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This study examined the dynamic, real-time associations between partner involvement in diabetes self-care and continuous glucose monitor (CGM) metrics in adults with type 2 diabetes.For 1 week, 63 participants wore Dexcom G4 CGMs and provided momentary reports of partner involvement in diabetes self-care five times per day. Dynamic structural equation models were used to estimate the reciprocal lagged effects of partner involvement on next-hour CGM metrics (and vice versa).Partner involvement predicted improved next-hour glucose control for five of six CGM metrics in analyses adjusted for time-varying covariates. The hour after partner involvement, the model predicted a 26.34 mg/dl decrease in glucose level (standardized β = -0.19), 30% greater odds of meeting target time in target range ( β = 0.07), 48% higher odds of target time below target range (TBR; β = 0.04; the only nonsignificant effect), 47% greater odds of target time above target range (β = 0.11), a 4.20 unit decrease in glucose standard deviation ( β = -0.19), and a 0.01 unit decrease in glucose coefficient of variation ( β = -0.08; all p values.05). There was less consistent support for the reverse pathway, with only two metrics significantly related to next-hour partner involvement: glucose level ( β = 0.15) and TBR ( β = 0.21), such that having higher levels and meeting target TBR were significantly predictive of next-hour partner involvement.This is the first study showing that partner involvement in daily diabetes management predicts short-term glucose control. More research is needed to understand how partners influence glycemic control and evaluate interventions that promote their involvement in diabetes care.

The purpose of this study was to determine whether intramyocellular glucose partitioning was altered in primary human myotubes derived from severely obese women with type 2 diabetes. Human skeletal muscle cells were obtained from lean nondiabetic and severely obese Caucasian females with type 2 diabetes [body mass index (BMI): 23.6 ± 2.6 vs. 48.8 ± 1.9 kg/m2, fasting glucose: 86.9 ± 1.6 vs. 135.6 ± 12.0 mg/dL, n = 9/group]. 1-[14C]-Glucose metabolism (glycogen synthesis, glucose oxidation, and nonoxidized glycolysis) and 1- and 2-[14C]-pyruvate oxidation were examined in fully differentiated myotubes under basal and insulin-stimulated conditions. Tricarboxylic acid cycle intermediates were determined via targeted metabolomics. Myotubes derived from severely obese individuals with type 2 diabetes exhibited impaired insulin-mediated glucose partitioning with reduced rates of glycogen synthesis and glucose oxidation and increased rates of nonoxidized glycolytic products, when compared with myotubes derived from the nondiabetic individuals ( P < 0.05). Both 1- and 2-[14C]-pyruvate oxidation rates were significantly blunted in myotubes from severely obese women with type 2 diabetes compared with myotubes from the nondiabetic controls. Lastly, concentrations of tricarboxylic acid cycle intermediates, namely, citrate ( P < 0.05), cis-aconitic acid ( P = 0.07), and α-ketoglutarate ( P < 0.05), were lower in myotubes from severely obese women with type 2 diabetes. These data suggest that intramyocellular insulin-mediated glucose partitioning is intrinsically altered in the skeletal muscle of severely obese women with type 2 diabetes in a manner that favors the production of glycolytic end products. Defects in pyruvate dehydrogenase and tricarboxylic acid cycle may be responsible for this metabolic derangement associated with type 2 diabetes.

Inhibition of the serine protease enteropeptidase (EP) opens a new avenue to the discovery of chemotherapeutics for the treatment of metabolic diseases. Camostat has been used clinically for treating chronic pancreatitis in Japan; however, the mechanistic basis of the observed clinical efficacy has not been fully elucidated. We demonstrate that camostat is a potent reversible covalent inhibitor of EP, with an inhibition potency (kinact/KI) of 1.5 × 104 M−1s−1. High-resolution liquid chromatography-mass spectrometry (LC-MS) showed addition of 161.6 Da to EP after the reaction with camostat, consistent with insertion of the carboxyphenylguanidine moiety of camostat. Covalent inhibition of EP by camostat is reversible, with an enzyme reactivation half-life of 14.3 hours. Formation of a covalent adduct was further supported by a crystal structure resolved to 2.19 A, showing modification of the catalytic serine of EP by a close analog of camostat, leading to formation of the carboxyphenylguanidine acyl enzyme identical to that expected for the reaction with camostat. Of particular note, minor structural modifications of camostat led to changes in the mechanism of inhibition. We observed from other studies that sustained inhibition of EP is required to effect a reduction in cumulative food intake and body weight, with concomitant improved blood glucose levels in obese and diabetic leptin-deficient mice. Thus, the structure-activity relationship needs to be driven by not only the inhibition potency but also the mechanistic and kinetic characterization. Our findings support EP as a target for the treatment of metabolic diseases and demonstrate that reversible covalent EP inhibitors show clinically relevant efficacy. SIGNIFICANCE STATEMENT Interest in targeted covalent drugs has expanded in recent years, particularly so for kinase targets, but also more broadly. This study demonstrates that reversible covalent inhibition of the serine protease enteropeptidase is a therapeutically viable approach to the treatment of metabolic diseases and that mechanistic details of inhibition are relevant to clinical efficacy. Our mechanistic and kinetic studies outline a framework for detailed inhibitor characterization that is proving essential in guiding discovery efforts in this area.

A novel series of guanidinebenzoate enteropeptidase and trypsin dual inhibitors has been discovered and SAR studies were conducted. Optimization was focused on improving properties for gut restriction, including increased aqueous solubility, lower cellular permeability, and reduced oral bioavailability. Lead compounds were identified with efficacy in a mouse fecal protein excretion study.

