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At least 19 recordsLinked to original sources
PubMed2026

Epigenetic Reactivation of TNFRSF19 Suppresses Mitophagy and Sensitizes Triple-Negative Breast Cancer to Doxorubicin.

Doxorubicin remains an important component of chemotherapy for triple-negative breast cancer (TNBC), yet chemoresistance severely limits its clinical efficacy. Here, we identify Tumor necrosis factor receptor superfamily member 19 (TNFRSF19) as an epigenetically silenced gene that critically regulates doxorubicin response. Integrative analyses of The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and clinical cohorts reveal that high TNFRSF19 expression predicts superior pathological complete response and improved survival in doxorubicin-treated TNBC patients. Mechanistically, TNFRSF19 binds the kinase domain of TGFBR1 via its intracellular domain, disrupting TGFBR1-SMAD3 complex formation and thereby inhibiting SMAD3 phosphorylation, nuclear translocation, and transcriptional activation of PTEN-induced putative kinase 1 (PINK1). This suppresses PINK1/Parkin-mediated mitophagy, contributing to mitochondrial dysfunction, reactive oxygen species (ROS) accumulation, and amplified DNA damage upon doxorubicin treatment. Notably, TNFRSF19 is downregulated in TNBC due to DNA hypermethylation, and decitabine restores its expression via promoter demethylation, thereby enhancing the therapeutic efficacy of doxorubicin in vitro and in vivo. Collectively, these findings establish TNFRSF19 as a critical epigenetic regulator of mitophagy, highlighting its potential as a predictive biomarker for doxorubicin response and a therapeutic target for sensitizing TNBC to doxorubicin.

DNA methylation↗
PubMed2026

Integrated analysis reveals the impact of obesity on triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous breast cancer subtype with limited therapeutic options. While the prevalence of overweight/obese (OW/OB) women continues to rise, the impact of obesity on molecular features of TNBC remains incompletely understood. We investigated clinicopathological and molecular data (including genomic, transcriptomic, proteomic and metabolomic profiling) using our original multi-omics database of TNBC (N = 465) for associations with patient body mass index (BMI). Multi-omics profiling revealed that OW/OB patients exhibited worse survival as well as elevated inflammation of tumor microenvironment, higher expression of immune checkpoints, and dysregulated lipid metabolism. Our in vivo experiments demonstrated that tumors in obese mice displayed faster growth rates, a higher proportion of PD-1+CD8+ T cells and enhanced responsiveness to anti-PD-1 treatment. In addition, we analyzed data from four independent clinical trials and discovered that OW/OB patients demonstrated higher pathological complete response rates and longer progression-free survival following anti-PD-1-based immunotherapy. In conclusion, our study systematically revealed that obesity is associated with coordinated immune-metabolic remodeling in TNBC, characterized by checkpoint enrichment and lipid dysregulation, which may help explain the enhanced anti-PD-1 responsiveness and should be taken into account in the field of precision medicine.

Immunity↗
PubMed2025

Molecular Landscape, Genomic Shift, and Prediction in the Neoadjuvant Setting of Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer.

The amplification or overexpression of human epidermal growth factor receptor 2 (HER2) defines a breast cancer subtype, which benefits from neoadjuvant HER2-targeted therapy. However, at least 40% of patients respond poorly or do not respond to treatment. We analyzed the main genomic alterations of 64 HER2+ patients by next-generation sequencing to identify new predictors of response and correlate them with clinicopathological parameters. We also compared the genomic alterations between primary and residual tumors after neoadjuvant treatment. The TP53 gene was the most frequently mutated gene, and in combination with ERBB2 overexpression, the 2 were predictive of residual cancer burden (P = .001). Furthermore, the combination of their immunohistochemical counterpart (p53 mutant and score 3+ for HER2) can predict complete pathological response and the grade of response (P = .038 and P = .031, respectively). Therefore, p53 could be included in the initial panel of breast cancer biomarkers to help therapeutic decision-making in HER2+ cases.

Humans↗
PubMed2026

Prognostic and predictive value of HRD in early triple negative breast cancer (TNBC).

