Lower body mass and lower adiposity are associated with differential responses to two treatment strategies for rheumatoid arthritis.

PURPOSE: To determine if body mass index (BMI) and adipokine levels identify rheumatoid arthritis (RA) patients most likely to benefit from initiation of tumour necrosis factor inhibitors (TNFi) after methotrexate inadequate response. METHODS: This is a secondary analysis of the Rheumatoid Arthritis Comparison of Active Treatments (RACAT) trial and the (TEAR) trial. Both studies compared treatment strategies starting with conventional disease-modifying anti-rheumatic drugs (DMARDs) (triple therapy) versus etanercept plus methotrexate. We compared response rates between TNFi and triple therapy among patients with different BMI. Adipokines were measured at enrolment and associations with treatment response were examined using regression, adjusting for age, sex, BMI and baseline disease activity. RESULTS: In RACAT (n=306), participants who were normal/underweight were more likely to benefit from TNFi versus triple therapy, with greater change in Disease Activity Score in 28 and greater ACR20 response (ACR 20: 64% vs 23%, p=0.001). In contrast, overweight/obese participants had similar response to TNFi versus triple therapy (p-for-interaction=0.001). Similarly, but modest patterns were observed in TEAR (n=601; ACR20: 67% vs 52%, p=0.05). In RACAT, adipokine scores consistent with lower adiposity also predicted greater response to TNFi (ACR20: 58% vs 37%, p=0.01) with better model fit compared with BMI alone. CONCLUSIONS: Lower BMI and evidence of lower adiposity based on adipokine profiles were associated with a superior response to TNFi compared with triple therapy. There was no difference between treatments among overweight/obese participants. The results support TNFi being a particularly important therapeutic among normal/underweight patients, with implications for clinical decisions and trial design.

Severe lactic acidosis during tenofovir disoproxil fumarate and cobicistat combination for HIV patient.

Lactic acidosis is a rare but serious side effect in individuals receiving nucleoside reverse transcriptase inhibitors. An underweight woman with HIV was admitted to our hospital because of nausea and diffuse myalgia. Her antiretroviral regimen had been changed to tenofovir disoproxil fumarate (TDF)/emtricitabine and darunavir/cobicistat 3 months prior, after which her renal function had gradually declined. After admission, she was diagnosed with lactic acidosis, and a liver biopsy suggested mitochondrial damage. Her plasma tenofovir levels were elevated at the onset of lactic acidosis. We hypothesise that the patient's low body weight, combined with the addition of cobicistat, induced renal dysfunction and led to elevated plasma tenofovir concentrations, resulting in mitochondrial damage and lactic acidosis. Careful monitoring of renal function and lactic acidosis is required during use of TDF-containing regimens for underweight HIV patients, particularly when combined with cobicistat.

Association of Body Mass Index With the Safety Profile of Nivolumab With or Without Ipilimumab.

