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Biomedical subjects

V Grill

Publications and source records attributed to V Grill.

At least 55 records · Page 3Linked to original sources
PubMed2000

Dysfunctional insulin secretion in type 2 diabetes: role of metabolic abnormalities.

Insulin secretion is finely tuned to the requirements of tissues by tight coupling to prevailing blood glucose levels. The normal regulation of insulin secretion is coupled to glucose metabolism in the pancreatic B cell, a major but not exclusive signal for secretion being closure of K+ ATP (adenosine' triphosphate)-dependent channels in the cell membrane through an increase in cytosolic ATP/adenosine diphosphate. Insulin secretion in type 2 diabetes is abnormal in several respects due to genetic causes but also due to the metabolic environment of the pancreatic B cells. This environment may be particularly important for the deterioration of insulin secretion which occurs with increasing duration of diabetes. Factors in the environment with potential importance include overstimulation, a negative effect of hyperglycemia per se ('glucotoxicity') as well as adverse effects of elevated fatty acids ('lipotoxicity'). Elucidating the mechanisms behind these factors as well as their clinical importance will pave the way for treatment which could preserve B-cell function in type 2 diabetic patients.

Diabetes Mellitus, Type 2↗
PubMed2000

Treatment with diazoxide causes prolonged improvement of beta-cell function in rat islets transplanted to a diabetic environment.

Prolonged hyperglycemia desensitizes beta cells. A role for hyperglycemia-induced excessive stimulation can be tested by diazoxide, which inhibits glucose-induced insulin secretion. Using diazoxide, we have investigated in a rat transplantation model whether excessive stimulation can induce lasting effects on beta cells. One batch with 150 islets and another with 20 islets isolated from Wistar-Furth rats were transplanted under the left-kidney capsule of syngeneic streptozotocin-diabetic recipients. In a first series, recipients were treated for 8 weeks with or without 0.2% diazoxide in the food. Graft-bearing kidneys were then perfused and excised. Diazoxide treatment increased by 5.5-fold the insulin response to 10 mmol/L arginine, by 4.1-fold the graft insulin content, and by 2.3-fold the preproinsulin mRNA versus nontreated diabetic controls. The persistence of these effects was assessed in a second series in which 8 weeks of diazoxide treatment was followed by 1 week of no treatment. Again, perfusion experiments showed a higher insulin response to arginine in diazoxide-treated rats (136.0 +/- 25.7 v 62.3 +/- 11.8 fmol/min, P < .05). Also, the response to 27.8 mmol/L glucose was increased (54.0 +/- 17.1 v 13.6 +/- 7.8 fmol/min, P < .05). The insulin content was increased (2.2 +/- 0.6 v 1.0 +/- 0.4 pmol/islet, P < .05), as well as the preproinsulin mRNA (0.60 +/- 0.08 v0.22 +/- 0.02 pg/islet, P < .05). In a third series, we tested the impact of diazoxide treatment when given only during the first 2 weeks following transplantation. When tested 6 weeks later, insulin secretion was unaffected, whereas there was a strong tendency for a higher preproinsulin mRNA and insulin content in grafts of diazoxide-treated rats. In conclusion, this study demonstrates that beta-cell function in transplanted islets is improved by diazoxide long after the end of treatment, an effect that is likely due to removal of hyperglycemia-induced excessive stimulation.

Animals↗
PubMed2000

Fatty acids and insulin secretion.

It has long been recognized that acute elevation of non-esterified fatty acids (NEFA) stimulates insulin secretion to a moderate extent both in vitro and in vivo. The effects of longer-term exposure to elevated fatty acids have, however, been investigated only recently. Our own studies in the rat have documented the time dependence of NEFA effects, with inhibition of glucose-induced insulin secretion being apparent after 6-24 h in vivo exposure to Intralipid or in vitro exposure to palmitate, oleate and octanoate. Evidence indicates that the inhibitory effects are coupled to fatty acid oxidation in B-cells, with ensuing reduction in glucose oxidation, in parallel with diminished activity of the pyruvate dehydrogenase enzyme. These findings were essentially confirmed in human pancreatic islets. In the db/db mouse, a model of type 2 diabetes with obesity, evidence was obtained for elevated NEFA playing a significant role in decreased glucose-induced insulin secretion. Evidence also indicates that elevated NEFA inhibit insulin biosynthesis and increase the proinsulin:insulin ratio of secretion. Results on experimentally induced elevations of NEFA in non-diabetic and diabetic humans are thus far inconclusive. Further studies are needed to ascertain the impact of elevated NEFA on insulin secretion in clinical settings.