This review explores the emerging role of homologous recombination deficiency (HRD) as both a prognostic and predictive biomarker in early-stage triple-negative breast cancer (TNBC). HRD arises from the defective repair of DNA double-strand breaks through homologous recombination, resulting in genomic instability and increased sensitivity to DNA-damaging agents such as platinum compounds. The review outlines the biological basis of HRD, including genomic signatures such as loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions, and highlights its prevalence in TNBC compared with other breast cancer subtypes. Clinical trials have shown that HRD-positive patients often achieve higher pathological complete response rates and improved disease-free survival when treated with chemotherapy. However, conflicting evidence across trials underscores the need for more reliable and standardized methods for HRD assessment. The review also explores the therapeutic potential of poly(ADP-ribose) polymerase inhibitors in TNBC, particularly in BRCA-mutated or HRD-positive tumors. Agents such as olaparib, talazoparib, and niraparib have demonstrated promising efficacy in both neoadjuvant and adjuvant settings with some trials suggesting that selected patients may avoid chemotherapy. Furthermore, HRD-positive tumors are characterized by increased genomic instability and a higher neoantigen burden, promoting immune cell infiltration, particularly of tumor-infiltrating lymphocytes, which may enhance responsiveness to immune checkpoint inhibitors. Overall, current evidence supports the role of HRD as a promising biomarker in TNBC. However, further research is required to refine its clinical utility and to integrate HRD testing into personalized treatment strategies, especially in combination with emerging therapies such as immunotherapy.

Humans↗
PubMed2026

The next-generation biomarkers in early-stage triple negative breast cancer.

PURPOSE OF REVIEW: Despite maximal neoadjuvant chemoimmunotherapy, nearly 40% of early-stage triple-negative breast cancer (TNBC) patients fail to achieve pathological complete response, underscoring an urgent need for biomarkers capable of guiding treatment modulation. This review summarizes recent advances in tumor-infiltrating lymphocytes (TILs), circulating tumor DNA (ctDNA), and genomic signatures, exploring their potential integration into clinical decision-making. RECENT FINDINGS: TILs remain the most validated, cost-effective prognostic biomarker, although standardized scoring is still needed to overcome interobserver variability. ctDNA has emerged as a dynamic, real-time prognostic tool, with postneoadjuvant detection strongly predicting relapse and worse outcomes. Nonetheless, optimal sampling timing remains undefined. Genomic signatures, particularly TNBC-DX, provide standardized, reproducible prognostic information by integrating immune and proliferative gene expression. Emerging data suggest that combining these biomarkers may offer a complementary and synergistic effect. SUMMARY: Multibiomarker integration, supported by prospective validation and automated models, represents a promising approach to personalize treatment algorithms in early-stage TNBC, balancing efficacy and toxicity while guiding escalation and de-escalation strategies.

artificial intelligence↗
PubMed2026

Chemoradiotherapy versus short-course radiotherapy for response-adapted organ preservation in early-stage and intermediate-stage rectal cancer (STAR-TREC): 12-month results of an international, multicentre, open-label, parallel-group, randomised, phase 2/3 trial.

