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  • 1
    ISSN: 1432-0428
    Keywords: Biguanides ; bile acids ; vitamin-B12-absorption ; phenformin ; buformin ; metformin ; intestinal bacterial overgrowth ; cholesterol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Since vitamin B12malabsorption has been described in diabetics on biguanides and inhibition of bile acid absorption found in rat ileum the effect of treatment with different biguanides (phenformin, buformin, metformin) on bile acid metabolism and vitamin B12 absorption was assessed in maturity onset diabetics. Biguanides did not alter faecal weight or faecal fat excretion, but they decreased faecal bile acid excretion. All biguanides tested increased deconjugation of glycocholic acid, as determined by a simple breath test technique. Vitamin B12 malabsorption was most prominent in patients on metformin. Discontinuation of biguanide treatment, or administration of antibiotics, normalized or improved the increased deconjugation of bile acids and the Schilling test. Decreased faecal bile acid excretion, positive14C-glycocholate breath tests, pathological Schilling tests and the reversal of pathological tests by antibiotic treatment suggest that small intestinal bacterial overgrowth, leading to binding of the intrinsic-factor-vitamin B12-complex to bacteria, is responsible for the previously observed pathological Schilling tests in diabetics on biguanides. Bile acid malabsorption, possibly responsible for the cholesterol-lowering effect of biguanides, does not occur in diabetics on biguanides. Whether qualitative changes in small intestinal bile acid composition might affect cholesterol metabolism remains to be determined.
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  • 2
    ISSN: 1432-0428
    Keywords: GIP release ; insulin release ; obesity ; glucose intolerance ; starvation ; food restriction ; weight reduction ; oral glucose load ; test meal ; triglyceride ingestion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The response of serum immunoreactive gastric inhibitory polypeptide (IR-GIP) and immunoreactive insulin (IRI) to a liquid mixed test meal, glucose or fat has been examined in obese subjects before and after starvation or reduced caloric intake (800 calories). Basal serum levels of IR-GIP increased significantly during starvation of obese persons and remained elevated over the whole starvation period while basal serum IRI levels decreased. The exaggerated IR-GIP response of obese subjects with normal or pathological glucose tolerance to a test meal and of obese subjects with glucose intolerance to 100 g glucose ingestion decreased significantly after starvation or food restriction. Simultaneously, the serum IRI response decreased. The exaggerated IR-GIP response of obese subjects to oral triglycerides which did not affect serum IRI or glucose levels was also significantly decreased after food restriction. The IR-GIP response of obese subjects to a test meal was already reduced after 5 days of food restriction together with an improved glucose tolerance. At this stage the IRI response was unchanged. After weight reduction in obese subjects there was a significant decrease of the IRI response to oral but not to intravenous glucose, while the glucose response decreased irrespectively of the mode of glucose administration. The IR-GIP response decreased only after oral glucose. The data are compatible with the hypothesis that the exaggerated IR-GIP response of obese subjects to oral glucose or fat load is secondary to the increased food intake and that changes in IRI response to oral glucose are related to changes in IR-GIP response.
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  • 3
    ISSN: 1432-0428
    Keywords: Juvenile diabetes ; HLA ; family history ; heterogeneity ; genetics ; haplotype concordance ; negative selection ; recombination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary HLA-typing was performed in two groups of juvenile-onset diabetics, one with (n = 58) and one without (n = 109) a family history of the disease. The association of this type of diabetes with certain HLA antigens (excess of B8 and B15, shortage of B7) was confirmed. No heterogeneiteis could be established between the two groups. This suggests that the aetiologic basis in single and familial cases of juvenile diabetes is the same. The hypothesis, that the B8 associated gene is more penetrant than the B15 associated gene, cannot be confirmed. Haplo-types were determined in families with one and two diabetic siblings. The findings of high haplotype concordance among diabetic siblings was confirmed: concordance of 2, 1 and 0 haplotypes in 7, 5 and 3 pairs respectively. There was a low degree of haplotype concordance between diabetics and non-affected siblings in the families with two diabetics: 2, 1, and 0 haplotypes in 2, 8 and 6 pairs respectively. This led to the hypothesis of negative selection against these HLA-linked “diabetogenic” genes. This tendency was not, however, observed in families with only one diabetic. The report of a high recombination rate in families with juvenile diabetics could not be confirmed.
