies have shown that patients can experience even better results with long-term CPAP treatment (≥ 3 months of daily use) for > 4 hours a night. Therefore, this improvement in glucose metabolism with the use of CPAP may contribute to T2DM prevention and decrease further progression of the disease. However, additional studies are needed to confirm these findings.

One of the most important characteristics of type 2 diabetes is insulin resistance, during which the patients normally experienced hyperinsulinism stress that would alter insulin signal transduction in insulin target tissues. We have previously found that early growth responsive gene-1 (Egr-1), a zinc finger transcription factor, is highly expressed in db/db mice and in the fat tissue of individuals with type 2 diabetes. In this report, we found that chronic exposure to hyperinsulinism caused persistent Erk/MAPK activity in adipocytes and enhanced insulin resistance in an Egr-1-dependent manner. An elevation in Egr-1 augmented Erk1/2 activation via geranylgeranyl diphosphate synthase (GGPPS). Egr-1-promoted GGPPS transcription increased Ras prenylation and caused Erk1/2 activation. The sustained activation of Erk1/2 resulted in the phosphorylation of insulin receptor substrate-1 at Serine 612. Phosphorylation at this site impaired insulin signaling in adipocytes and reduced glucose uptake. The loss of Egr-1 function, knockdown of GGPPS, or inhibition of Erk1/2 activity in insulin-resistant adipocytes restored insulin receptor substrate-1 tyrosine phosphorylation and increased insulin sensitivity. Our results suggest a new mechanism by which the Egr-1/GGPPS/Erk1/2 pathway is responsible for insulin resistance during hyperinsulinism. This pathway provides a new therapeutic target for increasing insulin sensitivity: inhibiting the function of Egr-1.

Exercise capacity is impaired in obstructive sleep apnea (OSA). There are conflicting reports on the effect of continuous positive airway pressure (CPAP) on maximal exercise capacity. The objective of this review was to determine if there is a change in exercise capacity and anaerobic threshold following CPAP treatment in OSA patients. We conducted a systematic review and meta-analyses to summarize the changes in peak rate of oxygen uptake (V̇O₂ peak) or maximum rate of oxygen uptake (V̇O2 max) and anaerobic threshold (AT) during cardiopulmonary exercise testing following CPAP intervention in patients with OSA. A systematic literature review was conducted to identify published literature on markers of V̇O₂ peak, V̇O₂ max, and AT pre- vs post-CPAP using a web-based literature search of PubMed/MEDLINE, Embase, CINAHL, and Cochrane review (CENTRAL) databases. Two independent reviewers screened the articles for data extraction and analysis. The total search of all the databases returned 470 relevant citations. Following application of eligibility criteria, 6 studies were included in the final meta-analysis for V̇O₂ peak, 2 studies for V̇O₂ max, and five studies for AT. The meta-analysis showed a mean net difference in V̇O₂ peak between pre- and post-CPAP of 2.69 mL·kg-1·min-1, P = .02, favoring treatment with CPAP. There was no difference in V̇O₂ max or AT with CPAP treatment (mean net difference 0.66 mL·kg-1·min-1 [P = .78] and -144.98 mL·min-1 [P = .20] respectively). There is a paucity of high-quality studies investigating the effect of CPAP on exercise capacity. Our meta-analysis shows that V̇O₂ peak increases following CPAP treatment in patients with OSA, but we did not observe any change in V̇O₂ max or AT. Our findings should be considered preliminary and we recommend further randomized controlled trials to confirm our findings and to clarify the peak and maximum rates of oxygen uptake adaptations with CPAP therapy.

Recent studies have indicated that Sodium-GLucose co-Transporter 2 Inhibitors (SGLT2Is) may increase insulin sensitivity (IS); however, these results are heterogeneous and need to be systematically assessed. We searched MEDLINE/PubMed, Embase, Web of Science, Scopus, Cochrane Library, Ovid, and ProQuest using a predefined search query. Randomized clinical trials on SGLT2Is with a passive control group or metformin controlled group were included. Risk of bias assessment was performed using the Cochrane risk of bias assessment tool. Meta-analysis was performed separately on studies with type 2 diabetes mellitus (T2DM) population and studies with non-T2DM population and also for passive- and active-controlled studies using standardized mean difference (SMD) as the measure of the effect size. Subgroup analysis was performed according to different types of SGLT2Is. Meta-regression analysis was performed according to the dose and duration of intervention. Twenty-two studies (6 on non-T2DM population) with a total of 1421 (243 non-T2DM) patients were included. Six studies (3 on T2DM and 3 on non-T2DM) were controlled by metformin, and others were passively controlled. SGLT2Is could significantly increase IS in T2DM patients (SMD = 0.72 [0.32-1.12]). SGLT2Is could reduce insulin resistance in non-T2DM population, but this was not significant. SGLT2Is were not inferior to metformin in reducing insulin resistance. Subgroup analysis indicated that dapagliflozin could significantly increase IS, but empagliflozin was not associated with significant improvement in IS. Meta-regression analysis indicated no effect fordose but duration of SGLT2I administrationon IS. SGLT2Is, particularly dapagliflozin, could increase IS. These results need to be consolidated by further studies.

