Incretin hormones: Their role in health and disease

Nauck, Michael A.; Meier, Juris J.

doi:10.1111/dom.13129

Cited by 563 publications

(475 citation statements)

References 167 publications

(313 reference statements)

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“…One emerging approach to improve the efficacy of GLP‐1 RAs is a pharmacological strategy targeting additional pathways implicated in nutrient and energy metabolism, such as glucose‐dependent insulinotropic peptide (GIP) . GIP is responsible for majority of the postprandial insulinotropic incretin effect in normal individuals and has important additional functions that are distinct from GLP‐1. GIP plays an important role in adipose tissue carbohydrate and lipid metabolism by its actions to regulate glucose uptake, lipolysis, and lipoprotein lipase activity .…”

Section: Introductionmentioning

confidence: 99%

Efficacy and tolerability of tirzepatide, a dual glucose‐dependent insulinotropic peptide and glucagon‐like peptide‐1 receptor agonist in patients with type 2 diabetes: A 12‐week, randomized, double‐blind, placebo‐controlled study to evaluate different dose‐escalation regimens

Frías

Nauck

Van

et al. 2020

Diabetes Obesity Metabolism

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148

163

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Aim: To assess the efficacy and tolerability of tirzepatide treatment using three different dose-escalation regimens in patients with type 2 diabetes. Materials and Methods:In this double-blind, placebo-controlled study, patients were randomized (1:1:1:1) to receive either once-weekly subcutaneous tirzepatide or placebo. The tirzepatide dose groups and dose-escalation regimens were: 12 mg (4 mg weeks 0-3; 8 mg weeks 4-7; 12 mg weeks 8-11), 15 mg-1 (2.5 mg weeks 0-1; 5 mg weeks 2-3; 10 mg weeks 4-7; 15 mg weeks 8-11) and 15 mg-2 (2.5 mg weeks 0-3; 7.5 mg weeks 4-7; 15 mg weeks 8-11). The primary objective was to compare tirzepatide with placebo in HbA1c change from baseline at 12 weeks.Results: Overall, 111 patients were randomized: placebo, 26; tirzepatide 12 mg, 29; tirzepatide 15 mg-1, 28; tirzepatide 15 mg-2, 28. The mean age was 57.4 years, HbA1c 8.4% and body mass index 31.9 kg/m 2 . At week 12, absolute HbA1c change from baseline (SE) was greater in the tirzepatide treatment groups compared with placebo (placebo, +0.2% [0.21]; 12 mg, −1.7% [0.19]; 15 mg-1, −2.0% [0.20]; 15 mg-2, −1.8% [0.19]). The incidence of nausea was: placebo, 7.7%; 12 mg group, 24.1%; 15 mg-1 group, 39.3%; 15 mg-2 group, 35.7%. Three patients discontinued the treatment because of adverse events, one from each of the placebo, 12 mg and 15 mg-1 groups.Conclusions: Tirzepatide treatment for 12 weeks resulted in clinically significant reductions in HbA1c. This suggests that lower starting doses and smaller dose increments are associated with a more favourable side effect profile.

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Section: Introductionmentioning

confidence: 99%

Efficacy and tolerability of tirzepatide, a dual glucose‐dependent insulinotropic peptide and glucagon‐like peptide‐1 receptor agonist in patients with type 2 diabetes: A 12‐week, randomized, double‐blind, placebo‐controlled study to evaluate different dose‐escalation regimens

Frías

Nauck

Van

et al. 2020

Diabetes Obesity Metabolism

Self Cite

148

163

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“…Ultrasound coupling gel heated to 34°C was applied to the chest area and a linear array transducer (18)(19)(20)(21)(22)(23) was positioned to obtain two-dimensional B-mode parasternal long and short axis views at the mid-ventricular level (Vevo 2100, VisualSonics). One-dimensional M-mode images were obtained for measurement in the short axis view to obtain cardiac wall thickness and chamber dimensions.…”

Section: Cardiovascular Imagingmentioning

confidence: 99%

Removing the Gβγ-SNAP25 brake on exocytosis enhances insulin action, promotes adipocyte browning, and protects against diet-induced obesity