BACKGROUND: Total mesorectal excision (TME) is the standard treatment for most early-stage and intermediate-stage rectal cancer but can cause substantial perioperative morbidity, functional impairment, and reduced quality of life. We assessed whether long-course chemoradiotherapy (LCCRT) or short-course radiotherapy (SCRT) could increase organ preservation and reduce surgery, toxicity, and quality-of-life harms without compromising oncological outcomes. METHODS: STAR-TREC is an international, multicentre, open-label, parallel-group, randomised, phase 2/3 trial in five European countries. Eligible patients were aged 16 years or older in the UK or aged 18 years or older elsewhere, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and rectal adenocarcinoma (≤40 mm staged as mrT1-T3bN0). In phase 2, participants were randomly assigned (1:1:1) to LCCRT-based organ preservation (LCCRT-OP; 50 Gy in 25 fractions plus oral capecitabine 825 mg/m2 twice daily), SCRT-based organ preservation (SCRT-OP; 25 Gy in five fractions), or primary TME. Phase 2 assessed feasibility, with recruitment at months 12 and 24 as the primary endpoint and feasibility thresholds of four or more and six or more randomisations per month, respectively. Phase 3 adopted a partially randomised patient-preference design, allowing participants to choose either organ preservation or TME. Participants that chose organ preservation were randomly assigned (1:1) to receive LCCRT-OP or SCRT-OP using centralised, computer-generated assignment, with stratification by country and MRI T category (≤T3a vs T3b) using minimisation. The phase 3 primary endpoint was organ-preservation 30 months after treatment initiation, defined as absence of TME, stoma, or local recurrence, which was assessed in the modified intention-to-treat population, which included participants in phase 2 and phase 3. After a planned interim analysis of unmasked phase 2 data, the trial steering committee and independent data monitoring committee recommended reporting a 12-month, modified intention-to-treat analysis of implementation outcomes for participants recruited before Aug 8, 2023. This study is registered with ISRCTN (14240288) and is closed. FINDINGS: Between June 14, 2017, and April 8, 2024, 503 participants were enrolled at 37 sites. Phase 2 enrolled 120 participants, with recruitment rates of three and six participants per month at months 12 and 24, respectively. Overall, 12-month TME-free survival was 60% (47 of 78 participants). After phase 3 recruitment ended, interim analysis of unmasked phase 2 data showed an early TME-free survival benefit with LCCRT versus SCRT (12-month median TME-free survival not reached [95% CI not reached-not reached] vs 7·6 months [95% CI 6·4-not reached]; hazard ratio [HR] 3·7 [95% CI 1·7-8·0]; posterior probability of superiority >99·5%). The trial steering committee and independent data monitoring committee therefore recommended expanded analysis of 426 participants recruited before Aug 8, 2023: 120 from phase 2 and 306 from phase 3. 17 participants withdrew before treatment, leaving 409 in the modified intention-to-treat population: 163 allocated to LCCRT, 168 to SCRT, and 78 to primary TME. 116 (28%) participants were female and 293 (72%) were male. Among participants who opted for organ preservation, 12-month TME-free survival was 78·5% (95% CI 72·4-85·1) with LCCRT and 60·6% (53·6-68·4) with SCRT (HR 1·90 [95% CI 1·29-2·81]). The most common grade 3-4 serious adverse events were gastrointestinal disorders (four [2%] with LCCRT vs six [4%] with SCRT vs six [8%] with TME) and procedural complications (three [2%] with LCCRT vs five [3%] with SCRT vs five [6%] with TME). One participant allocated to primary TME died after an anastomotic leak. INTERPRETATION: These early results support a response-adapted organ-preservation approach, with LCCRT appearing more effective than SCRT at 12 months. Organ-preservation might also reduce treatment-related toxicity compared with primary TME. Longer follow-up is needed for the prespecified 30-month endpoint and definitive functional and oncological outcomes. FUNDING: Cancer Research UK, Stand Up to Cancer, Dutch Cancer Society, Danish Cancer Society, Kom Op Tegen Kanker, Cancerfonden, ALF Region Stockholm, RCC Region Stockholm.

Humans↗
PubMed1978

Combination chemotherapy of diffuse histiocytic lymphoma with cyclophosphamide, adriamycin, vincristine and prednisone (CHOP).

Twenty-three patients with diffuse histiocytic lymphoma who had not had prior chemotherapy were treated with CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone). Sixteen of these patients had previously been treated with radiation therapy. Nine of these 23 patients had a pathologically documented complete response at the conclusion of CHOP with an overall complete response rate of 39%. In patients whose disease was confined to lymph nodes, the complete response rate was 7 of 8 or 88%, while in patients with stage IV disease, only 2 of 15 or 13% had complete responses. Although prior radiation therapy could not be demonstrated to be an adverse prognostic factor in this small series, it could have accounted for the low overall complete response rate noted. Complete response in this series was well sustained with an actuarial relapse-free survival of 75% and an actuarial survival of 89% at two years. No complete responses occurred in five patients who had received prior chemotherapy.

Adolescent↗
PubMed2026

Human Epidermal Growth Factor Receptor-2 positive metastatic salivary duct carcinoma with remarkable response to targeted therapy: a case report and therapeutic implications.

Salivary duct carcinoma (SDC) is a rare and highly aggressive malignancy that frequently overexpresses Human Epidermal Growth Factor Receptor 2 (HER2). Despite the increasing recognition of HER2-targeted strategies, evidence remains limited and largely derived from small trials and case series. We report the case of a middle-aged man with HER2-positive metastatic SDC who achieved near-complete pathologic and radiological response to trastuzumab and docetaxel, enabling surgical resection for locoregional control. This case highlights the role of anti-HER2 therapy as a first-line strategy in SDC and underscores the importance of individualized management plans integrating systemic treatment and locoregional measures.

Humans↗
PubMed1979

Estradiol and estetrol plasma levels before and after intravenous administration of dehydroepiandrosterone sulfate in normal and pathologic pregnancies.