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  • 4
    ISSN: 1432-0428
    Keywords: α-glucosidase-inhibitor ; sulphonylureatreated diabetics ; insulin-treated diabetics ; blood glucose control
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary BAY-g-5421 is an α-glucosidase-inhibitor which inhibits intestinal absorption of carbohydrates. In a double-blind cross over study 12 diabetics taking sulphonylureas and 12 insulin-treated diabetics were treated additionally with BAY-g-5421 or a placebo for two seven day periods. In the pretreatment period and on the 7th and 14th day of the treatment periods serial blood glucose profiles were measured. In comparison to placebo BAY-g-5421 significantly lowered the mean (140 versus 157 mg/dl) and the maximal (192 versus 230 mg/dl) blood glucose values and the integrated blood glucose response (3112 versus 3421 mg/dl · 24 h) in the sulphonylurea-treated group as well as in the insulin-treated group (mean blood glucose 161 versus 192 mg/dl, maximal blood glucose 238 versus 283 mg/dl, integrated blood glucose response 3109 versus 3857 mg/dl · 24 h). The amplitude of glycaemic excursions was significantly decreased only in the sulphonylurea-treated group (96 versus 129 mg/dl), but not in the insulin-treated diabetics. No influence on routine liver function, renal function or haematological tests was observed. Side effects included hypoglycaemia in 3 patients of the insulin-treated group and meteorism in both groups. BAY-g-5421 could be a useful additional treatment for diabetic patients.
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  • 5
    ISSN: 1432-0428
    Keywords: Keywords GLP-1 [7 ; 36 amide] ; incretin ; insulin ; glucagon ; pharmacokinetics.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Intravenous glucagon-like peptide (GLP)-1 [7–36 amide] can normalize plasma glucose in non-insulin-dependent diabetic (NIDDM) patients. Since this is no form for routine therapeutic administration, effects of subcutaneous GLP-1 at a high dose (1.5 nmol/kg body weight) were examined. Three groups of 8, 9 and 7 patients (61 ± 7, 61 ± 9, 50 ± 11 years; BMI 29.5 ± 2.5, 26.1 ± 2.3, 28.0 ± 4.2 kg/m2; HbA1 c 11.3 ± 1.5, 9.9 ± 1.0, 10.6 ± 0.7 %) were examined: after a single subcutaneous injection of 1.5 nmol/kg GLP [7–36 amide]; after repeated subcutaneous injections (0 and 120 min) in fasting patients; after a single, subcutaneous injection 30 min before a liquid test meal (amino acids 8 %, and sucrose 50 g in 400 ml), all compared with a placebo. Glucose (glucose oxidase), insulin, C-peptide, GLP-1 and glucagon (specific immunoassays) were measured. Gastric emptying was assessed with the indicator-dilution method and phenol red. Repeated measures ANOVA was used for statistical analysis. GLP-1 injection led to a short-lived increment in GLP-1 concentrations (peak at 30–60 min, then return to basal levels after 90–120 min). Each GLP-1 injection stimulated insulin (insulin, C-peptide, p 〈 0.0001, respectively) and inhibited glucagon secretion (p 〈 0.0001). In fasting patients the repeated administration of GLP-1 normalized plasma glucose (5.8 ± 0.4 mmol/l after 240 min vs 8.2 ± 0.7 mmol/l after a single dose, p = 0.0065). With the meal, subcutaneous GLP-1 led to a complete cessation of gastric emptying