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Share Facebook Twitter Pinterest LinkedIn Mail Print. Ian Neeland. The histograms were summed over the range of pixel values designated as fat by fitting two normal analysis distribution curves to them. In the morning on the day before the study, a blood sample for the determination of background 2 H 2 O enrichment was taken.
The following morning, subjects were admitted to the Clinical Research Center at h after a h overnight fast. A polyethylene cannula was inserted into an antecubital vein for the infusion of all test substances. A second catheter was inserted retrogradely into an ipsilateral wrist vein on the dorsum of the hand for blood sampling, and the hand was kept in a heated box at 65 C.
A primed μCi -constant infusion of 3-[ 3 H]glucose NEN Life Science Products, Boston, MA was started at h and continued at a rate of 0.
During the last 30 min of the basal equilibration period — min after the start of 3-[ 3 H]glucose , plasma samples were taken at 5- to min intervals for the determination of plasma glucose, FFA, and insulin concentrations and [ 3 H]glucose specific activity. After the start of the insulin infusion, the plasma glucose concentration was allowed to decline to 5.
Plasma samples were collected every 15 min from 0—90 min and every 5—10 min from 90— min for the determination of plasma glucose and insulin concentrations and [ 3 H]glucose specific activity. Plasma samples for the determination of GNG see below were taken before starting the [ 3 H]glucose infusion and at the end of the basal period.
The glucose concentration was determined by the glucose oxidase method Beckman II Glucose Analyzer, Beckman, Fullerton, CA. The plasma insulin concentration was measured by RIA Diagnostic Products, Los Angeles, CA.
The serum HbA 1c concentration was measured by affinity chromatography biochemical methodology, Drower , Isolab, Akron, OH. The plasma FFA concentration was measured spectrophotometrically Wako Chemicals GmbH, Neuss, Germany.
The pattern of 2 H incorporation into plasma glucose after 2 H 2 O ingestion was determined according to the method developed by Landau and recently modified 20 , Briefly, the fraction of glucose produced via GNG from all precursors can be quantified from the ratio of 2 H enrichment of carbon 5 C5 to that of water.
The precursor of the hydrogen bound to C5 of glucose is the hydrogen bound to carbon 2 of glyceraldehydephosphate. That hydrogen equilibrates with the hydrogen of body water in the isomerization of glyceraldehydephosphate with dihydroxyacetone phosphate, an intermediate in the conversion of glycerol to glucose, and binds in the hydration of phosphoenolpyruvate formed in the conversion of pyruvate to glucose.
Because during glycogen breakdown there is no binding of hydrogen from body water to C5 of the glucose formed, enrichment at C5 in blood glucose vs. water reflects the fractional contribution of total GNG, i. from both phosphoenolpyruvate precursors and glycerol. Plasma samples were first deproteinized using the Somogyi procedure.
Samples were then reconstituted with μl distilled water and injected into a high performance liquid chromatograph Waters Corp. Deuterium enrichment at C5 was obtained by converting glucose to xylose by the removal of carbon in position 6. Xylose was purified by HPLC; the C5 group was cleaved by oxidation with periodic acid, and formaldehyde was collected by distillation.
Formaldehyde was incubated with ammonia overnight. In the presence of ammonia, six molecules of formaldehyde react to form one molecule of hexamethylenetetramine.
This step is used to increase the sensitivity of the method. Enrichment of hexamethylenetetramine obtained from C5 was determined by gas chromatography-mass spectrometry GCMS by monitoring peaks of mass and The precision and accuracy of C5 have been reported previously 8.
Water enrichment in the body water pool was monitored by reacting a sample of plasma or urine with calcium carbide CaC2 , thereby obtaining acetylene C2H2.
The enrichment of acetylene was then determined by GCMS by monitoring peaks with masses of 26 and 27 All samples were run through the GCMS processing in duplicate or triplicate.
Glucose fluxes and plasma clearance rates were expressed per kilogram of FFM. During the baseline period of the study 0— min , both the plasma glucose concentration and [ 3 H]glucose specific activity were stable during the last 30 min of tracer infusion in all subjects.
Therefore, total EGO was calculated as the ratio of the [ 3 H]glucose infusion rate to the plasma [ 3 H]glucose specific activity mean of five determinations. At low rates of insulin-stimulated glucose disposal similar to those observed in the diabetic subjects in the present study , we have shown that the tracer-derived rates of Ra and Rd closely approximate the independently measured rates of whole body glucose disposal and glucose appearance Therefore, [ 3 H]glucose was not added to the exogenously infused glucose during the insulin clamp EGO during the insulin clamp was obtained as the difference between Ra and the exogenous glucose infusion rate.
Fasting plasma glucose clearance was calculated as the ratio between EGO and FPG, whereas insulin-mediated plasma glucose clearance was obtained as the ratio of Rd to plasma glucose concentration during the clamp. Data are given as the mean ± se. A comparison of group values was performed using ANOVA with Bonferroni-Dunn post hoc testing.
