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Department of Internal Medicine III, University Hospital Carl Gustav Carus Dresden, Dresden, Germany
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Comprehensive Heart Failure Center, Würzburg, Germany
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Objective
Combination therapies with gut hormone analogs represent promising treatment strategies for obesity. This pilot study investigates the therapeutic potential of modulators of the glucagon-like peptide 1 (GLP-1) and neuropeptide Y (NPY) system using GLP-1 receptor agonists (semaglutide) and antagonists (exendin 9-39), as well as non-selective and NPY-Y2-receptor selective peptide tyrosine tyrosine (PYY) analogs (PYY3-36/NNC0165-0020 and NNC0165-1273) and an NPY-Y2 receptor antagonist (JNJ31020028).
Methods
High-fat diet (HFD)-induced obese rats were randomized into following treatment groups: group 1, nonselective PYY analog + semaglutide (n = 4); group 2, non-selective and NPY-Y2 receptor selective PYY analog + semaglutide (n = 2); group 3, GLP-1 receptor antagonist + NPY-Y2 receptor antagonist (n = 3); group 4, semaglutide (n = 5); and group 5, control (n = 5). Animals had free access to HFD and low-fat diet. Food intake, HFD preference and body weight were measured daily.
Results
A combinatory treatment with a non-selective PYY analog and semaglutide led to a maximum body weight loss of 14.0 ± 4.9% vs 9.9 ± 1.5% with semaglutide alone. Group 2 showed a maximum weight loss of 20.5 ± 2.4%. While HFD preference was decreased in group 2, a strong increase in HFD preference was detected in group 3.
Conclusions
PYY analogs (especially NPY-Y2 selective receptor agonists) could represent a promising therapeutic approach for obesity in combination with GLP-1 receptor agonists. Additionally, combined GLP-1 and PYY3-36 receptor agonists might have beneficial effects on food preference.
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Xiamen Key Laboratory for Clinical Efficacy and Evidence-Based Research of Traditional Chinese Medicine, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
Fujian Province Key Laboratory of Diabetes Translational Medicine, The First Affiliated Hospital of Xiamen University, School of medicine, Xiamen University, Xiamen, China
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Objective
The aim of this study was to compare the differences in incident population, comorbidities, and glucose-lowering drug prescriptions between newly diagnosed patients with early-onset type 2 diabetes mellitus (T2DM) and those with late-onset T2DM to provide real-world evidence for clinical practice.
Methods
This study was based on the Shanghai Hospital Link Database (SHLD). Anonymized electronic medical record (EHR) data from 2013 to 2021 were included in this study. Newly diagnosed patients with T2DM were defined as those without related diagnostic records or glucose-lowering medicine prescriptions in the past 3 years. Early-onset T2DM was defined as patients who were aged 18–40 years old at the first visit for T2DM to represent those who were born after the 1980s. And late-onset T2DM was defined as those aged 65–80 years old to represent those who were born in a relatively undeveloped period. Descriptive statistical analyses were performed to describe their incidence number, glucose-lowering drug prescriptions, and comorbidities at the first visit to the hospital between two T2DM groups.
Results
There were a total of 35,457 newly diagnosed patients with early-onset T2DM and 149,108 newly diagnosed patients with late-onset T2DM included in this study. Patients with late-onset T2DM constituted the majority and their number increased by 2.5% on average by years, while the number of patients with early-onset T2DM remained stable each year. Compared with late-onset T2DM patients, more early-onset T2DM patients had dyslipidemia at the first visit to hospitals (9.5% vs 7.7%, P < 0.01) despite their significant age differences. Patients with early-onset T2DM were more likely to use metformin (74.8% vs 46.5, P < 0.01), dipeptidyl peptidase-4 inhibitors (DDP-4i) (16.7% vs 11.2%, P < 0.01), thiazolidinediones (TZD) (14.9% vs 8.4%, P < 0.01), sodium glucose cotransporter 2 inhibitors (SGLT2-i) (0.8% vs 0.3%, P < 0.01), and glucagon-like peptide 1 receptor agonists (GLP-1 RA) (3.7% vs 0.5%, P < 0.01) at their first visit to the hospital.
Conclusions
Different characteristics were observed between patients with early-onset T2DM and those with late-onset T2DM. Compared with patients with late-onset T2DM, those with early-onset T2DM were more prone to dyslipidemia and had novel organ-protective drugs prescribed.