for 30–45 min (p 〈 0.0001 statistically different from placebo) followed by emptying at a normal rate. As a consequence, integrated incremental glucose responses were reduced by 40 % (p = 0.051). In conclusion, subcutaneous GLP-1 [7–36 amide] has similar effects in NIDDM patients as an intravenous infusion. Preparations with retarded release of GLP-1 would appear more suitable for therapeutic purposes because elevation of GLP-1 concentrations for 4 rather than 2 h (repeated doses) normalized fasting plasma glucose better. In the short term, there appears to be no tachyphylaxis, since insulin stimulation and glucagon suppression were similar upon repeated administrations of GLP-1 [7–36 amide]. It may be easier to influence fasting hyperglycaemia by GLP-1 than to reduce meal-related increments in glycaemia. [Diabetologia (1996) 39: 1546–1553]
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  • 6
    ISSN: 1432-0428
    Keywords: Spontaneous diabetes ; diabetes in animals ; diabetes in man ; spiny mice ; Acomys cahirinus ; NZO mice ; mutationobob ; streptozotocin ; liver enzymes ; glycolysis ; Gluconeogenesis ; basement membrane ; muscle ; microangiopathy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Résumé L'épaisseur de la membrane basale vasculaire dans le muscle de la souris à piquants a été déterminée selon la méthode de Siperstein et al. (1968). L'épaisseur moyenne de la membrane basale des souris à piquants ayant une tolérance normale au glucose est de 73±16 nm celle des animaux avec une tolérance au glucose modérément ou sévèrement déséquilibrée est respectivement de 75±18 nm et de 80±18 nm. Chez la souris à piquants ayant un diabète cétosique franc de longue durée, l'épaisseur de la membrane basale est de 105±9 nm. Cette petite augmentation peut difficilement être reliée au diabète parce qu'elle reste dans les limites des dimensions de la membrane basale observées chez les souris blanches normales et bien en dessous des valeurs trouvées dans le diabète humain et le diabète expérimental de l'animal. — L'activité de différentes enzymes de la glycolyse et de la gluconéogénèse a été mesurée dans le foie d'animaux ayant un diabète expérimental ou spontané ainsi que dans le diabète non-traité de l'homme. L'activité de différentes enzymes hépatiques sous différentes conditions est en relation avec le type du diabète. Dans les cas d'une déficience en insuline (diabète aigu induit par la streptozotocine chez le rat, diabète cétosique de la souris à piquants et diabète juvénile non-traité chez l'homme), on observe une diminution de la glucokinase, de la phosphofructokinase et de la pyruvatekinase, alors que l'activité de la fructo-1,6-diphosphatase et la glucose-6-phosphatase sont accrues et l'activité de l'aldolase reste inchangée. Dans le diabète non-cétosique (diabète spontané léger de la souris à piquants, de la souris obèse-hyperglycémique de Bar Harbor, de la souris obèse de Nouvelle-Zélande et dans le diabète humain de type adulte), l'activité de la glucokinase est significativement accrue. Bien que l'activité des enzymes de la gluconéogénèse ne soit augmentée que dans les cas d'hyper glycémics les plus sévères, l'accroissement de l'activité de la pyruvatekinase n'est observé que dans les formes moins sévères de diabète non-cétosique.