Polymorphisms of the peroxisome proliferator–activated receptor-γ and its coactivator-1α genes in Chinese women with polycystic ovary syndrome

A Comparison of Aerobic Exercise and Resistance Training in Patients With and Without Chronic Kidney Disease

Obstructive sleep apnea syndrome (OSAS) and obesity are frequently associated with hypertension (HTN), dyslipidemia (DLP), and insulin resistance (IR). In patients with obesity and OSAS scheduled for bariatric surgery (BS), guidelines recommend at least 4 weeks of preoperative continuous positive airway pressure (CPAP). Low-calorie ketogenic diets (LCKDs) promote pre-BS weight loss (WL) and improve HTN, DLP, and IR. However, it is unclear whether pre-BS LCKD with CPAP improves OSAS more than CPAP alone. We assessed the clinical advantage of pre-BS CPAP and LCKD in patients with obesity and OSAS. Seventy patients with obesity and OSAS were randomly assigned to CPAP or CPAP+LCKD groups for 4 weeks. The effect of each intervention on the apnea–hypopnea index (AHI) was the primary endpoint. WL, C-reactive protein (CRP) levels, HTN, DLP, and IR were secondary endpoints. AHI scores improved significantly in both groups (CPAP, p=0.0231; CPAP+LCKD, p=0.0272). However, combining CPAP and LCKD registered no advantage on the AHI score (p=0.863). Furthermore, body weight, CRP levels, and systolic/diastolic blood pressure were significantly reduced in the CPAP+LCKD group after 4 weeks (p=0.0052, p=0.0161, p=0.0008, and p=0.0007 vs baseline, respectively), and CPAP+LCKD had a greater impact on CRP levels than CPAP alone (p=0.0329). The CPAP+LCKD group also registered a significant reduction in serum cholesterol, LDL, and triglyceride levels (p=0.0183, p=0.0198, and p<0.001, respectively). Combined with CPAP, LCKD-induced WL seems to not have a significant incremental effect on AHI, HTN, DLP, and IR but lower CRP levels demonstrated a positive impact on chronic inflammatory status.

Mice heterozygous for insulin receptor (IR) and IR substrate (IRS)-1 deficiency provide a model of polygenic type 2 diabetes in which early-onset, genetically programmed insulin resistance leads to diabetes. Protein-tyrosine phosphatase 1B (PTP1B) dephosphorylates tyrosine residues in IR and possibly IRS proteins, thereby inhibiting insulin signaling. Mice lacking PTP1B are lean and have increased insulin sensitivity. To determine whether PTP1B can modify polygenic insulin resistance, we crossed PTP1B-/- mice with mice with a double heterozygous deficiency of IR and IRS-1 alleles (DHet). DHet mice weighed slightly less than wild-type mice and exhibited severe insulin resistance and hyperglycemia, with approximately 35% of DHet males developing diabetes by 9-10 weeks of age. Body weight in DHet mice with PTP1B deficiency was similar to that in DHet mice. However, absence of PTP1B in DHet mice markedly improved glucose tolerance and insulin sensitivity at 10-11 weeks of age and reduced the incidence of diabetes and hyperplastic pancreatic islets at 6 months of age. Insulin-stimulated phosphorylation of IR, IRS proteins, Akt/protein kinase B, glycogen synthase kinase 3beta, and p70(S6K) was impaired in DHet mouse muscle and liver and was differentially improved by PTP1B deficiency. In addition, increased phosphoenolpyruvate carboxykinase expression in DHet mouse liver was reversed by PTP1B deficiency. In summary, PTP1B deficiency reduces insulin resistance and hyperglycemia without altering body weight in a model of polygenic type 2 diabetes. Thus, even in the setting of high genetic risk for diabetes, reducing PTP1B is partially protective, further demonstrating its attractiveness as a target for prevention and treatment of type 2 diabetes.

