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S Lillioja

Publications and source records attributed to S Lillioja.

At least 37 records · Page 2Linked to original sources
PubMed1991

Peripheral lymphatic cannulation for physiological analysis of interstitial fluid compartment in humans.

Analysis of peripheral interstitial concentrations of hormones or substrates in humans has undoubtedly been hampered by the difficulty in performing retrograde peripheral lymphatic cannulation and obtaining adequate flow rates of lymph. We now describe a technique for direct continuous sampling of peripheral lymph. A lymphatic vessel was cannulated in the lower legs of 14 males, and lymph was collected for 24-48 h. Adequate quantities of lymph were obtained basally and during physiological manipulations to make collections at 15-min intervals. Flow rates averaged 1.84 ml/h and ranged from 0.34 to 4.96 ml/h. We conclude that peripheral lymphatic vessels can be cannulated and flow rates are sufficient to measure interstitial concentration of hormones or substrates both at steady state and dynamically in adult humans.

Adult↗
PubMed1991

Insulin resistance associated with lower rates of weight gain in Pima Indians.

UNLABELLED: Insulin resistance is commonly associated with obesity and noninsulin-dependent diabetes. Whereas it predicts the development of diabetes, its effect on body weight change is unknown. We measured glucose disposal rates at submaximally- and maximally-stimulating insulin concentrations in 192 nondiabetic Pima Indians and followed their weight change over 3.5 +/- 1.8 y (mean +/- SD). RESULTS: (a) Insulin-resistant subjects gained less weight than insulin-sensitive subjects (3.1 vs. 7.6 kg, P less than 0.0001). (b) The percent weight change per year correlated with glucose disposal at submaximally-(r = 0.19, P less than 0.01) and maximally-stimulating (r = 0.34, P less than 0.0001) insulin concentrations independent of sex, age, initial weight, and 24-h energy expenditure; the correlations were stronger for glucose oxidation than for glucose storage. (c) Weight gain was associated with an increase in insulin resistance more than four times that predicted from the cross-sectional data. We conclude that insulin resistance is associated with a reduced risk of weight gain in nondiabetic Pima Indians.

Adolescent↗
PubMed1991

Exaggerated early insulin release and insulin resistance in a diabetes-prone population: a metabolic comparison of Pima Indians and Caucasians.

Pima Indians have the highest reported prevalence rate of noninsulin-dependent diabetes mellitus (NIDDM) in the world, so that metabolic comparisons with caucasians, who have a much lower rate, should provide insights into the pathogenesis of NIDDM. We have compared 81 caucasians with 211 Pima Indian nondiabetic subjects similar in age, sex, degree of obesity, and glucose tolerance. During a hyperinsulinemic euglycemic clamp at physiological insulin concentrations, Pima Indians were 17% more insulin resistant than caucasians after accounting for any differences in degree of obesity (P less than 0.0001). During oral glucose tolerance testing, mean plasma insulin concentrations were 33% higher in the Pimas (P less than 0.0001), but these differences were largely explained by the greater insulin resistance in the Pimas. Insulin clearance did not differ between the races. However, early insulin responses were exaggerated in the Indians and not explained by insulin resistance. After accounting for differences in insulin action, plasma insulin concentrations in Pima Indians were 50% higher than those in caucasians 3-5 min after iv glucose (P less than 0.0001), 38% higher 10 min after the end of a meal (P less than 0.0001), and 20% higher 30 min after an oral glucose load (P less than 0.006). These data suggest that in addition to insulin resistance, Pima Indians have exaggerated early insulin release and either increased beta-cell mass or enhanced beta-cell sensitivity to glucose. The data argue against low or delayed insulin secretion as primary factors leading to NIDDM in Pima Indians and favor insulin resistance as the underlying and initiating cause of the disease.

Administration, Oral↗
PubMed1991

Normal coding sequence of insulin gene in Pima Indians and Nauruans, two groups with highest prevalence of type II diabetes.

The nucleotide sequence of the insulin gene was determined in American Pima Indians and Micronesian Nauruans, two populations in whom the prevalence of non-insulin-dependent (type II) diabetes mellitus is the highest in the world. The insulin gene was amplified by the polymerase chain reaction to generate single-stranded DNA suitable for direct sequencing. The nucleotide sequences of the coding and adjacent regions of the insulin gene in six Pima Indians and two Nauruans with type II diabetes were identical to previously published insulin gene sequences of nondiabetic subjects.

