Heart failure signs and symptoms, hospital referrals, and prescription patterns in patients receiving sacubitril/valsartan in primary care and cardiologist settings in Germany.

AIMS: The aim of this paper was to analyse heart failure (HF) signs and symptoms, hospital referrals, and prescription patterns in patients receiving sacubitril/valsartan (sac/val) in primary care and cardiology settings in Germany. METHODS AND RESULTS: A retrospective cohort study of electronic medical records identified 1263 adults (aged ≥18 years) in the German IMS® Disease Analyzer database who were prescribed sac/val during 2016 and had at least 6 months of data following sac/val initiation. Clinical characteristics were collected during the 12 months before the first recorded sac/val prescription (index date) and 6 months post-index. Details of sac/val dose and prescription patterns were also recorded in the 6 months post-index. HF signs, symptoms, and all-cause hospital referrals were evaluated for 90 days pre-index and 30-120 days post-index. Most patients (62%) were prescribed the lowest sac/val dose of 24/26 mg twice daily (b.i.d.) at index; only 14% of patients initiated on 24/26 mg or 49/51 mg b.i.d. were up-titrated to the 97/103 mg b.i.d. target dose during the 6 months post-index, while 6% of patients initiated on either 49/51 mg or 97/103 mg b.i.d. were stably down-titrated. Evaluation of prescription patterns in relation to clinical characteristics did not clearly explain the reluctance to up-titrate in the majority of patients. More patients experienced HF signs or symptoms or all-cause referrals to hospital during the 90 days pre-index than during the 30-120 days post-index. CONCLUSIONS: The majority of patients receiving sac/val are not up-titrated, contrary to recommendations of the EU summary of product characteristics; this is not fully explained by patients' clinical characteristics. Further research is required to understand the reasons for clinician inertia.

Real-world treatment patterns of sacubitril/valsartan: a longitudinal cohort study in Germany.

AIMS: To analyse real-world treatment patterns of sacubitril/valsartan (sac/val) using data from a pharmacy database in Germany. METHODS AND RESULTS: A retrospective cohort study of 26 191 adult patients (aged ≥ 18 years) in the IMS® longitudinal prescriptions database in Germany who were dispensed sac/val from January 2016 to June 2017 was conducted. The analysis included sac/val dose titration assessed in the 6 months from first sac/val prescription; prescriptions of concomitant cardiovascular medications in the 6 months pre- and post-index and compliance and persistence during 12 months post-index. Two-thirds of patients were prescribed the lowest sac/val dose of 50 mg twice daily (b.i.d.) at index and up-titration during the first 6 months was attempted in 41% of these patients. Ten percent of patients prescribed 200 mg b.i.d. at index had to be stably down-titrated; among patients prescribed 50 or 100 mg b.i.d. at index that were up-titrated, > 80% remained on the higher dose. Overall, the mean daily diuretic dose decreased by 25% after initiation of sac/val. High compliance and persistence rates were observed across sac/val doses, increasing with higher sac/val dose at index. Prior dose of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker had only minor impact on first sac/val dose, compliance and persistence. CONCLUSIONS: Most patients prescribed sac/val are not initiated on the recommended dose nor up-titrated as recommended by the EU Summary of Product Characteristics. Initiation of sac/val was associated with high persistence and compliance and a dose reduction of diuretics. Barriers to up-titration must be explored.

Risk of Upper Gastrointestinal Bleeding and Gastroduodenal Ulcers in Persons With Schizophrenia: A Danish Cohort Study.

INTRODUCTION: There is little evidence about gastrointestinal (GI) disorders in patients with schizophrenia. We examined association of schizophrenia with upper GI bleeding (UGIB) and nonbleeding ulcers and associated risk factors and mortality. METHODS: We used the data linked from population-based registries in Denmark. Among patients with incident schizophrenia in 1980-2011, we computed cumulative incidences and standardized incidence ratios of UGIB, bleeding ulcers, and nonbleeding ulcers compared with the general population; evaluated risk factors for the 3 GI endpoints, including somatic and psychiatric comorbidity; and examined subsequent all-cause mortality. RESULTS: Among 39,998 patients with schizophrenia, the standardized incidence ratios were 2.92 (95% confidence interval (CI), 2.76-3.08) for UGIB, 2.36 (95% CI, 2.15-2.58) for bleeding ulcers, and 2.00 (95% CI, 1.87-2.15) for nonbleeding ulcers. Risk factors for UGIB and nonbleeding ulcers included age, somatic comorbidity, and medication use. UGIB and nonbleeding ulcers were associated with the subsequent increase in mortality. CONCLUSIONS: Schizophrenia is associated with an increased risk of UGIB and nonbleeding ulcers, whose risk factors in patients with schizophrenia are similar to those in the general population.

