Cardiometabolic Sequelae Research Articles

Effect of Curcumin on Glycaemic and Lipid Parameters in Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Polycystic ovary syndrome (PCOS) is a heterogeneous condition that affects women of reproductive age. It is associated with menstrual disturbances, hyperandrogenism, and polycystic ovaries. In addition to this, it results in altered anthropometric parameters, insulin resistance, and subsequently untoward cardio-metabolic sequelae. Therapeutic approaches that target weight loss and improve insulin sensitivity are used to address the metabolic complications in PCOS. Curcumin is a phytochemical which exhibits anti-inflammatory and anti-oxidant properties, and therefore, its use in PCOS has been a subject of substantial interest and research. The aim of this study was tosynthesize the existing evidence on the effects of curcumin on glycaemic and lipid parameters in PCOS. We searched PubMed, Embase, Web of Science, Scopus, and ClinicalTrials databases from inception to June 07, 2021. Only randomized controlled trials (RCT) presenting sufficient data on glycemic and lipid parameters in patients with PCOS at baseline and the end of the follow-up period in each group were included. Meta-analysis of five RCTs showed a significant reduction on fasting glucose (WMD: - 3.68mg/dL, 95% CI: - 5.11, - 2.25, p < 0.00001, I2 = 18%), insulin levels (WMD: - 1.72 µUI/mL, 95% CI: - 2.53, -0.92, p < 0001, I2 = 41%), and HOMA-IR index (WMD: - 0.94, 95% CI: - 1.73, - 0.16, p = 0.02, I2 = 90%) after curcumin therapy. None of the lipid indices were significantly altered by curcumin. Curcumin administration in PCOS resulted in significant improvement in glycaemic parameters; however, no significant changes were seen in lipid parameters with its use.

Assessing the Causal Relationships Between Insulin Resistance and Hyperuricemia and Gout Using Bidirectional Mendelian Randomization.

Hyperuricemia is closely associated with insulin resistance syndrome (and its many cardiometabolic sequelae); however, whether they are causally related has long been debated. We undertook this study to investigate the potential causal nature and direction between insulin resistance and hyperuricemia, along with gout, by using bidirectional Mendelian randomization (MR) analyses. We used genome-wide association data (n = 288,649 for serum urate [SU] concentration; n = 763,813 for gout risk; n = 153,525 for fasting insulin) to select genetic instruments for 2-sample MR analyses, using multiple MR methods to address potential pleiotropic associations. We then used individual-level, electronic medical record-linked data from the UK Biobank (n = 360,453 persons of European ancestry) to replicate our analyses via single-sample MR analysis. Genetically determined SU levels, whether inferred from a polygenic score or strong individual loci, were not associated with fasting insulin concentrations. In contrast, genetically determined fasting insulin concentrations were positively associated with SU levels (0.37 mg/dl per log-unit increase in fasting insulin [95% confidence interval (95% CI) 0.15, 0.58]; P = 0.001). This persisted in outlier-corrected (β = 0.56 mg/dl [95% CI 0.45, 0.67]) and multivariable MR analyses adjusted for BMI (β = 0.69 mg/dl [95% CI 0.53, 0.85]) (P < 0.001 for both). Polygenic scores for fasting insulin were also positively associated with SU level among individuals in the UK Biobank (P < 0.001). Findings for gout risk were bidirectionally consistent with those for SU level. These findings provide evidence to clarify core questions about the close association between hyperuricemia and insulin resistance syndrome: hyperinsulinemia leads to hyperuricemia but not the other way around. Reducing insulin resistance could lower the SU level and gout risk, whereas lowering the SU level (e.g., allopurinol treatment) is unlikely to mitigate insulin resistance and its cardiometabolic sequelae.