To factor out confounding variables, multivariate analysis was performed with the use of mixed models, including both continuous [age and body mass index BMI ] and nominal ethnicity, sex, and sulfonylurea treatment variables as independent variables; contrasts were used to estimate differences among levels of a nominal variable i.
tertiles of fasting glycemia or VF area. The strength of confounder-adjusted associations between the two variables of interest was expressed as the partial correlation coefficient. To examine the association between VF and metabolic control, the study cohort was divided into tertiles of fasting hyperglycemia.
Thus, group 1 included mildly hyperglycemic subjects, group 2 consisted of patients with moderate hyperglycemia, and group 3 included severely hyperglycemic patients Table 1. Except for a slight imbalance in sex distribution, the three groups were well matched for age, obesity BMI and percent fat mass , body fat distribution as determined by waist circumference and waist to hip ratio , and previous sulfonylurea treatment.
The serum lipid profile and arterial blood pressure levels were not significantly different among groups. Clinical characteristics in type 2 diabetic patients stratified by tertiles of fasting hyperglycemia. MA, Mexican-American; HDL, high-density lipoprotein; LDL, low-density lipoprotein.
As measured by MRI, abdominal SF area was similar across groups, whereas abdominal VF area was significantly greater in subjects with moderate to severe fasting hyperglycemia than in the mildly hyperglycemic subjects. group 2. In the whole cohort, VF increased with age in both males and females and with indexes of fatness, whereas SF was positively related only to fatness Table 2.
In the latter model, Mexican-American ethnicity and diabetes duration also were significant positive correlates of HbA 1c. With regard to glucose fluxes, EGO was progressively higher, and plasma glucose clearance was progressively lower across groups both during the fasting state and under insulinized conditions Table 3.
In contrast, the relation of EGO to VF was weak and not statistically significant Fig. Plasma insulin and FFA concentrations were similar in the three groups both at baseline and during the clamp.
Inverse relationship between insulin-stimulated glucose clearance top panel or EGO bottom panel and VF area in 63 patients with type 2 diabetes. The fitting line and r value are those of a power function.
Metabolic data in type 2 diabetic patients stratified by tertiles of fasting hyperglycemia. P value for the difference among groups after adjustment by sex, age, ethnicity, BMI, and sulfonylurea treatment.
In the subgroup of subjects 48 of 63 in whom GNG was measured, fasting EGO varied through FPG tertiles with a similar trend as in the whole cohort. This increment was entirely due to increased GNG Table 4. To examine whether VF contributed to enhance GNG, the percent GNG was regressed against VF, first singly and then after adjustment for confounders.
The inverse relationship between GLY and VF explains the lack of relationship between total EGO and VF. Components of fasting glucose production in type 2 diabetic patients stratified by tertile of fasting hyperglycemia. Association of VF accumulation with gluconeogenic and glycogenolytic flux in 48 patients with type 2 diabetes.
The lines connect the observed values plotted as the mean ± sem at each tertile of VF area. In the whole cohort, fasting plasma FFA levels were independently i. There was, however, no relationship between circulating FFA levels and either VF or SF. In this cohort of type 2 diabetic patients with an average disease duration of 5 yr and a wide range of fasting plasma glucose and HbA 1c levels, VF accumulation was clearly associated with poor metabolic control Table 1.
Upon stratifying the subjects by fasting glycemia, the resulting clinical phenotype was quite homogeneous, not only in terms of age, serum lipids and blood pressure, but also in terms of overall body size and fat distribution.
Only increased VF and, to a smaller extent, diabetes duration paralleled the increase in FPG. In a multiple regression model, which accounted for sex, age, BMI, and SF, only VF, diabetes duration, and Mexican-American ethnicity, in that order, were significant positive correlates of FPG.
Thus, if every other measured factor is the same, the selective accumulation of fat in the visceral area is a predictor of the severity of fasting hyperglycemia. Most importantly, VF is associated not only with the degree of fasting hyperglycemia, but even more strongly and independently with HbA 1c.
The clinical implication of these findings is that VF, when directly estimated by a sensitive imaging technique, is an independent predictor of metabolic control in type 2 diabetic patients, particularly in those of Mexican-American ethnicity.
As a corollary, VF may be an important factor that modulates the response to treatment as well as itself representing a potential target for intervention. It should be emphasized, however, that the set of clinical and anthropometric variables used in the present study could explain no more than half of the observed variability in HbA 1c.
Clearly, other determinants of glycemic control went unmeasured. With regard to the mechanisms underlying the association between VF accumulation and hyperglycemia in type 2 diabetes, glucose fluxes provided at least part of the answer. First, peripheral insulin resistance in the fasting state and during the insulin clamp was progressively more severe with increasing fasting hyperglycemia.