Importance: Increased survival with immune checkpoint inhibitors has been reported for patients with obesity vs a normal body mass index (BMI). However, the association of obesity with the safety of immune checkpoint inhibitors warrants study. Objective: To investigate associations between BMI and immune-related adverse events (irAEs) among patients with advanced cancers treated with nivolumab monotherapy and nivolumab plus ipilimumab combination therapy. Design, Setting, and Participants: This study was a retrospective pooled analysis of 3772 patients from 14 multicenter CheckMate clinical trials across 8 tumor types. Patients with advanced cancers received nivolumab, 3 mg/kg (n = 2746); nivolumab, 3 mg/kg, plus ipilimumab, 1 mg/kg (n = 713); or nivolumab, 1 mg/kg, plus ipilimumab, 3 mg/kg (n = 313). Baseline BMI was categorized as normal weight or underweight (<25), overweight (25 to <30), or obese (≥30) according to World Health Organization criteria. The studies began patient enrollment between February 9, 2012, and May 21, 2015, and patients were followed up to database lock on May 1, 2019. Data analysis was conducted from May 1 to September 1, 2019. Interventions: Nivolumab, 3 mg/kg; nivolumab, 3 mg/kg, plus ipilimumab, 1 mg/kg; and nivolumab, 1 mg/kg, plus ipilimumab, 3 mg/kg. Main Outcomes and Measures: Odds ratios (ORs) and 95% CIs for incidence of any-grade and grade 3 or 4 irAEs were calculated for patients with obesity vs normal weight or underweight BMI in the overall cohort and in subgroups based on patient and tumor characteristics. Analyses for nivolumab plus ipilimumab cohorts were exploratory. Results: A total of 3772 patients were included, 2600 were male (69%), and median age was 61 years (range, 18-90 years). For patients receiving monotherapy with nivolumab, 3 mg/kg (n = 2746), the incidence of any-grade irAEs was higher in patients with obesity (n = 543) vs those with normal weight or underweight BMI (n = 1266; OR, 1.71; 95% CI, 1.38-2.11). Incidence of grade 3 or 4 irAEs did not differ between patients with obesity and those with normal weight or underweight BMI (OR, 1.21; 95% CI, 0.92-1.61). Risk of any-grade and grade 3 or 4 irAEs appeared consistent with that in the overall population across all subgroups evaluated except for a higher likelihood of grade 3 or 4 irAEs among female patients with obesity vs normal weight or underweight BMI (OR, 1.73; 95% CI, 1.07-2.79). For patients receiving nivolumab plus ipilimumab, the incidence of irAEs appeared consistent across BMI categories. Conclusions and Relevance: Obesity appeared to be associated with an increased incidence of any-grade irAEs among patients treated with nivolumab monotherapy and with grade 3 or 4 irAEs among female patients only. These findings may inform the monitoring of patients at high risk of developing irAEs.

Differential benefit of induction chemotherapy according to body mass index in nasopharyngeal carcinoma - Pooled analysis of two randomized trials.

OBJECTIVE: Induction chemotherapy followed by concurrent chemoradiotherapy is the standard of care for patients with locoregionally advanced nasopharyngeal carcinoma (NPC). However, survival benefits from additional induction chemotherapy varied significantly among patients. This study aimed to determine the predictive value of body mass index (BMI) in induction chemotherapy in NPC. MATERIALS AND METHODS: This post-hoc analysis included patients from two multicenter, randomized, phase 3 trials (NCT01245959 and NCT01872962), in which patients were randomized to receive induction chemotherapy plus concurrent chemoradiotherapy or concurrent chemoradiotherapy alone. RESULTS: Among 960 patients participated, 957 were included in this analysis. 82 (8.6%) patients had baseline BMI < 18.5 kg/m2 (underweight) and 875 (91.4%) had BMI ≥ 18.5 kg/m2 (normal /overweight). Higher proportion of normal/overweight patients completed ≥2 cycles of induction chemotherapy than underweight patients (96.5% vs. 88.4%, p = 0.042). A strong trend for interaction was observed between BMI and induction chemotherapy regarding failure-free survival (FFS) and overall survival (OS, both pinteraction < 0.001). Normal/overweight patients benefited from induction chemotherapy regarding FFS (83.8% vs. 72.9%, p < 0.001) or OS (93.1% vs. 86.9%, p < 0.001), while underweight patients did not (p = 0.24 and p = 0.65, respectively). These results were confirmed in multivariate analysis and multiple sensitivity analyses. CONCLUSION: Using pooled data from two landmark phase III trials, we found that underweight patients might not benefit from additional induction chemotherapy in locoregionally advanced NPC. If confirmed in prospective studies, this could help guide individual treatment in the clinic.

Strategies to overcome relapse of immunotherapy-related hepatitis: dose reduction is not the key.

INTRODUCTION: Immunotherapy-related hepatitis accounts for 3-6% of all immune-related adverse events (irAE). Reintroduction of checkpoint inhibitors after irAE is matter of debate, weighing the risk of a relapse of adverse events against the possibility of improving disease control. Pharmacokinetic modelling has changed the paradigm of weight-based dosing to flat dose for checkpoint inhibitors, however, it is currently unknown if this poses underweight (<80 kg) patients to a higher risk of toxicity. Weight-based dosing has been opted as a less dangerous and more economic option, especially for underweight patients. Is dose reduction dosing a strategy to permit checkpoint inhibitors reintroduction after immune-related adverse events? METHODS: We describe a case of checkpoint inhibitor reintroduction after immunotherapy-related hepatitis, with dose reduction based on weight-based dosing (nivolumab 165 mg Q2w) in a patient with metastatic renal cell cancer. RESULTS: After three cycles, he had a relapse of hepatitis leading to prolonged steroid use and opportunistic infections. CONCLUSION: Dose reduction in underweight patients is not the preferred strategy to permit rechallenge after immunotherapy-related hepatitis. Exploration of other secondary prevention strategies is warranted.