Plant-predominant eating patterns – how effective are they for treating obesity and related cardiometabolic health outcomes? – a systematic review

The obesity epidemic is a main driver of the chronic disease epidemic; however, present treatment approaches have suboptimal efficacy. To assess the efficacy of plant-predominant (vegan, vegetarian, plant-based whole foods [PBWFs]) diets in treating obesity and its main cardiometabolic sequelae: hyperlipidemia (HLD); indices of insulin resistance, glycemic control, and diabetes mellitus type 2 (DM2); and cardiovascular disease (CVD), including hypertension (HTN). A systematic search of multiple databases was conducted for articles published between November 2019 and February 2020; databases searched included: PubMed, Medline (Ovid), Cochrane, CENTRAL, and CINAHL. All interventional trials (randomized controlled trials [RCTs] and trials of non-randomized experimental design) that met the inclusion criteria (English language, duration of at least 4 weeks, primary end point congruent with above objectives, no major flaws in research design that would prevent interpretation) were included in the review. A total of 3135 articles were scanned and 84 were selected. The articles were collated and summarized in 2 evidence tables. Risk of bias for RCTs was assessed using the Cochrane Risk-of-Bias tool 2 as a guide. For non-randomized trials, higher risk of bias was assumed, and the JBI Critical Appraisal tool was used as a guide to determine inclusion. Plant-based diets, in general, demonstrated improved weight control and cardiometabolic outcomes related to lipids, cardiovascular end points, blood pressure, insulin sensitivity, A1C, and fasting glucose, and a lower risk of diabetes compared with usual diets and in some cases standard health-oriented diets such as the American Heart Association (AHA), American Diabetic Association (ADA), and Mediterranean diets. Preliminary studies suggest plant-predominant diets practiced as part of healthy lifestyle interventions may stabilize or even reverse DM 2 and CVD. The acceptability and sustainability of plant-predominant diets where measured were generally similar to other health-oriented diets. Plant-predominant diets can play a major role in reversing the obesity and chronic disease epidemics. In the setting of sustained lifestyle intervention programs, they may arrest or even reverse DM2 and CVD. Further higher-level RCTs are needed to confirm and expand on these findings.

The Double Whammy of Obesity and Diabetes on Female Reproductive Health.

The rising global prevalence of obesity and diabetes, especially in youth, confers substantial metabolic consequences and increased mortality in affected individuals. While obesity is strongly tied to the development of insulin resistance and type 2 diabetes, emerging evidence shows that obesity rates are also increasing exponentially in those with type 1 diabetes, contributing to insulin resistance and cardiometabolic sequelae. In addition, both obesity and diabetes can exert adverse effects on female reproductive health independently, with the presence of both conditions likely to exacerbate reproductive dysfunction in this cohort. If the current trends in obesity and diabetes incidence persist, it is likely that more women will be at risk of obesity- and diabetes-related reproductive disorders. This review aims to describe the epidemiology and mechanisms of obesity in women with diabetes, and summarize current literature regarding reproductive disorders in diabetes and weight management strategies in this cohort.

CARDIOVASCULAR RISK FACTORS IN SOCIAL HOUSING RESIDENTS: A MULTI-SITE DESCRIPTIVE SURVEY IN OLDER ADULTS FROM ONTARIO, CANADA

Older adults living in subsidized housing are a vulnerable population with higher rates of poverty and increased risk of cardiovascular events. Larger population surveys may not adequately capture data from this population due to poor literacy and low participation rates. The purpose of this study was to determine the prevalence of cardiovascular disease risk factors in older adults residing in social housing. This was a cross-sectional study with interviewer-administered questionnaire and objective blood pressure (BP) measurement with a validated, automated device. Data was collected from residents aged 55 years and older residing in 25 subsidized social housing apartment buildings in five Ontario regions. Outcome measures were prevalence of cardiovascular risk factors in this population and association of the risk factors with measured high BP, controlled hypertension, and undiagnosed hypertension. In 1101 residents, mean age was 72.4 years, 78% were female, 87% white, and 69% had high school education or less. Self-reported risk factors included diabetes (29%), hypertension (59%), high cholesterol (44%), overweight (30%) or obese (39%), current smoker (29%), < 1 serving of fruit/vegetable daily (61%), and physical activity < 30 minutes daily (50%). Conditions that could indirectly impact cardiovascular health were limited mobility (58%), difficulty performing usual activities (41%), and pain/discomfort (70%). In a subset of 595 residents with BP measured, 304 (51%) had high BP. Any post-secondary education (OR=0.53, 95%CI 0.32-0.90), non-white ethnicity (OR=0.49, 95%CI 0.27-0.89), 75-84 years (OR=2.13, 95%CI 1.23-3.69), 85+ years (OR=2.77, 95%CI 1.26-6.12), and 1-4 medications (OR=1.90, 95%CI 1.06-3.42) were significantly associated with high BP. Non-white ethnicity (OR=0.36, 95%CI 0.17-0.78) was associated with uncontrolled hypertension. Physical activity (OR=0.41, 95%CI 0.20-0.85), 75-84 years (3.65, 95%CI 1.34-9.95), and 85+ years (OR=9.33, 95%CI 1.65-52.62) were associated with undiagnosed hypertension. There is a high prevalence of modifiable cardiovascular risk factors in this vulnerable population and the majority had either undiagnosed or unmanaged high BP. Although dietary risk factors were prevalent, they were not significantly associated with high BP, suggesting that other low-income factors may have a greater influence. Cardiometabolic sequelae are likely unless primary care interventions appropriate for this population are implemented.