Animals↗
PubMed2000

Cigarette smoking, oral moist snuff use and glucose intolerance.

OBJECTIVE: To investigate the association between cigarette smoking and use of oral moist snuff and impaired glucose tolerance and type 2 diabetes. DESIGN: We performed a population-based cross-sectional study of glucose intolerance and tobacco use in Stockholm during 1992-94. The sample consisted of 3128 men, aged 35-56 years, of whom 52% had a family history of diabetes. In an oral glucose tolerance test, we detected 55 men with type 2 diabetes and 172 with impaired glucose tolerance. Information on cigarette smoking and oral moist snuff use was collected by a questionnaire. RESULTS: The odds ratio of type 2 diabetes was increased for smokers of 25+ cigarettes day-1 (odds ratio = 2.6, 95% confidence interval = 1.1-5.9) as well as for moist snuff dippers of 3+ boxes week-1 (odds ratio = 2.7, 95% confidence interval = 1.3-5.5). The odds ratio of relatively high (highest tertile) fasting insulin levels in subjects with impaired glucose tolerance associated with cigarette smoking of 25+ cigarettes day-1 was 1.5 (95% confidence interval = 0.7-3.6). The corresponding estimate of a relatively low (lowest tertile) 2 h insulin response was 2.5 (95% confidence interval = 0.9-7.1). CONCLUSIONS: These results indicate that heavy users of cigarettes or moist snuff have an increased risk of type 2 diabetes. The results could suggest that tobacco use is associated with a low insulin response.

Adult↗
PubMed2000

Alcohol consumption, Type 2 diabetes mellitus and impaired glucose tolerance in middle-aged Swedish men.

AIMS: To investigate the association between alcohol consumption and impaired glucose tolerance and Type 2 diabetes mellitus. METHODS: A population-based cross-sectional study consisting of 3,128 Swedish men, aged 35-56 years. Oral glucose tolerance testing identified 55 cases of Type 2 diabetes and 172 cases of impaired glucose tolerance. Information on alcohol consumption, family history of diabetes, smoking and physical activity was obtained by questionnaire. RESULTS: After adjustment for family history, smoking, physical activity and body mass index, the odds ratio of diabetes was 2.1 (95% confidence interval (CI) 1.0-4.5) in men with high consumption of alcohol (corresponding to over 12 drinks per week) and 0.7 (0.3-1.8) in moderate consumers (7-12 drinks), compared to occasional drinkers. For impaired glucose tolerance, the corresponding odds ratios were 0.7 (0.5-1.1) and 0.6 (0.4-1.0), respectively. Separate analyses for type of beverage indicated that high consumers of beer, spirits and wine had an odds ratio for diabetes of 2.9 (1.2-6.9), 3.3 (1.4-7.8) and 1.2 (0.5-2.7), respectively. CONCLUSIONS: The results indicated that high consumption of alcohol increases the occurrence of Type 2 diabetes and that this may primarily concern consumption of beer and spirits. For impaired glucose tolerance, regular alcohol consumption was associated with a reduced prevalence, particularly at moderate levels.

Adult↗
PubMed2000

Aminoguanidine exerts a beta-cell function-preserving effect in high glucose-cultured beta-cells (INS-1).

We investigated the effects of aminoguanidine (AG) on beta-cell functions in an insulin secreting cell line (INS-1). Culture with 27mM glucose for one week markedly decreased both insulin release and insulin content compared to culture in 0.8 mM or 3.3 mM glucose. Relative to culture at 27 mM glucose alone, the co-exposure to 1 mM AG almost doubled basal as well as glucose or 25 mM KCl-stimulated insulin release and increased insulin content by 42%. AG failed to affect release and content in cells cultured at 0.8 or 3.3 mM glucose. Preproinsulin mRNA content in 27mM glucose-cultured cells was 52% suppressed compared to 0.8mM glucose-cultured cells, and AG treatment partially counteracted this decline. Advanced glycosylation end product (AGE)-associated fluorescence (370nm excitation and 440 nm emission) of cells' extracts did not differ between 27mM and 0.8mM glucose-cultured cells after 1 week of culture and fluorescence was unaffected by AG. Accumulation of nitrite into culture media was markedly increased from 27mM glucose-cultured cells, and this accumulation was 33% suppressed by AG. In conclusion, AG partially protects against glucotoxic effects in INS-1 cells. These beneficial effects may involve a decrease in early glycation products and/or nitric oxide synthase (NOS) activity. The effects which were obtained after one week of high glucose exposure may supplement AGE-associated effects seen after chronically elevated glucose.

