Acute intoxication with trichloroethene: clinical symptoms, toxicokinetics, metabolism, and development of biochemical parameters for renal damage

The present study was carried out to investigate a possible interaction between the effects of anxiety modulating drugs which act at the GABA-A receptor complex and selective N-methyl-D-aspartic acid (NMDA) coupled glycine receptor (GLY-B receptor) ligands within the dorsal periaqueductal gray (DPAG). The plus-maze performance of rats pretreated with diazepam (0.37 and 0.75 mg/kg, i.p.) or pentylenetetrazole (15 and 30 mg/kg, i.p.), standard anxiolytic and anxiogenic drugs respectively, was assessed following intra-periaqueductal injections of either glycine (0.2 M, 0.4 microl/30 s, i.c.) or its competitive antagonist, 7-chlorokynurenic acid (7ClKYN, 0.02 M, 0.4 microl/30 s, i.c.). Whilst diazepam produced a typical anxiolytic effect in intracranially-injected CSF rats, increasing open arm exploration, pentylenetetrazole displayed an opposite anxiogenic profile. Either anxiogenic or anxiolytic effects were seen in peripherally-injected vehicle rats following intra-periaqueductal injections of glycine or 7ClKYN, respectively. Intra-periaqueductal injection of glycine markedly attenuated the anxiolytic effect of diazepam. Moreover, while the anxiogenic effects of pentylenetetrazole were barely changed by glycine, they were markedly attenuated by intra-periaqueductal injection of 7ClKYN. Interaction of diazepam and 7ClKYN produced non-selective sedative-like effects which masked any possible anxiolytic action. Accordingly, the present results suggest that the NMDA-coupled glycine receptors located in the DPAG interfere with anxioselective effects of GABA-A acting drugs on the elevated plus-maze. In spite of the prevailing notion that the NMDA coupled glycine receptor is saturated at in vivo brain concentrations of glycine, our results also suggest that either unoccupied or low-affinity GLY-B receptors are likely to be activated by glycine injection into DPAG.     

Mannosidosis: clinical, morphologic, immunologic, and biochemical studies

The primary metabolic defect in mannosidosis is the deficiency of the acidic alpha-mannosidase A and B activites which results in the lysosomal accumulation of mannose-rich substrates. Out studies demonstrate that the enzymatic diagnosis of suspect homozygotes can be made reliably using plasma, isolated leukocytes, or cultured skin fibroblasts assayed carefully at the appropriate acidic pH. Immunologic studies of a mannosidosis homozygote revealed significant abnormalities of neutrophil function; these included a depressed chemotactic responsiveness and impaired phagocytosis of bacteria. Lymphocyte transformation studies showed a 20% of normal response to purified phytohemagglutinin and a 25% of normal response to concanavalin A. Three major components of alpha-mannosidase activity in normal human liver were resolved by ion exchange chromatography on DEAE-cellulose and electrophoresis on cellulose acetate gels. Electrophoresis of the liver extract from homozygote I with mannosidosis revealed only one band of activity which coelectrophoresed with the alpha-mannosidase C isozyme partially purified from normal liver. However, ion exchange chromatography revealed the presence of residual hepatic acidic activities; the residual A isozyme was eluted in a position corresponding to that of normal alpha-mannosidase A whereas the residual B activity was eluted at a slightly more electronegative position than that of normal B isozyme. The apparent Km values for alpha-mannosidase activity as determined from Linweaver-burk plots were 1.1 mM for normal liver and 0.9 mM for normal leukocytes. In contrast, the residual activity in these sources from homozygote 1 could not be saturated within the solubility range of the substrate; the apparent Km value was estimated at 15.4 mM in liver extracts. Zinc significantly lowered the apparent Km value of the acidic activity in normal liver (from 1.2 to 0.24 mM), whereas this metallic ion had little effect on the values for mannosidosis hepatic activity (from 15.4 to 12.3 mM). Unlike zinc, cobalt had its major effect on the acidic activity in the mannosidosis liver extract, lowering the apparent Km from 15.4 to 3.9 mM, whereas the apparent Km for the normal activity was increased from 1.2 to 1.9 mM. The residual acidic activities were markedly stimulated by zinc in both leukocytes (approximately 300%) and plasma ( approximately 400%) from the homozygotes and to a lesser extent in those sources from normal individuals. In contrast, cobalt enhanced the residual acidic activities in leukocytes (approximately 500%) and plasma (approximately 200%) from the homozygotes while inhibiting these acidic activities (78.9% and 47.7%, respectively) in normal individuals.     