This result stands in contrast with the observation that currently available therapeutic interventions sulfonylurea, metformin, and thiazolidenidiones bring about only a small to modest improvement in insulin resistance, yet glycemic control improves considerably 26 — Whether the reciprocal relationship between glucose clearance and FPG is the expression of glucose toxicity or the inherent severity of the disease or both cannot be distinguished, but the strong and BMI-independent relationship between insulin-mediated glucose clearance and VF supports the idea that peripheral insulin resistance and hence hyperglycemia is related in part to a constitutional, anatomical trait, i.
visceral adiposity. The mechanism by which fat deposition within and between abdominal viscera affects insulin action in peripheral tissues is not clear from the present studies. Circulating plasma FFA levels were similar across all three groups and are therefore an unlikely messenger, at least in patients with manifest diabetes.
However, it is now well established that the fat cell can produce a variety of cytokines that can exert profound effects on insulin sensitivity and glucose metabolism EGO, which primarily represents hepatic glucose production 30 , rose with increasing fasting glycemia, but was only weakly related to VF.
The components of EGO, however, showed a revealing pattern. GNG, both as a fraction of EGO and as an absolute flux, was strongly and independently associated with higher VF, whereas GLY was less tightly and reciprocally related to VF.
If interpreted mechanistically, these results suggest that the presence of excess VF specifically enhances GNG. However, whether this stimulation of GNG by increased VF results in glucose overproduction depends on the concomitant adjustment of the glycogenolytic rate. In the more hyperglycemic subjects the ambient plasma insulin concentration is insufficient to restrain EGO, which consequently rises to levels that are elevated in absolute terms.
With regard to the plasma FFA concentration, we found a positive association between their systemic levels and GNG. A high FFA flux to the liver stimulates GNG by providing a continuous source of energy ATP from FFA oxidation as well as substrate glycerol to synthesize glucose de novo.
Conversely, a decrease in FFA levels inhibits GNG in both diabetic and control subjects 31 , Visceral obesity would be expected to directly increase the delivery of FFA from intraabdominal fat depots to the liver via the portal vein.
Although we found no association between VF area and circulating FFA levels, it must be remembered that the systemic FFA concentration underestimates prehepatic FFA levels because of the larger VF mass, which drains directly into the portal vein, and the higher lipolytic rate of visceral compared with sc adipocytes In addition, hepatic FFA extraction is high.
Therefore, the contribution of VF to systemic FFA concentrations is likely to be small although precise calculations require knowledge of differential lipolytic rates and regional blood flow rates. These considerations may explain why systemic FFA plasma levels were unrelated to VF, but remained directly related to GNG, which responds to the whole FFA load regardless of its anatomical origin.
Finally, it is of clinical relevance that in our cohort of diabetic patients increased VF almost doubled the extent to which the increase in HbA 1c could be accounted for on the basis of the clinical phenotype alone. According to this model, HbA 1c is predicted to be 0.
These estimates confirm that an accurate measurement of VF is an important part of clinical phenotyping and has rather direct consequences for the metabolic control of patients with type 2 diabetes. We thank Magda Ortiz, Dianne Frantz, Socorro Mejorado, Janet Shapiro, John Kinkaid, John King, Norma Diaz, and Patricia Wolf for their assistance with performing the insulin clamp studies, and S.
Frascerra, Ph. Baldi, Ph. Ciociaro; and N. Pecori for their technical assistance with the measurement of GNG. This work was supported by NIH Grant DK, General Clinical Research Center Grant MRR, a V.
Merit Award, and funds from the V.
Anabolic steroid abuse details. Lean protein and muscle definition impact of subcutaneous Promoting gut health accumulation remains controversial. Viscefal study diabetez the association between visceral or subcutaneous fat area Fqt and SFA, respectively and diabetes mellitus DM among Japanese subjects. This was a cross-sectional study involving eligible participants men, ; women, who participated in a voluntary health check-up conducted at Juntendo University Hospital from January to Decemberin Tokyo, Japan. Receiver operating characteristic ROC curve analysis was used to assess appropriate cut-off values of VFA or SFA. The appropriate cut-off value of VFA in men was
Amalia Gastaldelli, Yoshinori Miyazaki, Maura Pettiti, Masafumi Matsuda, Diagetes Mahankali, Eleonora Promoting gut health, Fxt A. Visceral Promoting gut health Viscera, excess has dibetes associated with decreased peripheral insulin Locally Roasted Coffee and diabeets been suggested to Visceral fat and diabetes to hepatic Revitalize and hydrate resistance. However, the mechanisms by which VF impacts on hepatic glucose metabolism and the quantitative role of VF in glycemic control have not been investigated. In the present study 63 type 2 diabetic subjects age, 55 ± 1 yr; fasting plasma glucose, 5. In contrast, the relation of basal endogenous glucose output to VF was not statistically significant. We conclude that in patients with established type 2 diabetes, VF accumulation has a significant negative impact on glycemic control through a decrease in peripheral insulin sensitivity and an enhancement of gluconeogenesis.
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