PubMed Health⌕ Search

Biomedical subjects

C Hofmann

Publications and source records attributed to C Hofmann.

At least 73 records · Page 4Linked to original sources
PubMed1995

Insulin sensitization in diabetic rat liver by an antihyperglycemic agent.

This study aimed to demonstrate directly that the thiazolidinedione pioglitazone acts as an insulin sensitizer. We tested the hypothesis that pioglitazone treatment of diabetic rats alters liver function such that responsiveness of selected genes to subsequent insulin regulation is enhanced. Although flux through gluconeogenic/glycolytic pathways involves regulation of many enzymes, we presently report the effects of insulin on expression of two key enzymes in these metabolic pathways, ie, phosphoenolpyruvate carboxykinase (PEPCK) and glucokinase (GK). Rats were either studied as nondiabetic controls or injected with streptozotocin as a model for insulin-deficient diabetes. Diabetic animals were treated without or with pioglitazone and subsequently examined for acute responses to insulin. Pioglitazone treatment of diabetic animals significantly enhanced the effects of insulin to reverse elevated blood glucose. Although the mean level of liver mRNA transcripts encoding PEPCK was increased to nearly 300% in diabetic animals as compared with nondiabetic controls (100%), it was significantly lower in pioglitazone-treated diabetic rats (119% of control) than in diabetic rats without pioglitazone (223% of control) after insulin treatment. By contrast, mRNA transcripts encoding GK were not detectable in diabetic animals, but were increased markedly by insulin treatment in all animal groups. Insulin-enhanced expression of GK was significantly greater in liver from animals that were treated earlier with pioglitazone (291% of control) than in liver from those that were untreated (214% of control). An amplified acute response of liver to insulin thus established pioglitazone as an insulin sensitizer. Our findings further showed that such sensitization can be developed even in the insulin-deficient state.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Compensatory alterations for insulin signal transduction and glucose transport in insulin-resistant diabetes.

Insulin binding activates the receptor tyrosine kinase toward the insulin receptor substrate-1 (IRS-1). Phosphorylated IRS-1 then interacts with the p85 alpha subunit of phosphatidylinositol 3-kinase (PI3K), Nck, growth factor receptor-bound protein 2 (GRB2), and Syp, thus branching insulin's signal for both mitogenic and metabolic responses. To determine whether the expression of these proteins is altered in insulin resistance, the levels of these proteins were compared in adipose and liver tissues of nondiabetic mice and obese insulin-resistant diabetic KKAy mice. IR and PI3K p85 alpha protein levels were significantly lower in KKAy mice than in control nondiabetic mice, whereas IRS-1 protein levels were not altered. In contrast, the protein levels of GRB2, Nck, Syp, and GLUT-1 were dramatically elevated in KKAy fat, with less striking changes in liver. Treatment of diabetic animals with pioglitazone, an insulin-sensitizing antihyperglycemic agent, partially corrected the expression of some of these proteins. Taken together, these findings suggest that the insulin-resistant diabetic condition is characterized by changes in expression of insulin signal transduction components that may be associated with altered glucose metabolism.

Adaptation, Physiological↗
PubMed1995

Mechanism and timing of nasopharyngeal closure during swallowing and belching.

The mechanism(s) of nasopharyngeal closure (NPC) and its temporal relationship with other biomechanical events during swallowing and belching were studied in seven healthy volunteers, aged 26-39 yr, by concurrent videoendoscopic, videofluoroscopic, and manometric technique. Analysis of the videoendoscopic recordings showed that deglutitive NPC consisted of elevation of the soft palate and adduction of the superior pharyngeal constrictor muscle. Videofluoroscopy identified only the palatal elevation clearly. During belching, however, only palatal elevation occurred. Deglutitive NPC ranged between 0.73 and 0.94 s (0.8 +/- 0.04 SE), with a tendency to be longer with larger swallowed volumes. Onset of NPC was identified earlier endoscopically than as seen fluoroscopically. Complete NPC preceded the arrival of barium bolus into the pharynx, and this pattern was seen for all volumes tested. Manometric onset of upper esophageal sphincter (UES) relaxation was seen before the onset of NPC, but the physical opening of the UES as seen fluoroscopically occurred after complete closure of the nasopharynx. We conclude the following: 1) The mechanism of NPC during swallowing and belching is different. During swallowing, NPC has two tiers of closure, palatal elevation and superior pharyngeal muscle adduction; during belching only palatal elevation occurs. 2) NPC is tightly coordinated with other biomechanical events during swallowing and belching.

