AMG 151 (ARRY-403), a novel glucokinase activator, decreases fasting and postprandial glycaemia in patients with type 2 diabetes.

Phase I studies have shown that AMG 151 activates glucokinase, a key enzyme in glucose homeostasis. The present randomized, placebo-controlled phase IIa study evaluated the dose-effect relationship of the glucokinase activator AMG 151 relative to placebo on fasting plasma glucose (FPG) in 236 patients (33-35 patients per arm) with type 2 diabetes treated with metformin. Patients received oral AMG 151 at 50, 100 or 200 mg twice daily, AMG 151 at 100, 200 or 400 mg once daily or matching placebo for 28 days. A significant linear dose-effect trend was observed with the twice-daily regimen (p = 0.004) for change in FPG to day 28. No trend was observed with the once-daily regimen. A higher incidence of hypoglycaemia and hypertriglyceridaemia was observed with AMG 151 administration. AMG 151 significantly reduced FPG when administered twice daily but not when administered once daily in patients with type 2 diabetes treated with metformin.

A review of treatment response in type 2 diabetes: assessing the role of patient heterogeneity.

The response to treatment for type 2 diabetes typically varies among individuals within a study population. This variation is known as heterogeneity of treatment response. We conducted a comprehensive literature review to identify factors that account for heterogeneity of treatment response in patients treated for type 2 diabetes. Three databases (PubMed, EMBASE and Cochrane Library) were searched for articles published in the last 10 years describing investigations of factors associated with treatment response and outcomes among people with type 2 diabetes receiving pharmacological treatment. Of the 43 articles extracted and summarized, 35 (81%) discussed clinical factors, 31 (72%) described sociodemographic factors and 17 (40%) reported on comorbidity or behavioural factors. Clinical factors identified included baseline glycated hemoglobin A1c or fasting plasma glucose (FPG) levels, insulin response or sensitivity, C-peptide, body composition, adipose tissue proteins, lipid profile, plasma albumin levels and duration of disease or insulin treatment. Other factors identified included age, sex, race, socioeconomic status and comorbidities. This review identified the following research gaps: use of multiple definitions for response, few patient-reported measures and lack of evidence regarding whether factors were associated with treatment response for only specific medications or across pharmacological therapies. Furthermore, identification of factors associated with type 2 diabetes treatment response was generally a secondary objective in the research reviewed. Understanding which patient subgroups are more likely to respond to treatment and identifying factors associated with response may result in targeted treatment decisions and alter the interpretation of efficacy or effectiveness of results. In conclusion, accounting for these factors in clinical trials and when making clinical treatment decisions may improve therapy selection and individual patient outcomes.

Accuracy of body mass index in diagnosing obesity in the adult general population.

BACKGROUND: Body mass index (BMI) is the most widely used measure to diagnose obesity. However, the accuracy of BMI in detecting excess body adiposity in the adult general population is largely unknown. METHODS: A cross-sectional design of 13 601 subjects (age 20-79.9 years; 49% men) from the Third National Health and Nutrition Examination Survey. Bioelectrical impedance analysis was used to estimate body fat percent (BF%). We assessed the diagnostic performance of BMI using the World Health Organization reference standard for obesity of BF%>25% in men and>35% in women. We tested the correlation between BMI and both BF% and lean mass by sex and age groups adjusted for race. RESULTS: BMI-defined obesity (> or =30 kg m(-2)) was present in 19.1% of men and 24.7% of women, while BF%-defined obesity was present in 43.9% of men and 52.3% of women. A BMI> or =30 had a high specificity (men=95%, 95% confidence interval (CI), 94-96 and women=99%, 95% CI, 98-100), but a poor sensitivity (men=36%, 95% CI, 35-37 and women=49%, 95% CI, 48-50) to detect BF%-defined obesity. The diagnostic performance of BMI diminished as age increased. In men, BMI had a better correlation with lean mass than with BF%, while in women BMI correlated better with BF% than with lean mass. However, in the intermediate range of BMI (25-29.9 kg m(-2)), BMI failed to discriminate between BF% and lean mass in both sexes. CONCLUSIONS: The accuracy of BMI in diagnosing obesity is limited, particularly for individuals in the intermediate BMI ranges, in men and in the elderly. A BMI cutoff of> or =30 kg m(-2) has good specificity but misses more than half of people with excess fat. These results may help to explain the unexpected better survival in overweight/mild obese patients.