Introduction: Clinical studies have found disparities in gestational diabetes mellitus (GDM) outcomes due to individual racial and economic differences. In contrast, this pilot study examines the association of structures variations with GDM outcomes by race. Methods: Data were obtained from a healthcare system for a study population of 2,189 women with GDM, 18 years and above, singleton births, who delivered between January 1, 2014 and December 31, 2018. Clinical data were merged with structural measures of mothers’ census tracts of residence from the U.S. Census Bureau. Outcome variables are mother and infant birth complications. Data are analyzed using zero correlations by race. Results: Mother’s: white mothers tended to have fewer complications (r=-0.07, p Conclusion: Selected results show variations in complications among different races by neighborhood characteristics. The influence of race on GDM outcomes is linked to income and socioeconomic status. Income may be more important to GDM outcomes than race. Disclosure L. Thomas: None. M.R. Fawcett: None. C. Jurkovitz: None. J. Lenhard: Speaker’s Bureau; Self; Janssen Pharmaceuticals, Inc. Funding National Institutes of Health (U54GM104941)

The partitioning of glucose toward glycolytic end products rather than glucose oxidation and glycogen storage is evident in skeletal muscle with severe obesity and type 2 diabetes. The purpose of the present study was to determine the possible mechanism by which severe obesity alters insulin-mediated glucose partitioning in human skeletal muscle. Primary human skeletal muscle cells (HSkMC) were isolated from lean (BMI = 23.6 ± 2.6 kg/m2, n = 9) and severely obese (BMI = 48.8 ± 1.9 kg/m2, n = 8) female subjects. Glucose oxidation, glycogen synthesis, non-oxidized glycolysis, pyruvate oxidation, and targeted TCA cycle metabolomics were examined in differentiated myotubes under basal and insulin-stimulated conditions. Myotubes derived from severely obese subjects exhibited attenuated response of glycogen synthesis (20.3%; 95% CI [4.7, 28.8]; P = 0.017) and glucose oxidation (5.6%; 95% CI [0.3, 8.6]; P = 0.046) with a concomitant greater increase (23.8%; 95% CI [5.7, 47.8]; P = 0.004) in non-oxidized glycolytic end products with insulin stimulation in comparison to the lean group (34.2% [24.9, 45.1]; 13.1% [8.6, 16.4], and 2.9% [−4.1, 12.2], respectively). These obesity-related alterations in glucose partitioning appeared to be linked with reduced TCA cycle flux, as 2-[14C]-pyruvate oxidation (358.4 pmol/mg protein/min [303.7, 432.9] vs. lean 439.2 pmol/mg protein/min [393.6, 463.1]; P = 0.013) along with several TCA cycle intermediates, were suppressed in the skeletal muscle of severely obese individuals. These data suggest that with severe obesity the partitioning of glucose toward anaerobic glycolysis in response to insulin is a resilient characteristic of human skeletal muscle. This altered glucose partitioning appeared to be due, at least in part, to a reduction in TCA cycle flux.

Knowledge of subsurface light nonaqueous phase liquid (LNAPL) saturation is important for developing a conceptual model and a plan for addressing LNAPL contaminated sites. Investigators commonly predict LNAPL mobility and potential recoverability using information such as LNAPL physical properties, subsurface characteristics, and LNAPL saturations. Several models exist that estimate the LNAPL specific volume and transmissivity from fluid levels in monitoring wells. Commonly, investigators use main drainage capillary pressure&ndash, saturation relations because they are more frequently measured and available in the literature. However, main drainage capillary pressure&ndash, saturation relations may not reflect field conditions due to capillary pressure&ndash, saturation hysteresis. In this paper, we conduct a preliminary test of a recent analytical model that predicts subsurface LNAPL saturations, specific volume, and transmissivity against data measured at a LNAPL contaminated site. We call our test preliminary because we compare only measured and predicted vertical LNAPL saturations at a single site. Our results show there is better agreement between measured and predicted LNAPL saturations when imbibition capillary pressure&ndash, saturation relations are employed versus main drainage capillary pressure&ndash, saturation relations. Although further testing of the model for different conditions and sites is warranted, the preliminary test of the model was positive when consideration was given to capillary pressure&ndash, saturation hysteresis, which suggests the model can yield reasonable predictions that can help develop and update conceptual site models for addressing subsurface LNAPL contamination. Parameters describing capillary pressure&ndash, saturation relations need to reflect conditions existing at the time when the fluid levels in a well are measured.

Leakage of hydrocarbon fuel (light nonaqueous-phase liquid, LNAPL) from petroleum processing facilities and storage tanks may result in significant subsurface contamination. Remediating the contaminated areas represent considerable challenges, especially when remediation resources are limited and site data are incomplete. A reasonable management strategy under this scenario may be to identify sites where LNAPL recovery operations should be located that would provide the largest LNAPL recovery initially while minimizing the LNAPL remaining in the subsurface (entrapped and residual LNAPL), which may serve as future sources for groundwater contamination. To accomplish this objective, we use estimates of subsurface recoverable and total LNAPL specific volumes and LNAPL transmissivities to generate GIS maps that can be combined to highlight locations where to develop LNAPL recovery operations. When the approach is applied to a LNAPL-contaminated area in Iran, we were able to narrow the locations for potential LNAPL recovery operations. Specifically, we combine maps of the LNAPL specific yield, an introduced term, and the LNAPL transmissivity where the LNAPL specific yield is the ratio of the recoverable to total LNAPL specific volumes. The LNAPL specific yield is a relative measure of the amount of LNAPL that potentially can be recovered while minimizing residual LNAPL in soils. The approach can be applied to sites where the recoverable and total LNAPL specific volumes and LNAPL transmissivities can be estimated using data from boreholes in the contaminated area.

Digital, Background: Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease. Methods: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952. Findings: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m2 (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1-5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77-0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68-0·87; p, Ciencias Médicas y de la Salud

Digital, Background Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A1c (HbA1c) concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control. Methods This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952. Findings Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA1c 7·2% [IQR 6·6–8·1], 4589 [46·3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). During a median follow-up of 5·4 years (IQR 5·1–5·9), the primary composite outcome occurred in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in 663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio [HR] 0·88, 95% CI 0·79–0·99; p=0·026). All-cause mortality did not differ between groups (536 [10·8%] in the dulaglutide group vs 592 [12·0%] in the placebo group; HR 0·90, 95% CI 0·80–1·01; p=0·067). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p, Ciencias Médicas y de la Salud