Adult↗
PubMed1995

Hepatocyte-specific binding of L/S-HBV particles expressed in insect cells.

The genome of hepatitis B virus (HBV) codes for three surface antigen proteins. Two of them are essential components of infectious viral particles. Whereas expression of the small (S) antigen led to formation of virus-like particles in different systems so far, secretion of neither the large antigen nor budding of virus-like particles containing both antigens could be observed. Using modified large antigen genes in dual expression vectors we were able to demonstrate secretion of virus-like particles in the baculovirus insect cell system. N-terminal fusion of an insect protein (melittin) derived signal sequence and destruction of the myristylation site resulted in secretion of the large antigen. Particles consisting of about 95% small and 5% large antigen bind specifically to hepatocytes. These pseudovirions could serve as a HBV vaccine and as a useful component of future hepatocyte-specific gene transfer vehicles.

Animals↗
PubMed1995

Reduced expression of hexokinase II in insulin-resistant diabetes.

The regulation of hexokinase II (HKII) was examined in fat and skeletal muscle of an animal model of non-insulin-dependent diabetes mellitus, the KKAY mouse. These tissues require insulin for facilitated transport of glucose and express the insulin-responsive transporter GLUT4. The combined data from two experiments (n = 12 for each experimental condition) demonstrated mean concentrations of plasma insulin in pmol/l and glucose in mmol/l of 122 and 7.2 (control nondiabetic C57 mouse) vs. 1,118 and 29.6 (diabetic mouse), respectively. The tissues of diabetic mice compared with control mice demonstrated a reduction of HKII mRNA abundance of 68% in epididymal fat (P = 0.0001) and 34% in the quadriceps muscles (P < 0.001), with concordant reduction in the abundance of GLUT4 mRNA of 60% in epididymal fat (P < 0.001). In comparison with the results in untreated diabetic mice, diabetic animals treated with the insulin-sensitizing drug pioglitazone demonstrated an increase in the abundance of HKII mRNA with a concordant increase of GLUT4 mRNA in epididymal fat (P = 0.03 and < 0.01, respectively), and an increase of HKII mRNA in the quadriceps muscles (P < 0.05). Separate experiments demonstrated a reduction of HKII protein abundance by 61% in epididymal fat (P < 0.001, n = 12 for each experimental condition) and by 71% in the quadriceps muscles (P < 0.001, n = 6 for each experimental condition). In comparison with untreated diabetic mice, there was an increase in the abundance of HKII protein in epididymal fat of animals treated with pioglitazone (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

[Demonstration of cells of the mononuclear phagocyte system of the cat using enzyme and immunohistochemistry methods].

The suitability of enzyme- and immunohistochemical methods for the demonstration of mononuclear phagocytes in cats is treated. The activity of nonspecific esterases with the substrates alpha-naphthyl-acetate, alpha-naphthyl-butyrate and naphthol-AS-acetate, and of acid phosphatases with the substrate naphthol-AS-BI-phosphate is demonstrated in paraffin and plastic sections of the liver, lungs, spleen and lymph node. Even with modified methods, only slight reactions were obtained in cat tissues compared to sections of rat organs. Four antibodies against human macrophage antigens were tested in paraffin sections. Only the antibody against alpha-1-antichymotrypsin showed no cross-reactions in the cat. Neutrophilic granulocytes reacted strongly, macrophages only very slight with the anti-lysozyme-antisera and the monoclonal antibody MAC 387. Apart from some macrophages, interdigitating reticulum cells, B- and T-lymphocytes in the cat were stained by the anti HLA-DR antibody TAL-1B5.