Perceptions of heart failure symptoms, disease severity, treatment decision-making, and side effects by patients and cardiologists: a multinational survey in a cardiology setting.

PURPOSE: Explore the extent to which heart failure (HF) symptoms and side effects of HF treatment experienced by patients are recognized by cardiologists, and concordance between patient-cardiologist perceptions of HF severity and patients' contributions to treatment decision-making. METHODS: A multinational, cross-sectional survey of cardiologists and patients with HF was conducted. Patient-record forms (PRFs) were completed by cardiologists for consecutive consulting patients with HF, who completed a patient self-completion questionnaire (PSC). Responses from PRFs with an associated PSC were analyzed to compare patient- and cardiologist-reported occurrences of HF symptoms and treatment side effects, patient-perceived severity of HF and cardiologists' perceived risk of death within 12 months, and patient input into treatment decisions. Concordance was calculated as the number of response agreements between PSCs and PRFs for total number of matched pairs. Over- or underreporting of symptoms and side effects by cardiologists relative to patient-reported occurrences were calculated. RESULTS: Overall, 2,454 patient-cardiologist pairs were identified. High levels of concordance between matched pairs were observed for the occurrence of reported HF symptoms (93%), side effects (77%-98%) and degree of patient input into treatment decisions (74%); for perceived HF severity, concordance was 54%. Most symptoms (except dyspnea when active and fatigue/weakness, experienced by >50% of patients) were underreported by cardiologists. Of patients reporting to have been informed by their cardiologist that their HF was mild, 28% were perceived by their cardiologist to have a moderate-high/very high risk of death within 12 months. Treatment choice was not discussed with almost a third of patients. When discussed, 94% of patients (n=1,540) reported the cardiologist made the final decision. Cardiologists more often under- than overreported the occurrence of side effects reported by patients. CONCLUSION: Improved patient-cardiologist dialogue and shared decision-making is required for optimizing patient care and outcomes in HF.

Characteristics of early sacubitril/valsartan patients and considerations for studies in electronic health record data.

AIM: We examined characteristics of early sacubitril/valsartan users in a large US electronic health records database. PATIENTS & METHODS: We identified three cohorts of patients with heart failure (HF): sacubitril/valsartan patients with a prior HF diagnosis; patients with HF with reduced ejection fraction; and patients with HF treated with an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker and a ß-blocker. RESULTS: Sacubitril/valsartan patients were younger than patients in the other cohorts; the mean age of sacubitril/valsartan patients increased by 2 years in the first 15 months of marketing. Most sacubitril/valsartan patients had prior use of HF treatment. CONCLUSION: Overall, sacubitril/valsartan patients resembled those in the HF with reduced ejection fraction cohort, and commonly used other drugs for HF.

Care pathways and treatment patterns for patients with heart failure in China: results from a cross-sectional survey.

PURPOSE: The objective of this study was to describe the clinical care pathways, management and treatment patterns, and hospitalizations for patients with heart failure (HF) in China. SUBJECTS AND METHODS: A cross-sectional survey of cardiologists and their patients with HF was conducted. Patient record forms were completed by 150 cardiologists for 10 consecutive patients. Patients for whom a patient record form was completed were invited to complete a patient self-completion questionnaire. RESULTS: Most of the 1,500 patients (mean [SD] age 66 [10] years; 55% male) included in the study received care in tier-2 and -3 hospitals in large cities. Cardiologists were responsible for initial consultation, diagnosis, and treatment of patients with HF. The use of guideline-recommended diagnostics was high. However, guideline-recommended double- and triple-combination therapy was received by only 51% and 18% of patients, respectively. In total, 20% of patients with HF reported that they were not consulted on the choice of therapy. Concordance was high (≥80%) between matched cardiologist and patient pairs for the occurrence of side effects, while cardiologists more often under- than overreported the occurrence of side effects of treatment reported by patients. CONCLUSION: The management of HF was predominantly overseen by cardiologists. The use of diagnostic tests was high, but the use of guideline-recommended treatment was low in this population. Improved communication between patients and cardiologists is essential to optimize treatment decision making and to increase awareness of treatment side effects.