Caprine mucopolysaccharidosis-IIID: clinical, biochemical, morphological and immunohistochemical characteristics

Laparoscopic antireflux surgery is rapidly replacing traditional operations for the treatment of medically refractory gastroesophageal reflux disease. These procedures are technically demanding. Troublesome side effects can be minimized by carefully selecting patients and using a meticulous and appropriate technique. Extensive follow-up data are now emerging and indicate that these procedures can offer long-term control of symptoms with few permanent side effects.     

The fish odour syndrome: biochemical, familial, and clinical aspects

OBJECTIVES: To study the biochemical, familial, and clinical features of the fish odour syndrome among subjects with suspected body malodour. DESIGN: Subjects who responded to a newspaper article were screened for the fish odour syndrome by interview and biochemical tests. Families of subjects with the syndrome were tested if possible. SETTING: St Mary's Hospital, London, and some interviews at subjects' homes. SUBJECTS: 187 subjects (28 males) with suspected body malodour, of whom 156 (19 males) underwent biochemical tests. Five families of six of the subjects with the fish odour syndrome agreed to further tests. MAIN OUTCOME MEASURES: Amounts of trimethylamine and trimethylamine N-oxide in urine collected over 24 hours under normal dietary conditions and for eight hours after oral challenge with 600 mg trimethylamine. RESULTS: The fish odour syndrome was diagnosed in 11 subjects: the percentage of total trimethylamine excreted in their urine samples that was oxidised to trimethylamine N-oxide was < 55% under normal dietary conditions and < 25% after oral challenge with trimethylamine (in normal subjects > 80% of trimethylamine was N-oxidised). Parents of six of the subjects with the syndrome were tested: all showed impaired N-oxidation of excreted trimethylamine (< 80%) after oral challenge, indicating that they were heterozygous carriers of the allele for the syndrome. The syndrome was associated with various psychosocial reactions including clinical depression. CONCLUSIONS: The fish odour syndrome can be inherited in an autosomal recessive fashion. It should be considered as a possible causative factor in patients complaining of body malodour.     

Human mucopolysaccharidosis IIID: clinical, biochemical, morphological and immunohistochemical characteristics

Mucopolysaccharidosis IIID (MPS IIID) is one of the rarest of the MPS-III syndromes. To date, the clinical manifestations of 10 patients have been reported, the deficient N-acetylglucosamine 6-sulfatase (G6S) enzyme has been purified, and the G6S gene has been cloned, sequenced and localized. However, morphological manifestations of this condition have not been reported and the pathogenesis of the severe neurological deficits remains an enigma. In this paper we describe and correlate the clinical, biochemical and pathological observations for 2 cases of MPS IIID. We used monoclonal antibodies against heparan sulfate (HS) and GM2-ganglioside, thin layer chromatography, mass spectrometry, and morphological techniques to demonstrate the nature and the distribution of the uncatabolized substrates. The majority of the cells in various tissues showed morphological changes expected with lysosomal storage of HS. The central nervous system (CNS) was most severely affected because of the secondary storage of GM2 and GM3 gangliosides in addition to the primary accumulation of HS. The extent as well as the distribution of the diverse storage materials varied within and among different neurons as observed in MPS-III A, B, and C syndromes. This study supports the hypothesis that the neurological dysfunction and neurodegeneration common to the Sanfilippo syndromes is, in part, due to the secondary metabolic perturbations induced by HS accumulation.     

