PMID- 35563608 OWN - NLM STAT- MEDLINE DCOM- 20220517 LR - 20230308 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 23 IP - 9 DP - 2022 May 6 TI - Incretin Response to Mixed Meal Challenge in Active Cushing's Disease and after Pasireotide Therapy. LID - 10.3390/ijms23095217 [doi] LID - 5217 AB - Cushing's disease (CD) causes diabetes mellitus (DM) through different mechanisms in a significant proportion of patients. Glucose metabolism has rarely been assessed with appropriate testing in CD; we aimed to evaluate hormonal response to a mixed meal tolerance test (MMTT) in CD patients and analyzed the effect of pasireotide (PAS) on glucose homeostasis. To assess gastro-entero-pancreatic hormones response in diabetic (DM+) and non-diabetic (DM-) patients, 26 patients with CD underwent an MMTT. Ten patients were submitted to a second MMTT after two months of PAS 600 microg twice daily. The DM+ group had significantly higher BMI, waist circumference, glycemia, HbA1c, ACTH levels and insulin resistance indexes than DM- (p < 0.05). Moreover, DM+ patients exhibited increased C-peptide (p = 0.004) and glucose area under the curve (AUC) (p = 0.021) during MMTT, with a blunted insulinotropic peptide (GIP) response (p = 0.035). Glucagon levels were similar in both groups, showing a quick rise after meals. No difference in estimated insulin secretion and insulin:glucagon ratio was found. After two months, PAS induced an increase in both fasting glycemia and HbA1c compared to baseline (p < 0.05). However, this glucose trend after meal did not worsen despite the blunted insulin and C-peptide response to MMTT. After PAS treatment, patients exhibited reduced insulin secretion (p = 0.005) and resistance (p = 0.007) indexes. Conversely, glucagon did not change with a consequent impairment of insulin:glucagon ratio (p = 0.009). No significant differences were observed in incretins basal and meal-induced levels. Insulin resistance confirmed its pivotal role in glucocorticoid-induced DM. A blunted GIP response to MMTT in the DM+ group might suggest a potential inhibitory role of hypercortisolism on enteropancreatic axis. As expected, PAS reduced insulin secretion but also induced an improvement in insulin sensitivity as a result of cortisol reduction. No differences in incretin response to MMTT were recorded during PAS therapy. The discrepancy between insulin and glucagon trends while on PAS may be an important pathophysiological mechanism in this iatrogenic DM; hence restoring insulin:glucagon ratio by either enhancing insulin secretion or reducing glucagon tone can be a potential therapeutic target. FAU - Barbot, Mattia AU - Barbot M AUID- ORCID: 0000-0002-1081-5727 AD - Endocrinology Unit, Department of Medicine DIMED, University-Hospital of Padova, Via Ospedale Civile 105, 35128 Padova, Italy. FAU - Mondin, Alessandro AU - Mondin A AUID- ORCID: 0000-0002-6046-5198 AD - Endocrinology Unit, Department of Medicine DIMED, University-Hospital of Padova, Via Ospedale Civile 105, 35128 Padova, Italy. FAU - Regazzo, Daniela AU - Regazzo D AUID- ORCID: 0000-0002-1942-7202 AD - Endocrinology Unit, Department of Medicine DIMED, University-Hospital of Padova, Via Ospedale Civile 105, 35128 Padova, Italy. FAU - Guarnotta, Valentina AU - Guarnotta V AD - Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza "G. D'Alessandro", UOC di Malattie Endocrine, del Ricambio e della Nutrizione, Universita degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy. FAU - Basso, Daniela AU - Basso D AUID- ORCID: 0000-0001-8745-6171 AD - Laboratory Medicine Unit, Department of Medicine DIMED, University-Hospital of Padova, 35128 Padova, Italy. FAU - Giordano, Carla AU - Giordano C AUID- ORCID: 0000-0003-1731-9395 AD - Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza "G. D'Alessandro", UOC di Malattie Endocrine, del Ricambio e della Nutrizione, Universita degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy. FAU - Scaroni, Carla AU - Scaroni C AD - Endocrinology Unit, Department of Medicine DIMED, University-Hospital of Padova, Via Ospedale Civile 105, 35128 Padova, Italy. FAU - Ceccato, Filippo AU - Ceccato F AD - Endocrinology Unit, Department of Medicine DIMED, University-Hospital of Padova, Via Ospedale Civile 105, 35128 Padova, Italy. LA - eng PT - Journal Article DEP - 20220506 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Blood Glucose) RN - 0 (C-Peptide) RN - 0 (Glycated Hemoglobin A) RN - 0 (Incretins) RN - 0 (Insulin) RN - 51110-01-1 (Somatostatin) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9007-92-5 (Glucagon) RN - 98H1T17066 (pasireotide) SB - IM MH - Blood Glucose/metabolism MH - C-Peptide MH - *Diabetes Mellitus MH - *Diabetes Mellitus, Type 2/metabolism MH - Gastric Inhibitory Polypeptide MH - Glucagon MH - Glucagon-Like Peptide 1 MH - Glycated Hemoglobin MH - Humans MH - Incretins/therapeutic use MH - Insulin/metabolism MH - *Insulin Resistance MH - Meals MH - *Pituitary ACTH Hypersecretion/drug therapy MH - Somatostatin/analogs & derivatives PMC - PMC9105040 OTO - NOTNLM OT - Cushing's disease OT - diabetes mellitus OT - incretin OT - mixed meal test tolerance test OT - pasireotide COIS- The authors declare no conflict of interest. EDAT- 2022/05/15 06:00 MHDA- 2022/05/18 06:00 PMCR- 2022/05/06 CRDT- 2022/05/14 01:07 PHST- 2022/03/02 00:00 [received] PHST- 2022/04/27 00:00 [revised] PHST- 2022/05/04 00:00 [accepted] PHST- 2022/05/14 01:07 [entrez] PHST- 2022/05/15 06:00 [pubmed] PHST- 2022/05/18 06:00 [medline] PHST- 2022/05/06 00:00 [pmc-release] AID - ijms23095217 [pii] AID - ijms-23-05217 [pii] AID - 10.3390/ijms23095217 [doi] PST - epublish SO - Int J Mol Sci. 2022 May 6;23(9):5217. doi: 10.3390/ijms23095217.