Early insights into the characteristics and evolution of clinical parameters in a cohort of patients prescribed sacubitril/valsartan in Germany.

OBJECTIVES: This study aimed to provide early insights into sacubitril/valsartan (sac/val) prescription patterns and the demographic and clinical characteristics of patients prescribed sac/val in primary care and cardiology settings in Germany. METHODS: The study used electronic medical records from the German IMS® Disease Analyzer database. Patients with ≥1 prescription for sac/val during 1 January-31 December 2016 (n = 1643) were identified and followed up for ≤12 months from first prescription. Patients with ≥1 heart failure (HF) diagnosis during the study period, ≥1 additional HF diagnosis in the full history of the database, and ≥1 prescription for an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and a ß-blocker during the study period, without a prescription for sac/val (n = 25,264), were included as a reference cohort. Changes in clinical parameters in the 12 months before and after sac/val initiation were investigated and compared with those from the PARADIGM-HF study. RESULTS: The characteristics of patients prescribed sac/val more closely resembled those of patients enrolled in PARADIGM-HF (e.g. younger age, higher proportion of men than women, lower systolic blood pressure) than patients in the reference cohort. Most patients were initiated on the lowest dose of sac/val irrespective of clinical setting. Significant decreases (p < 0.001) in NT-proBNP and glycated haemoglobin levels were observed following sac/val initiation. CONCLUSIONS: Patients prescribed sac/val had similar baseline demographics and clinical characteristics to those from PARADIGM-HF, and most patients were initiated on the lowest dose. Changes in clinical parameters before and after initiation mirrored findings from the PARADIGM-HF study.

Genetic disruption of SOD1 gene causes glucose intolerance and impairs ß-cell function.

Oxidative stress has been associated with insulin resistance and type 2 diabetes. However, it is not clear whether oxidative damage is a cause or a consequence of the metabolic abnormalities present in diabetic subjects. The goal of this study was to determine whether inducing oxidative damage through genetic ablation of superoxide dismutase 1 (SOD1) leads to abnormalities in glucose homeostasis. We studied SOD1-null mice and wild-type (WT) littermates. Glucose tolerance was evaluated with intraperitoneal glucose tolerance tests. Peripheral and hepatic insulin sensitivity was quantitated with the euglycemic-hyperinsulinemic clamp. ß-Cell function was determined with the hyperglycemic clamp and morphometric analysis of pancreatic islets. Genetic ablation of SOD1 caused glucose intolerance, which was associated with reduced in vivo ß-cell insulin secretion and decreased ß-cell volume. Peripheral and hepatic insulin sensitivity were not significantly altered in SOD1-null mice. High-fat diet caused glucose intolerance in WT mice but did not further worsen the glucose intolerance observed in standard chow-fed SOD1-null mice. Our findings suggest that oxidative stress per se does not play a major role in the pathogenesis of insulin resistance and demonstrate that oxidative stress caused by SOD1 ablation leads to glucose intolerance secondary to ß-cell dysfunction.

The fate of taspoglutide, a weekly GLP-1 receptor agonist, versus twice-daily exenatide for type 2 diabetes: the T-emerge 2 trial.