Mary & Dick Allen Diabetes Center at Hoag Hospital, Newport Beach, California, USA
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The main objective of this article is to provide a comprehensive review of continuous glucose monitor (CGM) use in pregnant women with type 1 diabetes (T1D) from the CONCEPTT study including subanalyses. Literature search was accessed through MEDLINE (1966–September 2023) using the key terms: CONCEPTT, pregnancy, women, T1D, and CGM with limitations set to distinguish human subjects written in English. A total of 17 publications including one main clinical trial and 15 subanalyses have been published to date regarding the use of CGM in pregnant women with T1D which were conducted by a research group identified as the CONCEPTT Collaborative Group. While advances in maternal care have resulted in safer pregnancy for both the mother and child, women with preexisting T1D and pregnancy still experience higher rates of complications both in the short and long term. The use of CGM in pregnancy has not been studied extensively until more recently. The CONCEPTT clinical trial was a landmark study that involved several subanalyses. The main trial proved that CGM use in T1D pregnancy resulted in less hyperglycemia in the third trimester, reduced large for gestational age (LGA, >90th percentile), reduced neonatal intensive care unit admissions lasting longer than 24 h, and reduced neonatal hypoglycemia. Although subanalyses showed a variety of results including ‘inconclusive’ due to lack of prespecification, it is believed that CGM in T1D during pregnancy is to be recommended and used for overall improved outcomes.
Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
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Diabetes, Endocrinology and Metabolism Centre, Manchester University NHS Foundation Trust, NIHR Manchester Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester, UK
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Oxford Liver Unit, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, UK
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NIHR Oxford Health Biomedical Research Centre, and NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK
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NIHR Oxford Health Biomedical Research Centre, and NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK
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Background and aims
Non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common liver disease worldwide. Modern lifestyles have been linked to this rise in prevalence with changes in rhythmic human behaviour emerging as a possible mechanism. We investigated how shift working patterns and chronotype were associated with hepatic fat fraction and NAFLD in 282,303 UK Biobank participants.
Methods
We stratified participants into day, irregular-shift, and permanent night-shift workers. We then utilised multiple methods of disease identification including (i) Dallas steatosis index (DSI), (ii) ICD10 codes, and (iii) hepatic proton density fat fraction (PDFF) and examined how shift work exposure impacted these variables. We further assessed the relationship of baseline chronotype with liver phenotypes using these same outcome measures.
Results
Compared to day workers, irregular-shift workers were more likely to have a high DSI (OR 1.29 (1.2–1.4)) after adjusting for major covariates with some attenuation after additional adjustment for BMI (OR 1.12 (1.03–1.22)). Likelihood of high DSI was also increased in permanent night-shift workers (OR 1.08 (0.9–1.29)) in the fully adjusted model. Mediator analysis revealed that BMI was a significant mediator of the shift work effect. Compared to participants with intermediate chronotype, those with extreme late chronotype had a higher likelihood of high DSI defined NAFLD (OR 1.45 (1.34–1.56)) and a higher likelihood of NAFLD/NASH by ICD10 code (OR 1.23 (1.09–1.39)). Hepatic PDFF was elevated in irregular shift workers, but not permanent night-shift workers.
Conclusions
Irregular-shift work and extreme late chronotype are associated with pathological liver fat accumulation, suggesting circadian misalignment may have an underlying pathogenic role. These findings have implications for health interventions to mitigate the detrimental effect of shift work.
Zealand Pharma A/S, Søborg, Denmark
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Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Steno Diabetes Center Copenhagen, Herlev, Denmark
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Aims
Hyperglucagonaemia contributes to the pathophysiology in type 2 diabetes (T2D), but the mechanisms behind the inappropriate glucagon secretion are not fully understood. Glucagon and amino acids are regulated in a feedback loop referred to as the liver–α cell axis. Individuals with non-alcoholic fatty liver disease (NAFLD) appear to be glucagon resistant, disrupting the liver–α cell axis resulting in hyperglucagonaemia and hyperaminoacidaemia. We investigated the associations between circulating glucagon, amino acids, and liver fat content in a cohort of individuals with T2D.
Methods
We included 110 individuals with T2D in this cross-sectional study. Liver fat content was quantified using 1H magnetic resonance spectroscopy (MRS). Associations between liver fat content and plasma glucagon and amino acids, respectively, were estimated in multivariate linear regression analyses.