Trypsin is the major serine protease responsible for intestinal protein digestion. An inhibitor, camostat (CS), reduced weight gain, hyperglycemia, and dyslipidemia in obese rats; however, the mechanisms for these are largely unknown. We reasoned that CS creates an apparent dietary protein restriction, which is known to increase hepatic fibroblast growth factor 21 (FGF21). Therefore, metabolic responses to CS and a gut-restricted CS metabolite, FOY-251, were measured in mice. Food intake, body weight, blood glucose, branched-chain amino acids (LC/MS), hormone levels (ELISA), liver pathology (histology), and transcriptional changes (qRT-PCR) were measured in ob/ob, lean and diet-induced obese (DIO) C57BL/6 mice. In ob/ob mice, CS in chow (9–69 mg/kg) or FOY-251 (46 mg/kg) reduced food intake and body weight gain to a similar extent as pair-fed mice. CS decreased blood glucose, liver weight, and lipidosis and increased FGF21 gene transcription and plasma levels. In lean mice, CS increased liver FGF21 mRNA and plasma levels. Relative to pair feeding, FOY-251 also increased plasma FGF21 and induced liver FGF21 and integrated stress response (ISR) transcription. In DIO mice, FOY-251 (100 mg/kg po) did not alter peak glucose levels but reduced the AUC of the glucose excursion in response to an oral glucose challenge. FOY-251 increased plasma FGF21 levels. In addition to previously reported satiety-dependent (cholecystokinin-mediated) actions, intestinal trypsin inhibition engages non-satiety-related pathways in both leptin-deficient and DIO mice. This novel mechanism improves metabolism by a liver-integrated stress response and increased FGF21 expression levels in mice. NEW & NOTEWORTHY Trypsin inhibitors, including plant-based consumer products, have long been associated with metabolic improvements. Studies in the 1980s and 1990s suggested this was due to satiety hormones and caloric wasting by loss of protein and fatty acids in feces. This work suggests an entirely new mechanism based on the lower amounts of digested protein available in the gut. This apparent protein reduction may cause beneficial metabolic adaptation by the intestinal-liver axis to perceived nutrient stress.

Aims Osteopontin (OPN) and osteoprotegerin (OPG) are bone metabolism biomarkers potentially associated with nerve function. We evaluated the association of cardiovascular autonomic nerve function, OPN, and OPG in 50 individuals with type 2 diabetes mellitus (T2DM). Methods RR-variation during deep breathing (i.e., mean circular resultant (MCR) and expiration/inspiration (E/I) ratio) was used to assess parasympathetic nerve function. Participants' demographics, HbA1c, 25-hydroxyvitamin D (25(OH)D), BMI, HOMA-IR, calcium, parathyroid hormone, creatinine, OPN, and OPG were determined. Results Using stepwise multiple linear regression analysis with MCR or E/I ratio as the dependent variable, OPN was independently associated with reduced autonomic function. A previous report showed a significant association of cardiovascular autonomic function with age, 25(OH)D insufficiency, and the interaction of age×25(OH)D insufficiency. Here we report a novel association for OPN and its interaction with age indicating that for those who are younger, elevated OPN levels are related to a greater loss of autonomic function (MCR model R 2 =0.598, p 2 =0.594, p Conclusion Our results suggest that OPN is associated with reduced parasympathetic function, particularly in younger individuals with T2DM. Further studies are needed to determine if OPN is neuroprotective, involved in the pathogenesis of autonomic dysfunction, or a bystander.

Serum pigment epithelium-derived factor (PEDF) levels are correlated with adiposity, dyslipidemia, and renal dysfunction in type 2 diabetes (T2D) men. Major sources of circulating PEDF include the liver and adipose tissue. Cross-sectional studies have reported higher serum PEDF levels in T2D vs. controls. Although studies have suggested PEDF’s role in mediating insulin resistance, its potential role with regard to glycemic control remains unclear. We examined the association of serum PEDF and glycemic control in individuals with T2D (n=50; 21 men/29 women; age=63±10 years; CKD1.8; n=23; p1.8 (r=0.30, p=0.037), triglycerides (r=0.53, p1.8) was not (p=0.70). There was also a significant interaction of AST x creatinine (p=0.02). While some suggest that elevated PEDF levels are associated with insulin resistance, the lack of an association in our data is intriguing. It is possible that gluconeogenesis by the liver and kidney is associated with elevation in circulating PEDF and PEDF may be part of an incomplete self-defensive regulatory mechanism to limit hyperglycemia. The significant interaction suggests that the relationship between creatinine and PEDF depends on AST. Taken together, the association between PEDF and poor glycemic control in persons with T2D may suggest a preferentially protective compensatory response of PEDF against hyperglycemia but not insulin resistance. Disclosure R.E. Maser: None. J. Lenhard: Speaker's Bureau; Self; Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Sanofi. R. Pohlig: None. P. Balagopal: None.

As patients with diabetes continue to have greater problems with obesity, the need for more medications and higher doses of insulin has increased. Some patients are so insulin resistant that they require U-500 insulin.All insulins carry the risk of hypoglycemia. Despite being the most potent insulin available, the methodology for describing U-500 insulin administration varies. This paper examines the properties of U-500 insulin and suggests a unified method of defining how it is administered.A literature search for English language articles that reference U-500 insulin was performed. The 51 articles, and additional websites as applicable, were independently reviewed.Now that U-500 insulin has a specific syringe and a pen, all patients who use this should be converted to one of these two devices. The insulin dose should be described as the number of units administered.U-500 insulin is a potent formulation and carries the risk of hypoglycemia. A unified method of administration is now available, and the description of its use should reflect the number of units administered.