OBJECTIVE: Taspoglutide is a long-acting glucagon-like peptide 1 receptor agonist developed for treatment of type 2 diabetes. The efficacy and safety of once-weekly taspoglutide was compared with twice-daily exenatide. RESEARCH DESIGN AND METHODS: Overweight adults with inadequately controlled type 2 diabetes on metformin ± a thiazolidinedione were randomized to subcutaneous taspoglutide 10 mg weekly (n = 399), taspoglutide 20 mg weekly (n = 398), or exenatide 10 µg twice daily (n = 392) in an open-label, multicenter trial. The primary end point was change in HbA(1c) after 24 weeks. RESULTS: Mean baseline HbA(1c) was 8.1%. Both doses of taspoglutide reduced HbA(1c) significantly more than exenatide (taspoglutide 10 mg: -1.24% [SE 0.09], difference -0.26, 95% CI -0.37 to -0.15, P < 0.0001; taspoglutide 20 mg: -1.31% [0.08], difference -0.33, -0.44 to -0.22, P < 0.0001; exenatide: -0.98% [0.08]). Both taspoglutide doses reduced fasting plasma glucose significantly more than exenatide. Taspoglutide reduced body weight (taspoglutide 10 mg, -1.6 kg; taspoglutide 20 mg, -2.3 kg) as did exenatide (-2.3 kg), which was greater than with taspoglutide 10 mg (P < 0.05). HbA(1c) and weight effects were maintained after 52 weeks. More adverse events with taspoglutide 10 and 20 mg than exenatide developed over time (nausea in 53, 59, and 35% and vomiting in 33, 37, and 16%, respectively). Allergic and injection-site reactions were more common with taspoglutide. Discontinuations were greater with taspoglutide. Antitaspoglutide antibodies were detected in 49% of patients. CONCLUSIONS: Once-weekly taspoglutide demonstrated greater glycemic control than twice-daily exenatide with comparable weight loss, but with unacceptable levels of nausea/vomiting, injection-site reactions, and systemic allergic reactions.

ß-Adrenergic Responsive Induction of Insulin Resistance in Liver of Aging Rats.

INTRODUCTION. We previously demonstrated increases in ß-adrenergic receptor (ß-AR) density in rat liver, in association with increased ß-AR-mediated stimulation of glucose output in rat hepatocytes, during senescent aging. We therefore hypothesized that pharmacologic ß-adrenergic stimulation might induce insulin resistance and glucose output in liver of aging rats in vivo. METHODS. In this study, pancreatic clamps were performed on young adult (4-month-old) and senescent (24-month-old) Fischer 344 male rats by infusing somatostatin (3 µg/kg/min) at time 0 to inhibit insulin secretion, and then infusing insulin (1 mU/kg/min) to replace basal insulin concentrations. At time 0 rats also received either the ß-AR agonist isoproterenol (100 ng/kg/min) or saline (control). After 120 min the insulin infusion rate was increased to 4 mU/kg/min for an additional 120 min. Tritiated glucose was infused throughout the study to measure glucose turnover rates. RESULTS AND CONCLUSION. The results of the pancreatic clamp studies demonstrated that under saline control conditions hepatic glucose production (HGP) was suppressed during hyperinsulinemia in both young and old rats, with a trend toward reduced insulin sensitivity in the older animals. Isoproterenol infusion impaired insulin-induced suppression of HGP in both age groups. The results suggest that ß-AR stimulation by isoproterenol increases HGP and acutely induces hepatic insulin resistance in both young and old rats. A similar role for ß-adrenergic-mediated hepatic insulin resistance in aging humans would suggest a novel therapeutic target for the treatment or prevention of glucose dysregulation and diabetes developing with advancing age.

Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis.