Numerous experimental studies have demonstrated that acupuncture can correct various metabolic disorders such as hyperglycaemia, overweight, hyperphagia, hyperlipidaemia, inflammation, altered activity of the sympathetic nervous system, and insulin signalling defects, all of which contribute to the development of insulin resistance. To review human and animal studies investigating acupuncture as a treatment for insulin resistance, and to evaluate its potential to increase insulin sensitivity. PubMed was searched for relevant articles published between January 2008 and October 2015. Search terms used were 'acupuncture', 'insulin resistance', 'insulin sensitivity', and 'blood glucose'. Additional secondary sources of information included reference lists from retrieved papers and pertinent papers identified by hand searches of relevant journals not found in the database. In total, 31 articles were included in this review and comprised studies of the following insulin resistant conditions: obesity (n=9); diabetes mellitus (n=12); polycystic ovarian syndrome (n=7); skeletal muscle atrophy (n=1); ischaemic heart disease (n=1); and fatty liver disease (n=1). Of these articles, seven were human trials and 24 animal experiments. Collectively, the studies suggest that electroacupuncture (EA) at low intensity and low frequency can reduce insulin resistance and increase insulin sensitivity in a range of different insulin-resistant conditions. EA, used alone or in combination with other therapies, such as Chinese herbs or diet-exercise interventions, has the potential to be an effective treatment for insulin resistance. Additional controlled clinical studies of acupuncture are needed in subjects with diabetes mellitus, ischaemic heart disease, muscle atrophy, and fatty liver disease.

Traditional weight loss and dukan diets as to nutritional and laboratory results

Sleep-disordered breathing (SDB), which includes obstructive sleep apnea (OSA) as its most extreme variant, is characterized by intermittent episodes of partial or complete obstruction of the upper airway during sleep that disrupts normal ventilation and sleep architecture and is typically associated with snoring and daytime sleepiness. SDB is common, with an incidence in middle-aged men and women of 4% and 2%, respectively.1 Major risk factors for SDB include obesity, male gender, increasing age, and abnormalities of craniofacial morphology.2 There is an increasing perception that SDB/OSA via various mechanisms increases cardiovascular morbidity and mortality (Figure 1). However, many risk factors for SDB/OSA, such as obesity and male gender, are the same as for hypertension and cardiovascular disease.3 Thus, only recently has there been converging evidence that SDB is a risk factor for their development.4–6 Moreover, there is increasing information to indicate that SDB/OSA is linked to metabolic, vascular, hematologic, and genetic markers associated with increased cardiovascular disease risk. In addition, central sleep apnea (CSA), another form of SDB, appears to be an important factor that influences morbidity and mortality among those with heart failure (HF). Nevertheless, responsible mechanisms, the role of SDB as a risk factor “independent” of associated comorbidities, and whether treatment of SDB will mitigate this risk are unknown and remain to be determined. Figure 1. This illustrates the range of cardiovascular diseases and potential mechanisms that may be associated with sleep-disordered breathing. As illustrated in this figure, there is likely an interaction between multiple potential mechanisms, particularly in individuals who may have a genetic susceptibility for sleep-disordered breathing. This report summarizes the proceedings of a workshop sponsored by the National Center on Sleep Disorders Research and the National Heart, Lung, and Blood Institute on September 12 to 13, 2002, to assess a broad array …

Insulin resistance is a major risk factor for diseases such as type 2 diabetes and metabolic syndrome. Current methods for management of insulin resistance include pharmacological therapies and lifestyle modifications. Several clinical studies have shown that leguminous plants such as soybeans and pulses (dried beans, dried peas, chickpeas, lentils) are able to reduce insulin resistance and related type 2 diabetes parameters. However, to date, no one has summarized the evidence supporting a mechanism of action for soybeans and pulses that explains their ability to lower insulin resistance. While it is commonly assumed that the biological activities of soybeans and pulses are due to their antioxidant activities, these bioactive compounds may operate independent of their antioxidant properties and, thus, their ability to potentially improve insulin sensitivity via alternative mechanisms needs to be acknowledged. Based on published studies using in vivo and in vitro models representing insulin resistant states, the proposed mechanisms of action for insulin-sensitizing actions of soybeans, chickpeas, and their bioactive compounds include increasing glucose transporter-4 levels, inhibiting adipogenesis by down-regulating peroxisome proliferator-activated receptor-γ, reducing adiposity, positively affecting adipokines, and increasing short-chain fatty acid-producing bacteria in the gut. Therefore, this review will discuss the current evidence surrounding the proposed mechanisms of action for soybeans and certain pulses, and their bioactive compounds, to effectively reduce insulin resistance.

For preterm and very preterm infants, there is insufficient evidence to evaluate prophylactic CPAP compared to oxygen therapy and other supportive care. When compared to mechanical ventilation, prophylactic nasal CPAP in very preterm infants reduces the incidence of BPD, the combined outcome of death and BPD, and mechanical ventilation. There is probably no difference in neurodevelopmental impairment at 18 to 22 months of age. When prophylactic CPAP is compared to early CPAP, we are very uncertain about whether there is any difference between prophylactic and very early CPAP. There is no information about the effect of prophylactic or very early CPAP in late preterm infants. There is one study awaiting classification.