Reversibility of Schistosoma mansoni-associated morbidity after yearly mass praziquantel therapy: ultrasonographic assessment

OBJECTIVE: To study the outcome of osteoporosis assessment and rehabilitation in post-fracture patients. METHODS: This was a retrospective survey of the records of patients who had been referred to us from orthopaedic departments for rehabilitation after a fracture. RESULTS: A significant number of patients had had previous fractures (n = 17) or risk factors for osteoporosis (n = 16). The mortality rate was 4%. A significant proportion of patients (9/44) who had been living in their homes required placement in residential or nursing homes and additional care after rehabilitation. CONCLUSION: Our audit showed that post-fracture patients received optimum care, as set out in the Royal College of Physicians guidelines, but could benefit additionally from assessment and treatment of osteoporosis as set out in the Department of Health (DOH) Guidelines.     

Familial lipoprotein lipase deficiency in infancy: clinical, biochemical, and molecular study

Although almost all of the energy contained within the ultraviolet (UV) wavelengths of solar radiation is absorbed within the epidermis and upper layers of the dermis, UV irradiation can suppress the immune response to antigens introduced at distant, non-irradiated body sites. The production of immune modulatory cytokines, such as interleukin-10 (IL-10), by UV-irradiated keratinocytes and its effect on T helper type 1 (Th1)/Th2-cell balance are thought to play a major role in the induction of systemic immune suppression. Because it is suggested that costimulatory molecules, such as CD80 and CD86, differentially stimulate Th1 and Th2 cells we wished to investigate the role of these costimulatory molecules in the activation of immune suppression. We injected UV-irradiated mice with monoclonal antibodies to CD80 and CD86 and asked what effect, if any, this would have on UV-induced immune suppression. Anti-CD86, but not anti-CD80 or control rat IgG, blocked UV-induced immune suppression. Moreover, monoclonal anti-CD86 blocked the induction of suppressor T cells normally found in the spleens of the UV-irradiated mice. Monoclonal anti-CD86 also reversed the UV-induced impairment of systemic antigen-presenting cell function. IL-10 was detectable in the serum of UV-irradiated mice as compared with normal controls, and injecting UV-irradiated mice with anti-CD86, but not anti-CD80 or control rat IgG, blocked the secretion of IL-10 into the serum. We propose that UV exposure favours costimulation by CD86, which enhances the production of serum IL-10, thus suppressing Th1-cell-mediated immune reactions.     

Submandibular gland surgery: an audit of clinical findings, pathology and postoperative morbidity

A series of 86 patients who underwent submandibular gland surgery were reviewed retrospectively. Of the 92 glands excised, non-neoplastic disease accounted for 96% of cases. Preoperative clinical findings were inconsistent such that early surgery should be considered for an enlarged non-tender submandibular gland. The incidence of temporary paresis of the lower branches of the facial nerve was 36% with full recovery, on average, 4 months after surgery. The low 'non-identification' approach to the submandibular gland appears to be the technique which offers the least likelihood of permanent damage to the lower branches of the facial nerve.     

Erythritol: an interpretive summary of biochemical, metabolic, toxicological and clinical data

A critical and comprehensive review of the safety information on erythritol was undertaken. Numerous toxicity and metabolic studies have been conducted on erythritol in rats, mice and dogs. The toxicity studies consist of long-term feeding studies conducted to determine carcinogenic potential, intravenous and oral teratogenicity studies to determine the potential for effects on the foetus, oral studies in which erythritol was administered over one or two generations to determine the potential for reproductive effects, and studies in bacterial and mammalian systems to determine mutagenic potential. The majority of the safety studies conducted were feeding studies in which erythritol was mixed into the diet at concentrations as high as 20%. The metabolic studies in animals have shown that erythritol is almost completely absorbed, not metabolized systemically and is excreted unchanged in the urine. The safety studies have demonstrated that erythritol is well tolerated and elicits no toxicological effects. The clinical program for erythritol involved a series of single-dose and repeat-dose, short-duration studies which have been used to investigate the human correlates to the physiological responses seen in the preclinical studies. The clinical studies showed erythritol to be well tolerated and not to cause any toxicologically relevant effects, even following high-dose exposure. Erythritol administered orally to humans was rapidly absorbed from the gastrointestinal tract and quantitatively excreted in the urine without undergoing metabolic change. At high oral doses, urinary excretion accounted for approximately 90% of the administered dose with minimal amounts appearing in the faeces. A comparison of the human and animal data indicated a high degree of similarity in the metabolism of erythritol and this finding supports the use of the animal species used to evaluate the safety of erythritol for human consumption. It can be concluded, based on the available studies that erythritol did not produce evidence of toxicity.     