UNLABELLED: Pioglitazone treatment improves insulin resistance (IR), glucose metabolism, hepatic steatosis, and necroinflammation in patients with nonalcoholic steatohepatitis (NASH). Because abnormal lipid metabolism/elevated plasma free fatty acids (FFAs) are important to the pathophysiology of NASH, we examined the impact of pioglitazone therapy on adipose tissue insulin resistance (Adipo-IR) during the treatment of patients with NASH. To this end, we assessed glucose/lipid metabolism in 47 patients with impaired glucose tolerance/type 2 diabetes mellitus and NASH and 20 nondiabetic controls. All individuals underwent a 75-g oral glucose tolerance test (OGTT) in which we measured glucose tolerance, IR, and suppression of plasma FFAs. We also measured Adipo-IR index (fasting, FFAs x insulin), hepatic fat by magnetic resonance spectroscopy, and liver histology (liver biopsy). Patients were randomized (double-blind) to diet plus pioglitazone (45 mg/day) or placebo for 6 months, and all measurements were repeated. We found that patients with NASH had severe Adipo-IR and low adiponectin levels. Fasting FFAs were increased and their suppression during the OGTT was impaired. Adipo-IR was strongly associated with hepatic fat (r= 0.54) and reduced glucose clearance both fasting (r=0.34) and during the OGTT (r=0.40, all P <0.002). Pioglitazone significantly improved glucose tolerance and glucose clearance, steatosis and necroinflammation (all P<0.01-0.001 versus placebo). Fasting/postprandial plasma FFAs decreased to levels of controls with pioglitazone (P<0.02 versus placebo). Adipo-IR decreased by 47% and correlated with the reduction of hepatic fat (r=0.46, P=0.009) and with the reduction in hepatic necroinflammation (r=0.47, P=0.0007). CONCLUSION: Patients with NASH have severe Adipo-IR independent of the degree of obesity. Amelioration of Adipo-IR by pioglitazone is closely related to histological improvement and plays an important role during treatment of patients with NASH.

Whole body overexpression of PGC-1alpha has opposite effects on hepatic and muscle insulin sensitivity.

Type 2 diabetes is characterized by fasting hyperglycemia, secondary to hepatic insulin resistance and increased glucose production. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) is a transcriptional coactivator that is thought to control adaptive responses to physiological stimuli. In liver, PGC-1alpha expression is induced by fasting, and this effect promotes gluconeogenesis. To examine whether PGC-1alpha is involved in the pathogenesis of hepatic insulin resistance, we generated transgenic (TG) mice with whole body overexpression of human PGC-1alpha and evaluated glucose homeostasis with a euglycemic-hyperinsulinemic clamp. PGC-1alpha was moderately (approximately 2-fold) overexpressed in liver, skeletal muscle, brain, and heart of TG mice. In liver, PGC-1alpha overexpression resulted in increased expression of hepatocyte nuclear factor-4alpha and the gluconeogenic enzymes phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. PGC-1alpha overexpression caused hepatic insulin resistance, manifested by higher glucose production and diminished insulin suppression of gluconeogenesis. Paradoxically, PGC-1alpha overexpression improved muscle insulin sensitivity, as evidenced by elevated insulin-stimulated Akt phosphorylation and peripheral glucose disposal. Content of myoglobin and troponin I slow protein was increased in muscle of TG mice, indicating fiber-type switching. PGC-1alpha overexpression also led to lower reactive oxygen species production by mitochondria and reduced IKK/IkappaB signaling in muscle. Feeding a high-fat diet to TG mice eliminated the increased muscle insulin sensitivity. The dichotomous effect of PGC-1alpha overexpression in liver and muscle suggests that PGC-1alpha is a fuel gauge that couples energy demands (muscle) with the corresponding fuel supply (liver). Thus, under conditions of physiological stress (i.e., prolonged fast and exercise training), increased hepatic glucose production may help sustain glucose utilization in peripheral tissues.

Deleterious action of FA metabolites on ATP synthesis: possible link between lipotoxicity, mitochondrial dysfunction, and insulin resistance.

Insulin resistance is a characteristic feature of type 2 diabetes and obesity. Insulin-resistant individuals manifest multiple disturbances in free fatty acid (FFA) metabolism and have excessive lipid accumulation in insulin target tissues. Although much evidence supports a causal role for altered FFA metabolism in the development of insulin resistance, i.e., "lipotoxicity", the intracellular mechanisms by which elevated plasma FFA levels cause insulin resistance have yet to be completely elucidated. Recent studies have implicated a possible role for mitochondrial dysfunction in the pathogenesis of insulin resistance in skeletal muscle. We examined the effect of FFA metabolites [palmitoyl carnitine (PC), palmitoyl-coenzyme A (CoA), and oleoyl-CoA] on ATP synthesis in mitochondria isolated from mouse and human skeletal muscle. At concentrations ranging from 0.5 to 2 microM, these FFA metabolites stimulated ATP synthesis; however, above 5 microM, there was a dose-response inhibition of ATP synthesis. Furthermore, 10 microM PC inhibits ATP synthesis from pyruvate. Elevated PC concentrations (> or =10 microM) inhibit electron transport chain activity and decrease the mitochondrial inner membrane potential. These acquired mitochondrial defects, caused by a physiological increase in the concentration of FFA metabolites, provide a mechanistic link between lipotoxicity, mitochondrial dysfunction, and muscle insulin resistance.

