Mar 23, 2023
New study published investigating the role of circulating levels of gastrointestinal hormones in normoglycemia, prediabetes and diabetes
Prof. Nikolaos Perakakis & Carlotta Hoffmann
Gastrointestinal hormones such as GLP-1, glucagon and GIP are important and established regulators of energy and glucose homeostasis. However, despite the established or emerging role of these hormones in metabolism, it is still debated whether impairments (deficits or excesses) in their fasting or postprandial profiles are observed in metabolic diseases and whether they are contributing to progression of hyperglycaemia and development of type 2 diabetes. Now, researchers from the Paul Langerhans Institute Dresden teamed up with scientists from Tübingen, Boston, London and Zürich to compare the concentrations of GLP-1, glucagon and GIP and glicentin during an oral glucose tolerance test in patients with normal glucose tolerance, prediabetes and diabetes at onset, and one-year before, when all had prediabetes. The outcome of this study was now published in the renowned journal “Diabetes Research and Clinical Practice”.
In clinical research the gastrointestinal hormones glucagon-like peptide 1 (GLP-1), glucagon and gastric inhibitory peptide (GIP) are important and established regulators of energy and glucose homeostasis. They act on the regulation of glucose homeostasis via their differential actions on the liver, endocrine pancreas and gastrointestinal tract. They also play important roles in maintaining energy balance by modulating nutrient absorption, mobilization of fat stores from adipose tissue and appetite regulation. Agonists of GLP-1 receptor are routinely being used for the treatment of diabetes and obesity, while recently a newly developed dual GLP-1/GIP receptor agonist entitled Tirzepatide has been approved for the treatment of type 2 diabetes. Additionally, further dual or even triple agonists of GLP-1, GIP and/or glucagon receptor are currently under development. Moreover, the hormone glicentin is emerging as a potential useful marker of metabolic health, as it is a stronger predictor of one-year weight loss in morbidly obese patients than GLP-1.
“Despite the established or emerging role of the above gastrointestinal hormones in metabolism, it is still debated whether impairments (deficits or excesses) in their fasting or postprandial profiles are observed in metabolic diseases and whether they are contributing to progression of hyperglycaemia and development of type 2 diabetes”, explains the first author of the publication, Carlotta Hoffmann, MD student in the group of Prof. Dr. Nikolaos Perakakis who is group leader at the Paul Langerhans Institute of Helmholtz Munich at the University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden and head of the clinical study center at the medical clinic III of the University Hospital.
By utilizing an oral glucose tolerance test (OGTT), the scientists compared the fasting and postprandial circulating profiles of GLP-1, glucagon, GIP and glicentin in patients with normal glucose tolerance, prediabetes or type 2 diabetes at the time of the establishment of the diagnosis, as well as one-year before, when all subjects had prediabetes and aimed to assess whether and how the profiles of these hormones are related to different metabolic parameters, including insulin sensitivity, beta cell function, BMI, body composition and liver fat amount.
“We designed a nested case control study with a cross-sectional part and a prospective part with samples from participants of the prediabetes lifestyle intervention study (PLIS) of the German Center for Diabetes Research recruited in the University Study Center for Metabolic Diseases in Dresden and measured the concentrations of GLP-1, glucagon, GIP and glicentin in subjects with new onset type 2 diabetes, in subjects that had normal glucose tolerance test and in subjects that had prediabetes”, describes Prof. Perakakis the study. “We were able to demonstrate that in comparison to subjects with normal glucose tolerance patients with new onset diabetes have lower late postprandial increases of glicentin and GLP-1 in the OGTT, lower early postprandial suppression of glucagon levels and higher fasting GIP levels. Furthermore, we could show that the fasting and postprandial concentrations of incretins, glucagon and glicentin in prediabetic state cannot predict future development of diabetes or regression to normal glucose tolerance and that progression of hyperglycemia and of prediabetes to diabetes are associated with a concomitant reduction in postprandial increases of glicentin and GLP-1.”
It is known since decades that patients with type 2 diabetes demonstrate an impaired incretin effect, which has been primarily attributed to the loss of the insulinotropic effects of GIP, whereas only a slight impairment of the insulinotropic activity of GLP-1 has been observed. Here the researchers could show that progression of prediabetes to diabetes is accompanied by a reduction in the levels of GLP-1 and glicentin which suggests that a deficit in these hormones may at least in part contribute to the reduced incretin effect in diabetes, albeit a causal relationship cannot be established with the current study design. Albeit GLP-1/glicentin levels are no useful markers for predicting future diabetes development it seems as if glicentin levels are robustly regulated by glycemic state which suggests that glicentin may be a helpful marker of L-cell function and deserves to be studied more carefully in order to assess whether it has an important role in the regulation of glucose homeostasis.
Original publication:
Hoffmann C, Schwarz PE, Mantzoros CS, Birkenfeld AL, Wolfrum C, Solimena M, Bornstein SR, Perakakis N. Circulating levels of gastrointestinal hormones in prediabetes reversing to normoglycemia or progressing to diabetes in a year-A cross-sectional and prospective analysis. Diabetes Res Clin Pract. 2023 Mar 20;199:110636. doi: 10.1016/j.diabres.2023.110636.