Ceddia

Zurawski

et al. 2020

Preprint

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The Gβγ complex inhibits vesicle exocytosis by two mechanisms: inhibiting calcium entry by binding to voltage gated calcium channels, and binding to SNAP25 in the SNAP Receptor (SNARE) complex. To de-convolute the role of each of these mechanisms in vivo, we have made a mouse with the second mechanism disabled. The SNAP25Δ3 mutation renders the SNARE complex deficient in binding to Gβγ and was used to investigate the importance of the Gβγ-SNAP25 interaction in glucose stimulated insulin secretion (GSIS) and global metabolic homeostasis. GSIS and α2A adrenergic receptor-mediated inhibition of GSIS were not altered in SNAP25 Δ3/Δ3 mice. Nevertheless, SNAP25 Δ3/Δ3 mice exhibited a marked improvement in insulin sensitivity and were resistant to weight gain when challenged with a high fat diet (HFD). Reduced food consumption in the early stages of HFD feeding were partly responsible for the inability of SNAP25 Δ3/Δ3 mice to gain weight on HFD. Additionally, improved insulin-mediated glucose uptake into white adipose tissue and increased 'browning' were observed in SNAP25 Δ3/Δ3 mice, which is consistent with an impaired ability to retain energy stores. These phenotypic changes in SNAP25 Δ3/Δ3 mice are all metabolically protective, indicating that pharmacological targeting of the Gβγ-SNAP25 interaction may have a metabolic benefit. Introduction:G-protein coupled receptors (GPCRs) are canonically known to mediate downstream signaling events through the activation of heterotrimeric G-proteins. While the classical Gα-mediated signaling events are well known, and many represent important pharmacological targets (1), signaling via the Gβγ-subunits have received less attention and the therapeutic targeting of these signaling pathways has not been as widely exploited (2).One function of Gβγ is to inhibit exocytosis by two mechanisms, modulation of calcium entry, and direct binding to the exocytotic fusion complex (3). We have shown that Gβγ binding to the SNARE complex is mainly through the last three amino acids of SNAP25 (Soluble N-ethylmaleimide-sensitive factor Attachment Protein), in the SNAP Receptor (SNARE) complex (4). In order to specifically study the contribution of exocytosis at the exocytotic fusion step in vivo, we developed an allele of SNAP25 which lacks these last three amino acids, which we have called SNAP25Δ3 (5). The ability of SNAP25Δ3 to form SNARE complexes that undergo calciumsynaptotagmin mediated zipping and regulate exocytosis is identical to that of SNAP25, but its ability to interact with Gβγ, and GPCR-mediated inhibitory effects on exocytosis, is ablated. The SNAP25 Δ3/Δ3 mouse has demonstrated the importance of the Gβγ-SNARE pathway in a number of neurological processes, including stress and pain processing, as well as long-term potentiation (6) and spatial memory (5). We hypothesized that the SNAP25 Δ3/Δ3 mouse may have an altered metabolic phenotype because neurological processes use SNAREdependent signals to regulate a number of metabolically important processes, such as feeding behavior, ene...

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“…Obesity is associated with lower fasting GLP-1 and an attenuated postprandial release [28]. As will be discussed, liraglutide, a GLP-1 receptor agonist, is FDA-approved for the treatment of obesity, acting by slowing gastric emptying and promoting gastric distension.…”

Section: Pathophysiologymentioning

confidence: 99%

Trends in Obesity and Risk of Cardiovascular Disease

Lahey

Khan

2018

Curr Epidemiol Rep

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Purpose of review: The obesity epidemic is a global health crisis of staggering proportion. Excess body weight is a major risk factor for the development of cardiovascular disease (CVD). We review temporal trends in obesity rates, pertinent pathophysiology to understand mechanisms of disease, and treatment strategies in the context of reducing cardiovascular risk. Recent findings: The prevalence of obesity is increasing in recent decades and is driven by a complex interplay of economic, environmental, and biological factors. In developed countries, changes in foodintake, such as increased consumption of energy-dense and added sugar have contributed significantly to weight gain. Single nucleotide variations in genes and alterations in the gut microbiome have been associated with the obese phenotype. The description of an obesity paradox in patients with CVD may have several explanations, including limitations of body mass index (BMI) to assess adiposity, selection bias, and lead-time bias with earlier onset of disease. Evidence-based treatments for weight loss include lifestyle intervention, pharmacotherapy, and bariatric surgery. Data on the long-term effects of these therapies on cardiovascular risk are limited. Summary: Overweight and obesity are associated with increased cardiovascular morbidity and mortality over the lifespan. Despite our increasing understanding of biological and environmental drivers of obesity, more work is needed in developing effective prevention strategies and implementation of evidence-based treatments to promote cardiovascular health and reduce cardiovascular risk. Ultimately, efforts to prevent and postpone cardiovascular morbidity should include focus on maintenance of normal BMI (primordial prevention) for a longer and healthier life, free of CVD.

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Incretin hormones: Their role in health and disease

Cited by 563 publications

References 167 publications

Efficacy and tolerability of tirzepatide, a dual glucose‐dependent insulinotropic peptide and glucagon‐like peptide‐1 receptor agonist in patients with type 2 diabetes: A 12‐week, randomized, double‐blind, placebo‐controlled study to evaluate different dose‐escalation regimens

Efficacy and tolerability of tirzepatide, a dual glucose‐dependent insulinotropic peptide and glucagon‐like peptide‐1 receptor agonist in patients with type 2 diabetes: A 12‐week, randomized, double‐blind, placebo‐controlled study to evaluate different dose‐escalation regimens

Removing the Gβγ-SNAP25 brake on exocytosis enhances insulin action, promotes adipocyte browning, and protects against diet-induced obesity

Trends in Obesity and Risk of Cardiovascular Disease

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