Effect of acute physiological hyperinsulinemia on gene expression in human skeletal muscle in vivo.

This study was undertaken to test the hypothesis that short-term exposure (4 h) to physiological hyperinsulinemia in normal, healthy subjects without a family history of diabetes would induce a low grade inflammatory response independently of glycemic status. Twelve normal glucose tolerant subjects received a 4-h euglycemic hyperinsulinemic clamp with biopsies of the vastus lateralis muscle. Microarray analysis identified 121 probe sets that were significantly altered in response to physiological hyperinsulinemia while maintaining euglycemia. In normal, healthy human subjects insulin increased the mRNAs of a number of inflammatory genes (CCL2, CXCL2 and THBD) and transcription factors (ATF3, BHLHB2, HES1, KLF10, JUNB, FOS, and FOSB). A number of other genes were upregulated in response to insulin, including RRAD, MT, and SGK. CITED2, a known coactivator of PPARalpha, was significantly downregulated. SGK and CITED2 are located at chromosome 6q23, where we previously detected strong linkage to fasting plasma insulin concentrations. We independently validated the mRNA expression changes in an additional five subjects and closely paralleled the results observed in the original 12 subjects. A saline infusion in healthy, normal glucose-tolerant subjects without family history of diabetes demonstrated that the genes altered during the euglycemic hyperinsulinemic clamp were due to hyperinsulinemia and were unrelated to the biopsy procedure per se. The results of the present study demonstrate that insulin acutely regulates the levels of mRNAs involved in inflammation and transcription and identifies several candidate genes, including HES1 and BHLHB2, for further investigation.

Decreased non-insulin-dependent glucose clearance contributes to the rise in fasting plasma glucose in the nondiabetic range.

OBJECTIVE: To assess the contribution of decreased glucose clearance to the rise in fasting plasma glucose (FPG) in the nondiabetic range. RESEARCH DESIGN AND METHODS: A total of 120 subjects with normal glucose tolerance received an oral glucose tolerance test and euglycemic insulin clamp with 3-[(3)H]glucose. The basal and insulin-stimulated rates of glucose appearance, glucose disappearance, and glucose clearance and the basal hepatic insulin resistance index were calculated. Simple Pearson's correlation was used to assess the relationship between variables. RESULTS: The increase in FPG (range 75-125 mg/dl) correlated (r = 0.32, P < 0.0001) with the increase in BMI (20-50 kg/m(2)). The fasting plasma insulin (FPI) concentration also increased progressively with the increase in BMI (r = 0.62, P < 0.0001). However, despite increasing FPI, the basal glucose clearance rate declined and correlated with the increase in BMI (r = -0.56, P < 0.0001). Basal hepatic glucose production (HGP) decreased with increasing BMI (r = -0.51, P < 0.0001) and correlated inversely with the increase in FPI (r = -0.32, P < 0.0001). The hepatic insulin resistance (basal HGP x FPI) increased with rising BMI (r = 0.52, P < 0.0001). During the insulin clamp, glucose disposal declined with increasing BMI (r = -0.64, P < 0.0001) and correlated with the basal glucose clearance (r = 0.39, P < 0.0001). CONCLUSIONS: These results demonstrate that in nondiabetic subjects, rising FPG is associated with a decrease (not an increase) in basal hepatic glucose production and is explained by a reduction in glucose clearance.

Peripheral disruption of the Grb10 gene enhances insulin signaling and sensitivity in vivo.