Intravenous injections of 50 mg dehydroepiandrosterone sulfate (DHEAS) were given to 7 women with normal pregnancies and 5 with pathologic pregnancies and the serum levels of 17 beta-estradiol and estetrol were assayed before and at 15 or 30-minute intervals for three hours after the injection. All tests were carried out during the 25th to 36th week of amenorrhea. Serum estradiol rose rapidly in normal subjects and remained high to the end of the test. In patients with gestational pathology the estradiol pattern was not significantly different from that of the controls. Esterol plasma levels showed a biphasic pattern with an initial rise at 30 min. and a second rise at 90 min. in normal pregnancies, whereas in pathologic pregnancies this response was either lacking completely or was markedly reduced compared to the controls.

Dehydroepiandrosterone↗
PubMed1977

Measurement of digital blood pressure after local cooling.

A double-inlet plastic cuff was designed for local cooling and systolic blood pressure measurement on the middle phalanx of the fingers. With a tourniquet on the proximal phalanx of one finger, cooling for 5 min made the digital artery temperature equal the skin temperature. The difference between the systolic pressure in a control finger and in the cooled finger give the reopening pressure in the digital arteries. At 30, 25, 20, 15, and 10 degrees C, respectively the percent decrease of the finger pressure was 0.2 (0.2), 1.5 (2.5), 8.5 (3.7), 11.4 (3.4), and 15.3 (3.1) in normal young women. In patients with primary or secondary Raynaud's phenomenon, the arterial tone showed an abrupt increase that most often led to complete closure of the digital arteries. The pathological response was expressed as an increased threshold temperature or a well-defined closing temperature that showed only small variations during standardized conditions.

Adult↗
PubMed1978

Tibial dyschondroplasia (osteochondrosis) in the turkey. A morphologic investigation.

Sixty-seven Broadbreasted White Turkeys, 4 to 137 days old, were included in the investigation. Some were normal, while others were limping, and some had bowed legs. Immediately after destruction of the birds, the arteries of the legs were injected with Colorpaque, using a technique introduced by the author. The proximal part of one or both tibiae were examined radiographically, macroscopically, and microscopically. The microscopic examination included histology, microangiography, and microradiography. The normal development and morphology of the proximal tibia is presented. Thereafter an account is given of development and morphology of the tibia with dyschondroplastic lesions (retained cartilages). It was found that 39 of the 67 birds had some degree of tibial dyschondroplasia. The retained cartilage was seen in the posteromedial part of the proximal tibial metaphysis. The growth plate both of the normal and abnormal birds consisted of 3 layers of cells in order from the epiphysis--the one of proliferating cells, the one of transitional cells, and the one of hypertrophied cells. A main feature in tibial dyschondroplasia is accumulation of transitional cells, which do not have a vascular supply. By microangiographic means it was possible to demonstrate that the retained cartilage is surrounded by numerous vessels, which apparently cannot get into the cartilage. The reason for the loss of normal differentiation of the cartilage cells and concomitant disturbance of the endochondral ossification is obscure. It is speculated that changes on an ultrastructural and biochemical level are responsible for the pathologic condition. When the retained cartilage reaches a certain size, degenerative changes, necrosis, and fissures occur. Complete healing of the lesion was not seen in any of the birds, but partial disappearance of the proximal or distal part of the retained cartilage took place in some birds. It was concluded that the present investigation has shed light on the development and morphology of tibial dyschondroplasia, but it has also brought forward a number of questions about etiology. There seems to be good reason to believe that dyschondroplasia in the turkey is of similar nature as dyschondroplasia in broilers and osteochondrosis in domestic mammals.

Animals↗
PubMed1976

Pathogenesis of visna. III. Immune responses to central nervous system antigens in experimental allergic encephalomyelitis and visna.