    Abstract: Zusammenfassung Die Bestimmung des Durchmessers der Basalmembranen der Muskelcapillaren bei Stachelmäusen (Acomys cahirinus), nach der Methode von Siperstein et al. 1968 ergab bei Tieren mit normaler Glucosetoleranz 73±16 nM, bei Tieren mit leichter und schwerer Glucosetoleranzstörung 75±18 resp. 80±18 nM. Bei Tieren mit seit langem bestehendem ketotischen Diabetes betrug der 0 105±9 nM. Dieser Wert liegt deutlich unter denjenigen, die bei Diabetikern und diabetischen Tieren gefunden wurden und entspricht ungefähr denjenigen, die bei normalen weißen Mäusen gemessen werden. Es ist deshalb nicht wahrscheinlich, daß die geringe bei Stachelmäusen beobachtete Zunahme auf die diabetische Stoffwechselstörung zurückgeführt werden kann. — In Leberhomogenaten von Tieren mit spontanem und experimentellem Diabetes sowie von unbehandelten Diabetikern wurde die Aktivität verschiedener Schlüsselenzyme der Glykolyse und der Gluconeogenese gemessen. Dies erlaubte es, den verschiedenen Schweregraden hyperglykämischer Syndrome bestimmte Enzymmuster zuzuordnen. Im Falle eines Insulinmangels mit Keto-Acidose fand sich bei Mensch und Tieren ein Abfall der Aktivität von GK, PFK und PK. während die Aktivität von FD Pase und G-6-Pase anstieg und die Aldolase-Aktivität unverändert blieb. Nicht ketotische Hyperglykämie war durch eine Erhöhung der Aktivität der Glucokinase charakterisiert; die Aktivität der Schlüsselenzyme der Gluconeogenèse war nur bei schwerer Hyperglykämie erhöht, während diejenige der Pyruvatkinase nur bei der leichten Form des nicht-ketotischen Diabetes erhöht war.
    Notes: Summary Vascular basement membrane thickness in the muscle was measured in spiny mice according to the method of Sipersteinet al. (1968). The mean basement membrane width in spiny mice with normal glucose tolerance was 73±16 nm and in spiny mice with moderately and severely impaired glucose tolerance 75±18 and 80±18 nm respectively. In spiny mice with long lasting overt ketotic diabetes the basement membrane width was 105±9 nm. This small increase is unlikely to be related to diabetes since it is within the range of basement membrane thickness measured in normal swiss mice and far below the range described in human and experimental diabetes. — The activity of different enzymes of glycolysis and gluconeogenesis was measured in the liver of animals with experimental and spontaneous diabetes and in untreated human diabetes. The pattern of liver enzyme activity found under the different conditions could be related to the type of diabetes present. In the case of insulin deficiency (acute streptozotocin diabetes of rats, ketotic type of diabetes of spiny mice and untreated human juvenile diabetes) there is a decrease in the activity of GK, PFK and PK while FDPase and G-6-Pase activity was increased and aldolase activity unchanged. In the case of non-ketotic diabetes (mild spontaneous diabetes of spiny mice, obese hyperglycemic Bar Harbor mice, New Zealand obese mice, human maturity onset type diabetes) the activity of glucokinase was significantly increased. While the activity of gluconeogenetic enzymes increased only in the more severe states of hyperglycemia, the activity of PK increased only in the milder forms of the non-ketotik diabetes.
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  • 7
    ISSN: 1432-0428
    Keywords: Norepinephrine infusion ; NEFA ; free glycerol ; lipolysis ; NEFA/glycerol ratio ; blood glucose ; ketone body metabolism ; obesity ; diabetes ; β-hydroxybutyrate/acetoacetate ratio ; insulin-like activity ; immunoreactive insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Résumé Les actions de la noradrénaline infusée par voie intraveineuse à une dose de 0.08 μg/kg/min ont été explorées chez des sujets obèses et de poids normal, diabétiques et non diabétiques. Les paramètres suivants ont été étudiés: La lipolyse, mesurée par l'accroissement du glycérol libre et des acides gras plasmatiques non estérifiés (NEFA), l'élévation de la concentration sanguine des corps cétoniques et les concentrations plasmatiques de l'insuline immunoréactive (IRI) et de l'activité insulinique (ILA). Les sujets de poids normal, diabétiques et non diabétiques ont montré le même accroissement de la lipolyse. —Un accroissement de la lipolyse significativement plus élevé a été observé chez des sujets obèses, diabétiques et non diabétiques. Même pendant l'infusion les concentrations absolues du glycérol libre et des NEFA ont été plus élevées chez les sujets obèses que chez les diabétiques insulino-dépendants qui présentèrent les valeurs de départ les plus hautes. Les sujets obèses ont eu une lipolyse plus grande même lorsque la noradrénaline a été infusée à une dose proportionnelle au poids normal théorique. La cause en est probablement la plus grande quantité de tissu adipeux des sujets obèses. —Chez les obèses diabétiques et non-diabétiques, la concentration des corps cétoniques était plus élevée que chez les sujets de contrôle, ce qui est en accord avec la lipolyse augmentée chez les obèses. Les diabétiques de poids normal insulino-dépendants ont présenté cependant une élévation des corps cétoniques significativement plus forte que les obèses. — Ceci indique que chez l'homme la cétonémie ne dépend pas seulement des acides gras plasmatiques non estérifiés (NEFA). — L'accroissement plus fort du quotientβ-hydroxybutyrate/ acétoacétate chez les diabétiques insulino-dépendants suggère une oxydation plus grande des NEFA dans le foie. ILA et IRI ont réagi d'une manière différente à la noradrénaline. Ceci démontre de nouveau qu'un changement d'ILA peut indiquer un changement d'IRI, mais pas nécessairement. — Ces données suggèrent que le métabolisme des acides gras et des corps cétoniques du diabétique obèse est déterminé par l'élément «obésité», celui du diabétique dépendant de l'insuline par l'élément «manque d'insuline».
    Abstract: Zusammenfassung Die Wirkung einer intravenösen Infusion von 0.08 μg/kg/min Noradrenalin auf die Lipolyse (gemessen am Anstieg des freien Glycerins und der unveresterten Fettsäuren (NEFA)), auf die Ketonkörper-konzentration im Blut und die Serumkonzentration des immunreaktiven Insulins (IRI) und der insulinähnlichen Aktivität (ILA) wurden bei normalgewichtigen und übergewichtigen Diabetikern und Nichtdiabetikern untersucht. — Normalgewichtige Diabetiker und Nichtdiabetiker zeigten die gleiche Lipolysesteigerung. Eine signifikant stärkere Lipolysesteigerung wurde bei den übergewichtigen Gruppen, sowohl bei Diabetikern, als auch bei Nichtdiabetikern, beobachtet. —Auch die absoluten Konzentrationen von freiem Glycerin und NEFA waren bei den fettsüchtigen Personen während der Infusion höher als bei den Insulinmangeldiabetikern, die die höchsten Ausgangswerte aufwiesen. Bei Fettsüchtigen wurde eine stärkere Lipolyse auch beobachtet, wenn Noradrenalin, auf kg theoretisches Normalgewicht dosiert, infundiert wurde. Als Ursache wird die größere Fettgewebsmasse der Adipösen angesehen. Bei fettsüchtigen Diabetikern und Nichtdiabetikern stieg die Ketonkörperkonzentration entsprechend der stärkeren Lipolyse stärker an als bei den Kontrollen. Die normalgewichtigen Insulmmangeldiabetiker zeigten jedoch einen signifikant höheren Ketonkörperanstieg als die Fettsüchtigen. Dies zeigt, daß beim Menschen die Ketonämie nicht allein von den peripheren NEFA-Spiegeln abhängt. Der höhere Anstieg desβ- Hydroxybutyrat/Acetoacetat Quotienten der Insulinmangeldiabetiker weist auf eine gesteigerte Fettsäureoxydation in der Leber hin. —ILA und IRI reagierten auf Noradrenalin in unterschiedlicher Weise. Dadurch wird wiederum demonstriert, daß ILA-Änderungen Änderungen der IRI bedeuten können, aber nicht müssen. 3-Nach den vorliegenden Untersuchungen scheint für den Fettsäure- und Ketonkörperstoffwechsel des Altersdiabetes der Faktor Übergewicht, für den des normalgewich-tigen Insulinmangeldiabetikers der Faktor Insulinmangel bestimmend zu sein.