The sodium/glucose cotransporters (SGLT1 and SGLT2) transport glucose across the intestinal brush border and kidney tubule. Dual SGLT1/2 inhibition could reduce hyperglycemia more than SGLT2-selective inhibition in patients with type 2 diabetes. However, questions remain about altered gastrointestinal (GI) luminal glucose and tolerability, and this was evaluated in slc5a1−/− mice or with a potent dual inhibitor (compound 8; SGLT1 Ki = 1.5 ± 0.5 nM 100-fold greater potency than phlorizin; SGLT2 Ki = 0.4 ± 0.2 nM). 13C6-glucose uptake was quantified in slc5a1−/− mice and in isolated rat jejunum. Urinary glucose excretion (UGE), blood glucose (Sprague-Dawley rats), glucagon-like peptide 1 (GLP-1), and hemoglobin A1c (HbA1c) levels (Zucker diabetic fatty rats) were measured. Intestinal adaptation and rRNA gene sequencing was analyzed in C57Bl/6 mice. The blood 13C6-glucose area under the curve (AUC) was reduced in the absence of SGLT1 by 75% (245 ± 6 vs. 64 ± 6 mg/dl⋅h in wild-type vs. slc5a1−/− mice) and compound 8 inhibited its transport up to 50% in isolated rat jejunum. Compound 8 reduced glucose excursion more than SGLT2-selective inhibition (e.g., AUC = 129 ± 3 vs. 249 ± 5 mg/dl⋅h for 1 mg/kg compound 8 vs. dapagliflozin) with similar UGE but a lower renal glucose excretion threshold. In Zucker diabetic fatty rats, compound 8 decreased HbA1c and increased total GLP-1 without changes in jejunum SGLT1 expression, mucosal weight, or villus length. Overall, compound 8 (1 mg/kg for 6 days) did not increase cecal glucose concentrations or bacterial diversity in C57BL/6 mice. In conclusion, potent dual SGLT1/2 inhibition lowers blood glucose by reducing intestinal glucose absorption and the renal glucose threshold but minimally impacts the intestinal mucosa or luminal microbiota in chow-fed rodents.

Roux-en-Y gastric bypass (RYGB) is an effective way to lose weight and reverse type 2 diabetes. We profiled the metabolome of 18 obese patients (nine euglycemic and nine diabetics) that underwent RYGB surgery and seven lean subjects. Plasma samples from the obese patients were collected before the surgery and one week and three months after the surgery. We analyzed the metabolome in association to five hormones (Adiponectin, Insulin, Ghrelin, Leptin, and Resistin), four peptide hormones (GIP, Glucagon, GLP1, and PYY), and two cytokines (IL-6 and TNF). PCA showed samples cluster by surgery time and many microbially driven metabolites (indoles in particular) correlated with the three months after the surgery. Network analysis of metabolites revealed a connection between carbohydrate (mannosamine and glucosamine) and glyoxylate and confirms glyoxylate association to diabetes. Only leptin and IL-6 had a significant association with the measured metabolites. Leptin decreased immediately after RYGB (before significant weight loss), whereas IL-6 showed no consistent response to RYGB. Moreover, leptin associated with tryptophan in support of the possible role of leptin in the regulation of serotonin synthesis pathways in the gut. These results suggest a potential link between gastric leptin and microbial-derived metabolites in the context of obesity and diabetes.

Roux-en-Y gastric bypass (RYGB) is an effective way to lose weight and reverse type 2 diabetes. We profiled the metabolome of 18 obese patients (nine euglycemic and nine diabetics) that underwent RYGB surgery and seven lean subjects. Plasma samples from the obese patients were collected before the surgery and one week and three months after the surgery. We analyzed the metabolome in association to five hormones (Adiponectin, Insulin, Ghrelin, Leptin, and Resistin), four peptide hormones (GIP, Glucagon, GLP1, and PYY), and two cytokines (IL-6 and TNF). PCA showed samples cluster by surgery time and many microbially driven metabolites (indoles in particular) correlated with the three months after the surgery. Network analysis of metabolites revealed a connection between carbohydrate (mannosamine and glucosamine) and glyoxylate and confirms glyoxylate association to diabetes. Only leptin and IL-6 had a significant association with the measured metabolites. Leptin decreased immediately after RYGB (before significant weight loss), whereas IL-6 showed no consistent response to RYGB. Moreover, leptin associated with tryptophan in support of the possible role of leptin in the regulation of serotonin synthesis pathways in the gut. These results suggest a potential link between gastric leptin and microbial-derived metabolites in the context of obesity and diabetes.

Surgical treatment for primary hyperparathyroidism (PHPT) improves bone metabolism. Osteocalcin (OC) and its undercarboxylated form (ucOC) are associated with bone and energy metabolism. Osteopontin (OPN), a multifunctional protein expressed in bone, is involved in resorption, along with β-carboxyl-terminal cross-linking telopeptide of type 1 collagen (β-CTX), and osteoprotegerin (OPG). Our aim was to investigate these biomarkers of bone metabolism in patients with PHPT.We examined 30 individuals with PHPT, in a clinical research facility, before and 1 month following parathyroidectomy. Circulating levels of OC, ucOC, OPN, β-CTX, and OPG were examined as bone biomarkers along with inflammatory markers (e.g., interleukin-6 [IL-6], lipocalin-2), insulin resistance (i.e., homeostasis model assessment for insulin resistance [HOMA-IR]), adiposity (i.e., leptin, adiponectin), PTH, calcium, 25-hydroxyvitamin D, creatinine, and demographics.Participants (27 females/3 males) were 60 ± 9 (mean±SD) years old. There was a significant reduction of ucOC (7.9 ± 5.1 [median±SIQR] vs. 6.6 ± 3.7 ng/mL, p = 0.022) and OPN (75.4 ± 14.5 vs. 54.5 ± 9.2 ng/mL, p 0.001) pre- versus post-parathyroidectomy. There were no univariate differences postoperatively for IL-6, HOMA-IR, leptin, or adiponectin. Regression analysis showed that postoperative levels of adiponectin, IL-6, and OPN were significantly associated with ucOC, while adjusting for PTH and albumin corrected calcium levels (model RThe lower 1-month postoperative OPN and ucOC levels in PHPT seem to indicate reduced bone resorption. Decreased ucOC levels may also suggest lower energy demands postoperatively.

