Postprandial hyperglycemia in patients with noninsulin-dependent diabetes mellitus. Role of hepatic and extrahepatic tissues.

Firth, Richard; Bell, P. M.; Marsh, H. Michael; Hansen, I.; Rizza, Robert A.

doi:10.1172/jci112467

Cited by 283 publications

(268 citation statements)

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“…Two strategies can be used to overcome this problem. The first is to fit the tracer data either to equation (1), or its solution (3). When this is done, spurious errors in slope are eliminated and the calculations of R a (and R d ) show a consistent pattern for the duration of the study, as illustrated in the studies shown here.…”

Section: Discussionmentioning

confidence: 91%

“…After the determination of k from equation (2), R a was determined from equation (1). The rate of glucose disappearance or utilization, R d , was then calculated as:…”

Section: Methodsmentioning

confidence: 99%

“…Some studies show that a strong correlation exists between fasting glucose concentrations and its production over a wide range of glycaemia, suggesting a causative role for excessive glucose output in hyperglycaemia [1,8]. Other measurements, however, show almost no correlation between glucose production rates and concentrations [9±14], Diabetologia (2001) …”

mentioning

confidence: 99%

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Production and metabolic clearance of glucose under basal conditions in Type II (non-insulin-dependent) diabetes mellitus

Radziuk

Pye

2001

Diabetologia

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The relative importance of glucose over-production and inadequate peripheral removal in the postabsorptive (fasting) hyperglycaemia of Type II (non-insulin dependent) diabetes mellitus has produced diverse estimates. Some studies show that a strong correlation exists between fasting glucose concentrations and its production over a wide range of glycaemia, suggesting a causative role for excessive glucose output in hyperglycaemia [1,8]. Other measurements, however, show almost no correlation between glucose production rates and concentrations [9±14], Diabetologia (2001) AbstractAims/hypothesis. The pathogenesis of fasting hyperglycaemia in Type II (non-insulin-dependent) diabetes mellitus has yet to be clarified. Rates of glucose production (R a ), utilization and metabolic clearance rate were therefore measured during an extended fast, in control subjects and in Type II diabetic patients. Methods. Nine subjects with newly-diagnosed or diettreated diabetes and seven control subjects matched for age and weight (BMI 36.0 2.4 and 35.3 3.1 kg/ m 2 respectively) underwent an overnight fast followed by a 10-h unprimed infusion of [6-3 H]glucose. Plasma tracer concentrations were fitted by a singlecompartment model. Results. The metabolic clearance rate was near-constant [61.7 + 2.4 ml/(min-m 2 )] in diabetic patients and [75.5 3.3 ml/(min-m 2 )] in control subjects (p < 0.05). It was correlated to the glucose concentrations both at t = 0 (r = ±0.752, p = 0.0008) and t = 10 h (r = ±0.675, p = 0.004). The calculated volume of distribution was 17.3 1.4 l (18.2 % weight, diabetes), 19.6 2.4 l (18.4 % weight, control). Glycaemia fell from 10.7 0.8 mmol/l to 6.5 0.3 mmol/l by 10 h (p < 0.05) in diabetes and from 5.6 0.6 to 4.8 0.1 mmol/l in control subjects (p < 0.05). The rate of glucose production decreased in parallel, from 563 33 to 363 23 mmol/(min-m 2 ) (p < 0.05) in diabetes from 419 20 to 347 32 mmol/(min-m 2 ) in control subjects. Initial R a was higher in diabetic patients than in control subjects (p < 0.05) and was highly correlated to glycaemia (r = 0.836, p = 0.0001). By 10 h, R a had converged in diabetic patients and control subjects and all correlation with glycaemia was lost (r = 0.0017, p = 0.95). Conclusions/interpretation. In relatively early diabetes, the more ªlabileº portion of fasting hyperglycaemia, which subsequently decreased, was closely related to the simultaneously decreasing R a . The 25 % increase in glucose concentrations which persisted as stabilized R a , resulted from about a 20 % lower metabolic clearance rate. [Diabetologia (2001) 44: 983± 991]

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Section: Discussionmentioning

confidence: 91%

“…After the determination of k from equation (2), R a was determined from equation (1). The rate of glucose disappearance or utilization, R d , was then calculated as:…”

Section: Methodsmentioning

confidence: 99%

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Production and metabolic clearance of glucose under basal conditions in Type II (non-insulin-dependent) diabetes mellitus

Radziuk

Pye

2001

Diabetologia

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“…Fasting blood glucose levels are mainly determined by the rate of endogenous glucose production [38]. Postprandial changes in glucose concentrations, however, are related to numerous factors, including glucose uptake by skeletal muscle and peripheral insulin sensitivity, as well as by the rate of endogenous glucose production [38,39]. Given the relative paucity of hepatic IGF-I receptors [40], our observation is consistent with IGF-I mainly influencing peripheral glucose uptake in the postprandial state, either directly or indirectly via its effects on the action of insulin to dispose of glucose.…”