Breast Cancer Endocrine Therapy Promotes Weight Gain With Distinct Adipose Tissue Effects in Lean and Obese Female Mice.

Breast cancer survivors treated with tamoxifen and aromatase inhibitors report weight gain and have an elevated risk of type 2 diabetes, especially if they have obesity. These patient experiences are inconsistent with, preclinical studies using high doses of tamoxifen which reported acute weight loss. We investigated the impact of breast cancer endocrine therapies in a preclinical model of obesity and in a small group of breast adipose tissue samples from women taking tamoxifen to understand the clinical findings. Mature female mice were housed at thermoneutrality and fed either a low-fat/low-sucrose (LFLS) or a high-fat/high-sucrose (HFHS) diet. Consistent with the high expression of Esr1 observed in mesenchymal stem cells from adipose tissue, endocrine therapy was associated with adipose accumulation and more preadipocytes compared with estrogen-treated control mice but resulted in fewer adipocyte progenitors only in the context of HFHS. Analysis of subcutaneous adipose stromal cells revealed diet- and treatment-dependent effects of endocrine therapies on various cell types and genes, illustrating the complexity of adipose tissue estrogen receptor signaling. Breast cancer therapies supported adipocyte hypertrophy and associated with hepatic steatosis, hyperinsulinemia, and glucose intolerance, particularly in obese females. Current tamoxifen use associated with larger breast adipocyte diameter only in women with obesity. Our translational studies suggest that endocrine therapies may disrupt adipocyte progenitors and support adipocyte hypertrophy, potentially leading to ectopic lipid deposition that may be linked to a greater type 2 diabetes risk. Monitoring glucose tolerance and potential interventions that target insulin action should be considered for some women receiving life-saving endocrine therapies for breast cancer.

ADP Induces Blood Glucose Through Direct and Indirect Mechanisms in Promotion of Hepatic Gluconeogenesis by Elevation of NADH.

Extracellular ADP, a derivative of ATP, interacts with the purinergic receptors in the cell membrane to regulate cellular activities. This signaling pathway remains unknown in the regulation of blood glucose in vivo. We investigated the acute activity of ADP in mice through a peritoneal injection. In the lean mice, in response to the ADP treatment, the blood glucose was elevated, and pyruvate tolerance was impaired. Hepatic gluconeogenesis was enhanced with elevated expression of glucogenic genes (G6pase and Pck1) in the liver. An elevation was observed in NADH, cAMP, AMP, GMP and citrate in the liver tissue in the targeted metabolomics assay. In the primary hepatocytes, ADP activated the cAMP/PKA/CREB signaling pathway, which was blocked by the antagonist (2211) of the ADP receptor P2Y13. In the circulation, gluconeogenic hormones including glucagon and corticosterone were elevated by ADP. Insulin and thyroid hormones (T3 and T4) were not altered in the blood. In the diet-induced obese (DIO) mice, NADH was elevated in the liver tissue to match the hepatic insulin resistance. Insulin resistance was intensified by ADP for further impairment in insulin tolerance. These data suggest that ADP induced the blood glucose through direct and indirect actions in liver. One of the potential pathways involves activation of the P2Y13/cAMP/PKA/CREB signaling pathway in hepatocytes and the indirect pathway may involve induction of the gluconeogenic hormones. NADH is a signal for gluconeogenesis in the liver of both DIO mice and lean mice.

Peptidomics of enteroendocrine cells and characterisation of potential effects of a novel preprogastrin derived-peptide on glucose tolerance in lean mice.