Background The diet and microbiome contribute to metabolic disease in part due to increased intestinal inflammation and permeability. Dietary tryptophan is metabolized by both mammalian and bacterial enzymes. Using in vitro, in vivo models, and clinical data, we tested whether bacterial tryptophan indole derivatives underlie the positive benefits of microbiota on inflammation that is associated with metabolic disease. Methods In high-fat diet (HFD)-fed mice intestinal permeability and plasma endotoxin levels were measured after indole-3-propionic acid (IPA; 20 mg kg−1 p.o. for 4 days). Tryptophan derivatives effect on permeability and gene expression were assessed in T84 intestinal cell monolayers, in the presence or absence of pro-inflammatory cytokines. Plasma tryptophan metabolites were analyzed from lean, or obese T2D subjects undergoing Roux-en-Y gastric bypass surgery (RYGB). Key Results IPA reduced the increased intestinal permeability observed in HFD-fed mice. Of 16 metabolites tested in vitro, only IPA, and tryptamine reduced T84 cell monolayer permeability compromised by pro-inflammatory cytokines. In T84 cells, IPA reversed the IFN-γ induced increase of fructose transporter SLC2A5 (GLUT5) mRNA, but not induction of inflammatory or metabolic genes. In obese subjects, IPA levels were reduced relative to lean counterparts, and these levels were increased by 3 months after RYGB. Conclusions and Inferences The novel findings are that obese subjects have lower levels of IPA, a solely bacterially derived tryptophan derivative, and IPA improved intestinal barrier function in vitro and DIO mice. Reduced plasma IPA levels and reversal by surgery may be a consequence of intestinal indole-producing microbiota but underlying mechanisms warrant further investigation.

Design, synthesis, and biological evaluation of pyridazine-based, 4-bicyclic heteroaryl-piperidine derivatives as potent stearoyl-CoA desaturase-1 (SCD1) inhibitors are described. In a chronic study of selected analog (3e) in Zucker fa/fa (ZF) rat, dose-dependent decrease of body weight gain and plasma fatty acid desaturation index (DI) in both C16 and C18 are also demonstrated. The results indicate that the plasma fatty acid DI may serve as an indicator for direct target engagement and biomarker for SCD1 inhibition.

Pregnancies affected by type 1 diabetes (T1D) carry a major risk for poor fetal, neonatal and maternal outcomes. Achieving normoglycemia while minimizing the risk of hypoglycemia is a major goal in the management of T1D as this can greatly reduce the risk of complications. However, maintaining optimal glucose levels is challenging because insulin requirements are not uniform throughout the course of the pregnancy. Over the past decade, there has been significant improvement in the methods for glucose monitoring and insulin administration, accompanied by an increase in the number of treatment options available to pregnant patients with T1D. Through study of the scientific literature and accumulated evidence, we review advances in the management of T1D in pregnancy and offer advice on how to achieve optimal care for the patient.

Background The objective was to determine if a free, voluntary diabetes screening program as a part of the blood donation process might be cost-effective. Study Design and Methods During the first 6 months of the program, 26,415 donors were screened using a single random plasma glucose (RPG) level. All donors were asked to eat before donation. Low-, moderate-, and high-risk groups were formed based on RPG levels ( 200 mg/dL). Contact with a telephone questionnaire was made with 139 of 178 (78%) of the persons in the high-risk group with 33 new cases of diabetes diagnosed by the donor's physician and 26 donors indicating that they were not diagnosed with diabetes. Sex- and age-matched donors in the low- and moderate-risk groups were contacted and administered the same questionnaire. Results The three risk groups were similar, except for body mass index (28.1 ± 5.4 kg/m2 vs. 29.9 ± 5.5 kg/m2 vs. 32.7 ± 5.6 kg/m2, p

Obesity is associated with autonomic imbalance. With respect to cardiovascular autonomic dysfunction, this is characterized by reduced heart rate variability (HRV). Our objective was to determine the effect of surgically induced weight loss on cardiovascular autonomic nerve fiber function in subjects with severe obesity and examine whether an association with reduced insulin resistance exists. The setting was a hospital and private practice in the United States.A total of 32 morbidly obese patients (body mass index 51 ± 11 kg/m(2)) underwent laparoscopic Roux-en-Y gastric bypass. Measures of HRV (e.g., power spectral analysis, RR variation during deep breathing) were used to evaluate autonomic function before and 6 months after surgery. The homeostasis model assessment of insulin resistance index (HOMA-IR) was used to assess insulin resistance.At 6 months after bariatric surgery, the patients had lost 58% excess body mass index with improvement in the HOMA-IR (3.0 ± 1.4 versus 1.1 ± .7; P.001). Measures of RR variation during deep breathing and total spectral power, low frequency (LF) power (influenced by sympathetic and parasympathetic activity), and high frequency (HF) power (parasympathetic activity) increased with weight loss. The LF/HF ratio was lower (1.5 ± 1.5 versus .9 ± .7, P.05) with a reduction in weight. Spectral analysis of HRV combined with spectral analysis of respiratory activity generated the respiration frequency area (RFA) and low frequency area. The RFA was increased, and the LFA/RFA ratio was reduced with weight loss. HOMA-IR and HRV did not correlate.Surgically induced weight loss has a favorable effect on autonomic function, but it does not appear to be directly attributable to reduced insulin resistance.

Highlights • We examined pre-heparin LPL mass in type 2 diabetes mellitus (T2DM). • Association of adiponectin, pre-heparin LPL mass, and HDL-C was examined in T2DM. • Pre-heparin LPL mass may mediate the adiponectin and HDL-C association in T2DM., Aim Lipoprotein lipase (LPL) is a major enzyme in lipid metabolism. Dyslipidemia, characterized by decreased high-density lipoprotein cholesterol (HDL-C), is prevalent in persons with type 2 diabetes mellitus (T2DM). The aim of this study was to determine whether pre-heparin LPL mass mediates the association between adiponectin and HDL-C in individuals with T2DM. Methods Pre-heparin LPL mass was measured via an enzyme-linked immunosorbent assay, adiponectin by radioimmunoassay, and HDL-C was determined enzymatically. Participants’ (n = 50) demographics, HbA1c, adiposity, homeostasis model assessment for insulin resistance (HOMA-IR), serum creatinine, and lipids were measured. Path analysis was utilized to test whether pre-heparin LPL mass is a mediator in the relationship between adiponectin and HDL-C. Results All four criteria for mediation were satisfied in the path analysis. The indirect effect of adiponectin on HDL-C through pre-heparin LPL mass was significant, p = 0.001, whereas the direct effect of adiponectin on HDL-C was not significant, p = 0.074. These results remained consistent even after adjustments for age, gender, body mass index, HOMA-IR, and serum creatinine in the model. Conclusion The findings in this study suggest that pre-heparin LPL mass may mediate the association between adiponectin and HDL-C in T2DM. This relationship for measures of HDL-C functionality requires future investigation.