Section: Discussionmentioning

confidence: 99%

Marked differences in the IGF system that are associated with migration in comparable populations of Gujaratis living in Sandwell, UK, and Gujarat, India

et al. 2005

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Aims/hypotheses: We previously reported independent links between the IGF system and the development of impaired glucose tolerance and cardiovascular risk. This study tests the hypothesis that the lifestyle change which accompanies population migration, with attendant increases in cardiovascular risk, is reflected by changes in the IGF system. Materials and methods: We compared a specific Gujarati community in Sandwell, UK (n=205), with people still resident in the same villages of origin near Navsari, India (n=246). We performed anthropometry and measured fasting plasma insulin, IGF-I, insulin-like growth factor binding protein (IGFBP)-1 and IGFBP-3. Results: Daily calorie intake, BMI and WHR were significantly higher in UK Gujaratis than in Indian Gujaratis. IGFBP-1 was significantly lower in UK migrants (mean 29.5 [95% CI 25.9-33.0] vs 56.5 [50.6-62.5]μg/l; F=48.4, p<0.001). Conversely, fasting insulin, IGFBP-3 and IGF-I were all higher in UK Gujaratis (mean IGF-I 145.9 [138.1-153.6]ng/ml in UK Gujaratis and 100.9 [94.6-107.3] ng/ml in Navsari Gujaratis; F=76.6, p<0.001). These differences were still apparent when adjustment was made for BMI by location for IGF-I (F=57.4, p<0.001) and IGFBP-3 (F=5.7, p=0.02), but were no longer apparent for IGFBP-1 and insulin. At the population level, the decrease in IGFBP-1 for a given increase in insulin was significantly smaller in UK Gujaratis, suggesting greater hepatic insulin resistance in this group. Conclusions/interpretation: Environmental factors have profound effects on circulating IGF system components and on the relationship between IGFBP-1, IGF-I and related metabolic variables. This may have long-term implications for the development of worsening glucose tolerance and cardiovascular disease.

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“…Despite intensive work, the fate of oral glucose remains surprisingly controversial. Reports of the cumulative appearance of oral glucose in plasma have varied from about 70% (34,35) to nearly 100% (36,37), and the maximal rates of glucose appearance have varied about 2-fold. Livesey et al (36) reported a study of glucose kinetics in 12-h fasted humans after an oral glucose load, using stable isotopes and mass spectrometry to detect gastric absorption of [ 13 C 6 ]glucose oral glucose.…”

Section: Discussionmentioning

confidence: 99%

Increased Hepatic Fructose 2,6-Bisphosphate after an Oral Glucose Load Does Not Affect Gluconeogenesis

Jin

Uyeda

Kawaguchi

et al. 2003

Journal of Biological Chemistry

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The generally accepted metabolic concept that fructose 2,6-bisphosphate (Fru-2,6-P 2 ) inhibits gluconeogenesis by directly inhibiting fructose 1,6-bisphosphatase is based entirely on in vitro observations. To establish whether gluconeogenesis is indeed inhibited by Fru-2,6-P 2 in intact animals, a novel NMR method was developed using [U-13 C]glucose and 2 H 2 O as tracers. The method was used to estimate the sources of plasma glucose from gastric absorption of oral [U-13 C]glucose, from gluconeogenesis, and from glycogen in 24-h fasted rats. Liver Fru-2,6-P 2 increased ϳ10-fold shortly after the glucose load, reached a maximum at 60 min, and then dropped to base-line levels by 150 min. The gastric contribution to plasma glucose reached ϳ50% at 30 min after the glucose load and gradually decreased thereafter. Although the contribution of glycogen to plasma glucose was small, glucose formed from gluconeogenesis was substantial throughout the study period even when liver Fru-2,6-P 2 was high. Liver glycogen repletion was also brisk throughout the study period, reaching ϳ30 mol/g at 3 h. These data demonstrate that Fru-2,6-P 2 does not inhibit gluconeogenesis significantly in vivo.Plasma glucose is preserved by gluconeogenesis after exhaustion of glycogen stores during a moderate fast. Following an oral glucose load, gluconeogenesis is thought to be modulated by allosteric regulation of fructose-1,6-bisphosphatase (1). This is an eminently satisfying model because a key regulatory site in glycolysis and gluconeogenesis occurs at level of fructose-6-P and fructose-1,6-P 2 (Fig. 1). Phosphofructokinase-1, the glycolytic enzyme, is potently activated by fructose-2,6-P 2 , whereas fructose-1,6-bisphosphatase, the gluconeogenic enzyme, is thought to be inhibited by this same effector molecule (2, 3). Thus, by regulating the activities of phosphofructo-1-kinase and fructose-1,6-bisphosphatase in a reciprocal manner, Fru-2,6-P 2 is thought to serve as an elegant regulator of glucose usage/production by the liver after an oral glucose load. This generally accepted model is based on kinetic analysis of fructose-1,6-bisphosphatase in vitro, which shows that Fru-2,6-P 2 competes with Fru-1,6-P 2 for the active site of fructose-1,6-bisphosphatase and that both molecules have similar affinity constants, 1-5 M (4 -6). However, the in vivo concentrations of Fru-1,6-P 2 in fasted and fed livers are 20 and 35 M, respectively, whereas those of Fru-2,6-P 2 are 1 and 8 M, respectively (7-9). This suggests that it would be difficult for Fru-2,6-P 2 to have a significant direct effect on fructose-1,6-bisphosphatase activity in vivo based simply upon concentration differences. Some evidence has been presented that suggests Fru-2,6-P 2 is not a potent inhibitor of gluconeogenesis in intact animals. For example, Kuwajima et al. (10) reported continual production of liver glycogen in sucrose-fed rats despite high levels of Fru-2,6-P 2 , and Hue and Bartrons (11) observed stimulated glucose production by glucagon in isolated hepatocytes reg...

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Postprandial hyperglycemia in patients with noninsulin-dependent diabetes mellitus. Role of hepatic and extrahepatic tissues.

Cited by 283 publications

References 40 publications

Production and metabolic clearance of glucose under basal conditions in Type II (non-insulin-dependent) diabetes mellitus

Production and metabolic clearance of glucose under basal conditions in Type II (non-insulin-dependent) diabetes mellitus

Marked differences in the IGF system that are associated with migration in comparable populations of Gujaratis living in Sandwell, UK, and Gujarat, India

Increased Hepatic Fructose 2,6-Bisphosphate after an Oral Glucose Load Does Not Affect Gluconeogenesis

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