Grb10 is a pleckstrin homology and Src homology 2 domain-containing protein that interacts with a number of phosphorylated receptor tyrosine kinases, including the insulin receptor. In mice, Grb10 gene expression is imprinted with maternal expression in all tissues except the brain. While the interaction between Grb10 and the insulin receptor has been extensively investigated in cultured cells, whether this adaptor protein plays a positive or negative role in insulin signaling and action remains controversial. In order to investigate the in vivo role of Grb10 in insulin signaling and action in the periphery, we generated Grb10 knockout mice by the gene trap technique and analyzed mice with maternal inheritance of the knockout allele. Disruption of Grb10 gene expression in peripheral tissues had no significant effect on fasting glucose and insulin levels. On the other hand, peripheral-tissue-specific knockout of Grb10 led to significant overgrowth of the mice, consistent with a role for endogenous Grb10 as a growth suppressor. Loss of Grb10 expression in insulin target tissues, such as skeletal muscle and fat, resulted in enhanced insulin-stimulated Akt and mitogen-activated protein kinase phosphorylation. Hyperinsulinemic-euglycemic clamp studies revealed that disruption of Grb10 gene expression in peripheral tissues led to increased insulin sensitivity. Taken together, our results provide strong evidence that Grb10 is a negative regulator of insulin signaling and action in vivo.

Pioglitazone treatment increases whole body fat but not total body water in patients with non-alcoholic steatohepatitis.

BACKGROUND/AIMS: Non-Alcoholic Steatohepatitis (NASH) is a chronic liver disease frequently associated with insulin resistance and type 2 diabetes mellitus (T2DM). Pioglitazone reverses the metabolic and histological abnormalities of patients with impaired glucose tolerance or T2DM and NASH, but also leads to weight gain. To understand the nature of weight gain associated with pioglitazone treatment in NASH we analyzed 35 patients who completed tests for determination of whole body fat (WBF) and total body water (TBW). METHODS: Twenty-one patients received pioglitazone and 14 placebo in a double-blind, randomized fashion for a period of 6 months. WBF and TBW were measured before and after treatment using DXA, a water dilution technique and bioimpedance. RESULTS: Pioglitazone increased body weight (from 93.6+/-4.2 to 96.1+/-4.5 kg, p<0.003) and WBF measured with DXA (from 32.9+/-2.1 to 35.4+/-2.5 kg, p<0.002) while no changes were seen with placebo. Total body water was not altered significantly either after pioglitazone (from 45.4+/-2.3 to 45.6+/-2.7 l, p=NS) or placebo. Muscle hydration and extracellular water were unchanged both by pioglitazone and placebo treatments. CONCLUSIONS: Six months of pioglitazone treatment in patients with NASH is associated with weight gain that is attributable to an increase in adipose tissue mass and not to water retention.

The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients.

AIMS/HYPOTHESIS: Vildagliptin is a selective dipeptidyl peptidase IV inhibitor that augments meal-stimulated levels of biologically active glucagon-like peptide-1. Chronic vildagliptin treatment decreases postprandial glucose levels and reduces hemoglobin A1c in type 2 diabetic patients. However, little is known about the mechanism(s) by which vildagliptin promotes reduction in plasma glucose concentration. METHODS: Sixteen patients with type 2 diabetes (age, 48+/-3 yr; body mass index, 34.4+/-1.7 kg/m2; hemoglobin A1c, 9.0+/-0.3%) participated in a randomized, double-blind, placebo-controlled trial. On separate days patients received 100 mg vildagliptin or placebo at 1730 h followed 30 min later by a meal tolerance test (MTT) performed with double tracer technique (3-(3)H-glucose iv and 1-(14)C-glucose orally). RESULTS: After vildagliptin, suppression of endogenous glucose production (EGP) during 6-h MTT was greater than with placebo (1.02+/-0.06 vs. 0.74+/-0.06 mg.kg-1.min-1; P=0.004), and insulin secretion rate increased by 21% (P=0.003) despite significant reduction in mean plasma glucose (213+/-4 vs. 230+/-4 mg/dl; P=0.006). Consequently, insulin secretion rate (area under the curve) divided by plasma glucose (area under the curve) increased by 29% (P=0.01). Suppression of plasma glucagon during MTT was 5-fold greater with vildagliptin (P<0.02). The decline in EGP was positively correlated (r=0.55; P<0.03) with the decrease in fasting plasma glucose (change=-14 mg/dl). CONCLUSIONS: During MTT, vildagliptin augments insulin secretion and inhibits glucagon release, leading to enhanced suppression of EGP. During the postprandial period, a single dose of vildagliptin reduced plasma glucose levels by enhancing suppression of EGP.