Experimental allergic encephalomyelitis (EAE) was induced in sheep in pursuit of the hypothesis that an immune response against central nervous system antigens might play a role in the pathogenesis of visna. Nine to 12 days after sensitization with whole sheep brain and complete Freund's adjuvant, approximately 50% of sheep developed a fulminating lethal form of EAE. Following a second sensitization, another 20% of animals developed EAE whereas a residual 30% failed to develop any signs or histologic evidence of disease. A histologic comparison of EAE and visna indicated considerable similarity in the nature of the pathologic process. However, the distribution of lesions was quite different, suggesting cellular responses to two different antigens, Cell-mediated immunity to myelin basic protein, as measured by lymphocyte blast transformation, was minimally elevated in sheep sensitized with whole brain suspension in complete Freund's adjuvant, whereas no response could be detected in visna-infected sheep. Complement-fixing antibody titers to basic protein and to a lipid antigen of brain, probably galactocerebroside, rose briskly after sensitization. In visna-infected sheep, on the other hand, there was no increase in either antibody. A large proportion of both Hampshire and Icelandic sheep had low levels of complement-fixing antibody to central nervous system antigens prior to induction of EAE or infection with visna virus. The origin of this antibody is undetermined, but it appeared to have no effect on the course of either disease. Immunosuppression of sheep with antilymphoid serum prevented induction of EAE. Acute EAE was, thus, successfully induced in sheep and used as a model to measure immune responses to central nervous system antigens and as an index of immunosuppression. However, these comparative studies did not provide any evidence for the role of an autoimmune response, to the two central nervous system antigens tested, in the pathogenesis of visna.

Animals↗
PubMed1979

Remittent painful ophthalmoplegia: the Tolosa-Hunt syndrome? A report of seven cases and review of the literature.

Seven patients with remittent painful ophthalmoplegia for which no specific local cause was found were seen during a period of five years. One had coincidental rheumatoid arthritis, and another had actinomycosis of the ipsilateral middle ear and contralateral parotid gland. The other five had no evidence of generalised autoimmune disease nor any other systemic disorder, two having separate episodes affecting each side. A history of relapsing and remitting painful ophthalmoplegia is suggestive of the Tolosa-Hunt syndrome, but it is rarely possible to confirm that the lesion in the cavernous sinus is the result of non-specific granulomatous infiltration so that the diagnosis remains one of exclusion. Carotid arteriography may show narrowing of the intracavernous part of the internal carotid artery. Orbital venography may also be helpful, particularly when the carotid arteriogram is normal. We believe that the Tolosa-Hunt syndrome is more common in England than is generally realised, but that its clinical features do not necessarily indicate a single pathological entity. Its recognition is important since the response to steroids, although not specific, is rapid in most patients, and the prognosis for complete recovery is relatively good.

Actinomycosis↗
PubMed1979

[Evaluation of the pituitary reserve of gonadotropins and seminal function of the testis in subjects operated for cryptorchism].

76 patients (prepuberal, puberal and adults) who had undergone surgery for monolateral (35) or bilateral (41) cryptorchidism in childhood were studied. Testicular volume (76 cases), seminiferal function (18 cases) and pituitary gonadotropin reserve (51 cases) were evaluated. We obtained the following results: 1) the prepuberal patients had a normal testicular volume, while 70% of the puberal and adult patients had a mean testicular volume below normal levels. 2) 55.6% of the adults who underwent spermiogram had a pathological seminiferal function. 3) The number of patients whith exagerated gonadotropin response to GnRH-test increases with increasing puberal stage and reaches its highest significance after complete puberal development. These data confirm that: 1) the long permanence of one or both testis out of their natural position has a negative influence on their trophism; 2) the long-term prognosis of the tubular function of the testis after orchidopessis is poor in a high percentage of cases. 3) the endocrine anomalies which follow the early morphologic and functional changes of the cryptorchid testis are more easily detected during puberty as a reduced hypothalamic feedback of the gonadotropin secretion.

Adolescent↗
PubMed2026

Deconstructing Exceptional Responses to Immune Checkpoint Inhibition in Recurrent or Metastatic Head and Neck Carcinoma: A Site-Specific Clinical-Biological Synthesis.