Somatotropic Axis and Obesity: Is There Any Role for the Mediterranean Diet?

Obesity is associated with reduced spontaneous and stimulated growth hormone (GH) secretion and basal insulin-like growth factor I (IGF-1) levels—which in turn is associated with increased prevalence of cardiovascular risk factors. The aim of this study was to investigate: (1) the association of somatotropic axis with cardiometabolic status; (2) the association of somatotropic axis with the Mediterranean diet and nutritional pattern in people with obesity. Cross-sectional observational study was carried out in 200 adult women, aged 36.98 ± 11.10 years with severe obesity (body mass index—BMI of 45.19 ± 6.30 kg/m2). The adherence to the Mediterranean diet and the total calorie intake was assessed. Anthropometric measurements, body composition and biochemical profile were determined along with Growth Hormone (GH)/Insulin like Growth Factor 1 (IGF-1) axis and insulin resistance (homeostatic model assessment for insulin resistance—HoMA-IR). The enrolled subjects were compared after being divided according to GH peak response and according to IGF-1 standard deviation scores (SDS). Derangements of GH peak were detected in 61.5% of studied patients while IGF-1 deficiency was detected in 71% of the population. Both blunted GH peak response and IGF-1 SDS were indicators of derangements of somatotropic axis and were associated with comparable results in terms of cardiometabolic sequelae. Both GH peak and IGF-1 levels were inversely associated with anthropometric and metabolic parameters. The adherence to the Mediterranean diet predicts GH peak response. Fatty liver index (FLI), fat mass (FM) and phase angle (PhA) were predictive factors of GH peak response as well. In conclusion derangements of somatotropic axis is associated with a worse cardiometabolic profile in people with obesity. A high adherence to the Mediterranean diet—and in particular protein intake—was associated with a better GH status.

Managing vascular risk factors among obese quitters with diabetes: how intensive lifestyle intervention and novel pharmacotherapy can work in concert?

Obese smokers with diabetes are a special risk category for all-cause mortality and major adverse cardiovascular events (MACE). Weight loss and smoking cessation are key interventions advocated for the management of diabetes in almost all the guidelines across the globe. However, there is a substantial risk of weight gain following smoking cessation which may, in some cases, cause a transient worsening of glycaemic control in people with diabetes. The risk of weight gain and the potential for worsening of HbA1c may put off some obese smokers to quit. The cardiometabolic sequelae of smoking cessation in people with and without diabetes are different. The benefit of smoking cessation, in terms of reduced cardiovascular and all-cause mortality, in people without diabetes is evident within three years of quitting. However, it may take up to 10 years for people with diabetes to get this benefit. Post-cessation weight gain is much more detrimental to obese quitters with diabetes than those without. The aim of this review is to explore how best these high-risk individuals can be supported to remain abstinent long-term, and manage their vascular risk profile proactively, by concerted lifestyle intervention with judicious use of new and novel pharmacotherapy.