Laparoscopic sleeve gastrectomy (LSG) is a bariatric surgery in which 60% to 80% of the stomach is removed longitudinally, resulting in a smaller stomach that takes the shape of a "sleeve." The mechanism for weight loss is gastric restriction and possible neurohormonal changes resulting from lower levels of ghrelin (an appetite-stimulating hormone), as a consequence of removing the gastric fundus. LSG may be more desirable than laparoscopic adjustable gastric banding because there is no foreign object inside the abdomen and no need for postsurgery appointments to adjust the band. LSG may be preferred over Roux-en-Y gastric bypass (RYGB) because LSG is a less complicated operation that does not result in dumping syndrome or malabsorption, yet weight loss is comparable to RYGB. While LSG is suggested to have advantages over the commonly performed laparoscopic adjustable gastric banding and RYGB, there are no long-term (>5 years) outcomes and few studies specific to nutrition care for LSG patients. This article will present a protocol for pre- and postsurgery nutrition care for LSG and the important role the registered dietitian plays in the multidisciplinary team. Postsurgery diet progression from liquids to solids during 6 to 8 weeks should focus on meeting protein and fluid needs. In addition, LSG patients are at risk for nutrient deficiencies due to decreased hydrochloric acid and intrinsic factor from removed parietal cells and reduced dietary intake due to decreased ghrelin levels. Therefore, LSG patients should take daily micronutrient supplements, including vitamin B-12 and potentially supplemental iron, to prevent deficiencies.

Surgery is the only treatment that has been proved to have beneficial long-term effects for the morbidly obese (body mass index40 kg/m(2)). One of the requirements for the Centers for Excellence program instituted by American Society for Bariatric Surgery is to have a system in place to provide comprehensive follow-up care. A recent study showed that the complication rate after bariatric surgery is 39.6% during the 180 days after discharge. Inadequate adherence to follow-up care has been recognized as contributory to the development of complications after bariatric surgery. The purpose of this study was to examine the variables that relate to patients' adherence to scheduled appointments after bariatric surgery.A block entry logistic regression analysis was done from a database of an outpatient bariatric program that contained cross-sectional data collected for 1 year. Patient adherence to follow-up was defined as having 1 postoperative follow-up appointment within 90 days of undergoing surgery. A total of 375 subjects completed the preoperative program and underwent either laparoscopic Roux-en-Y gastric bypass (84.3%) or gastric banding (15.7%).Of the 14 variables used in the analysis, 5 were statistically significant (P.05) predictors of adherence: age, body mass index, marital status, employment status, and insurance coverage.Incorporation of the identified predictors into preoperative screening tools to flag patients at risk of nonadherence might improve follow-up care. Additional research is needed on possible interventions to decrease complications after bariatric surgery.

Objective: To determine the impact of surgically induced weight loss on cardiovascular autonomic function in subjects with severe obesity and examine whether the effect was comparable for persons with and without diabetes. Research Methods and Procedures: Twenty-six severely obese individuals (BMI = 48 ± 7 kg/m2) underwent bariatric surgery (laparoscopic Roux-en-Y gastric bypass, n = 21; laparoscopic adjustable gastric banding, n = 5). Cardiovascular autonomic function (heart rate variation during deep breathing and the Valsalva maneuver) was assessed before and 6 and 12 months after surgery. Results: Twelve months after bariatric surgery, there was a 28% decrease in BMI. There was an increase in all parasympathetic indices of autonomic function (all assessment modalities, p < 0.05) with weight loss. The amount of improvement from baseline for all measures of autonomic function did not differ for those with or without diabetes. Discussion: Surgically induced weight loss 12 months after surgery has a favorable effect on cardiovascular autonomic function in severely obese individuals with and without diabetes.

Continuous subcutaneous insulin infusion (CSII) is an increasingly popular modality for intensive diabetes treatment (IT). Appropriate patient selection is a key component for success with CSII. Current guidelines for patient selection are largely based on consensus or expert opinion. While most published studies have shown a modest but significant improvement in glycemic control when patients are switched to CSII, other studies have shown no benefit. One possible reason for this is patient selection criteria, ifmentioned at all, are significantly different. Any attempt at a comparison of existing studies may be confounded by the lack of patient selection criteria. This not only makes itdifficult to compare studies, but may introduce a bias into the conclusions that are reached. The selection of patients for CSII may depend as much upon the availability of a skilled and motivated team as on the patients themselves.

Context: The aim of this article was to review the importance of the clinical identification of persons with cardiovascular autonomic neuropathy (CAN) and discuss potential treatment interventions. Evidence Acquisition: A MEDLINE search was conducted for articles published during the last 20 yr. In addition, subsequent references of retrieved articles were reviewed. Search strategies included using key terms such as CAN, heart rate variability, orthostatic hypotension, and diabetes mellitus. Evidence Synthesis: CAN is a common form of diabetic autonomic neuropathy and causes abnormalities in heart rate control as well as central and peripheral vascular dynamics. The clinical manifestations of CAN include exercise intolerance, intraoperative cardiovascular lability, orthostatic hypotension, painless myocardial ischemia, and increased risk of mortality. CAN contributes to morbidity, mortality, and reduced quality of life for persons with diabetes. The American Diabetes Association has recently published a statement that provides guidelines for prevention, detection, and management of neuropathy, including CAN, for healthcare providers who care for patients with diabetes. Algorithms for the evaluation and treatment of the patient with CAN, even if the patient is asymptomatic, are provided in this review. Conclusions: Once CAN is identified in a patient with diabetes, healthcare providers may consider altering the prescribed exercise regimen, increasing surveillance for cardiac ischemia, carefully reexamining the list of prescribed medications, and aggressively treating cardiovascular risk factors (e.g. hypertension) that may be associated with the development of CAN. (J Clin Endocrinol Metab 90: 5896–5903, 2005)