OBJECTIVES: To analyse the peptidomics of mouse enteroendocrine cells (EECs) and human gastrointestinal (GI) tissue and identify novel gut derived peptides. METHODS: High resolution nano-flow liquid chromatography mass spectrometry (LC-MS/MS) was performed on (i) flow-cytometry purified NeuroD1 positive cells from mouse and homogenised human intestinal biopsies, (ii) supernatants from primary murine intestinal cultures, (iii) intestinal homogenates from mice fed high fat diet. Candidate bioactive peptides were selected on the basis of species conservation, high expression/biosynthesis in EECs and evidence of regulated secretionin vitro. Candidate novel gut-derived peptides were chronically administered to mice to assess effects on food intake and glucose tolerance. RESULTS: A large number of peptide fragments were identified from human and mouse, including known full-length gut hormones and enzymatic degradation products. EEC-specific peptides were largely from vesicular proteins, particularly prohormones, granins and processing enzymes, of which several exhibited regulated secretion in vitro. No regulated peptides were identified from previously unknown genes. High fat feeding particularly affected the distal colon, resulting in reduced peptide levels from GCG, PYY and INSL5. Of the two candidate novel peptides tested in vivo, a peptide from Chromogranin A (ChgA 435-462a) had no measurable effect, but a progastrin-derived peptide (Gast p59-79), modestly improved glucose tolerance in lean mice. CONCLUSION: LC-MS/MS peptidomic analysis of murine EECs and human GI tissue identified the spectrum of peptides produced by EECs, including a potential novel gut hormone, Gast p59-79, with minor effects on glucose tolerance.

Comparative Effects of Dietary Hemp and Poppy Seed Oil on Lipid Metabolism and the Antioxidant Status in Lean and Obese Zucker Rats.

The objective of this study was to compare the effects of the dietary inclusion of hemp seed oil (HO) and poppy seed oil (PO) on the lipid metabolism and antioxidant status of lean and genetically obese Zucker rats. The rats were fed a control diet for laboratory rodents or a modification with HO or PO. Both oils reduced body and epididymal fat and liver cholesterol levels and promoted oxidative stress in the liver of obese rats. The HO reduced plasma triglycerides and had a stronger liver cholesterol-lowering effect in obese rats than PO. In the lean rats, HO and PO had no effects on the body fat content, plasma lipid profile, or lipid metabolism in the liver. HO considerably elevated the content of α-linolenic acid in the liver and increased the liver ratio of reduced glutathione (GSH)/oxidized glutathione (GSSG) in the lean rats. In conclusion, the regular consumption of both oils increases the accumulation of essential fatty acids in the liver of healthy animals, whilst not having any adverse effects on the body, whereas in genetically obese rats, the effects of both dietary oils on the lipid metabolism and antioxidant status are unequivocal and only partially beneficial.

Use of cyproheptadine to stimulate appetite and body weight gain: A systematic review.

OBJECTIVE: A systematic review identifying the use of cyproheptadine (CY) as an appetite stimulant was completed. METHOD: Studies of any design exploring the efficacy of CY as an appetite stimulant in all age groups and populations were included. Primary outcomes of studies included were weight gain, appetite stimulation, and/or caloric/nutritional intake increase. The review was completed in accordance with PRISMA standards. RESULTS: A total of 46 articles across 21 different treatment populations met criteria for the review, including 32 randomized controlled trials, 4 prospective cohort studies, 4 retrospective cohort studies, 4 case reports and 2 case series. Of these, 39 demonstrated that CY resulted in significant weight gain in the sample under study. Studies exploring the use of CY in those with malignant/progressive disease states, such as HIV and cancer, showed minimal to no benefit of the medication. Transient mild to moderate sedation was the most commonly reported side effect. Studies included were heterogeneous in terms of methods as well as study patient demographics, characteristics and concurrent medical conditions. Few studies provided objective measures of appetite change. DISCUSSION: CY appears to be a safe, generally well-tolerated medication that has utility in helping facilitate weight gain in patients drawn from a variety of underweight populations. Future prospective randomized controlled studies in low weight patients that include objective measures of appetite and intake are needed to better understand the mechanism by which CY augments weight gain.

A case of lean polycystic ovary syndrome with early stage of type 1 diabetes successfully treated with metformin.