Upper Body Subcutaneous Fat Is Associated with Cardiometabolic Risk Factors

BackgroundUpper body subcutaneous fat is a distinct fat depot that may confer increased cardiometabolic risk. We examined the cross-sectional associations between upper body subcutaneous fat volume and cardiometabolic risk factors. MethodsParticipants were patients from the Framingham Heart Study who underwent multi-detector computed tomography between 2008 and 2011. Sex-specific multivariable-adjusted regression analyses were conducted. Covariates included age, ethnicity, smoking status, alcohol intake, physical activity, postmenopausal status, and hormone replacement therapy. Additional models included adjustment for body mass index (BMI), neck circumference, or abdominal visceral adipose tissue. ResultsThere were 2306 participants (mean age 60 years, 54.4% women) included. Mean upper body subcutaneous fat was 309.9 cm3 in women and 345.6 cm3 in men. Higher upper body subcutaneous fat volume was associated with adverse cardiometabolic risk factors. In women and men, each additional 50-cm3 increment in upper body subcutaneous fat was associated with a 3.23 and 2.65 kg/m2 increase in BMI; 2.16 and 0.88 mm Hg increase in systolic blood pressure; 2.53 and 1.66 mg/dL increase in fasting plasma glucose; 0.12 and 0.11 mg/dL increase in log triglycerides; and 4.17 and 3.68 mg/dL decrease in high-density lipoprotein cholesterol, respectively (all P ≤.008). Similar patterns were observed with prevalent cardiometabolic risk factors. These associations remained significant after additional adjustment for BMI, neck circumference, or abdominal visceral adipose tissue. ConclusionsHigher upper body subcutaneous fat is cross-sectionally associated with adverse cardiometabolic risk factors. Our findings underscore the importance of subcutaneous adiposity in the upper body region that may provide a better understanding of the pathogenic properties of obesity in the development of cardiometabolic sequelae.

Dietary intake and prospective changes in cardiometabolic risk factors in children and youth.

Only few studies examined the effect of diet on prospective changes in cardiometabolic (CM) risk factors in children and youth despite its importance for understanding the role of diet early in life for cardiovascular disease in adulthood. To test the hypothesis that dietary intake is associated with prospective changes in CM risk factors, we analyzed longitudinal observations made over a period of 2 years among 448 students (aged 10-17 years) from 14 schools in Canada. We applied mixed effect regression to examine the associations of dietary intake at baseline with changes in body mass index, waist circumference (WC), systolic and diastolic blood pressure (SBP and DBP), and insulin sensitivity score between baseline and follow-up while adjusting for age, sex, and physical activity. Dietary fat at baseline was associated with increases in SBP and DBP z scores (per 10 g increase in dietary fat per day: β = 0.03; p < 0.05) and WC (β = 0.31 cm; p < 0.05) between baseline and follow-up. Every additional gram of sodium intake at baseline was associated with an increase in DBP z score of 0.04 (p < 0.05) between baseline and follow-up. Intake of sugar, vegetables and fruit, and fibre were not associated with changes in CM risk factors in a statistically significant manner. Our findings suggest that a reduction in the consumption of total dietary fat and sodium may contribute to the prevention of excess body weight and hypertension in children and youth, and their cardiometabolic sequelae later in life.

Feasibility and acceptability of integrated cardiac rehabilitation in outpatients referred for autologous bone marrow transplantation.

139 Background: High-dose chemotherapy (HDCT) and bone marrow/hematopoietic cell transplantation (BMT) is established therapy for many malignancies. While advances in transplant practise have led to improved cancer-specific outcomes, HDCT negatively impacts healthy organ function via direct effects (ie high-dose cytotoxic injury to organ systems) and indirect effects (i.e., functional disability). The resulting cardiometabolic sequelae such as dyslipidemia, hypertension, diabetes, and weight gain (with lean body mass loss) contribute to the significantly increased rates of cardiovascular (CV) mortality and heart failure (HF) observed in HDCT survivors. Cardiac rehabilitation/secondary prevention (CR/SP) programs are a level 1 recommendation in multiple CV diseases, reducing CV risk and events. Currently, the feasibility of integrating standard CR/SP programs in outpatients (PTS) referred for HDCT is unknown. Aim: To prospectively evaluate feasibility and acceptability of routine referral tocardiovascular rehabilitation/secondary prevention (CR/SP) in unselected lymphoma PTSreferred for autologous HDCT/BMT. Methods: Lymphoma PTS referred for HDCT/BMT were screened and referred to the CR/SP program. Baseline exercise testing was performed prior to HDCT/BMT. Upon recovery (6 weeks) testing was repeated, and PTS were invited to participate in a 6-week standard CR/SP program of exercise rehabilitation and CV risk reduction education. Results: 20 PTS were referred for HDCT/BMT from January 1, 2015 to July 1, 2015. All were referred to the CR/SP program. 100% underwent exercise testing, and all proceeded to BMT without adverse cardiovascular outcomes or mortality. High levels of satisfaction of CR/SP program components were reported. Conclusions: In unselected PTS, seamless integration of CR/SP within standard HDCT/BMT care is feasible and acceptable. We expect short term measurable impacts including reduced symptom burden and improved quality of life. Longer term impacts will evaluate CV morbidity and mortality. This work will inform patient-centered care and improve supportive and survivorship care across the cancer continuum.