Adult↗
PubMed1991

Pathogenesis of NIDDM in Pima Indians.

The Pima Indians of Arizona have the highest reported prevalence and incidence of non-insulin-dependent diabetes mellitus (NIDDM) of any population in the world. A cross-sectional and longitudinal study was begun in 1982 to determine the metabolic characteristic(s) that is (are) predictive of the development of NIDDM and to document the sequence of metabolic events that occur with the transition from normal to impaired glucose tolerance and then to diabetes. Preliminary analyses suggest that insulin resistance is a primary abnormality predisposing Pima Indians to develop impaired glucose tolerance, and that the development of diabetes occurs with subsequent pancreatic failure.

Arizona↗
PubMed1990

Low ratio of fat to carbohydrate oxidation as predictor of weight gain: study of 24-h RQ.

Reduced oxidation of fat leading to a positive fat balance could be a factor in the development of obesity. Twenty-four-hour respiratory quotient (RQ) was measured in 152 nondiabetic Pima Indians fed a weight-maintenance diet [87 males and 65 females; 27 +/- 6 yr (mean +/- SD); 93.9 +/- 22.9 kg; 32 +/- 9% fat]. Twenty-four-hour RQ varied from 0.799 to 0.903. Prior change in body weight, 24-h energy balance, sex, and percent body fat explained 18% of the variance in 24-h RQ (P less than 0.001). In a subgroup of 66 siblings from 28 families, family membership explained 28% of the remaining variance in 24-h RQ (P less than 0.05). In 111 subjects for whom follow-up data (25 +/- 11 mo) were available, 24-h RQ was correlated with subsequent changes in body weight and fat mass (r = 0.27, P less than 0.01 and r = 0.19, P less than 0.05, respectively). Subjects with higher 24-h RQ (90th percentile) independent of 24-h energy expenditure were at 2.5 times higher risk of gaining greater than or equal to 5 kg body weight than those with lower 24-h RQ (10th percentile). We conclude that in Pima Indians fed a standard diet 1) family membership is the principal determinant of the ratio of fat to carbohydrate oxidation, and 2) a low ratio of fat to carbohydrate oxidation is associated with subsequent weight gain independent of low energy expenditure and may contribute to the familial aggregation of obesity.

Adult↗
PubMed1990

The amino acid sequence of the insulin receptor is normal in an insulin-resistant Pima Indian.

Insulin resistance is an early predictor of development of noninsulin-dependent diabetes mellitus (NIDDM) in Pima Indians, a population with the highest reported prevalence of NIDDM. The insulin receptor plays a central role in mediating insulin action, and previous studies have demonstrated that mutations in the insulin receptor gene may cause insulin resistance. Therefore, we have cloned the insulin receptor cDNA from an insulin-resistant Pima Indian to determine if there is a mutation in the patient's insulin receptor gene. We obtained nine cDNA clones spanning exons 4-10 and 12-22 of the patient's insulin receptor gene. Polymorphisms in the nucleotide sequences for codons 523 (Ala), 1058 (His), and 1062 (Leu) provided useful markers to differentiate the patient's two alleles of the insulin receptor gene. These substitutions were silent, in that they did not alter the predicted amino acid sequence. The sequence of exons 1-3 and 11 was determined directly from genomic DNA that had been amplified using the polymerase chain reaction catalyzed by Taq DNA polymerase. Other investigators have reported defects in insulin binding and insulin receptor tyrosine kinase activity in diabetic Pima Indians. However, we did not detect any mutations in this patient's insulin receptor gene. Thus, these observations are consistent with the interpretation that the defects in insulin receptor function are acquired rather than derived from defects in the primary structure of the receptor.

Adult↗
PubMed1990

Brain glucose metabolism in noninsulin-dependent diabetes mellitus: a study in Pima Indians using positron emission tomography during hyperinsulinemia with euglycemic glucose clamp.