Background: Recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is an aggressive malignancy with a historically poor prognosis. Although immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have established a new first-line standard of care, durable clinical benefit is restricted to a minority of patients, while primary or acquired resistance remains a major clinical challenge. This narrative review aims to provide a conceptual clinical-biological synthesis of immunotherapy in R/M HNSCC through an anatomical and biomarker-driven lens, with a focus on characterizing potential shared features of "exceptional responders". Methods: A targeted narrative literature search was conducted across PubMed/MEDLINE and to identify key clinical trials and representative clinical reports of exceptional response to ICIs in R/M HNSCC. The literature was not systematically synthesized to construct a conceptual clinical-biological framework of response and resistance. Results: Landmark clinical data confirm durable survival benefits with frontline pembrolizumab-based regimens in selected PDL-1 positive populations compared to historical chemotherapy. Qualitative appraisal of illustrative cases and translational cohorts suggests a potential biological hypothesis: exceptional responders, defined as patients achieving unexpected, multi-year complete radiological, pathological, or metabolic remissions, often align with a favorable confluence of a pre-existing "hot" or inflamed tumor microenvironment, preserved antigen presentation machinery, and elevated antigenic novelty driven by viral oncoproteins (HPV, EBV) or high mutational/indel burdens. Conversely, primary and acquired resistance are conceptually associated with defects in antigen processing, immunosuppressive cellular barriers, and alternative immune checkpoints. Conclusions: Immunotherapy has fundamentally transformed R/M HNSCC management, yet exceptional single-agent responses remain rare. Rather than a definitive or proven biological biomarker, the proposed blueprint represents an integrative hypothesis highlighting the complex interplay of baseline immune inflammation, genomic features, and viral drivers. Translating these observations into broader clinical benefit will require validated biomarker-driven personalization and rationally designed combination regimens.

Epstein-Barr virus (EBV)↗
PubMed1979

[Isolated rheumatic tricuspid insufficiency (author's transl)].

Insufficiency on the tricuspid valve alone due to cardioarticular rheumatism is a rare condition. A 12-year-old boy had had six episodes of rheumatic fever over the previous 5 years. The only damage done to the heart was insufficiency of the tricuspid valve; none of the other valves were affected. The phonocardiographic response to the amyl nitrate and methoxamine tests as well as the correct evaluation of the jugular phlebogram confirmed the diagnosis of this valve pathology. The study of this heart condition was completed with the diagnosis of rheumatic fever (Jones' criteria, modified) and an angiohemodynamic evaluation of the patient (which must include left and right ventriculography using a Bourassa catheter on the right). This pathology is extremely rare and we have found no reference to it in the literature in this country.

Child↗
PubMed1979

Electrophysiologic and pathologic correlations in six cases of atrioventricular block.

1) A prolonged A-H interval suggested A-V nodal involvement. 2) A prolonged duration of the His potential suggested moderate His bundle involvement. 3) Complete block distal to H appeared to reflect total disruption of both bundle branches. 4) The lesion at the penetrating portion of the His bundle could be responsible for A-H block. 5) A-H block occurred in a case of cellular infiltration in the A-V node and the His bundle, in which bilateral bundle branch showed severe fibrosis. 6) A combination of right bundle branch block, marked left axis deviation and H-V prolongation suggested trifascicular disease. 7) In case 6, there was a severe pathologic lesion at the origin of the left bundle branch, yet left bundle branch block was not indicated electrocardiographically. This study revealed a close correlation between electrophysiologic and pathologic findings in 4 out of 6 cases.

Aged↗
PubMed1979

Impaired feedback control of fat induced gastric inhibitory polypeptide (GIP) secretion by insulin in obesity and glucose intolerance.

To investigate the role of endogenous insulin on the secretion of immunoreactive gastric inhibitory polypeptide (IR-GIP) the response of IR-GIP and immunoreactive insulin (IRI) to an oral fat load (100 g triglyceride) alone and during an intravenous glucose infusion (0.7 g/kg/h) was examined in normal weight and obese subjects. In normal weight subjects the fat induced integrated rise of IR-GIP was 112.7 +/- 9.4 ng/ml/120 min. When glucose and fat were given together this IR-GIP response was lowered to 46.2 +/- 2.9 ng/ml/120 min while the serum IRI response to i.v. glucose and the glucose tolerance were enhanced by fat ingestion. In obese subjects with normal glucose tolerance the GIP suppressing effect of i.v. glucose infusion was less marked than in controls. The integrated IR-GIP response to fat ingestion was 225.6 +/- 20.3 mg/ml/120 min and to fat plus glucose 152.6 +/- 14.8 ng/ml/120 min. In obese subjects with glucose intolerance i.v. glucose completely failed to lower the exaggerated secretion of IR-GIP following oral fat. Thus, a graded abnormality of the GIP response to glucose induced insulin release occurs in obesity with normal and pathological glucose tolerance. After reducing the ideal body weight of six obese subjects with glucose intolerance by hypocaloric diet for 3 weeks the exaggerated rise of IR-GIP after oral fat was reversed and the lowering effect of i.v. glucose on the IR-GIP response re-established.

Adult↗