Altered Circulating Leptin, hGH, and IGF-I in Prediabetes and Screening-Diagnosed T2DM Unrelated to Metabolic Syndrome in Women Post Gestational Diabetes.

Recently, we proposed two pathophysiologic subtypes of type 2 diabetes mellitus (T2DM), one related and one unrelated to metabolic syndrome. To begin to understand the pathophysiology of the subtype unrelated to metabolic syndrome, we now measured selected hormones and signaling molecules in affected individuals. In this cross-sectional analysis, we examined 138 women out of the monocenter, post gestational diabetes study PPSDiab. Of these women, 73 had prediabetes or screening-diagnosed T2DM, 40 related to metabolic syndrome and 33 unrelated. The remaining 65 women were normoglycemic controls. Our analysis included medical history, anthropometrics, oral glucose tolerance testing, laboratory chemistry, and cardiopulmonary exercise testing. In addition, plasma proinsulin/insulin ratio, growth hormone (hGH) nadir during oral glucose tolerance testing, Insulin-like Growth Factor I (IGF-I), Leptin, Resistin, Adiponectin, Fetuin-a, FGF21, and myostatin were measured. Compared to controls, women with prediabetes or screening-diagnosed T2DM unrelated to metabolic syndrome depicted higher plasma Leptin [10.47(6.6-14.57) vs. 5.52(3.15-10.02); p<0.0001] and IGF-I [193.01(171.00-213.30) vs. 167.97(138.77-200.64); p=0.0008], as well as a lower hGH nadir [0.07(0.05-0.15) vs. 0.14(0.08-0.22; p<0.0001]. These differences were independent of body adiposity. Women with prediabetes or T2DM related to metabolic syndrome, in comparison to controls, displayed elevated Leptin, Fetuin-a, and FGF21, as well as reduced Adiponectin and hGH nadir. Based on our study, altered Leptin and hGH/IGF-I signaling could potentially contribute to the pathophysiology of prediabetes and T2DM unrelated to metabolic syndrome. Further mechanistic investigations of these signaling pathways in the context of lean T2DM are necessary to test causal relationships.

The liver-alpha cell axis associates with liver fat and insulin resistance: a validation study in women with non-steatotic liver fat levels.

AIMS/HYPOTHESIS: Many individuals who develop type 2 diabetes also display increased glucagon levels (hyperglucagonaemia), which we have previously found to be associated with the metabolic syndrome. The concept of a liver-alpha cell axis provides a possible link between hyperglucagonaemia and elevated liver fat content, a typical finding in the metabolic syndrome. However, this association has only been studied in individuals with non-alcoholic fatty liver disease. Hence, we searched for a link between the liver and the alpha cells in individuals with non-steatotic levels of liver fat content. We hypothesised that the glucagon-alanine index, an indicator of the functional integrity of the liver-alpha cell axis, would associate with liver fat and insulin resistance in our cohort of women with low levels of liver fat. METHODS: We analysed data from 79 individuals participating in the Prediction, Prevention and Subclassification of Type 2 Diabetes (PPSDiab) study, a prospective observational study of young women at low to high risk for the development of type 2 diabetes. Liver fat content was determined by MRI. Insulin resistance was calculated as HOMA-IR. We conducted Spearman correlation analyses of liver fat content and HOMA-IR with the glucagon-alanine index (the product of fasting plasma levels of glucagon and alanine). The prediction of the glucagon-alanine index by liver fat or HOMA-IR was tested in multivariate linear regression analyses in the whole cohort as well as after stratification for liver fat content ≤0.5% (n = 39) or >0.5% (n = 40). RESULTS: The glucagon-alanine index significantly correlated with liver fat and HOMA-IR in the entire cohort (ρ = 0.484, p < 0.001 and ρ = 0.417, p < 0.001, respectively). These associations resulted from significant correlations in participants with a liver fat content >0.5% (liver fat, ρ = 0.550, p < 0.001; HOMA-IR, ρ = 0.429, p = 0.006). In linear regression analyses, the association of the glucagon-alanine index with liver fat remained significant after adjustment for age and HOMA-IR in all participants and in those with liver fat >0.5% (ß = 0.246, p = 0.0.23 and ß = 0.430, p = 0.007, respectively) but not in participants with liver fat ≤0.5% (ß = -0.184, p = 0.286). CONCLUSIONS/INTERPRETATION: We reproduced the previously reported association of liver fat content and HOMA-IR with the glucagon-alanine index in an independent study cohort of young women with low to high risk for type 2 diabetes. Furthermore, our data indicates an insulin-resistance-independent association of liver fat content with the glucagon-alanine index. In summary, our study supports the concept that even lower levels of liver fat (from 0.5%) are connected to relative hyperglucagonaemia, reflecting an imminent impairment of the liver-alpha cell axis.