Guidelines for detection of individuals with gestational diabetes mellitus (GDM) indicate that glucose testing for women with a history of GDM should occur as soon as feasible with retesting of an initially negative screen to occur between the 24th and 28th week of gestation. The aim of this study was to evaluate medical records for individuals enrolled in a GDM management program that presented with two subsequent pregnancies with GDM and to determine if more specific guidelines for detection are needed. Records (n=60) from both pregnancies were reviewed for gestational age at enrollment, delivery, and when insulin was started, infant birth weights and complications (e.g., hypoglycemia), and maternal complications (e.g., emergency cesarean section). Over half [33/60 (55%)] of the women required insulin during both pregnancies, while 16.7% (10/60) required insulin during the second enrollment for GDM but not the first. For those requiring insulin during both pregnancies, 88% (29/33) required it earlier during the subsequent pregnancy (31.5±2.7 vs. 21.6±8.4 weeks of gestation, P

This study evaluated the effect of losartan, an angiotensin II receptor antagonist, on cardiovascular autonomic function and large sensory nerve fiber function in individuals with diabetes mellitus. In a double-blind placebo-controlled trial, individuals were randomly assigned to treatment with a daily oral dose of 50-mg losartan (n=24) or placebo (n=20) for 12 months. Tests of cardiovascular autonomic function (i.e., RR-variation during deep breathing and the Valsalva maneuver) and of large sensory nerve fiber function (i.e., vibratory thresholds) were measured at baseline and at 12 months. No significant difference at baseline was found for duration of diabetes, glycemic control, blood pressure, or body mass index (BMI) between the two groups. After 12 months, the decline in RR-variation that occurs over time appeared to be less for those taking losartan. There was, however, no statistically significant change in the results for any of the tests of cardiovascular autonomic function or vibratory thresholds between the groups. Multivariate analyses in the losartan study group revealed an independent association of duration of diabetes, change in (reduced) systolic blood pressure (SBP), and improved vibratory thresholds. This association was particularly noted for women. Pharmacologic agents may affect cardiovascular autonomic function by favorable or detrimental changes in the electrophysiology of the heart. The results of this study indicate that, although losartan may have slowed the normal decline in RR-variation, it did not result in any significant improvement in cardiovascular autonomic nerve fiber function. An association of vibratory thresholds and SBP was observed.

BACKGROUND Many patients with diabetes fail to receive recommended monitor- ing tests. One reason might be inadequate continuity of care. This study exam- ined the association between provider continuity and completion of monitoring tests for patients with diabetes mellitus. METHODS A cross-sectional analysis was conducted on claims data from a private national health plan for 1 year (January 1,1999, through December 31,1999). Participants had a diagnosis of diabetes mellitus and at least 2 outpatient visits during the study year (N = 1,795). The association was measured between conti- nuity of care with an individual provider and completion of 3 diabetes monitor- ing tests: a glycosylated hemoglobin test, a lipid profile, and an eye examination. RESULTS Eighty-one percent of patients had a glycosylated hemoglobin test, 66% had a lipid profile, and 28% had an eye examination during the study year. After controlling for demographics, number of diabetes visits, case mix, and diabetes complications, provider continuity was not significantly associated with the receipt of a glycosylated hemoglobin test (odds ratio (OR) = 0.61, 95% confidence interval (CI), 0.32-1.16), a lipid profile (OR = 0.97, 95% CI, 0.57-1.64) or an eye examination (OR = 0.60, 95% CI, 0.30-1.19). When continuity was meas- ured only among primary care providers, there was no significant association for receipt of a glycosylated hemoglobin test (OR = 0.73, 95% CI, 0.41-1.33), a lipid profile (OR = 0.88, 95% CI, 0.53-1.47) or an eye examination (OR = 0.70, 95% CI, 0.35-1.36). CONCLUSIONS This study found no association between provider continuity and completion of diabetes monitoring tests in a national privately insured popula- tion. Whereas continuity might benefit other aspects of health care, it does not appear to benefit improved monitoring for diabetes.

OBJECTIVE Vitamin D insufficiency is prevalent in subjects with type 2 diabetes mellitus (T2DM) and is associated with peripheral neuropathy. However, there are little data regarding vitamin D status in patients with cardiovascular autonomic neuropathy. Our objective was to evaluate the association of cardiovascular autonomic function, 25-hydroxyvitamin D (25[OH]D) insufficiency (i.e., levels

The aim of this study was to evaluate the influence of gestational diabetes mellitus (GDM) and positional aortocaval compression on cardiovascular autonomic nervous system (ANS) function in late pregnancy.Pregnant women with (n=31) and without (n=12) GDM were evaluated at 30-35weeks gestation and 2-3months postpartum. Measures of ANS function included power spectral analysis (performed sitting) and RR-variation during deep breathing (performed supine). Time-related changes (late pregnancy versus 2-3months postpartum) for measurements of cardiovascular ANS function were analyzed using multivariate analysis of variance for repeated measures.Baseline characteristics were similar for both groups. Comparing ANS measures for GDM+versus GDM- women during pregnancy and postpartum revealed no significant differences. Time related changes indicated that during late pregnancy total spectral power, low frequency (LF) power, high frequency (HF) power, and RR-variation during deep breathing were significantly reduced (p0.001 for all). The LF/HF ratio, however, was not significantly affected during late pregnancy (p=0.678).Our results suggest decreased activity in both branches of the ANS during mid-third trimester pregnancy, but no significant change in sympathovagal balance. Aortocaval compression appears to affect ANS function whether tests were performed sitting or supine for GDM+and GDM- women.