Animals↗
PubMed2000

Cell proliferation rates and fibronectin arrangement as parameters for biocompatibility evaluation of dental metal alloys in vitro.

A short-term (72-96 hours) biocompatibility evaluation in vitro of four single phase dental metal alloys was conducted by determining cell proliferation rates correlated to the organization of the extracellular matrix protein fibronectin in human fibroblast cultures. Immunocytochemical methods were performed to detect both cell proliferation rates by 5-bromodeoxyuridine (BrdU) incorporation, and fibronectin arrangement, i.e., diffuse in the extracellular matrix, organized in fibrils or in focal adhesions. We showed that cell proliferation rates were related to fibronectin expression. In particular, a higher percentage of cells in the S-phase were related to a predominance of fibronectin organized both in fibrils and in focal adhesions. The alloy with the highest Au content seemed the most biocompatible among those tested, since it behaved in a very similar manner to the controls. On the contrary, fibroblasts exposed to the alloy with the highest percentage of Ag had the most different behavior as compared to the controls. We can assume that a correlation exists between fibronectin organization and the percentage of BrdU-positive cells and that these parameters are varying with the different metal composition of the alloys. The observation of fibronectin arrangement together with cell proliferation rates could be considered a useful tool to determine the biocompatibility of these biomaterials.

Biocompatible Materials↗
PubMed1999

The pro-apoptotic drug camptothecin stimulates phospholipase D activity and diacylglycerol production in the nucleus of HL-60 human promyelocytic leukemia cells.

It has recently been reported (T. Shimizu et al., J. Biol. Chem., 273: 8669-8674, 1998) that the pro-apoptotic drug, camptothecin, an inhibitor of topoisomerase I, induces a protein kinase C-alpha-mediated phosphorylation of lamin B in HL-60 cells, which precedes both degradation of lamin B and fragmentation of DNA. In this paper, we report that, in HL-60 cells exposed to camptothecin, there is a rapid and sustained increase of nuclear protein kinase C-alpha activity that is due to an increase in the amount of protein kinase C-alpha present in the nucleus. The enhancement of nuclear kinase C activity is preceded by an increase in the mass of nuclear diacylglycerol. As demonstrated by its sensitivity to propranolol, the nuclear diacylglycerol mass increase is due to the activation of a phospholipase D. Indeed, inhibitors of neither phosphatidylcholine-specific phospholipase C nor phosphoinositide-specific phospholipase C blocked the rise in nuclear diacylglycerol. In vitro assays also demonstrated the activation of a nuclear phospholipase D, but not of a phosphoinositide-specific phospholipase C, after treatment with camptothecin. Propranolol was also able to block the rise in nuclear protein kinase C-alpha activity, thus suggesting that the increase in diacylglycerol mass is important for the activation of the kinase at the nuclear level. Moreover, propranolol was capable of drastically reducing the number of HL-60 cells that underwent apoptosis after treatment with camptothecin. Our results show the activation during apoptosis of a phospholipase D-mediated signaling pathway operating at the nuclear level. This pathway may represent an attractive therapeutic target for the modulation of apoptotic events in human disease.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Biochemical and morphological changes in the nuclear matrix prepared from apoptotic HL-60 cells: effect of different stabilizing procedures.

Apoptotic cell death is characterized by deep morphological changes that take place in the nucleus. It is unclear whether modifications also occur in the nuclear matrix, a mainly proteinaceous structure that conceivably acts as a nuclear framework. We have investigated whether biochemical and morphological alterations of the nuclear matrix prepared from apoptotic HL-60 cells were dependent on the manipulations to which isolated nuclei were subjected before DNase I digestion and 2 M NaCl extraction. Our results showed that the stabilizing procedures employed to preserve the inner fibrogranular network and nucleolar remnants of the matrix (i.e., a 37 degrees C incubation; exposure to sodium tetrathionate at 4 degrees C; exposure to sodium tetrathionate at 37 degrees C) had no effect on the protein recovery of apoptotic nuclear matrices, which was always approximately two- to fivefold less than in control matrices. Moreover, one- and two-dimensional gel analysis of nuclear matrix proteins showed that, in apoptotic samples, striking quantitative changes were present, as compared with controls. Once again, these changes were seen irrespective of the stabilizing procedures employed. Also, transmission electron microscope analysis showed similar morphological alterations in all types of apoptotic nuclear matrices. By contrast, the immunofluorescent distribution of the 240-kDa NuMA protein seen in apoptotic samples was more sensitive to the stabilizing treatments. Our results indicate that the biochemical and morphological changes of the apoptotic nuclear matrix are largely independent of the isolation protocols and strengthen the contention that destruction of the nuclear matrix network is one of the key events leading to apoptotic nuclear destruction.