Polycystic ovary syndrome (PCOS) is common in obese women with insulin resistant type 2 diabetes for which metformin treatment is getting established in addition to clomiphene. However, lean PCOS patients are sometimes accompanied with type 1 diabetes. It remains unclear whether these patients are insulin resistant and whether metformin is effective for them. A 32-year-old woman, who suffered from acne, hirsutism, and menstrual disorders since age 29, was diagnosed as PCOS by serum high LH levels and polycystic ovary on echography. Interestingly, her body mass index (BMI) had consistently been 21.0 kg/m2 since age 20. She was first treated with clomiphene for one year for infertility but it did not improve her menstrual cycle nor did she get pregnant during that period. She was then assessed with diabetes mellitus and subsequently diagnosed as type 1 diabetes with mild hyperglycemia (HbA1c 6.0%). Since her insulin secretion was still well preserved, to assess insulin sensitivity, hyperinsulinemic-euglycemic clamp test was performed and showed her to be insulin resistant. Low dose insulin and low dose metformin treatment was started without clomiphene. After her ovulation and menstrual cycle were ameliorated only one month later, her treatment was supplemented with clomiphene for the next three months enabling her to at last become pregnant. This report highlights the efficacy of metformin in lean PCOS with type 1 diabetes. Insulin therapy is essential for type 1 diabetes but hyperinsulinemia potentially exacerbates PCOS through hyperandrogenism. Metformin is therefore recommended for treatment of lean PCOS with type 1 diabetes as well as common obese PCOS with type 2 diabetes.

Pharmacology of manipulating lean body mass.

Dysfunction and wasting of skeletal muscle as a consequence of illness decreases the length and quality of life. Currently, there are few, if any, effective treatments available to address these conditions. Hence, the existence of this unmet medical need has fuelled large scientific efforts. Fortunately, these efforts have shown many of the underlying mechanisms adversely affecting skeletal muscle health. With increased understanding have come breakthrough disease-specific and broad spectrum interventions, some progressing through clinical development. The present review focuses its attention on the role of the antagonistic process regulating skeletal muscle mass before branching into prospective promising therapeutic targets and interventions. Special attention is given to therapies in development against cancer cachexia and Duchenne muscular dystrophy before closing remarks on design and conceptualization of future therapies are presented to the reader.

Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones.

Despite decades of speculation that inhibiting endogenous insulin degradation might treat type-2 diabetes, and the identification of IDE (insulin-degrading enzyme) as a diabetes susceptibility gene, the relationship between the activity of the zinc metalloprotein IDE and glucose homeostasis remains unclear. Although Ide(-/-) mice have elevated insulin levels, they exhibit impaired, rather than improved, glucose tolerance that may arise from compensatory insulin signalling dysfunction. IDE inhibitors that are active in vivo are therefore needed to elucidate IDE's physiological roles and to determine its potential to serve as a target for the treatment of diabetes. Here we report the discovery of a physiologically active IDE inhibitor identified from a DNA-templated macrocycle library. An X-ray structure of the macrocycle bound to IDE reveals that it engages a binding pocket away from the catalytic site, which explains its remarkable selectivity. Treatment of lean and obese mice with this inhibitor shows that IDE regulates the abundance and signalling of glucagon and amylin, in addition to that of insulin. Under physiological conditions that augment insulin and amylin levels, such as oral glucose administration, acute IDE inhibition leads to substantially improved glucose tolerance and slower gastric emptying. These findings demonstrate the feasibility of modulating IDE activity as a new therapeutic strategy to treat type-2 diabetes and expand our understanding of the roles of IDE in glucose and hormone regulation.

Potential role of mirtazapine in underweight older adults.

Changes in body weight can affect the overall health of an older patient and should not be considered a normal part of the aging process. In particular, weight loss can lead to numerous adverse health outcomes affecting daily activities, loss of functional status, and increased mortality. Approximately 15% to 20% of older adults experience unintentional weight loss and require intervention to maintain quality of life. Currently, there are no pharmacologic agents indicated to treat unintentional weight loss in older adults; however, several medications may aid by stimulating appetite and/or promoting weight gain. In recent years, mirtazapine has gained attention not only for its antidepressant effects, but also for its potential benefits in underweight patients. This agent has been found to increase appetite and weight in adults compared with placebo and other antidepressants, but further clinical investigation is necessary to determine the role of mirtazapine in the older underweight population.

Effects of high glucose on vascular endothelial growth factor synthesis and secretion in aortic vascular smooth muscle cells from obese and lean Zucker rats.