Congenital dyserythropoietic anaemias: clinical features, haematological morphology and new biochemical data

Three types of congenital dyserythropoietic anaemia (CDA) were originally identified on the basis of the pattern of dysplastic changes in the erythroblasts and the results of the acidified serum lysis test (Ham test). These were designated CDA types I, II and III. Several other types have been described subsequently and new forms continue to be reported. Some patients with CDA develop iron overload even without repeated blood transfusion and may present with the complications of severe iron overload. Dysmorphic features are seen in some cases, especially of CDA type I. In CDA type II, incomplete processing of N-linked oligosaccharides leads to a marked reduction of polylactosamines associated with band 3 of the red cell membrane. A few cases of CDA type III develop lymphoid neoplasms. Some of the Swedish cases of CDA type III have developed a retinal abnormality characterized by angioid streaks and macular degeneration. The chromosomal localizations of the disease gene in CDA types I and II and in the Swedish family with CDA type III are now known, but the identities of the mutant genes are still unknown. Cases of CDA type I have shown a partial haematological response to interferon-alpha, however the biochemical basis of this response is unclear. An important step in the diagnosis of sporadic cases of CDA is the exclusion of known causes of acquired dyserythropoiesis.     

Coping with chronic stress at Three Mile Island: Psychological and biochemical evidence.

Examined the effectiveness of different coping styles in the face of a chronic and unique stressor—the accident at Three Mile Island and its 2-yr aftermath. Psychological, biochemical, and behavioral aspects of stress were measured in 70 Ss during a protracted stress situation and were compared to indices of coping provided by a ways of coping inventory. Because stress was chronic and the sources of stress were not easily changed, reappraisal-based emotional management appeared to be more effective in reducing psychological and behavioral consequences of stress. The use of denial or problem-oriented modes of coping under these conditions was less useful in reducing stress. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Smith-Lemli-Opitz syndrome: a variable clinical and biochemical phenotype

We have reviewed all known UK cases of Smith-Lemli-Opitz syndrome. Among 49 cases with proven 7-dehydrocholesterol reductase deficiency, half had been terminated or had died in infancy. The minimum incidence is 1 in 60,000. The frequent occurrence of hypospadias may account for 71% of recognised cases being male. Important common features which emerged include short thumbs, severe photosensitivity, aggressive behaviour, and atrioventricular septal defect. The typical facial appearance becomes less obvious with age and 20% of cases did not have 2/3 toe syndactyly. Biochemical measurements of serum 7-dehydrocholesterol did not correlate with clinical severity.     

Leigh syndrome: clinical features and biochemical and DNA abnormalities

The morphology and number of cells in the trophectoderm (TE) and inner cell mass (ICM) of buffalo blastocysts derived from in vitro fertilization and cultured in the presence or absence of insulin-like growth factor-I (IGF-I) were analyzed by differential fluorochrome staining technique. The total cell number (TCN), TE number, and ICM cell number were significantly higher in blastocysts developed in vitro in the presence of IGF-I as compared to blastocysts developed without IGF-I (P < 0.01). It was observed that the buffalo blastocyst took 5-9 days postfertilization to develop in vitro. In order to correlate the time required for blastocyst development and the allocation of cells to TE and ICM, blastocysts were designated as fast (developing on or before day 7) or slow (developing after day 7). The TCN, TE, and ICM cells of fast-developing blastocysts cultured in the presence of IGF-I were significantly higher than slow-developing blastocysts (P < 0.01). The blastocysts developed on day 6 had a mean total cell number 118.6 +/- 21.4, which significantly decreased to 85.6 +/- 17.4, 62.0 +/- 14.5, and 17.0 +/- 4.0 on days 7, 8, and 9, respectively (P < 0.05). Normal development of buffalo embryo showed that, on average, embryos reached compact morula stage at the earliest between days 4.5-5.5. Blastocysts developed, at the earliest, between days 5.0-6.0, and it took them, on average, 6.5 days to hatch from the zona pellucida. TCN, TE, and ICM increased three times from morula to blastocyst; however, the proportion of ICM to TCN remained the same, in both embryonic stages. TE approximately doubled in hatched blastocysts, as compared to unhatched blastocysts (P < 0.05). However, ICM cells were decreased. The time required for development of parthenogenetic blastocysts was observed to be greater as compared to in vitro fertilized (IVF) blastocysts. The total cell number of parthenogenetic blastocysts was 100.8 +/- 11.3, including 59.2 +/- 8.4 cells of TE and 42.1 +/- 6.9 cells of ICM.     