Animals↗
PubMed1995

[The peripartal disease complex of the sow in the industrial swine breeding facility. 4. The effect of prophylactic oral medication on the occurrence of the peripartal disease complex of the sow with the symptoms of urinary tract infection and vaginal-vulvar discharge].

In an industrial pig production unit 20 sows were selected at random. All the sows had a puerperal disease in their anamnesis. The sows were divided in two groups consisting of ten sows each. Group 1 received Ampicillin per os (3 g per sow and day) four days a.p. and four days p.p. The majority of the sows showed a significant E. coli bacteriuria and non of the sows showed a significant Enterococcus bacteriuria prior to treatment. The development of puerperal disease was registered. The treated group showed less occurrence of disease compared to the control. Group 1 revealed significant (p < 0.05) less early postnatal losses than the untreated control. Group 1 showed better four weeks weaning weights as well. It is the authors opinion that sows having significant bacteriuria a.p. should be treated a.p. and p.p. before periparturient disease occurs.

Ampicillin↗
PubMed1994

Glucose transporters (GLUT1, 2, & 4) in fat, muscle and liver in a rat model of endotoxic shock.

To explore the mechanisms for hypoglycemia in our rat model of septic shock, we examined whether changes occur in glucose transporter isoform protein level. Total membrane protein fractions were collected from tissues 6 to 8 hours after endotoxin injection at which time animals exhibited hypoglycemia (7.2 +/- 0.5 vs. 2.6 +/- 1.2mM) and lactacidemia (1.0 +/- 1.0 vs. 5.1 +/- 1.8mM/L) as compared to saline-treated controls. The protein level of glucose transporter isoforms GLUT1 and 4 in fat did not significantly change in septic shock when compared to control animals (126 +/- 22% and 114 +/- 79%, respectively). Likewise, no change was seen in GLUT1 or 4 in muscle (124 +/- 52% and 101 +/- 28%, respectively). The protein abundance of isoforms GLUT1 and 2 in liver were not significantly altered (123 +/- 35% and 101 +/- 23%, respectively). Septic shock induced hypoglycemia cannot be directly explained by changes in total glucose transporter protein levels.

Adipose Tissue↗
PubMed1994

Phase I study of the novel distamycin derivative tallimustine (FCE 24517).

BACKGROUND: Tallimustine, a benzoyl nitrogen mustard derivative of the antiviral agent distamycin A, is a new alkylating agent which binds to A-T rich regions of DNA in the minor groove producing highly sequence-specific alkylations. Its main preclinical features are a significant antitumor activity in animal models and a lack of cross-resistance in vitro and in vivo with L-PAM. Myelotoxicity was dose-limiting in animals, with a more than 100-fold difference in bone marrow sensitivity between mice and dogs. PATIENTS AND METHODS: Forty adult patients (pts) with solid malignancies were entered in the study. The drug was administered as an IV bolus every 4 weeks. CBC was repeated twice a week and serial assessments of renal function were performed in the week following the first cycle. From the starting dose of 50 micrograms/m2, corresponding to 1/3 of the highest non-toxic dose (HNTD) in dogs, there were increases through 10 dose levels, with reliance only on the features of the myelotoxicity observed. RESULTS: The main toxic effect was neutropenia which was dose-limiting, selective and short-lasting. Only previously-untreated pts received doses of 750 micrograms/m2 or more, with grade 4 neutropenia occurring in > or = 75% of the cycles. The maximally tolerable dose (MTD) was defined as 1250 micrograms/m2, with 3 of 3 pts developing febrile neutropenia requiring IV antibiotics. A platelet count of < 100 x 10(3)/microliters was observed in only one pt. Bone marrow aspiration performed in selected pts on days 8 and 15 confirmed a highly selective impairment by tallimustine of the myeloid lineage, with rapid recovery of the proliferative compartment. Pharmacokinetic studies performed at 1000 micrograms/m2 and 1250 micrograms/m2 showed a rapid fall of the plasma levels within the first 2 hours with drug concentrations between 100 ng/ml and 400 ng/ml within the first hour. A partial response of 4 months' duration was reported in one previously-untreated pt with cutaneous recurrences of malignant mesothelioma. CONCLUSIONS: The report of some antitumour efficacy, the high selectivity of neutropenia, the lack of significant non-hematological toxic effects and the occurrence of detectable but still low plasma drug concentrations suggest that further clinical evaluation of higher doses of tallimustine in combination with colony-stimulating factors would be justified.