The objective was to determine if a free, voluntary diabetes screening program as a part of the blood donation process might be cost-effective.During the first 6 months of the program, 26,415 donors were screened using a single random plasma glucose (RPG) level. All donors were asked to eat before donation. Low-, moderate-, and high-risk groups were formed based on RPG levels (140, 140-200, and200 mg/dL). Contact with a telephone questionnaire was made with 139 of 178 (78%) of the persons in the high-risk group with 33 new cases of diabetes diagnosed by the donor's physician and 26 donors indicating that they were not diagnosed with diabetes. Sex- and age-matched donors in the low- and moderate-risk groups were contacted and administered the same questionnaire.The three risk groups were similar, except for body mass index (28.1 ± 5.4 kg/m2 vs. 29.9 ± 5.5 kg/m2 vs. 32.7 ± 5.6 kg/m2 , p 0.001). The discriminative effectiveness of screening was evaluated by the area under the receiver operating characteristics (AROC) curve. The AROC curve was 0.950 (95% confidence interval, 0.920-0.979) for the identification of diabetes. Using a RPG cutoff of 200 mg/dL, sensitivity was 100%, specificity was 82%, and positive predictive value was 56%. Cost analyses showed that the mean cost to screen, per donor, was less than $1. Cost per case identified was estimated to be less than $500 for a RPG cutoff of 200 mg/dL.Screening during the blood donation process appears to be accurate, convenient, and inexpensive.

Objective To report the first known case of a successful outcome of pregnancy in a patient with generalized lipoatrophic diabetes. Methods We present a detailed case report of a patient who achieved and successfully completed a pregnancy despite having lipoatrophic diabetes. Results With careful attention to glycemic control with use of U-500 insulin and strict avoidance of dietary fat, a 23-year-old woman with lipoatrophic diabetes maintained a pregnancy to 28 weeks. The infant weighed 1,235 g and was devoid of serious metabolic complications. Three months after childbirth, the patient died of gastrointestinal bleeding. Conclusion We are not aware of any previously published report of a successful pregnancy in a patient with generalized, acquired lipoatrophic diabetes. Because of the involvement of multiple organ systems in generalized lipoatrophic diabetes, female patients should be thoroughly advised of the serious pregnancy-associated risks to both the mother and the fetus and the need for extremely close monitoring. (Endocr Pract. 2000;6:34-36)

Aims Experimental models support a role for the sympathetic nervous system in bone metabolism. Beta-adrenoreceptors have been demonstrated on osteoblast-like cells. Beta-blocker use is associated with higher bone mineral density (BMD) in some epidemiologic studies. The aim of this study was to determine if measures of the autonomic nervous system (ANS) were associated with reduced BMD in type 1 diabetes. Methods We studied 66 individuals with type 1 diabetes. Dual-energy X-ray absorptiometry was used to measure BMD and bone mineral content (BMC). Measures of heart rate variability (HRV) (e.g., power spectral analysis, mean circular resultant) and circulating norepinephrine levels were used to evaluate autonomic function. Results BMD/BMC were examined by gender for individuals with a normal versus elevated low-frequency (LF) band (expressed in normalized units). No significant differences in BMD/BMC were shown for individuals with an elevated LF band. Direct-entry linear regression models with BMD/BMC as the dependent variable were performed. Duration, gender, BMI, HbA 1c , insulin dose/kg, activity energy expenditure, and measures of HRV were entered as potential independent variables. No measures of HRV, or norepinephrine, were independently associated with BMD/BMC. Conclusions The ANS, as assessed by measures of HRV, does not appear to impact BMD/BMC in type 1 diabetes.

The prevalence of obesity is rising to epidemic proportions in many countries worldwide. Obesity seriously increases an individual's risk of developing many health problems including diabetes. Diabetes, like obesity, is also in epidemic proportions with 300 million adults predicted to have the disease by 2025. Investigating strategies for the prevention and treatment of obesity and diabetes is vitally important. Autonomic dysfunction is evident in both obesity and diabetes. In persons with diabetes, impaired cardiovascular autonomic activity is characterized by a reduction in parasympathetic tone with a relative increase in sympathetic activity and is specifically associated with a number of clinically significant manifestations including exercise intolerance, intraoperative cardiovascular lability, orthostatic hypotension, silent myocardial ischemia, and increased risk of mortality. In obesity, parasympathetic function is decreased while regional heterogeneity of increased sympathetic activity may occur. Autonomic dysfunction increases cardiovascular workload, hemodynamic stress, serious dysrhythmias, and significant cardiac pathology. Thus, cardiac autonomic imbalance may also be an important link between obesity and increased morbidity and mortality. Beyond the obese and diabetic state, multiple variables associated with these conditions such as insulin, glucose, leptin, adiponectin and free fatty acids have an affect on the autonomic nervous system. Autonomic disturbances, however, appear to be reversible with weight reduction. Since autonomic imbalance is a marker of adverse risk, improvement obtained from weight loss should be beneficial for the health of individuals with obesity and diabetes. This overview will examine the relationship of the autonomic nervous system in obesity and diabetes and explore the effect of weight loss on autonomic function.

Sleep-disordered breathing (SDB) is an independent risk factor for cardiovascular morbidity. Dysfunction of the cardiovascular autonomic nervous system may be a potential mechanism whereby SDB is linked to cardiovascular disease. Repetitive sympathetic activation during apneic episodes may impair cardiovascular reflex function, and increased sympathetic activity can stimulate renin release. Given that patients with SDB may have reduced cardiovascular autonomic function, the purpose of this study was to determine whether treatment with continuous positive airway pressure (CPAP) for 6 weeks would improve autonomic function.Twenty-nine participants with a diagnosis of SDB, who completed 6 weeks of CPAP therapy, were evaluated for cardiovascular autonomic nerve fiber function at baseline and post therapy. Autonomic function tests included the following: R-R interval variation during deep breathing measured by vector analysis (ie, mean circular resultant [MCR]) and expiration/inspiration (E/I) ratio; and the Valsalva maneuver. Participants were also evaluated prior to CPAP therapy for plasma renin activity levels.Participants in this study showed improved cardiovascular autonomic function after 6 weeks of treatment (baseline vs follow-up) as assessed by the mean (+/- SD) MCR (33.2 +/- 22.5 vs 36.9 +/- 24.2, respectively; p0.05) and E/I ratio (1.20 +/- 0.12 vs 1.24 +/- 0.14, respectively; p0.01). Improved vagal tone was also noted for subjects with elevated renin levels.Treatment of SDB with CPAP for 6 weeks improved vagal tone and may be beneficial in reducing the risk of developing clinical manifestations of cardiovascular autonomic dysfunction (eg, increased risk of mortality).