Hemoglobinopathies affecting maternal-fetal oxygen gradient during pregnancy: molecular, biochemical and clinical studies

OBJECTIVES: Evaluate the efficacy of chorioretinal venous anastomosis in patients with nonischemic retinal vein occlusions with progressive visual loss and to concentrate on complications. DESIGN: Case series of 6 patients, retrospective study. Six patients with nonischemic central retinal vein occlusions and progressive visual loss. Laser photocoagulation was performed to create a chorioretinal venous anastomosis to be able to supply venous blood to the choroid, bypassing the occlusion. Visual acuity, funduscopic appearance and fluorescein angiographic appearance were determined. RESULTS: Two patients showed a chorioretinal anastomosis (33%), whereas in the other 4 patients the anastomosis could not be created. Yet 1 patient consequently had a neovascular tuft under the laser site. These new vessels caused minor vitreous hemorrhage and a tractional membrane which regressed after 10 months. CONCLUSION: The utilization of a chorioretinal venous anastomosis by laser as a therapeutic modality should be further questioned and thoroughly evaluated and caution must be exercised to avoid vision-threatening complications.     

Intracoronary artery thrombus formation in unstable angina: a clinical, biochemical and angiographic correlation

OBJECTIVES: We examined the relation between the level of urinary fibrinopeptide A and the presence of angiographic intracoronary thrombus in patients with unstable angina to determine whether this marker predicts active thrombus formation. BACKGROUND: Although it is known that thrombus plays a role in acute ischemic syndromes, a noninvasive method to predict its presence in individual patients with unstable angina has not been determined. Fibrinopeptide A is a polypeptide cleaved from fibrinogen by thrombin and thus is a sensitive marker of thrombin activity and fibrin generation. METHODS: Angiographic thrombus, graded 0 to 4, and the presence of ST segment depression or T wave inversions, or both, on the electrocardiogram (ECG) were related to fibrinopeptide A levels in 24 patients with rest angina of new onset, 18 with crescendo angina, 19 with stable angina and 9 with chest pain but without coronary artery disease. All patients had chest pain within the 24 h of sample acquisition. RESULTS: The angiographic incidence of thrombus was significantly higher in patients with new onset of rest angina (67%, p < 0.001) and crescendo angina (50%, p < 0.001) as were fibrinopeptide A levels (p = 0.002). Fibrinopeptide A levels correlated significantly (p < 0.001) with the presence of a filling defect (grade 4 intracoronary thrombus) or contrast staining (grade 3). All patients with fibrinopeptide A > or = 8 ng/mg creatinine showed grade 3 to 4 thrombus and 15 of 16 patients with levels > or = 6.0 ng/mg creatinine exhibited angiographic evidence of thrombus (13 with grades 3 to 4). Patients with reversible ST changes on the ECG had significantly higher levels of fibrinopeptide A (p < 0.001), and ST changes correlated significantly with the presence of angiographic thrombus (p < 0.001). Nonetheless, a significant minority of patients with unstable angina had neither angiographic nor biochemical evidence of thrombus. CONCLUSIONS: Elevated fibrinopeptide A levels in unstable angina reflected active intracoronary thrombus formation and were present in patients with angina of new onset as well as crescendo angina. Reversible ST changes are accompanied by thrombin activity and angiographic thrombus formation. However, a sizable percentage of patients with unstable angina had no evidence of thrombus and these patients may have had transient platelet aggregation without fibrin thrombus formation.     