Adult↗
PubMed1994

Altered gene expression for tumor necrosis factor-alpha and its receptors during drug and dietary modulation of insulin resistance.

As obesity is a major risk factor for noninsulin-dependent diabetes mellitus, adipose tissue may generate a mediator that influences the activity of insulin on various target tissues. Recent evidence suggests that a cytokine, tumor necrosis factor-alpha (TNF alpha), may serve this role. This study investigates whether the expression of TNF alpha and its receptors is modulated during drug treatment to reduce insulin resistance. The effects of moderate weight loss by dietary restriction were also examined. We show here that a marked induction of TNF alpha mRNA occurs in adipose tissues from a mouse model of obesity-linked diabetes (KKAy) compared to that in nondiabetic mice (C57). Likewise, RNA transcripts encoding TNF R2 receptors (p75) were significantly increased in fat tissues of the obese diabetic animals. In muscle from these diabetic animals, RNA transcripts encoding both TNF R1 (p55) and R2 were significantly elevated, although R2 transcript abundance was less elevated than in fat. We also observed that the overexpression of mRNA for TNF alpha and both of its receptors could be at least partly normalized by treatment of the diabetic animals with the insulin-sensitizing agent pioglitazone. Treating of the obese diabetic animals by food restriction reduced the expression of mRNA for TNF R2 in muscle, but not fat. These results clearly indicate that gene expression for the TNF systems can be regulated by an insulin-sensitizing drug and reduction of body weight. Such findings support a role for this cytokine in the insulin-resistant diabetic state and show its modulation by therapies that reverse the disorder.

Animals↗
PubMed1994

[The peripartal disease complex of the mother sow in the industrial swine facility. 3. Slaughter findings of old sows with anamnesis of peripartal diseases].

In an industrial pig production unit ten sows were selected at random. All the sows had a puerperal disease in their anamnesis. The sows were slaughtered after weaning and subjected to pathological examination. The mammary glands, uteri and bladder of ten slaughtered sows were examined for gross pathological alterations. All the sows showed symptoms of chronic mastitis (abscess, granuloma, fibrosis or cysts). Four of the examined uteri showed pathological alterations. Nine out of the ten bladders examined revealed pathological findings.

Abattoirs↗
PubMed1994

[The peripartum disease complex of the sow in industrial swine breeds. 1. Peripartum course of bacteriuria of sows with vaginal-vulvar discharge in a modern swine breeding facility].

In an industrial pig production unit ten sows were selected at random. All the sows had puerperal disease in their anamnesis and all of them revealed at the time of selection--during their late pregnancy--Urinary Tract Infection (UT)I and vaginal-vulvar discharge (VD). Mid-stream early morning urine samples were collected during four days ante partum and during four days post partum. The samples were semiquantitatively examined for E. coli and gram positive cocci. Three sows showed ante partum non significant bacteriuria which turned into significant bacteriuria post partum. The majority of the reminding sows revealed a significant bacteriuria during the whole period of examination.

Animals↗
PubMed1994

[The peripartum disease complex of the sow in commercial swine breeding. 2. The effect of prepartum bacteriuria on the peripartum and postpartum occurrence of puerperal diseases in the sow with anamnesis of urinary tract infection and vaginal-vulvar discharge].

In an industrial pig production unit ten sows were selected at random. All the sows had puerperal disease in their anamnesis and all of them revealed at the time of selection--during their late pregnancy--urinary tract infection (UTI) and vaginal-vulvar discharge (VD) and most of them had significant bacteriuria a.p. All the sows were evaluated using Bilkei's MMA early detection system. The majority of the sows which have had significant bacteriuria a.p. developed a puerperal disease.

Animals↗
PubMed1993

[Topical treatment of psoriasis with calcipotriol. Report of clinical experience].