Apoptosis↗
PubMed1999

Family history of diabetes in middle-aged Swedish men is a gender unrelated factor which associates with insulinopenia in newly diagnosed diabetic subjects.

We have investigated the association of a family history of diabetes with glucose tolerance in a population of Swedish men. All men 35-54 years of age in 1992 and living in four different local municipalities of the outer Stockholm area were screened by questionnaire. From 10236 completed questionnaires 1622 men, selected for presence of such a history but without known diabetes, as well as 1507 men without a family history underwent an oral glucose tolerance test. Diabetes (2 h-plasma glucose levels > 11.0 mmol/l) was detected in 55 and impaired glucose tolerance (plasma glucose levels 7.8-11.0 mmol/l) in 172 subjects. The odds ratio of diabetes, associated with a family history, was 4.1, confidence interval 2.1-8.3 and for impaired glucose tolerance 1.6, confidence interval 1.2-2.3. Influence of a family history was measurable also within the range of normal 2-h glucose concentrations: compared to 2-h glucose levels < 3.8 mmol/l; the odds ratio associated with a family history was 1.4, confidence interval 1.1-1.7 and 1.3, confidence interval 1.1-1.6 for concentrations 4.8-5.7 mmol/l and 5.8-7.7 mmol/l respectively. The odds ratio of diabetes and impaired glucose tolerance among men with a family history increased with number and closeness of relatives with diabetes but was not affected by the gender of the family member. Overweight (BMI > 25.0 kg/m2) increased the odds ratio of diabetes in subjects with a family history, the odds ratio being 24, confidence interval 3-177, when both conditions were present. In subjects with Type II (non-insulin-dependent) diabetes mellitus discovered during the investigation, the presence of a family history of diabetes was associated with decreased insulin secretion rather than insulin resistance as assessed by fasting insulin, homeostasis model assessment, and the 2-h insulin response to the oral glucose tolerance test. We conclude that a family history of diabetes strongly but independently of gender associates with decreased glucose tolerance. Furthermore, the results are compatible with a major role for low insulin secretion in the diabetogenic influence of a family history of diabetes in middle-aged Swedish men. Lastly, the very high risk for diabetes in middle-aged men with both a family history of diabetes and obesity indicates that such people should, for the purpose of therapeutic intervention, be identified in the general population.

Adult↗
PubMed1999

Enhancing effects of long-term elevated glucose and palmitate on stored and secreted proinsulin-to-insulin ratios in human pancreatic islets.

Relative hypersecretion of proinsulin is a feature of type 2 diabetes. We investigated to what extent this feature can be induced in human pancreatic islets by elevated glucose or fatty acids, two major abnormalities of the diabetic state. A 48-h culture period with 27 mmol/l glucose increased the intraislet proinsulin-to-insulin (PI/I) ratio 5.0-fold, owing to preferential decrease of insulin. The PI/I ratio in culture medium was enhanced 1.9-fold versus islets cultured with 5.5 mmol/l glucose. This effect of elevated glucose persisted after normalization of glucose levels: during 60-min postculture incubations at a basal glucose concentration (3.3 mmol/l), the PI/I ratio of secretion increased 4.9-fold. The ratio was also increased (14-fold) after renewed postculture stimulation with 16.7 mmol/l glucose. Diazoxide was added to culture medium to block glucose-induced insulin secretion and thus investigate the importance of overstimulation. In cultures at 27 mmol/l glucose, the presence of diazoxide decreased the PI/I ratio of islet contents by 76%, the accumulated secretion to culture medium by 70%, and the release at 3.3 or 16.7 mmol/l glucose during postculture incubations by 85 and 86%, respectively. None of these PI/I-decreasing effects of diazoxide were reproduced during or after coculture with 5.5 mmol/l glucose. Culture with 0.2 mmol/l palmitate and 5.5 mmol/l glucose decreased islet contents of proinsulin and insulin and increased the secreted products in culture media without affecting PI/I ratios. During postculture conditions, however, prior palmitate culture enhanced the PI/I ratio of release at 3.3 mmol/l glucose (from 2.2 +/- 0.4 to 5.4 +/- 0.9%, P < 0.05). Culture with palmitate together with 27 mmol/l glucose decreased islet contents of proinsulin and insulin and further enhanced intraislet PI/I ratios (from 9.3 +/- 1.1 to 13.4 +/- 2.5%, P < 0.05). However, palmitate failed to affect PI/I ratios in culture medium. In contrast, in postculture incubations at 3.3 mmol/l glucose, prior palmitate culture further elevated the PI/I ratio of secretion (from 10.8 +/- 1.2 after previous 27 mmol/l glucose alone to 13.9 +/- 2.8% after palmitate and glucose, P < 0.05). We conclude that 1) long-term exposure of human islets to elevated glucose leads to preferential secretion of proinsulin, and this effect persists also after glucose normalization; 2) the glucose effect appears secondary to depletion of mature insulin granules; and 3) elevated fatty acids influence PI/I ratios of secretion by mechanisms that are, in part, incongruous with an over-stimulation effect.