    Notes: Summary The effects of an intravenous infusion of norepinephrine, 0.08 μg/kg.min on lipolysis (as measured by an increase of free glycerol and nonesterified fatty acids (NEFA)), on the blood concentration of ketone bodies and on the serum concentrations of immunoreactive insulin (IRI) and insulin-like activity (ILA) were studied in normal weight and obese nondiabetics and diabetics. Normal weight diabetics and nondiabetics showed the same increase in lipolysis. A significantly higher rate of lipolysis occurred in obese persons, irrespective of whether they were diabetic or not. Even the maximum absolute concentrations of free glycerol and NEFA during the infusion were higher in obese persons than in insulindependent diabetics, who showed the highest values before the beginning of the infusion. — In obese subjects, the infusion of norepinephrine according to the theoretical normal weight was still sufficient to produce a higher rate of lipolysis than in normal weight subjects. This probably reflects the greater mass of adipose tissue in obese subjects. — In diabetic and nondiabetic obese persons, the concentration of ketone bodies rose higher than in control subjects, which is in agreement with the higher rate of lipolysis in the obese groups. On the other hand, the normal weight insulin-dependent diabetics showed a significantly higher increase in the concentration of ketone bodies than the obese persons. This demonstrates that the degree of ketonaemia in man is not exclusively determined by the plasma level of NEFA. — The higher increase in theβ-hydroxybutyrate/acetoacetate ratio in insulindependent diabetics points to a higher rate of oxidation of fatty acids in the liver. —ILA and IRI responded in a different way to norepinephrine infusion, demonstrating again, that changes in ILA can, but may not always reflect changes in immunoreactive insulin. According to these results, changes in the rate of lipolysis and in ketonaemia in obese diabetics are determined by the factor “obesity”, whereas changes in these parameters in insulindependent diabetics are determined by the factor “insulin deficiency”.
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  • 8
    ISSN: 1432-0428
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-0428
    Keywords: Type 2 (non-insulin-dependent) diabetes mellitus ; incretin hormones ; glucagon-like peptide 1 (7-36 amide) ; pancreatic glucagon ; enteroinsular axis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Glucagon-like peptide 1 (GLP-1) (7-36 amide) is a physiological incretin hormone that is released after nutrient intake from the lower gut and stimulates insulin secretion at elevated plasma glucose concentrations. Previous work has shown that even in Type 2 (non-insulin-dependent) diabetic patients GLP-1 (7-36 amide) retains much of its insulinotropic action. However, it is not known whether the magnitude of this response is sufficient to normalize plasma glucose in Type 2 diabetic patients with poor metabolic control. Therefore, in 10 Type 2 diabetic patients with unsatisfactory metabolic control (HbAlc 11.6±1.7%) on diet and sulphonylurea therapy (in some patients supplemented by metformin or acarbose), 1.2 pmol ×kg−1×min−1 GLP-1 (7-36 amide) or placebo was infused intravenously in the fasting state (plasma glucose 13.1±0.6 mmol/l). In all patients, insulin (by 17.4±4.7 nmol ×1−1×min; p=0.0157) and C-peptide (by 228.0±39.1 nmol×1−1×min; p=0.0019) increased significantly over basal levels, glucagon was reduced (by -1418±308 pmol ×1−1×min) and plasma glucose reached normal fasting concentrations (4.9±0.3 mmol/l) within 4 h of GLP-1 (7-36 amide) administration, but not with placebo. When normal fasting plasma glucose concentrations were reached insulin returned towards basal levels and plasma glucose concentrations remained stable despite the ongoing infusion of GLP-1 (7-36 amide). Therefore, exogenous GLP-1 (7-36 amide) is an effective means of normalizing fasting plasma glucose concentrations in poorly-controlled Type 2 diabetic patients. The glucose-dependence of insulinotropic actions of GLP-1 (7-36 amide) appears to be retained in such patients.
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  • 10
    ISSN: 1432-0428
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
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