BACKGROUND: Numerous clinical studies have demonstrated the efficacy of calcipotriol, a synthetic vitamin D3 analogue, in the treatment of mild to moderate chronic psoriasis. METHOD: Report on clinical experience of 40 psoriasis patients treated with calcipotriol, alone or in combination with phototherapy. RESULTS: After four weeks of treatment, the condition had largely cleared up in eleven out of 18 patients (61%) receiving calcipotriol alone, and in 20 out of 22 patients (91%) receiving combination treatment with UVB or UVA plus UVB. The new anti-psoriasis agent was well tolerated and readily accepted by the patients. CONCLUSION: Calcipotriol represents a valuable addition to the available therapy spectrum in chronic psoriasis.

Administration, Topical↗
PubMed1993

Antidiabetic agent pioglitazone enhances adipocyte differentiation of 3T3-F442A cells.

Adipocytes play an important role in normal physiology as a major site for systemic energy homeostasis. In disorders such as diabetes, adipocyte function is markedly altered. In this study, we investigated the effect of pioglitazone, a novel antidiabetic agent known to lower plasma glucose in animal models of diabetes mellitus, on cellular differentiation and expression of adipose-specific genes. Treatment of confluent 3T3-F442A preadipocyte cultures for 7 days with pioglitazone (Pio; 1 microM) and insulin (Ins; 0.17 microM) resulted in > 95% cell differentiation into lipid-accumulating adipocytes in comparison with 60-80% cell differentiation by treatment with either agent alone. Analysis of triglyceride accumulation showed increases of triglyceride content over time above untreated preadipocytes by treatment of the cells with Ins, Pio, and especially with Ins + Pio. Basal glucose transport, as measured by cellular uptake of 2-deoxy-D-[14C]glucose, was likewise enhanced in a time-dependent manner by treatment of preadipocytes with Ins, Pio, or Ins + Pio, such that a synergistic effect resulted from the combined treatment with both agents. It was further determined that RNA transcript abundance for genes encoding glucose transporters GLUT-1 and GLUT-4, as well as the adipose-specific genes encoding adipsin and aP2, were increased by the Ins, Pio, or Ins + Pio treatment. Taken together, these findings indicate that pioglitazone is a potent adipogenic agent. By promoting differentiation, this agent may move cells into a state active for glucose uptake, storage, and metabolism.

3T3 Cells↗
PubMed1993

The antidiabetic agent pioglitazone increases expression of glucose transporters in 3T3-F442A cells by increasing messenger ribonucleic acid transcript stability.

Whereas adipocytes normally play an important role as a major site for systemic energy homeostasis, adipocyte function is markedly altered in disorders such as diabetes. In this study, we investigated the effect of pioglitazone, a novel antidiabetic agent known to lower plasma glucose in animal models of diabetes mellitus, on expression of glucose transporters GLUT1 and GLUT4 in 3T3-F442A cells. Treatment of confluent 3T3-F442A preadipocyte cultures for 7 days with pioglitazone (1 microM) and insulin (1 microgram/ml) resulted in nearly 100% differentiation of cells to lipid-accumulating adipocytes, and such adipocytes showed a markedly increased capacity for glucose uptake. Analysis of messenger RNA transcripts encoding GLUT1 and GLUT4 glucose transporters over the 7-day differentiation period indicated time-dependent increases in abundance of each type that were maximal at more than 5-fold with the combined presence of insulin and pioglitazone. In accord, GLUT1 and GLUT4 protein levels also increased to maximal levels of 10-fold and 7-fold, respectively, over those in undifferentiated preadipocytes. Increased messenger RNA half-lives from 2.2 to greater than 24 h for GLUT1 and from 1.2 to greater than 24 h for GLUT4 correlated with this induced adipocyte differentiation. Taken together, these findings indicated that pioglitazone markedly enhanced expression of cellular glucose transporters, and the mechanism for this action was mainly stabilization of transporter messenger RNA transcripts. Such increased expression of glucose transporters in adipocytes establishes the cells in a state active for glucose uptake, thus ultimately facilitating storage and metabolism as well.

3T3 Cells↗