Results
Individuals with NAFLD (n = 52) had higher plasma glucagon concentrations than individuals without NAFLD (n = 58). The positive association between plasma glucagon concentrations and liver fat content was confirmed in the multivariable regression analyses. Plasma concentrations of isoleucine and glutamate were increased, and glycine and serine concentrations were decreased in individuals with NAFLD. Concentrations of other amino acids were similar between individuals with and without NAFLD, and no clear association was seen between liver fat content and amino acids in the regression analyses.
Conclusion
MRS-diagnosed NAFLD in T2D is associated with hyperglucagonaemia and elevated plasma concentrations of isoleucine and glutamate and low plasma concentrations of glycine and serine. Whether NAFLD and glucagon resistance per se induce these changes remains to be elucidated.
Clinical Research Center for Metabolic Disease, Gansu Province, Lanzhou, Gansu, China
The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
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The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
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The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
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The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
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Clinical Research Center for Metabolic Disease, Gansu Province, Lanzhou, Gansu, China
The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
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Aims
Aging, obesity, and type 2 diabetes mellitus (T2DM) form a metabolic disease continuum that has a continuously increasing prevalence. Lipidomics explains the complex interactions between lipid metabolism and metabolic diseases. We aimed to systematically investigate the plasma lipidome changes induced by newly diagnosed impaired glucose tolerance (IGT) and T2DM in overweight/obese elderly individuals and to identify potential biomarkers to differentiate between the IGT, T2DM, and control groups.
Methods
Plasma samples from 148 overweight/obese elderly individuals, including 52 patients with IGT, 47 patients with T2DM, and 49 euglycemic controls, were analyzed using a high-coverage nontargeted absolute quantitative lipidomics approach.
Results
We quantified 1840 lipids from thirty-eight classes and seven lipid categories. Among overweight/obese elderly individuals, the lipidomic profiles of IGT and T2DM patients were significantly different from those of controls, while they were similar in the IGT and T2DM groups. The concentrations of diglycerides, triglycerides, phosphatidylcholines, and ceramides were obviously altered in the IGT and T2DM groups. Particularly, IGT and T2DM induced the accumulation of triglycerides with longer carbon atom numbers (C44–50) and saturated or lower double bond numbers (n (C=C) = 0–2). Furthermore, a total of 17 potential lipidic biomarkers were identified to successfully differentiate between the IGT, T2DM, and control groups.
Conclusions
In overweight/obese elderly patients, IGT and T2DM induced apparent lipidome-wide changes. This study’s results may contribute to explaining the complex dysfunctional lipid metabolism in aging, obesity, and diabetes.
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Insulin administration remains vital to the treatment of diabetes and although there have been advances in insulin delivery, evidence suggests that many people with diabetes on insulin therapy have suboptimal glycemic management. Recent advancements in insulin administration techniques include connected insulin devices, such as connected insulin pens and pen caps. In this review, we provide an overview of the literature on the use of connected insulin pens and pen caps to further elucidate the clinical benefits and drawbacks of these devices. We discuss the development of these devices, outlining the characteristics of insulin pens and pen caps with regulatory approvals. These devices have different features that can ease the burden of diabetes management, including automatic recording of insulin dose information, tracking of insulin-on-board, bolus calculators, and missed dose alerts. Despite the advantages of connected pens and pen caps, a small percentage of insulin users are currently using these devices, due to many factors, including lack of health-care professional awareness, initial training for prescribers, and setup of the device. Overcoming these barriers and publishing more data demonstrating the glycemic outcomes associated with these systems could improve diabetes management for people living with diabetes. As health-care systems become increasingly digital, connected insulin pens have the potential to allow a data-driven approach to diabetes management for people who are not interested in, cannot afford, or do not have intensive insulin regimens that might warrant use of insulin pumps or automated insulin delivery systems.
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Obesity is a major cause of type 2 diabetes. Transition from obesity to type 2 diabetes manifests in the dysregulation of hormones controlling glucose homeostasis and inflammation. As metabolism is a dynamic process that changes across 24 h, we assessed diurnal rhythmicity in a panel of 10 diabetes-related hormones. Plasma hormones were analysed every 2 h over 24 h in a controlled laboratory study with hourly isocaloric drinks during wake. To separate effects of body mass from type 2 diabetes, we recruited three groups of middle-aged men: an overweight (OW) group with type 2 diabetes and two control groups (lean and OW). Average daily concentrations of glucose, triacylglycerol and all the hormones except visfatin were significantly higher in the OW group compared to the lean group (P < 0.001). In type 2 diabetes, glucose, insulin, C-peptide, glucose-dependent insulinotropic peptide and glucagon-like peptide-1 increased further (P < 0.05), whereas triacylglycerol, ghrelin and plasminogen activator inhibitor-1 concentrations were significantly lower compared to the OW group (P < 0.001). Insulin, C-peptide, glucose-dependent insulinotropic peptide and leptin exhibited significant diurnal rhythms in all study groups (P < 0.05). Other hormones were only rhythmic in 1 or 2 groups. In every group, hormones associated with glucose regulation (insulin, C-peptide, glucose-dependent insulinotropic peptide, ghrelin and plasminogen activator inhibitor-1), triacylglycerol and glucose peaked in the afternoon, whereas glucagon and hormones associated with appetite and inflammation peaked at night. Thus being OW with or without type 2 diabetes significantly affected hormone concentrations but did not affect the timing of the hormonal rhythms.
