Relationship between insulin-mediated glucose disposal and lipid metabolism in man.

To assess the possible effects of lipid metabolism on insulin-mediated glucose disposal, 18 nondiabetic Pima Indian women (age 18-35 yr) were studied using 1-14C-palmitate infusion to measure free fatty acid turnover rate followed by a euglycemic clamp (clamp) to measure in vivo insulin-mediated glucose disposal (M). Indirect calorimetry was performed in the basal state and during the clamp. This was used to assess glucose oxidation rate, lipid oxidation rate, and to calculate nonoxidative glucose disposal (storage). Basal and clamp lipid oxidation rate correlated with basal plasma free fatty acid concentration (r = 0.81, P less than or equal to 0.0001, r = 0.67, P less than 0.003, respectively). The fall in lipid oxidation was highly correlated with the increase in glucose oxidation during the insulin infusion (r = 0.96, P less than or equal to 0.0001). The clamp lipid oxidation rate negatively correlated with the glucose oxidation rate (r = -0.85, P less than 0.0001) and with the M value (r = -0.60, P less than 0.01) but was not correlated with the clamp glucose storage (r = -0.2, P = 0.4). On the other hand, glucose storage appeared to make a greater contribution to the difference in M value between the upper and lower extremes of M than did glucose oxidation, as evidenced by an increase in glucose storage of 0.59 mg/kg fat-free mass times minute per 1 mg/kg fat-free mass times minute increase in glucose disposal. The M value was negatively correlated with obesity as measured by percent body fat (r = -0.64, P less than 0.004), but neither basal free fatty acid concentration, basal free fatty acid turnover, basal lipid oxidation, nor clamp lipid oxidation correlated with percent body fat. We conclude that an interaction of lipid and glucose metabolism in a glucose fatty acid cycle, as proposed by Randle et al. (1), may be operative in the regulation of glucose oxidation in man. The disposal of glucose however has two components. The storage component does not appear to be associated with lipid oxidation in the way that the oxidative component is and may be regulated by a different mechanism. Since the results show that the glucose storage component plays a significant role in distinguishing between those with low and high M values, we suggest that the glucose fatty acid cycle can, at best, only partially explain impaired in vivo insulin-mediated glucose disposal. Furthermore, the data suggest that the impact of obesity on in vivo insulin resistance appears to be mediated by factors other than changes in lipid availability or metabolism.     

Fetal gallstones

Routine obstetric ultrasound (US) examinations in a 33-year-old woman revealed a normal fetal gallbladder at 24 menstrual weeks but multiple structures in the gallbladder with findings typical of gallstones at 37 menstrual weeks. No other abnormalities were present. Three days after a term delivery, an abdominal US examination again demonstrated multiple gallstones. When the infant was 6 weeks old, a follow-up abdominal US study showed no evidence of gallstones. This case, as well as one previously reported, demonstrates that findings typical of gallstones may be seen in the fetus, and that these structures may spontaneously resolve.     

PREVALENCE OF MITRAL VALVE PROLAPSE IN HONG KONG CHINESE A CLINICAL AND AUTOPSY STUDY

The prevalence of mitral valve pro.lapse in Chinese was determined by screening 156 heal- thy subjects and by patholobic examination of 86 adult autopsies. Mitral valve prolapse was found in 7.7% in the clinical study and 5.8% in the autopsy study. A slight female preponderance was noted.     

Congenital susceptibility to NIDDM. Role of intrauterine environment

Non-insulin-dependent diabetes mellitus (NIDDM) during pregnancy in Pima Indian women results in offspring who have a higher prevalence of NIDDM (45%) at age 20-24 yr than in offspring of nondiabetic women (1.4%) or offspring of prediabetic women (8.6%), i.e., women who developed diabetes only after the pregnancy. These differences persist after taking into account paternal diabetes, age at onset of diabetes in the parents, and the offspring's weight relative to height. The findings suggest that the intrauterine environment is an important determinant of the development of diabetes and that its effect is in addition to effects of genetic factors.     