Premature guinea pigs: a new paradigm to investigate the late-effects of preterm birth.

Preterm birth is common and the associated short-term morbidity well described. The adult-onset consequences of preterm birth are less clear, but cardiovascular and metabolic health may be adversely affected. Although large animal models of preterm birth addressing important short-term issues exist, long-term studies are hampered by significant logistical constraints. Current small animal models of prematurity require terminal caesarean section of the mother; both caesarean birth and early maternal care modify offspring adult cardio-metabolic function. We describe a novel method for inducing preterm labour in guinea pigs. With support comparable to that received by moderately preterm human infants, preterm pups are viable. Growth trajectories between preterm and term-born pups differ significantly; between term equivalent age and weaning ex-preterm animals demonstrate increased weight and ponderal index. We believe this novel paradigm will significantly improve our ability to investigate the cardio-metabolic sequelae of preterm birth throughout the life course and into the second generation.

Influence Of Genetic Variation On Metabolic Outcomes Among Survivors Of Pediatric Hematopoietic Cell Transplantation

BackgroundChildhood hematopoietic cell transplant (HCT) survivors have been shown to be at increased risk for a variety of long-term cardiometabolic sequelae. However, it is unclear if genetic factors can modify the levels of various quantitative cardiometabolic traits in this population. MethodsProspective cross-sectional study of ≥2-year survivors of pediatric allogeneic (n=47) or autologous (n=27) HCT recruited from two centers. Allogeneic HCT survivors had to be free of chronic GVHD and off immunosuppression at time of assessment. All participants underwent detailed physiologic measurements (euglycemic insulin clamp, body composition assessments, blood pressure, fasting lipids) and also provided DNA samples (both donor and host if allogeneic HCT recipient). A panel of carefully annotated genes and respective single nucleotide polymorphisms (SNPs) associated with each cardiometabolic trait (fat mass, body mass index, insulin resistance, triglyceride, HDL and LDL cholesterol) was assembled based on evidence from the general population using the Human Genome Epidemiology (HuGE) Navigator (accessed March 2013). For each trait, we estimated the least square mean values and determined the overall and pairwise p-values among genotypes. Multiple comparisons were controlled for using Benjamini and Hochberg's false discovery rate. For initial validation, a separate dataset of 134 ≥2-year pediatric allogeneic HCT survivors without active chronic GVHD and retrospectively collected phenotypes was available. ResultsAmong the primary study participants (n=74), 73% were exposed to total body irradiation, and their median current age was 24 years (range 10-50), with median interval since HCT of 11.4 years (range 2.6-27.6). 95% of these survivors self-reported White non-Hispanic race/ethnicity. Host polymorphisms in LPL (rs319; p=0.0009) and ADRB2 (rs12654778; p=0.002) were found to be significantly associated with differences in triglyceride levels and body mass index, respectively. While several other genes (all host) had SNPs that were associated with various outcomes (e.g. ADIPOQ and insulin resistance, CETP with both HDL and LDL-cholesterol; all p<0.01), none met statistical significance as defined by the false discovery rate (Table). No donor polymorphisms was found to be associated. Among the validation sample (74% exposed to total body irradiation, 100% White non-Hispanic), host rs319 had no association with triglyceride levels (p=0.81). An effort to validate the other polymorphisms listed above is ongoing. ConclusionIt is possible that underlying genetic factors may influence subsequent development of adverse metabolic traits, even among heavily treated childhood cancer survivors. However, any associations require further validation. Furthermore, the relatively small numbers of such patients at most centers limit the power of such genetic investigations. Future efforts should focus on developing appropriate consortia in which samples may be pooled. Application of rigorous phenotype definitions may also enhance the likelihood of identifying true genetic associations. Disclosures:No relevant conflicts of interest to declare.

