GIP Affects Hepatic Fat and Brown Adipose Tissue Thermogenesis but Not White Adipose Tissue Transcriptome in Type 1 Diabetes

Abstract

Aims/hypothesis Glucose-dependent insulinotropic polypeptide (GIP) has been proposed to exert insulin-independent effects on lipid and bone metabolism. We investigated the effect of a 6-day s.c. GIP infusion on circulating lipids, white adipose tissue (WAT), brown adipose tissue (BAT), hepatic fat content, inflammatory markers, respiratory exchange ratio (RER), and bone homeostasis in patients with type 1 diabetes. Methods In a randomized, placebo-controlled, double-blind, crossover study, 20 men with type 1 diabetes underwent a 6-day continuous s.c. infusion with GIP (6 pmol/kg/min) and placebo (saline), with an interposed 7-day washout period. Results During GIP infusion, participants (26 ± 8 years [mean ± SD]; BMI 23.8 ± 1.8 kg/m2; HbA1c 51 ± 10 mmol/mol [6.8 ± 3.1%]) experienced transiently increased circulating concentrations of NEFA (p = 0.0005), decreased RER (p = 0.009), indication of increased fatty acid β-oxidation, and decreased levels of the bone resorption marker C-terminal telopeptide (p = 0.000072) compared to placebo. After six days of GIP infusion, hepatic fat content was increased by 12.6% (p = 0.007) and supraclavicular skin temperature, a surrogate indicator of BAT activity, was increased by 0.29°C (p < 0.000001) compared to placebo. WAT transcriptomic profile as well as circulating lipid species, proteome, markers of inflammation, and bone homeostasis were unaffected. Conclusions/interpretation Six days s.c. GIP infusion in men with type 1 diabetes transiently decreased bone resorption and increased NEFA and β-oxidation. Further, hepatic fat content, and supraclavicular skin temperature were increased without affecting WAT transcriptomics, the circulating proteome, lipids, or inflammatory markers.

The importance of glucose‐dependent insulinotropic polypeptide receptor activation for the effects of tirzepatide

“…The aforementioned 6‐day continuous subcutaneous infusion of GIP in patients with type 1 diabetes resulted in a 12.6% ± 4.2% increase in hepatic lipid content compared with placebo, consistent with earlier proposals of the involvement of GIP in the lipid metabolism 66 . Moreover, levels of endogenous GIP have been linked to various inflammatory processes 91–93 and autonomic disturbances of the cardiovascular system, 94 but no causalities have been established.…”

“…Thus, only acute studies of the effects of natural GIP are available, apart from a single study with a 6-day infusion of GIP in patients with type 1 diabetes. 65,66 Recently (May 2023), Novo Nordisk announced termination of the development of a onceweekly GIP receptor agonist (NNC0480-0389) because of a lack of effect on glycaemia and body weight following 34 weeks of treatment with or without concomitant treatment with the GLP-1 receptor agonist semaglutide in patients with type 2 diabetes. 67 By contrast, Eli Lilly and Company presented body weight loss and reduced fasting plasma glucose using a long-acting GIP analogue (LY3537021) for 2 months in both patients with type 2 diabetes and healthy individuals.…”

“…After 6 days of continuous GIP infusion in patients with type 1 diabetes, hepatic fat content was increased, whereas the otherwise rather large GIP-induced reduction in the bone resorption marker carboxy-terminal collagen crosslinks, observed during short-term infusions and confirmed at the beginning of the study, had disappeared (Table 2). 66 The long-term implications of targeting the GIP receptors in bones are unknown and bone health should be an area of focus during tirzepatide treatment, even although, to date, the data disclose no risk of bone weakness. 103 Long-term, continuous exposure to the endogenous hormones is, however, already widely utilized with DPP-4 inhibitors in the treatment of type 2 diabetes, 116 because DPP-4 inhibition augments the concentrations of the active form of both of the incretin hormones.…”

“…For GIP, no therapeutic compound that only targets the GIP receptor is available. Thus, only acute studies of the effects of natural GIP are available, apart from a single study with a 6‐day infusion of GIP in patients with type 1 diabetes 65,66 . Recently (May 2023), Novo Nordisk announced termination of the development of a once‐weekly GIP receptor agonist (NNC0480‐0389) because of a lack of effect on glycaemia and body weight following 34 weeks of treatment with or without concomitant treatment with the GLP‐1 receptor agonist semaglutide in patients with type 2 diabetes 67 .…”

Effect of incretins on skeletal health

“…This study also reported an increase in P1NP during GIP administration which is suggestive of bone anabolic effects of GIP [47 && ]. However, the effect of GIP on bone turnover may be transient as a six-day infusion of GIP only displayed a decrease in CTX at the initiation of the infusion, but not after one or six days compared to placebo in patients with type 1 diabetes [48]. This suggests that GIP should be given pulsatile if it should be used as a target in the treatment of osteoporosis.…”