Acute HIV infection syndrome mimicking COVID-19 vaccination side effects: a case report.

BACKGROUND: Symptoms of primary HIV infection, including fever, rash, and headache, are nonspecific and are often described as flu-like. COVID-19 vaccination side effects, such as fever, which occur in up to 10% of people following COVID-19 vaccination, can make the diagnosis of acute HIV infection even more challenging. CASE PRESENTATION: A 26-year-old man presented with fever and headache following COVID-19 vaccination. The symptoms were initially thought to be vaccine side effects. A diagnostic workup was conducted due to persisting fever and headache > 72 h following vaccination, and he was diagnosed with Fiebig stage II acute HIV infection, 3 weeks after having unprotected anal intercourse with another man. CONCLUSION: Thorough anamnesis is key to estimating the individual risk of primary HIV infection, in patients presenting with flu-like symptoms. Early diagnosis and initiation of antiretroviral therapy is associated with better prognosis and limits transmission of the disease.

Influence of a Structured Microbiological Endotracheal Monitoring Program on the Outcome of Critically Ill COVID-19 Patients: An Observational Study.

BACKGROUND: In past influenza pandemics and the current COVID-19 pandemic, bacterial endotracheal superinfections are a well-known risk factor for higher morbidity and mortality. The goal of this study was to investigate the influence of a structured, objective, microbiological monitoring program on the prognosis of COVID-19 patients with mechanical ventilation. METHODS: A structured microbiological monitoring program (at intubation, then every 3 days) included collection of endotracheal material. Data analysis focused on the spectrum of bacterial pathogens, mortality, as well as intensive care unit (ICU), hospital, and mechanical ventilation duration. RESULTS: A total of 29% of the patients showed bacterial coinfection at the time of intubation, and within 48 h, 56% developed ventilator-associated pneumonia (VAP). Even though patients with VAP had significantly longer ICU, hospital, and mechanical ventilation durations, there was no significant difference in mortality between patients with VAP pneumonia and patients without bacterial infection. CONCLUSION: VAP is a common complication in COVID-19 patients. In contrast to already published studies, in our study implementing a structured microbiological monitoring program, COVID-19 patients with bacterial coinfection or VAP did not show higher mortality. Thus, a standardized, objective, microbiological screening can help detect coinfection and ventilator-associated infections, refining anti-infective therapy and positively influencing patient outcomes.

Galactomannan-Antigen Testing from Non-Directed Bronchial Lavage for Rapid Detection of Invasive Pulmonary Aspergillosis in Critically Ill Patients: A Proof-of-Concept Study.

Invasive pulmonary aspergillosis is associated with high mortality. For diagnosis, galactomannan-antigen in serum and bronchoalveolar lavage fluid is recommended, with higher sensitivity in bronchoalveolar lavage fluid. Because of invasiveness, bronchoalveolar lavage might be withheld due to patients' or technical limitations, leading to a delay in diagnosis while early diagnosis is crucial for patient outcome. To address this problem, we performed an analysis of patient characteristics of intubated patients with invasive pulmonary aspergillosis with comparison of galactomannan-antigen testing between non-directed bronchial lavage (NBL) and bronchoalveolar lavage fluid. A total of 32 intubated ICU patients with suspected invasive pulmonary aspergillosis could be identified. Mycological cultures were positive in 37.5% for A. fumigatus. Galactomannan-antigen in NBL (ODI 4.3 ± 2.4) and bronchoalveolar lavage fluid (ODI 3.6 ± 2.2) showed consistent results (p-value 0.697). Galactomannan-antigen testing for detection of invasive pulmonary aspergillosis using deep tracheal secretion showed comparable results to bronchoalveolar lavage fluid. Because of widespread availability in intubated patients, galactomannan-antigen from NBL can be used as a screening parameter in critical risk groups with high pretest probability for invasive aspergillosis to accelerate diagnosis and initiation of treatment. Bronchoalveolar lavage remains the gold standard for diagnosis of invasive aspergillosis to be completed to confirm diagnosis, but results from NBL remove time sensitivity.