To determine whether insulin or noninsulin-dependent diabetes mellitus affects brain glucose metabolism, brain glucose utilization was studied in the basal state and during hyperinsulinemic euglycemic glucose clamps in nondiabetic and diabetic Pima Indians by positron emission tomography with 2-[18F]fluoro-2-deoxy-D-glucose (18FDG). Glucose utilization in 75 brain areas was determined by analysis of single scans and by least squares estimation of the rate parameters for the FDG model; these data were compared to results in normal caucasian volunteers. No effect of ethnicity or diabetic status on brain glucose utilization was observed. During the hyperinsulinemic clamps (mean insulin, 11,708 +/- 3,026 pmol/L), clearance of 18FDG from blood was accelerated, and accumulation of brain radioactivity was reduced. However, glucose utilization by the brain was identical to results during sham glucose clamps (mean insulin, 204 +/- 56 pmol/L) performed in the same patients. During the studies with hyperinsulinemia, k4 (representing loss of tissue radioactivity) was increased in most brain areas (mean increase, 0.0031 +/- 0.0018 min-1; P less than 0.02). The possible mechanisms for this effect are multiple, and the physiological significance, if any, is unknown. Further studies of the effects of insulin on brain glucose metabolism are needed.

Adult↗
PubMed1989

Adenosine 3',5'-monophosphate-dependent protein kinase activity decreases in human muscle after insulin infusion.

We have previously reported that the increase in glycogen synthase activity in human muscle during a euglycemic clamp was not associated with a measured increase in glycogen synthase phosphatase activity after a 200-min insulin administration. To investigate further the mechanism of the regulation of human muscle glycogen synthase by insulin, we measured the activity of cAMP-dependent protein kinase before and after a 200-min hyperinsulinemic euglycemic clamp in Southwest American Indians. Insulin infusion resulted in a decreased cAMP-dependent protein kinase activity assayed at physiological cAMP concentration with increased glycogen synthase activity in all subjects (n = 5; P less than 0.01). No significant change was observed in cAMP-independent protein kinase activity. These results suggest that 200 min of insulin administration during a euglycemic clamp may regulate human muscle glycogen synthase activity by mechanisms other than the stimulation of phosphatase; one probable mechanism is by decreasing the activity of cAMP-dependent protein kinase.

Adult↗
PubMed1989

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.

Adult↗
PubMed1988

Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians.

Impaired glucose tolerance often presages the development of non-insulin-dependent diabetes mellitus. We have studied insulin action and secretion in 24 Pima Indians before and after the development of impaired glucose tolerance and in 254 other subjects representing the whole spectrum of glucose tolerance, including subjects with overt non-insulin-dependent diabetes. The transition from normal to impaired glucose tolerance was associated with a decrease in glucose uptake during hyperinsulinemia, from 0.018 to 0.016 mmol per minute (from 3.3 to 2.8 mg per kilogram of fat-free body mass per minute) (P less than 0.0003). Mean plasma insulin concentrations increased during an oral glucose-tolerance test, from 1200 to 1770 pmol per liter (from 167 to 247 microU per milliliter). In 151 subjects with normal glucose tolerance, the insulin concentration measured during an oral glucose-tolerance test correlated with the plasma glucose concentration (r = 0.48, P less than or equal to 0.0001). This relation was used to predict an insulin concentration of 1550 pmol per liter (216 microU per milliliter) in subjects with impaired glucose tolerance (actual value, 1590 pmol per liter [222 microU per milliliter]; P not significant), suggesting that these subjects had normal secretion of insulin. In contrast, plasma insulin concentrations in the diabetics decreased as glucose concentrations increased (r = -0.75, P less than or equal to 0.0001), suggesting deficient secretion of insulin. This relative insulin deficiency first appears at the lower end of the second (diabetic) mode seen in population frequency distributions of plasma glucose concentrations. Our data show that impaired glucose tolerance in our study population is primarily due to impaired insulin action. In patients with non-insulin-dependent diabetes mellitus, by contrast, impaired insulin action and insulin secretory failure are both present.

Adult↗
PubMed1988

Reduced rate of energy expenditure as a risk factor for body-weight gain.