Fatty acid desaturases in human adipose tissue: relationships between gene expression, desaturation indexes and insulin resistance.

AIMS/HYPOTHESIS: Fatty acid desaturases introduce double bonds into growing fatty acid chains. The key desaturases in humans are Delta5-desaturase (D5D), Delta6-desaturase (D6D) and stearoyl-CoA desaturase (SCD). Animal and human data implicate hepatic desaturase activities in insulin resistance, obesity and dyslipidaemia. However, the role of desaturase activity in adipose tissue is uncertain. We therefore evaluated relationships between adipose mRNA expression, estimated desaturase activities (fatty acid ratios) in adipose tissue and insulin resistance. METHODS: Subcutaneous adipose tissue mRNA expression of D5D (also known as FADS1), D6D (also known as FADS2) and SCD was determined in 75 individuals representative of the study population of 294 healthy 63-year-old men. Desaturation indexes (product/substrate fatty acid ratios) were generated from adipose tissue fatty acid composition in all individuals. Insulin resistance was defined as the upper quartile of the updated homeostasis model assessment (HOMA-2) index. RESULTS: The relevant desaturation indexes (16:1/16:0, 18:1/18:0, 20:4/20:3 and 18:3/18:2) reflected expression of SCD, but not of D5D or D6D in adipose tissue. Insulin-resistant individuals had a higher adipose tissue 18:1/18:0, but not 16:1/16:0 ratio than insulin-sensitive individuals. Individuals with a high adipose tissue 18:1/18:0 ratio were 4.4-fold (95% CI 1.8-11.8) more likely to be insulin resistant [threefold (95% CI 1.1-8.6) after adjustment for waist circumference and plasma triacylglycerol]. In a multiple regression model predicting HOMA-2, the independent effect of the 18:1/18:0 ratio was borderline (p=0.086). CONCLUSIONS/INTERPRETATION: Adipose tissue desaturation indexes of SCD reflect the expression of the gene encoding the enzyme in this tissue. Elevated SCD activity within adipose tissue is closely coupled to the development of insulin resistance.

Recognition, diagnosis and management of obesity after myocardial infarction.

OBJECTIVE: We investigated the documentation of obesity as a medical problem, and subsequent management recommendations, in patients after myocardial infarction (MI). DESIGN: We performed a cross-sectional analysis of a randomly selected sample of 627 patients discharged after an MI, from five US teaching hospitals between 1/1/01 and 12/31/02. Information was extracted from clinical notes using standardized definitions. RESULTS: Mean body mass index (BMI) was 31+/-13 kg/m2, which was documented in only 14% of patients and had to be calculated post hoc in the rest. Waist circumference and waist/hip ratio were not documented at all; 83% of patients were overweight, 55% obese, and 8% morbidly obese. In only 20% of patients with BMI> or =30 kg/m2 was the diagnosis of obesity documented either as a current medical problem, as part of past medical history or as a final diagnosis. A dietary counseling was carried out in 61% of patients with BMI> or =25 kg/m2 and in 61% of patients with BMI<25 kg/m2, P=0.96. Weight loss was described as part of the goals/plan at discharge in 7% of overweight and 9% of obese patients. There was no change in either the level of recognition of obesity (22 vs 19%, P=0.3) or in the proportion of obese patients for whom weight loss was described as part of the goals/plan at discharge (8 vs 10%, P=0.7) before (n=301) compared to after (n=326) the Call to Action in Obesity by the Surgeon General in December 2001. CONCLUSION: Obesity is underecognized, underdiagnosed and undertreated in persons with acute MI.

Inhaled furosemide: a whole new mechanism of action.

The use of aerosolized furosemide has been increasing throughout Mexico, primarily because of its mechanism and site of action as well as its local and systemic effect. We hypothesize that its effect on the respiratory system is totally independent from its diuretic activity and that it is primarily caused by its interaction with the chlorine channels. Furthermore, there is also evidence that furosemide induces prostaglandin synthesis, blocks the sodium-calcium pump, producing relaxation of the smooth muscle that narrows the airway and causes reduced nerve responsiveness to the Neurokinin A produced in acute asthma attacks.