Type 1 diabetes is characterized by insulin deficiency, type 2 by both insulin deficiency and insulin resistance: in both conditions, hyperglycaemia is accompanied by an increased cardiovascular risk, due to increased atherosclerotic plaque formation/instabilization and impaired collateral vessel formation. An important factor in these phenomena is the Vascular Endothelial Growth Factor (VEGF), a molecule produced also by Vascular Smooth Muscle Cells (VSMC). We aimed at evaluating the role of high glucose on VEGF-A(164) synthesis and secretion in VSMC from lean insulin-sensitive and obese insulin-resistant Zucker rats (LZR and OZR). In cultured aortic VSMC from LZR and OZR incubated for 24 h with d-glucose (5.5, 15 and 25 mM) or with the osmotic controls l-glucose and mannitol, we measured VEGF-A(164) synthesis (western, blotting) and secretion (western blotting and ELISA). We observed that: (i) d-glucose dose-dependently increases VEGF-A(164) synthesis and secretion in VSMC from LZR and OZR (n = 6, ANOVA p = 0.002-0.0001); (ii) all the effects of 15 and 25 mM d-glucose are attenuated in VSMC from OZR vs. LZR (p = 0.0001); (iii) l-glucose and mannitol reproduce the VEGF-A(164) modulation induced by d-glucose in VSMC from both LZR and OZR. Thus, glucose increases via an osmotic mechanism VEGF synthesis and secretion in VSMC, an effect attenuated in the presence of insulin resistance.

Safety and efficacy of a lipid emulsion containing a mixture of soybean oil, medium-chain triglycerides, olive oil, and fish oil: a randomised, double-blind clinical trial in premature infants requiring parenteral nutrition.

OBJECTIVES: Safety, tolerability, and efficacy of a novel lipid emulsion containing a mixture of soybean oil, medium-chain triglycerides, olive oil, and fish oil (SMOFlipid 20%) with reduced n-6 fatty acids (FA), increased monounsaturated and n-3 FA, and enriched in vitamin E were evaluated in premature infants compared with a soybean oil-based emulsion. PATIENTS AND METHODS: Sixty (30/30) premature neonates (age 3-7 days, gestational age ≤ 34 weeks, birth weights 1000-2500 g) received parenteral nutrition (PN) with either SMOFlipid 20% (study group) or a conventional lipid emulsion (Intralipid 20%, control group) for a minimum of 7 up to 14 days. Lipid supply started at 0.5 g · kg body weight(-1) · day(-1) on day 1 and increased stepwise (by 0.5 g) up to 2 g · kg body weight(-1) · day(-1) on days 4 to 14. Safety and efficacy parameters were assessed on days 0, 8, and 15 if PN was continued. RESULTS: Adverse events, serum triglycerides, vital signs, local tolerance, and clinical laboratory did not show noticeable group differences, confirming the safety of study treatment. At study end, γ-glutamyl transferase was lower in the study versus the control group (107.8 ± 81.7 vs 188.8 ± 176.7 IU/L, P < 0.05). The relative increase in body weight (day 8 vs baseline) was 5.0% ± 6.5% versus 5.1% ± 6.6% (study vs control, not significant). In the study group, an increase in n-3 FA in red blood cell phospholipids and n-3:n-6 FA ratio was observed. Plasma α-tocopherol (study vs control) was increased versus baseline on day 8 (26.35 ± 10.03 vs 3.67 ± 8.06 µmol/L, P < 0.05) and at study termination (26.97 ± 18.32 vs 8.73 ± 11.41 µmol/L, P < 0.05). CONCLUSIONS: Parenteral infusion of SMOFlipid was safe and well tolerated and showed a potential beneficial influence on cholestasis, n-3 FA, and vitamin E status in premature infants requiring PN.

Therapeutic response to metformin in an underweight patient with polycystic ovarian syndrome.

OBJECTIVE: To report a case where insulin sensitization restored menses in an underweight woman with polycystic ovarian syndrome (PCOS). DESIGN: Case report. SETTING: Tertiary care center. PATIENT(S): A 19-year-old woman with a body mass index of 16.9 kg/m(2), severe hirsutism, and oligomenorrhea. INTERVENTION(S): Insulin sensitization with metformin. MAIN OUTCOME MEASURE(S): Impact of metformin therapy on menstrual cycle and serum T and fasting insulin levels. RESULT(S): Metformin, without weight loss or increased physical activity, resulted in restoration of menstrual cycle, reduction in serum T, and improvement in insulin resistance (IR). CONCLUSION(S): This case highlights the contribution of PCOS-related IR, distinct from visceral adiposity, and demonstrates the effectiveness of pharmacological insulin-sensitization independent of weight loss or lifestyle adjustments.

