Twincretin as a potential therapeutic for the management of type 2 diabetes with obesity

Abstract

Unimolecular peptide‐based dual agonists against glucagon‐like peptide‐1 receptor (GLP‐1R) and glucose‐dependent insulinotropic polypeptide receptor (GIPR) have been gaining much attention recently as novel antidiabetic agents that can potentially control glycemia and bodyweight. Although GLP‐1 and GIP both enhance insulin secretion and subsequently ameliorate postprandial glucose excursion, most research has focused on GLP‐1R as a therapeutic target for type 2 diabetes. This is partly because the effects of GIPR activation on glycemia and bodyweight have been controversial. GIPR‐deficient mice showed impaired glucose tolerance with reduced β‐cell function and resistance to high‐fat diet‐induced obesity, whereas GIPR agonists improved glycemia and prevented high‐fat diet‐induced obesity in mice. Conflicting results in mice might be explained by pharmacological levels of GIP signal in the central nervous systems decreasing food intake and overcoming the obesogenic effects of GIP at physiological levels in adipose tissues. Thus, GIPR activation at pharmacological levels might result in bodyweight reduction. Indeed, bodyweight reduction by GIPR/GLP‐1R dual agonists was greater than GLP‐1R single agonists in individuals with type 2 diabetes. Thus, GLP‐1R/GIPR dual agonists can add additional therapeutic efficacy to tailored diabetes care, especially among obese individuals with type 2 diabetes. However, caution should be exercised as to whether or not these drugs are appropriate for the management of Asian type 2 diabetes patients, which are primarily characterized by non‐obesity and impaired β‐cell function, as well as in that of elderly adults with type 2 diabetes, who tend to develop sarcopenia and frailty as a result of poor energy intake.

Drug Therapy in Obesity: A Review of Current and Emerging Treatments

“…A synergistic action in which glucagon receptor activation enhances energy expenditure whilst GLP-1 receptor agonists reduce calorie intake and both GLP-1/GIP potentiate the incretin effect to modulate the diabetogenic effect of glucagon agonists. Two triple agonists are currently in early stages of clinical trials with no yet published clinical trial data [48]. However, preclinical studies of these drugs demonstrate supportive results in rodent and mice models [53][54][55], and we await further clinical trial data with anticipation.…”

“…Several clinical trials have observed significant weight loss associated with the use of these drugs from 2.1 to 3.1 kg [46,47]. Encouragingly, there are several ongoing and unreported preclinical, phase I/II trials investigating drugs utilising this dual mechanism of action [48].…”

“…Promising results have been observed for the GLP-1/GIP agonist LY3298176 in overweight or Summarises the use and weight loss efficacy of available GLP-1 analogue monotherapy a Additional weight loss compared with control b Absolute weight loss obese people with T2D, noting a weight loss between 0.9 and 11.3 kg in participants using the dual agent compared with 0.4 kg and 2.7 kg in those using placebo or dulaglutide respectively [52]. Further preclinical and clinical trials utilising these dual agonists are ongoing, though results are unpublished at the time of writing [48].…”

Diabetic cases controlled with low carbohydrate diet (LCD) and GLP-1 receptor agonist (GLP-1 RA)

“…From the physiological point of view, it is meaningful to compare the functions of three kinds of related hormones, which are GLP-1, gastric inhibitory polypeptide (GIP) and glucagon. These factors seem to have various effects on several organs, such as the brain, gastrointestinal tract, pancreas, liver, adipose tissue and bone [17]. Among them, GLP-1 and GIP is a pair of two incretin hormones, which are secreted from the gut for the ingestion of nutrients.…”

The journey to understanding incretin systems: Theory, practice and more theory

“…However, novel findings from basic research on GLP‐1, as well as GIP, are still changing our views on how incretin‐based drugs exert their glucose‐lowering effects, and how such effects can be maximized by lifestyle modifications. In contrast, newer incretin‐based drugs, including unimolecular peptide‐based dual agonists against GLP‐1 and GIP receptors, are providing clues as to how pharmacological levels of GIP affect appetite loss and bodyweight reduction. Although it has been >100 years since the discovery of the incretin concept by Moore et al ,.…”