The contribution of reduced energy expenditure to the development of obesity has been a point of controversy. We measured 24-hour energy expenditure (adjusted for body composition, age, and sex), in a respiratory chamber, in 95 southwestern American Indians. Energy expenditure correlated with the rate of change in body weight over a two-year follow-up period (r = -0.39, P less than 0.001). The estimated risk of gaining more than 7.5 kg in body weight was increased fourfold in persons with a low adjusted 24-hour energy expenditure (200 kcal per day below predicted values) as compared with persons with a high 24-hour energy expenditure (200 kcal per day above predicted values; P less than 0.01). In another 126 subjects, the adjusted metabolic rate at rest at the initial visit was also found to predict the gain in body weight over a four-year follow-up period. When the 15 subjects who gained more than 10 kg were compared with the remaining 111 subjects, the initial mean (+/- SD) adjusted metabolic rate at rest was lower in those who gained weight (1694 +/- 103 vs. 1764 +/- 109 kcal per day; P less than 0.02) and increased to 1813 +/- 134 kcal per day (P less than 0.01) after a mean weight gain of 15.7 +/- 5.7 kg. In a group of 94 siblings from 36 families, values for adjusted 24-hour energy expenditure aggregated in families (intraclass correlation = 0.48). We conclude that a low rate of energy expenditure may contribute to the aggregation of obesity in families.

Adolescent↗
PubMed1988

Obesity and insulin resistance: lessons learned from the Pima Indians.

Diabetes and obesity are epidemic in the Pima Indians of the Southwestern United States, and the prevalence of diabetes is increasing. The most likely link between obesity and diabetes is tissue insulin resistance. If obesity is defined as an excess of body fat, then it can only be accurately assessed by measurements of body composition and not by approximations such as body mass index or percent of ideal weight. To compare the metabolic data of individuals of varying size, an accurate measure of metabolic size is needed. Total body weight is not an appropriate means of comparing individuals since obese subjects have a greater proportion of nonmetabolizing mass (triglyceride). Body surface area shows a sex difference, and this may distort data if both sexes are present. From studies of metabolic rate we have determined that metabolic rate is directly proportional to the fat-free mass plus 18 kg, and we suggest that this weight can be equated with metabolic size. Glucose storage in skeletal muscle appears to be important in the disposal of an intravenous glucose load. Consistent with its role in glycogen storage, glycogen synthase enzyme is activated in proportion to the ability to dispose of glucose during a hyperinsulinemic, euglycemic clamp. The role of glycogen synthase is most notable at supraphysiological plasma insulin concentrations; and since glucose uptake at these insulin concentrations is highly familial independent of the degree of obesity, we suggest that there may be a specific genetic defect expressed in skeletal muscle that reduces insulin responsiveness in some subjects. The lack of correlation between 24 hour respiratory quotient measured in a metabolic chamber (a measure of the proportion of fat derived calories) and degree of obesity indicates that in obese Pima Indians insulin resistance is not due to an inhibition of glucose metabolism by free fatty acids (glucose-fatty acid-ketone cycle). Obesity is associated with an increase in fat-free mass almost kilogram- for kilogram with fat mass when compared to the lean state. A role for this increase in fat-free tissue in producing insulin resistance has been given insufficient attention in the past. With an increase in fat-free mass, muscle cells are hypertrophied and capillaries in muscle are more widely spaced. We propose that these biophysical changes in muscle mediate, at least in part, the effects of obesity to produce a reduction in insulin sensitivity and the abnormal kinetics of insulin action found in the obese.(ABSTRACT TRUNCATED AT 400 WORDS)

Body Surface Area↗
PubMed1988

Glucose-6-phosphate stimulation of human muscle glycogen synthase phosphatase.

The influence of glucose-6-phosphate (glucose-6-P) on skeletal muscle glycogen synthase phosphatase was examined in normal glucose-tolerant Southwest American Indians. Phosphatase was stimulated with physiological concentrations of glucose-6-P and inhibited by ATP (5 mmol/L) and glycogen (0.1%). Phosphatase activity was measured before and after insulin infusion using the euglycemic clamp technique. Although glycogen synthase fractional activity increased in all subjects, this increase was not related to a change in phosphatase activity in the absence or presence of glucose-6-P. These results suggest that glycogen synthase phosphatase from human muscle can be regulated by physiological concentrations of glucose-6-P, ATP, and glycogen, and that insulin does not alter glucose-6-P stimulation of the enzyme in normal subjects.

Adenosine Triphosphate↗