Adult↗
PubMed1999

Low birth weight, family history of diabetes, and glucose intolerance in Swedish middle-aged men.

OBJECTIVE: To investigate the association between low birth weight and glucose intolerance in relation to family history of diabetes. RESEARCH DESIGN AND METHODS: We conducted a population-based cross-sectional study of 2,237 men born in 1938-1957 in four municipalities in the outskirts of Stockholm, 50% of whom had a family history of diabetes (at least one first-degree or two second-degree relatives with diabetes). Oral glucose tolerance testing detected 35 cases of type 2 diabetes, 102 cases of impaired glucose tolerance, and 57 cases of impaired fasting glucose. RESULTS: In subjects without a family history of diabetes, low (< or = 3,000 g) birth weight was associated with an odds ratio of 2.3 (95% confidence intervals = 0.4-14.4) for diabetes, 1.8 (0.7-4.3) for impaired glucose tolerance, and 3.3 (1.0-10.4) for impaired fasting glucose. In subjects with a family history of diabetes, the corresponding figures were approximately similar, except for diabetes, for which the odds ratio was 5.4 (2.0-14.9). For men with low birth weight in combination with a family history of diabetes, the odds ratio was 10.9 (2.9-41.2) for diabetes, 2.4 (1.1-5.6) for impaired glucose tolerance, and 5.9 (2.1-16.3) for impaired fasting glucose. CONCLUSIONS: This study indicated that low birth weight is associated with type 2 diabetes, impaired glucose tolerance, and impaired fasting glucose in men. This finding was most pronounced in subjects with diabetes in the family, but it was also indicated in those without a family history of diabetes. Men with the combination of low birth weight and family history of diabetes seem to be at particularly high risk of developing type 2 diabetes.

Adult↗
PubMed1998

Weight history, glucose intolerance, and insulin levels in middle-aged Swedish men.

The association between weight history and glucose intolerance was examined in a cross-sectional study consisting of 3,128 Swedish men aged 35-56 years, 52 percent of whom had a family background of diabetes mellitus. Oral glucose tolerance testing detected 55 cases of type 2 (non-insulin-dependent) diabetes and 172 cases of impaired glucose tolerance. Among men with no family history of diabetes, the estimated odds ratios for impaired glucose tolerance associated with short (<5 years) and long (> or =10 years) durations of obesity (body mass index (weight (kg)/height2 (m2) > or =25.0) were 1.3 (95% confidence interval (CI) 0.2-7.7) and 11.8 (95% CI 3.3-41.9), respectively. Among men with a family history of diabetes, the odds ratios were 2.0 (95% CI 0.8-4.7) and 4.0 (95% CI 1.8-9.1), respectively. Corresponding estimates of the odds of type 2 diabetes, adjusted for family history of diabetes, were 1.9 (95% CI 0.5-7.1) and 7.3 (95% CI 2.2-23.7), respectively. The odds of high (> or =30.0 mU/liter) fasting insulin levels in subjects with impaired glucose tolerance were 6.9 (95% CI 0.6-74.2) and 21.0 (95% CI 2.1-206.4) for short and long durations of obesity, respectively. Corresponding estimated odds of low 2-hour insulin response (< or =71.9 mU/liter) were 0.7 (95% CI 0.2-2.9) and 3.3 (95% CI 1.2-8.9). Homeostasis model assessment of insulin resistance yielded an odds ratio of 6.7 (95% CI 0.6-73.4) for a short duration of obesity and 20.0 (95% CI 2.0-200.6) for a long duration. Examination of beta-cell function with homeostasis model assessment resulted in odds ratios of 0.2 (95% CI 0.0-1.6) and 2.0 (95% CI 0.7-5.4) for short and long durations of obesity, respectively. These data indicate that obesity decreases glucose tolerance by way of progressively increased insulin resistance and, in the case of prolonged duration, by decreased insulin secretion as well.