Metformin improves polycystic ovary syndrome symptoms irrespective of pre-treatment insulin resistance.

OBJECTIVE: Insulin resistance (IR) and obesity are common features of the polycystic ovary syndrome (PCOS). Insulin-sensitizing agents have been shown to improve both reproductive and metabolic aspects of PCOS, but it remains unclear whether it is also beneficial in lean patients without pre-treatment IR. The aim of this study was to determine the influence of metformin on the clinical and biochemical parameters of PCOS irrespective of the presence of basal obesity and IR. DESIGN: The effect of 6 months of metformin treatment was prospectively assessed in 188 PCOS patients, divided into three groups according to body mass index (BMI; lean: BMI<25 kg/m2, overweight: BMI 25-29 kg/m2, and obese: BMI30 kg/m2). Outcome parameters, which were also assessed in 102 healthy controls, included body weight, homeostasis model assessment for IR (HOMA-IR), fasting glucose and insulin levels, area under the curve of insulin response (AUCI), hyperandrogenism, and menstrual irregularities. RESULTS: In comparison with the respective BMI-appropriate control groups, only obese but not lean and overweight PCOS patients showed differences in fasting insulin and HOMA-IR. Metformin therapy significantly improved all outcome parameters except fasting glucose levels. Subgroup analyses revealed that in the group of lean PCOS patients without pre-treatment IR, metformin significantly improved HOMA-IR (1.7+/-1.0 vs 1.1+/-0.7 micromol/lxmmol/l2) and fasting insulin levels (7.7+/-4.2 vs 5.4+/-3.9 mU/l), in addition to testosterone levels (2.6+/-0.9 vs 1.8+/-0.7 nmol/l), anovulation rate (2.3 vs 59.5%), and acne (31.8 vs 11.6%; all P<0.017). In the overweight and obese PCOS groups, metformin also showed the expected beneficial effects. CONCLUSION: Metformin improves parameters of IR, hyperandrogenemia, anovulation, and acne in PCOS irrespective of pre-treatment IR or obesity.

The effects of rosiglitazone and metformin on insulin resistance and serum androgen levels in obese and lean patients with polycystic ovary syndrome.

AIM: The aim of this study was to assess the effects of metformin and rosiglitazone on insulin resistance and serum androgen levels in both obese and lean patients with polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: Forty lean [body mass index (BMI) < 25 kg/m2] and 40 overweight and obese (BMI > 25 kg/m2) patients were included in the study. Waist and hip measurements, serum sex steroid levels, insulin response to 75-g oral glucose tolerance test, fasting insulin, fasting C-peptide levels and homeostasis model assessment of insulin resistance (HOMA-IR) were determined in all patients. The degree of hirsutism was determined by the Ferriman-Gallwey scoring system. Patients were divided into two groups, with 40 (20 overweight and obese; 20 non-obese) patients each. One group was treated with metformin (MET group) 850 mg bid while the other received rosiglitazone (ROSI group) 4 mg/day for 12 weeks. All measurements were repeated at the end of this period. RESULTS: After the 12-week treatment period, HOMA-IR, area under the curve of insulin, fasting insulin and C-peptide levels were observed to have be decreased significantly in all groups. The decrease in the parameters mentioned above was similar in the four groups. The serum levels of free testosterone, androstenedione and DHEA-S decreased in all groups, but the decrease was statistically significant only in the ROSI groups. Within the lean MET group one patient became pregnant and was hence excluded from the final data analysis. Menstruations became regular after metformin therapy in 41.6% of lean and 35.7% of obese patients who had menstrual disturbance prior to the study. Rosiglitazone therapy improved menstrual disturbance in 61.5 % of lean and 53.8% of obese patients. CONCLUSIONS: Our data showed that both metformin and rosiglitazone increased insulin sensitivity in obese patients with PCOS as expected, and in lean patients as well. Rosiglitazone seemed to be more effective in decreasing the androgen levels and in achieving slightly greater improvement in menstrual disturbance than metformin.