Diagnosis of mycobacterial disease by biochemical and immunological parameters

A definitive diagnosis of tuberculosis requires the recovery of M. tuberculosis organisms from a patient's secretions, body fluids, or tissues. However, the detection rate of M. tuberculosis is not high in tuberculous pleural effusions. Several studies demonstrated that adenosine deaminase (ADA) level in pleural effusion above 50 IU/L was strongly associated with tuberculosis. ADA has been found to be elevated in serum and several body fluids that are infected by M. tuberculosis. Recently, the simultaneous skin tests of PPDs (M. tuberculosis), PPD-B (M. intracellulare), PPD-Y (M. kansasii) and PPD-F (M. fortuitum), have been reported to be useful in diagnosing mycobacteriosis in the early stage of the disease. Although serodiagnosis of tuberculosis has long been the subject of investigation, no serodiagnostic approach is currently of widespread and clinical utility. At the present time, several serodiagnostic test using enzyme-linked immunosorbent assay (ELISA) for the measurement of IgG antibody to some protein (38-kDa, 30-kDa, 16-kDa and so on) and nonprotein (lipoarabinomannan and cord factor) antigens. Despite an explosion in the techniques of rapid identification of mycobacteria by molecular genetic means, the relative simplicity and low cost of serodiagnosis remain attractive.     

Adenylosuccinase deficiency: clinical and biochemical findings in 5 Czech patients

Polycythemia and hyperhomocysteinemia are risk factors for thrombosis. Since red blood cells actively metabolize methionine to homocysteine, we investigated whether or not patients with polycythemia have increased plasma levels of homocysteine, which might contribute to their increased thrombotic risk. In ten patients with polycythemia, the plasma homocysteine levels were measured before phlebotomy, three days after the procedure and 1-2 months later. The baseline mean plasma homocysteine levels in patients (9.7 +/- 1.6 mumol/L [+/-SD]) did not differ significantly from that found in 30 sex- and age-matched healthy controls (12.2 +/- 6.9). Despite a fall in the patients' mean [+/-SD] hematocrit from 0.50 +/- 0.02 at baseline to 0.47 +/- 0.03 three days after phlebotomy (significant at 95%) and to 0.48 +/- 0.02 after 1 to 2 months (not significant), the mean plasma homocysteine levels did not change significantly (9.9 +/- 2.3 mumol/L at 3 days and 9.7 +/- 2.1 mumol/L at 1-2 months). It is unlikely that high plasma homocysteine levels contribute to the increased thrombotic risk of polycythemic patients.     

Schistosoma mansoni, intestinal parasites and perceived morbidity indicators in schoolchildren in a rural endemic area of western C?te d'Ivoire

There is a great need for rapid and low-cost identification of communities at high risk of intestinal schistosomiasis. We report the development of a questionnaire approach that may do so. In the first phase, 209 schoolchildren from 3 neighbouring villages in a rural area endemic for intestinal schistosomiasis in western C?te d'Ivoire were screened for Schistosoma mansoni and other helminths on 4 consecutive days using Kato-Katz thick smears. Daily infection prevalences of S. mansoni were high (60%-71%) and the cumulative infection prevalence was 92.3%. Infections with hookworms and Ascaris lumbricoides were also frequent, with cumulative prevalences of 60.8% and 38.3%, respectively. On day 3, the presence of Entamoeba histolytica/E. dispar and Giardia lamblia was assessed by a faecal concentration procedure. In the second phase, focus group discussions (FGD) were conducted: in each village one FGD with heavily infected children and one FGD with lightly or S. mansoni-uninfected schoolchildren to assess their perception of morbidity. The aim was to establish local terms indicating S. mansoni infections. 'Diarrhoea', 'blood in the stools', 'stomach disorders' and 4 terms in the local Yacouba/Dioula languages were frequently used by infected children. A simple questionnaire was then developed and the headteachers interviewed all schoolchildren individually. 'Blood in stools', gnon and toto were reported significantly more frequently among moderately and heavily S. mansoni-infected children than by those not or only lightly infected. The term gloujeu indicated borderline significance. The best diagnostic performance was found for 'blood in stool' (sensitivity: 47%; specificity: 76%; positive predictive value: 66%; negative predictive value: 60%). All schistosomiasis infections were treated with a single oral dose of praziquantel (40 mg/kg body weight) and the same questionnaire was re-administered 6 weeks post-treatment. Statistically significantly less children reported having had 'blood in stool' and 'gloujeu' after treatment (McNemar's (chi2-test, P < 0.01). We conclude that 'blood in stool', 'gnon', 'toto' and 'gloujeu' are the most reliable reported symptoms for rapid and low-cost identification of communities that are at high risk of S. mansoni infections in C?te d'Ivoire.     