Body Mass Index↗
PubMed1998

Metformin increases circulating tumour necrosis factor-alpha levels in non-obese non-diabetic patients with coronary heart disease.

Metformin reduces insulin resistance and hyperinsulinaemia, as well as lipid levels and body weight. The mechanisms behind these effects are likely to involve intracellular insulin signalling. Recent evidence implicates tumour necrosis factor-alpha (TNF-alpha) as a modulatory factor on insulin resistance. The present investigation was undertaken to clarify whether metformin affects TNF-alpha and soluble TNF receptor levels. Sixty non-diabetic men with coronary heart disease were treated with diet and lifestyle advice and lovastatin 40 mg/day during a 4-week run-in period. During this period TNF-alpha and soluble TNF receptor p75 remained unchanged, whereas soluble TNF receptor p55 increased by 8% (P < 0.05). Twelve weeks of metformin treatment increased TNF-alpha by 33% (P < 0.05). This effect was restricted to non-obese patients in whom TNF-alpha increased by 68% (P < 0.01). Soluble TNF receptors p55 and p75 remained unchanged in the whole group, whereas soluble TNF receptor p55 increased by 11% (P < 0.05) in non-obese patients. Since metformin reduces insulin resistance both in obese and non-obese subjects but increases TNF-alpha levels only in the latter, it is concluded that the drug does not exert its effect on insulin resistance through regulation of circulating TNF-alpha levels.

Adult↗
PubMed1998

Evidence for dissociation of insulin- and weight-reducing effects of metformin in non-diabetic male patients with coronary heart disease.

Metformin effects on insulin resistance and insulin/glucose relationships during an oral glucose tolerance test (OGTT) were investigated in 60 non-diabetic male patients previously treated with coronary artery bypass surgery or angioplasty in an open, 12 week prospective study. During a 4 week run-in period, all patients were treated with diet and lifestyle advice and lovastatin 40 mg daily. Lovastatin treatment was continued in all the patient throughout the study. After randomization, the metformin group got additional treatment with metformin up to 2000 mg/day. Fasting plasma glucose levels and glucose area during OGTT remained unaffected by metformin treatment. Insulin resistance, assessed as the insulin area/glucose area ratio during OGTT decreased by 24% (P = 0.028) in the whole group and by 30% in obese subjects (P = 0.049). Notably, the reduction in body weight by metformin treatment did not correlate with amelioration of insulin resistance or changes in lipid levels. However, changes in insulin resistance correlated with changes in lipid levels. Hence, metformin effects on insulin resistance and body weight appear to be mediated, at least partly, by different mechanisms, while metformin effects on insulin resistance and lipid metabolism are associated in non-diabetic subjects.

Adult↗
PubMed1998

The effect of hyperglycaemia on regional cerebral glucose oxidation in humans studied with [1-11C]-D-glucose.

The effect of hyperglycaemia on regional cerebral glucose utilization was studied in five healthy males fasted over-night using positron emission tomography. Selectively labelled glucose, [1-11C]-D-glucose, was used as a tracer. After correction for the small loss of [11C]CO2 from the tissue, this tracer measures the rate of glucose oxidation rather than the total rate of glucose metabolism. Each subject was investigated twice: during normoglycaemia (plasma glucose 5.3 +/- 0.3 mumol mL-1) and at the end of a 2-h period of hyperglycaemia (plasma glucose 13.8 +/- 0.7 mumol mL-1). Assuming unchanged rate constant for loss of labelled CO2 at normo- and hyperglycaemia the oxidative metabolic rate of glucose was found to be slightly larger at combined hyperglycaemia and hypersulinemia (0.30 +/- 0.01 mmol mL-1 min-1) than at normal glucose and insulin levels (0.25 +/- 0.01 mmol mL-1 min-1). This suggests that the process of glucose phosphorylation might not be fully saturated in the human brain or, alternatively, that the glycogen deposition increases during short-term hyperglycaemia. The relative increase of oxidative metabolic rate was considerably larger (approximately 50%) in white matter than in the brain as a whole (20%). The brain glucose content was found to increase non-linearly with increasing plasma glucose. Together with data from previous studies these results suggest that the free glucose in the human brain is close to zero when the plasma glucose is below 2 mumol mL-1.

Adult↗