Function outperforms morphology in the assessment of muscular contribution to insulin sensitivity in premenopausal women.

INTRODUCTION: Skeletal muscle contributes significantly to insulin sensitivity in humans. However, which non-invasive measurement best reflects this contribution remains unknown. Consequently, this paper compares morphologic and functional measurements. RESEARCH METHODS AND DESIGN: We conducted a cross-sectional analysis of 144 premenopausal women enrolled in the "Prediction, Prevention, and Sub-classification of Type 2 Diabetes" (PPSDiab) cohort study. For the analysis, we quantified insulin sensitivity by oral glucose tolerance testing and, in a subgroup of 30 women, euglycemic clamp. To assess skeletal muscle, we measured volume by magnetic resonance imaging, intramyocellular lipid content by magnetic resonance spectroscopy, and physical fitness by cardiopulmonary exercise testing. RESULTS: The mean age of the cohort was 35.7 ± 4.1 years and 94 participants (65%) had a history of gestational diabetes mellitus. Of the morphologic and functional muscle parameters, the maximum workload achieved during cardiopulmonary exercise testing associated most closely with insulin sensitivity (standardized beta = 0.39; p < .001). Peak oxygen uptake also demonstrated significant associations, whereas muscle volume and intramyocellular lipid content displayed none. CONCLUSION: Functional measurements provided a better assessment of the muscular contribution to insulin sensitivity than morphologic measurements in premenopausal women. In particular, exercise testing rendered an easy and cost-effective method applicable in clinical settings and other human studies.

A Normalized Real-Life Glucose Profile After Diet-Induced Remission of Type 2 Diabetes: A Pilot Trial.

Background/objective Type 2 diabetes related to metabolic syndrome is often partially reversible after weight loss. We conducted a pilot trial on whether complete remission to the point of a normalized real-life glucose profile, measured by continuous subcutaneous monitoring, can be achieved. Methods We conducted a mono-center, single-arm intervention trial between January 20, 2020, and January 12, 2021, in Munich, Germany. Ten participants had type 2 diabetes related to metabolic syndrome for a maximum of six years. They received a six-month lifestyle intervention including up to three months of a very-low-calorie formula diet, followed by stepwise food reintroduction and regular behavioral lifestyle counseling. The primary outcome was the status of glucose control at the end of the intervention. Complete remission was defined as normalization of the real-life glucose profile without glucose-lowering medication over at least five days. We measured anthropometric and biochemical parameters, body fat distribution by MRI, and insulin secretory reserve by an arginine stimulation test. Results Seven participants completed the trial, one reached complete remission, three achieved partial remission, and three displayed improved glucose control still in the diabetic range. A reduction of median glycosylated hemoglobin by -10 mmol/mol (-22.0 to -5.0; p = 0.016) co-occurred with weight loss of -6.4 kg (-14.2 to -3.5; p = 0.031). The insulin secretory reserve remained unchanged. Conclusions Complete remission of type 2 diabetes related to metabolic syndrome to the point of a normalized real-life glucose profile is possible through lifestyle intervention. Full intervention success remains challenging even with intensive counseling and support.

Association of Serum Myostatin with Body Weight, Visceral Fat Volume, and High Sensitivity C-Reactive Protein But Not With Muscle Mass and Physical Fitness in Premenopausal Women.

BACKGROUND: The myokine myostatin regulates muscle mass and has been linked to insulin resistance and metabolic syndrome. However, data on its role in humans is still limited. We, therefore, investigated the associations of serum myostatin with muscle mass, physical fitness, and components of the metabolic syndrome in a cohort of premenopausal women. METHODS: We undertook a cross-sectional analysis of 233 women from the monocenter study PPSDiab, conducted in Munich, Germany. Participants had recently completed a pregnancy with or without gestational diabetes. Our analysis included medical history, anthropometrics, oral glucose tolerance testing, laboratory chemistry, cardiopulmonary exercise testing, and magnetic resonance imaging (n=142) of visceral fat volume, left quadriceps muscle mass, and muscle fat content. Serum myostatin was quantified by a competitive enzyme-linked immunosorbent assay. RESULTS: We observed positive correlations of serum myostatin with body mass index (ρ=0.235; p=0.0003), body fat percentage (ρ=0.166; p=0.011), waist circumference (ρ=0.206; p=0.002), intraabdominal fat volume (ρ=0.182; p=0.030) and high-sensitivity C-reactive protein (ρ=0.175; p=0.008). These correlations were reproduced in linear regression analyses with adjustment for age and time after delivery. We saw no correlations with muscle mass, physical fitness, insulin sensitivity, triglycerides, HDL cholesterol, and blood pressure. CONCLUSIONS: Our observation of elevated serum myostatin in women with a higher body fat percentage, visceral obesity, and elevated c-reactive protein suggests that this myokine contributes to the altered muscle-adipose tissue crosstalk in metabolic syndrome. Elevated myostatin may advance this pathophysiologic process and could also impair the efficacy of exercise interventions. Further mechanistic studies, therefore, seem warranted.