Mitochondria and diabetes. Genetic, biochemical, and clinical implications of the cellular energy circuit

Physiologically, a postprandial glucose rise induces metabolic signal sequences that use several steps in common in both the pancreas and peripheral tissues but result in different events due to specialized tissue functions. Glucose transport performed by tissue-specific glucose transporters is, in general, not rate limiting. The next step is phosphorylation of glucose by cell-specific hexokinases. In the beta-cell, glucokinase (or hexokinase IV) is activated upon binding to a pore protein in the outer mitochondrial membrane at contact sites between outer and inner membranes. The same mechanism applies for hexokinase II in skeletal muscle and adipose tissue. The activation of hexokinases depends on a contact site-specific structure of the pore, which is voltage-dependent and influenced by the electric potential of the inner mitochondrial membrane. Mitochondria lacking a membrane potential because of defects in the respiratory chain would thus not be able to increase the glucose-phosphorylating enzyme activity over basal state. Binding and activation of hexokinases to mitochondrial contact sites lead to an acceleration of the formation of both ADP and glucose-6-phosphate (G-6-P). ADP directly enters the mitochondrion and stimulates mitochondrial oxidative phosphorylation. G-6-P is an important intermediate of energy metabolism at the switch position between glycolysis, glycogen synthesis, and the pentose-phosphate shunt. Initiated by blood glucose elevation, mitochondrial oxidative phosphorylation is accelerated in a concerted action coupling glycolysis to mitochondrial metabolism at three different points: first, through NADH transfer to the respiratory chain complex I via the malate/aspartate shuttle; second, by providing FADH2 to complex II through the glycerol-phosphate/dihydroxy-acetone-phosphate cycle; and third, by the action of hexo(gluco)kinases providing ADP for complex V, the ATP synthetase. As cytosolic and mitochondrial isozymes of creatine kinase (CK) are observed in insulinoma cells, the phosphocreatine (CrP) shuttle, working in brain and muscle, may also be involved in signaling glucose-induced insulin secretion in beta-cells. An interplay between the plasma membrane-bound CK and the mitochondrial CK could provide a mechanism to increase ATP locally at the KATP channels, coordinated to the activity of mitochondrial CrP production. Closure of the KATP channels by ATP would lead to an increase of cytosolic and, even more, mitochondrial calcium and finally to insulin secretion. Thus in beta-cells, glucose, via bound glucokinase, stimulates mitochondrial CrP synthesis. The same signaling sequence is used in the opposite direction in muscle during exercise when high ATP turnover increases the creatine level that stimulates mitochondrial ATP synthesis and glucose phosphorylation via hexokinase. Furthermore, this cytosolic/mitochondrial cross-talk is also involved in activation of muscle glycogen synthesis by glucose. The activity of mitochondrially bound hexokinase provides G-6-P and stimulates UTP production through mitochondrial nucleoside diphosphate kinase. Pathophysiologically, there are at least two genetically different forms of diabetes linked to energy metabolism: the first example is one form of maturity-onset diabetes of the young (MODY2), an autosomal dominant disorder caused by point mutations of the glucokinase gene; the second example is several forms of mitochondrial diabetes caused by point and length mutations of the mitochondrial DNA (mtDNA) that encodes several subunits of the respiratory chain complexes. Because the mtDNA is vulnerable and accumulates point and length mutations during aging, it is likely to contribute to the manifestation of some forms of NIDDM.(ABSTRACT TRUNCATED)