The 20-Year Public Health Impact and Direct Cost of Testosterone Deficiency in U.S. Men

Testosterone deficiency (TD) imposes a substantial public health burden in the U.S. We modeled the costs associated with TD-related sequelae including cardiovascular disease (CVD), diabetes mellitus (DM), and osteoporosis-related fractures (ORFs). To quantify the incremental cost burden imposed by TD's cardiometabolic sequelae. Incidence, prevalence, and mortality of these conditions were collected for men ages 45-74 from six national databases and large cross-sectional studies. Relative risk (RR) rates were determined for these sequelae in patients with T < 300 ng/dL. The prevalence of TD was determined for this cohort of men. Adjusted incidence and prevalence were determined. Annual costs for the three TD-related sequelae were inflated at a real rate of 3% for 20 years. Actual and adjusted (normalized for T deficiency) rates of CVD, DM, and ORFs in U.S. men aged 45-74 assuming a TD prevalence of 13.4% were calculated. We determined that, over a 20-year period, T deficiency is projected to be involved in the development of approximately 1.3 million new cases of CVD, 1.1 million new cases of DM, and over 600,000 ORFs. In year 1, the attributed cost burden of these diseases was approximately $8.4 billion. Over the entire 20-year period, T deficiency may be directly responsible for approximately $190-$525 billion in inflation-adjusted U.S. health care expenditures. TD may be a significant contributor to adverse public health. Further study is needed to definitively describe the whether TD is a modifiable risk factor for CVD, DM, and ORFs. This may represent an opportunity for nationwide public health initiatives aimed at preventive care.

Loss-of-function mutations in the immunoglobulin superfamily member 1 gene (IGSF1) cause a novel, X-linked syndrome of central hypothyroidism and testicular enlargement

BackgroundCongenital central hypothyroidism occurs either as isolated thyroid-stimulating hormone (TSH) deficiency or in conjunction with other pituitary hormone deficits. Undetected central hypothyroidism is associated with developmental delay in children and adverse cardiometabolic sequelae in adults. Hitherto, mutations in the thyrotropin-releasing hormone receptor gene (TRHR) or the TSHb subunit gene (TSHB) are the only known causes of isolated TSH deficiency. MethodsUsing whole exome and candidate gene sequencing, we have studied 11 unrelated families with males exhibiting isolated TSH deficiency, testicular enlargement, and variably low serum prolactin levels. FindingsWe have identified eight distinct mutations and two whole gene deletions disrupting the X-linked immunoglobulin superfamily member 1 gene (IGSF1) in affected males. IGSF1 encodes a pituitary-enriched plasma membrane glycoprotein; disease-associated mutations block trafficking of IGSF1 from the endoplasmic reticulum to the membrane, consistent with loss-of-protein function. Adult male IGSF1 null mice exhibit central hypothyroidism with decreased pituitary TSH content and circulating T3 levels; TSH secretion in response to TRH is blunted and pituitary TRHR mRNA levels are decreased, suggesting that impaired TRH signalling may provide the basis for hypothyroidism. InterpretationOur observations delineate a novel X-linked syndrome in which loss-of-function mutations in IGSF1 cause central hypothyroidism, testicular enlargement, and variable prolactin deficiency, and identify a previously unsuspected role for IGSF1 in hypothalamic-pituitary control of thyroid and testicular function. Variable biochemical penetrance in these families highlights the importance of genetic ascertainment in this syndrome, so that asymptomatic affected individuals can benefit from early initiation of thyroxine treatment. FundingWellcome Trust and National Institute for Health Research Biomedical Research Centre.