Muscle and liver insulin resistance indexes derived from the oral glucose tolerance test.

OBJECTIVE: To derive indexes for muscle and hepatic insulin sensitivity from the measurement of plasma glucose and insulin concentrations during an oral glucose tolerance test (OGTT). RESEARCH DESIGN AND METHODS: A total of 155 subjects of Mexican-American origin (58 male and 97 female, aged 18-70 years, BMI 20-65 kg/m(2)) with normal glucose tolerance (n = 100) or impaired glucose tolerance (n = 55) were studied. Each subject received a 75-g OGTT and a euglycemic insulin clamp in combination with tritiated glucose. The OGTT-derived indexes of muscle and hepatic insulin sensitivity were compared with hepatic and muscle insulin sensitivity, which was directly measured with the insulin clamp, by correlation analysis. RESULTS: The product of total area under curve (AUC) for glucose and insulin during the first 30 min of the OGTT (glucose(0-30)[AUC] x insulin(0-30)[AUC]) strongly correlated with the hepatic insulin resistance index (fasting plasma insulin x basal endogenous glucose production) (r = 0.64, P < 0.0001). The rate of decay of plasma glucose concentration from its peak value to its nadir during the OGTT divided by the mean plasma insulin concentration (dG/dt / I) strongly correlated with muscle insulin sensitivity measured with the insulin clamp (P = 0.78, P < 0.0001). CONCLUSIONS: Novel estimates for hepatic and muscle insulin resistance from OGTT data are presented for quantitation of insulin sensitivity in nondiabetic subjects.

A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis.

BACKGROUND: No pharmacologic therapy has conclusively proved to be effective for the treatment of nonalcoholic steatohepatitis, which is characterized by insulin resistance, steatosis, and necroinflammation with or without centrilobular fibrosis. Pioglitazone is a thiazolidinedione that ameliorates insulin resistance and improves glucose and lipid metabolism in type 2 diabetes mellitus. METHODS: We randomly assigned 55 patients with impaired glucose tolerance or type 2 diabetes and liver biopsy-confirmed nonalcoholic steatohepatitis to 6 months of treatment with a hypocaloric diet (a reduction of 500 kcal per day in relation to the calculated daily intake required to maintain body weight) plus pioglitazone (45 mg daily) or a hypocaloric diet plus placebo. Before and after treatment, we assessed hepatic histologic features, hepatic fat content by means of magnetic resonance spectroscopy, and glucose turnover during an oral glucose tolerance test ([14C]glucose given with the oral glucose load and [3H]glucose given by intravenous infusion). RESULTS: Diet plus pioglitazone, as compared with diet plus placebo, improved glycemic control and glucose tolerance (P<0.001), normalized liver aminotransferase levels as it decreased plasma aspartate aminotransferase levels (by 40% vs. 21%, P=0.04), decreased alanine aminotransferase levels (by 58% vs. 34%, P<0.001), decreased hepatic fat content (by 54% vs. 0%, P<0.001), and increased hepatic insulin sensitivity (by 48% vs. 14%, P=0.008). Administration of pioglitazone, as compared with placebo, was associated with improvement in histologic findings with regard to steatosis (P=0.003), ballooning necrosis (P=0.02), and inflammation (P=0.008). Subjects in the pioglitazone group had a greater reduction in necroinflammation (85% vs. 38%, P=0.001), but the reduction in fibrosis did not differ significantly from that in the placebo group (P=0.08). Fatigue and mild lower-extremity edema developed in one subject who received pioglitazone; no other adverse events were observed. CONCLUSIONS: In this proof-of-concept study, the administration of pioglitazone led to metabolic and histologic improvement in subjects with nonalcoholic steatohepatitis. Larger controlled trials of longer duration are warranted to assess the long-term clinical benefit of pioglitazone. (ClinicalTrials.gov number, NCT00227110 [ClinicalTrials.gov] .).