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Objective
Real-world-based population data about the optimal low-density lipoprotein cholesterol (LDL-C) level for preventing cardiovascular disease in very high-risk populations is scarce.
Methods
From 2009 to 2012, 26,922 people aged ≥ 40 years with type 2 diabetes mellitus (T2DM) who had a history of percutaneous coronary intervention (PCI) were analyzed. Data from the Korean National Health Insurance System were used. They were followed up to the date of a cardiovascular event or the time to death, or until December 31, 2018. Endpoints were recurrent PCI, newly stroke or heart failure, cardiovascular death, and all-cause death. Participants were divided into the following categories according to LDL-C level: <55 mg/dL, 55–69 mg/dL, 70–99 mg/dL, 100–129 mg/dL, 130–159 mg/dL, and ≥ 160 mg/dL.
Results
Compared to LDL-C < 55 mg/dL, the hazard ratios (HR) for re-PCI and stroke increased linearly with increasing LDL-C level in the population < 65 years. However, in ≥ 65 years old, HRs for re-PCI and stroke in LDL-C = 55–69 mg/dL were 0.97 (95% CI: 0.85–1.11) and 0.96 (95% CI: 0.79–2.23), respectively. The optimal range with the lowest HR for heart failure and all-cause mortality were LDL-C = 70–99 mg/dL and LDL-C = 55–69 mg/dL, respectively, in all age groups (HR: 0.99, 95% CI: 0.91–1.08 and HR: 0.91, 95% CI: 0.81–1.01).
Conclusion
LDL-C level below 55 mg/dL appears to be optimal in T2DM patients with established cardiovascular disease aged < 65 years, while an LDL-C level of 55–69 mg/dL may be optimal for preventing recurrent PCI and stroke in patients over 65 years old.
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Background
Obesity and arterial stiffness are strongly associated with cardiovascular disease; however, their relationship remains controversial.
Methods
Body mass index was measured using anthropometric evaluation, and visceral fat area was calculated using an absorptiometry scan.
Results
The data of 5309 participants were collected from NHANES (National Health and Nutrition Examination Survey) (2011–2018). Based on the normal-weight normal visceral fat group that was considered as a reference, ePWV increased in all other groups, with the obese grade 2 visceral obesity group increasing the most by 26.35 cm/s (95% CI: 13.52, 39.18, P < 0.001), followed by normal-weight visceral obesity group 24.43 cm/s (95% CI: 1.88, 46.98, P = 0.035), which was even higher than obese grade 1 visceral obesity (β: 21.16, 95% CI: 9.24, 33.07, P = 0.001), obese grade 2 normal visceral fat group (β: 13.8; 95% CI: 0.10, 27.5, P = 0.048) and overweight visceral obesity group (β: 10.23; 95% CI: 1.89, 18.57, P = 0.018). For the 10-year cardiovascular risk, the obese grade 2 visceral obesity group had a 9.56-fold increase in compared with the control (OR: 10.56, 95% CI: 4.06, 27.51, P < 0.0001). Normal-weight visceral obesity, obese grade 1 visceral obesity, and overweight visceral obesity groups increased by 8.03-fold (OR: 9.03, 95% CI: 2.66, 30.69; P < 0.001), 7.91-fold (OR: 8.91, 95% CI: 3.82, 20.79, P < 0.001), and 7.28-fold (OR: 8.28, 95% CI: 3.19, 21.46, P < 0.001). The risk was lower in the normal visceral fat group. Except for the obese grade 2 normal visceral fat group, there was no significant difference in other groups.
Conclusions
Normal-weight visceral obesity was associated with higher arterial stiffness and 10-year cardiovascular risk.