82nd Annual Meeting of the American Thyroid AssociationMEETING ABSTRACTS &amp; PROGRAM

82nd Annual Meeting of the American Thyroid AssociationMEETING ABSTRACTS &amp; PROGRAM

11β-Hydroxysteroid dehydrogenase type 1 inhibition in type 2 diabetes mellitus

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyses the intracellular conversion of inert cortisone to physiologically active cortisol, functioning to enhance local cortisol action beyond what would be predicted based on simple plasma exposures. Adipose tissue overexpression of 11β-HSD1 in rodents to levels observed in human obesity can lead to a near complete metabolic syndrome phenotype, and inhibition of 11β-HSD1 has been proposed to be of potential therapeutic benefit to patients with type 2 diabetes mellitus (T2DM). Recently published clinical results with the selective 11β-HSD1 inhibitor, INCB13739, have, for the first time, provided evidence substantiating this hypothesis, and suggest that 11β-HSD1 activity may be important in regulating glycaemia and cardiometabolic risk. In patients with T2DM failing metformin monotherapy, INCB13739 treatment achieves significant reductions in haemoglobin A1c (HbA1c) and fasting plasma glucose (FPG), and when present improves hyperlipidaemia and hypertriglyceridaemia. Interestingly, these positive effects are observed primarily in subjects categorized as obese (body mass index, BMI > 30 kg/m²) and not in subjects categorized as overweight (BMI ≤ 30 kg/m²), underscoring the likely importance of adipose tissue 11β-HSD1 activity to the cardiometabolic sequelae of obesity. This review summarizes the therapeutic rationale for 11β-HSD1 inhibition, and describes in detail the metabolic and endocrinologic changes observed in patients with T2DM treated with INCB13739.

Regulation of lipid metabolism by energy availability: a role for the central nervous system

The central nervous system (CNS) is crucial in the regulation of energy homeostasis. Many neuroanatomical studies have shown that the white adipose tissue (WAT) is innervated by the sympathetic nervous system, which plays a critical role in adipocyte lipid metabolism. Therefore, there are currently numerous reports indicating that signals from the CNS control the amount of fat by modulating the storage or oxidation of fatty acids. Importantly, some CNS pathways regulate adipocyte metabolism independently of food intake, suggesting that some signals possess alternative mechanisms to regulate energy homeostasis. In this review, we mainly focus on how neuronal circuits within the hypothalamus, such as leptin- ghrelin-and resistin-responsive neurons, as well as melanocortins, neuropeptide Y, and the cannabinoid system exert their actions on lipid metabolism in peripheral tissues such as WAT, liver or muscle. Dissecting the complicated interactions between peripheral signals and neuronal circuits regulating lipid metabolism might open new avenues for the development of new therapies preventing and treating obesity and its associated cardiometabolic sequelae.

Critical Role of the Endocannabinoid System in the Regulation of Food Intake and Energy Metabolism, with Phylogenetic, Developmental, and Pathophysiological Implications

The endocannabinoid system (ECS) consists of two receptors (CB(1) and CB(2)), several endogenous ligands (primarily anandamide and 2-AG), and over a dozen ligand-metabolizing enzymes. The ECS has deep phylogenetic roots and regulates many aspects of embryological development and homeostasis, including neuroprotection and neural plasticity, immunity and inflammation, apoptosis and carcinogenesis, pain and emotional memory, and the focus of this review: hunger, feeding, and metabolism. The ECS controls energy balance and lipid metabolism centrally (in the hypothalamus and mesolimbic pathways) and peripherally (in adipocytes and pancreatic islet cells), acting through numerous anorexigenic and orexigenic pathways (e.g., ghrelin, leptin, orexin, adiponectin, endogenous opioids, and corticotropin-releasing hormone). Obesity leads to excessive endocannabinoid production by adipocytes, which drives CB(1) in a feed-forward dysfunction. Phylogenetic research suggests the genes for endocannabinoid enzymes, especially DAGLalpha and NAPE-PLD, may harbor mildly deleterious alleles that express disease-related phenotypes. Several CB(1) inverse agonists have been developed for the treatment of obesity, including rimonabant, taranabant, and surinabant. These drugs are efficacious at reducing food intake as well as abdominal adiposity and cardiometabolic risk factors. However, given the myriad beneficial roles of the ECS, it should be no surprise that systemic CB(1) blockade induces various adverse effects. Alternatives to systemic blockade include CB(1) partial agonists, pleiotropic drugs, peripherally restricted antagonists, allosteric antagonists, and endocannabinoid ligand modulation. The ECS offers several discrete targets for the management of obesity and its associated cardiometabolic sequelae.