Distribution of in vivo insulin action in Pima Indians as mixture of three normal distributions

If a single gene produced insulin resistance, with environmental effects creating some additional variance, insulin action might be distributed as a mixture of two normal distributions if the gene is dominant or recessive or as a mixture of three normal distributions if the gene is codominant. To estimate maximal insulin-stimulated glucose uptake rates (MaxMs), hyperinsulinemic-euglycemic clamps were performed on 245 nondiabetic Pima Indians (126 men, 119 women). Five models (for 1, 2, 3, 4, or 5 components each, normally distributed with a common variance) were fitted to the frequency distribution of MaxM by iterative maximum-likelihood estimation. The three-component model fit the data significantly better than a single normal distribution (chi 2 = 14.3 with 4 df P less than .01) or a mixture of two normal distributions (chi 2 = 9.9 with 2 df, P less than .01). Mixtures of four or five normal distributions did not fit the data significantly better than a mixture of three normal distributions. The first component of the distribution comprised 23%, the second 48%, and the third 29% of the total distribution. Similarly, the frequency distributions of fasting plasma insulin concentrations and a principal component score derived from MaxM and fasting insulin were best fitted by a mixture of three normal distributions. These results are consistent with the hypothesis that among Pimas, insulin resistance is determined by a single gene with a codominant mode of inheritance. Segregation analyses of studies performed in pedigrees are indicated to prove or disprove this genetic hypothesis.     

Clinical experience with docetaxel for Chinese breast cancer patients: Hematological toxicity profiles

BACKGROUND: Asians are generally regarded to tolerate cytotoxic drugs less well than their Caucasian counterpart. A substantial proportion of patients receive suboptimal doses of chemotherapy for fear of severe toxicity. This retrospective study aims to evaluate the adverse events, especially hematological, of docetaxel in Chinese patients with breast cancer. PATIENTS AND METHODS: Fifty-nine patients, age ranged from 33 to 70 (median=47) years, were assigned to receive 3 to 6 (median=4) cycles of Docetaxel 100 mg/m2 every 21 days as neoadjuvant (n=3), adjuvant (n=26), neoadjuvant plus adjuvant (n=3), or active therapy for metastatic or relapsed breast cancer (n=27). RESULTS: A total of 56 (95%) patients completed the assigned whole regimen and only 3 (5%) patients discontinued due to either poor tolerance to the drug's side effects or worsening of disease leading to death. On average, the received dose intensity (RDI) was 0.86 for docetaxel 100 mg/m2 in this study. Among all the clinical adverse events, hematological toxicities were not excessively higher. Of the total 59 patients, major adverse events of all grades were leukopenia (22%), neutropenia (20%), fever (19%), and febrile neutropenia (14%). Only 12% and 14% of patients experienced grade 3 or 4 leukopenia and neutropenia, respectively. CONCLUSION: In view of the increasing breast cancer incidence and the acceptable toxicity profile of docetaxel among Chinese patients, a dosage of 100 mg/m2 can be recommended for use among Asians.     

Increasing incidence of proteinuria and declining incidence of end-stage renal disease in diabetic Pima Indians

The introduction of more efficacious treatments for diabetic kidney disease may slow its progression, but evidence for their effectiveness in populations is sparse. We examined trends in the incidence of clinical proteinuria, defined as a urinary protein-to-creatinine ratio >0.5 g/g, and diabetic end-stage renal disease (ESRD), defined as death from diabetic nephropathy or onset of dialysis, in Pima Indians with type 2 diabetes between 1967 and 2002. The study included 2189 diabetic subjects >/=25 years old. During follow-up, 366 incident cases of proteinuria occurred in the subset of 1715 subjects without proteinuria at baseline. The age-sex-adjusted incidence rate of proteinuria increased from 24.3 cases/1000 person-years (pyrs) (95% confidence interval (CI) 18.7-30.0) in 1967-1978 to 35.4 cases/1000 pyrs (95% CI 28.1-42.8) in 1979-1990 and 38.9 cases/1000 pyrs (95% CI 31.2-46.5) in 1991-2002 (P(trend)<0.0002). In each period, the age-sex-adjusted incidence of proteinuria increased with diabetes duration, but diabetes duration-specific incidence was stable throughout the study period (P=0.8). The age-sex-adjusted incidence of ESRD increased between 1967 and 1990 and declined thereafter. The incidence of proteinuria increased over 36 years in Pima Indians as the proportion of people with diabetes of long duration increased. On the other hand, the incidence of ESRD declined after 1990, coinciding with improved control of blood pressure, hyperglycemia, and perhaps other risk factors.