BackgroundObesity and obstructive sleep apnea tend to coexist and are associated with inflammation, insulin resistance, dyslipidemia, and high blood pressure, but their causal relation to these abnormalities is unclear.MethodsWe randomly assigned 181 patients with obesity, moderate-to-severe obstructive sleep apnea, and serum levels of C-reactive protein (CRP) greater than 1.0 mg per liter to receive treatment with continuous positive airway pressure (CPAP), a weight-loss intervention, or CPAP plus a weight-loss intervention for 24 weeks. We assessed the incremental effect of the combined interventions over each one alone on the CRP level (the primary end point), insulin sensitivity, lipid levels, and blood pressure.ResultsAmong the 146 participants for whom there were follow-up data, those assigned to weight loss only and those assigned to the combined interventions had reductions in CRP levels, insulin resistance, and serum triglyceride levels. None of these changes were observed in the group receiving CPAP alone. Blood pressure was reduced in all three groups. No significant incremental effect on CRP levels was found for the combined interventions as compared with either weight loss or CPAP alone. Reductions in insulin resistance and serum triglyceride levels were greater in the combined-intervention group than in the group receiving CPAP only, but there were no significant differences in these values between the combined-intervention group and the weight-loss group. In per-protocol analyses, which included 90 participants who met prespecified criteria for adherence, the combined interventions resulted in a larger reduction in systolic blood pressure and mean arterial pressure than did either CPAP or weight loss alone.ConclusionsIn adults with obesity and obstructive sleep apnea, CPAP combined with a weight-loss intervention did not reduce CRP levels more than either intervention alone. In secondary analyses, weight loss provided an incremental reduction in insulin resistance and serum triglyceride levels when combined with CPAP. In addition, adherence to a regimen of weight loss and CPAP may result in incremental reductions in blood pressure as compared with either intervention alone. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT0371293.)

Insulin resistance is one of the main factors that lead to the development of type 2 diabetes mellitus (T2DM). The effect of alkaloids on insulin resistance has been extensively examined according to multiple scientific researches. In this work, we aimed to summarize the interesting results from preclinical and clinical studies that assessed the effects of natural alkaloids (berberine, nigelladine A, piperine, trigonelline, capsaicin, nuciferine, evodiamine, mahanine, and magnoflorine) on impaired insulin sensitivity and worsened insulin resistance, which play a pivotal role in the pathogenesis of type 2 diabetes. In the current review, PubMed, ScienceDirect, Springer, and Google Scholar databases were used. The inclusion criteria were based on the following keywords and phrases: insulin sensitivity, insulin resistance, alkaloids and insulin resistance, alkaloids and type 2 diabetes, mechanisms of action, and alkaloids. The outcomes reported in this review demonstrated that the selected alkaloids increased insulin sensitivity and reduced insulin resistance in vitro and in vivo evidence, as well as in clinical trials, through improving insulin-signaling transduction mainly in hepatocytes, myocytes, and adipocytes, both at cellular and molecular levels. Insulin signaling components (InsR, IRS-1, PI3K, Akt, etc.), protein kinases and phosphatases, receptors, ion channels, cytokines, adipokines, and microRNAs, are influenced by alkaloids at transcriptional and translational levels, also in terms of function (activity and/or phosphorylation). Multiple perturbations associated with insulin resistance, such as ectopic lipid accumulation, inflammation, ER stress, oxidative stress, mitochondrial dysfunction, gut microbiota dysbiosis, and β-cell failure, are reversed after treatment with alkaloids. Furthermore, various indices and tests are employed to assess insulin resistance, including the Matsuda index, insulin sensitivity index (ISI), oral glucose tolerance test (OGTT), and insulin tolerance test (ITT), which are all enhanced by alkaloids. These improvements extend to fasting blood glucose, fasting insulin, and HbA1c levels as well. Additionally, the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and the Homeostasis Model Assessment of β-cell function (HOMA-β) are recognized as robust markers of insulin sensitivity and β-cell function, and it is noteworthy that alkaloids also lead to improvements in these two markers. Based on the findings of the current review, alkaloids may serve as both preventive and curative agents for metabolic disorders, specifically type 2 diabetes. Nonetheless, there is an urgent need for additional clinical trials to explore the potential benefits of alkaloids in both healthy individuals and those with type 2 diabetes. Additionally, it is crucial to assess any possible side effects and interactions with antidiabetic drugs.