Pre-diabetes, diabetes and fluctuations of glucose tolerance after gestational diabetes mellitus: 5-year follow-up of a contemporary, prospective study in Germany.

INTRODUCTION: Ten years ago, Germany started offering screening for gestational diabetes mellitus (GDM) to all pregnant women. This approach revealed more but also, on average, less severe cases of GDM than the risk-based screening practiced previously. We now examined the incidence of pre-diabetes and diabetes following a GDM diagnosis in the era of universal screening in Germany and compared our results with studies in the previous period. Additionally, we examined the year-to-year fluctuations of glucose tolerance after a pregnancy complicated by GDM. RESEARCH DESIGN AND METHODS: We report 5-year follow-up data from 202 women in the prospective, monocenter, postpartum study PPSDiab. Consecutive recruitment took place in Munich, Germany between 2011 and 2016. In the study, we conducted yearly examinations that included anthropometrics, laboratory chemistry and oral glucose tolerance testing. RESULTS: During the first 5 years post partum, 111 (55%) and 12 (6%) of the women developed pre-diabetes and type 2 diabetes, respectively, while 2 (1%) developed type 1 diabetes. Impaired fasting glucose (IFG) was the most common first manifestation of disturbed glucose tolerance, followed by impaired glucose tolerance (IGT), the combination of IFG and IGT, and diabetes. Glucose tolerance did not deteriorate steadily in most women but fluctuated from year to year. CONCLUSIONS: In our analysis, the incidence of diabetes, both type 1 and type 2, after GDM diagnosed in universal screening was substantially lower than in studies from the previous period of risk-based screening. Nevertheless, the high incidence of pre-diabetes we observed after GDM still confirms the importance of this diagnosis as a risk marker. Additionally, we documented frequent fluctuations of glucose tolerance from 1 year to the next. Therefore, a single postpartum glucose tolerance test, as currently practiced in routine care, may be insufficient for reliable risk stratification after GDM.

Overweight/obesity as the potentially most important lifestyle factor associated with signs of pneumonia in COVID-19.

OBJECTIVE: The occurrence of pneumonia separates severe cases of COVID-19 from the majority of cases with mild disease. However, the factors determining whether or not pneumonia develops remain to be fully uncovered. We therefore explored the associations of several lifestyle factors with signs of pneumonia in COVID-19. METHODS: Between May and July 2020, we conducted an online survey of 201 adults in Germany who had recently gone through COVID-19, predominantly as outpatients. Of these, 165 had a PCR-based diagnosis and 36 had a retrospective diagnosis by antibody testing. The survey covered demographic information, eight lifestyle factors, comorbidities and medication use. We defined the main outcome as the presence vs. the absence of signs of pneumonia, represented by dyspnea, the requirement for oxygen therapy or intubation. RESULTS: Signs of pneumonia occurred in 39 of the 165 individuals with a PCR-based diagnosis of COVID-19 (23.6%). Among the lifestyle factors examined, only overweight/obesity was associated with signs of pneumonia (odds ratio 2.68 (1.29-5.59) p = 0.008). The observed association remained significant after multivariate adjustment, with BMI as a metric variable, and also after including the antibody-positive individuals into the analysis. CONCLUSIONS: This exploratory study finds an association of overweight/obesity with signs of pneumonia in COVID-19. This finding suggests that a signal proportional to body fat mass, such as the hormone leptin, impairs the body's ability to clear SARS-CoV-2 before pneumonia develops. This hypothesis concurs with previous work and should be investigated further to possibly reduce the proportion of severe cases of COVID-19.