Spontanhypoglykämien: Eine diagnostische Herausforderung

Zusammenfassung Anamnese Die Vorstellung einer 59-jährigen Frau erfolgte zur endokrinologischen Abklärung rezidivierender Spontanhypoglykämien. Die Beschwerden waren stets nach Kohlenhydrataufnahme regredient. Aufgrund eines klassischen adrenogenitalen Syndroms erhielt die Patientin seit jungen Jahren eine Substitutionstherapie mit Hydrocortison. Untersuchung Die Patientin präsentierte sich in einem altersentsprechenden Allgemein- und leicht übergewichtigen Ernährungszustand. Der Blutzucker lag zum Aufnahmezeitpunkt bei 87 mg/dl. Weiterhin konnten unter Substitution mit retardiertem Hydrocortison ein unauffälliges Cortisol sowie adrenokortikotropes Hormon (ACTH) nachgewiesen werden. Im Mixed-Meal-Tolerance-Test (MMTT, standardisierter Frühstückstest) zeigte sich keine reaktive Hypoglykämie. Im anschließenden 72-Stunden-Hungerversuch trat nach 36 Stunden eine symptomatische Hypoglykämie auf. Bei einem Blutzucker von 46 mg/dl (Referenzbereich: 74–106) fand sich ein vermindertes Insulin. Auffällig waren jedoch ein niedriges Cortisol sowie ein deutlich erhöhtes ACTH, hinweisend auf eine Unterversorgung mit Hydrocortison zum Zeitpunkt der Hypoglykämie. Therapie und Verlauf Aufgrund der vermuteten therapeutischen Lücke wurde mit der Patientin eine Dosiserhöhung des morgendlichen retardierten Hydrocortisons besprochen. Da dies keinen klinischen Erfolg hatte, wurde die Applikationsform auf morgens und abends geändert. Folgerung Die vorliegende Kasuistik demonstriert, dass nicht nur ein endogener Hyperinsulinismus ursächlich für Spontanhypoglykämien sein kann, sondern ebenfalls eine fehlerhafte Gegenregulation zu symptomatischen Unterzuckerungen führen kann. Der MMTT sowie der 72-Stunden-Hungerversuch sollten zur Diagnostik angewendet werden. Hierbei ist darauf zu achten, dass in der Hypoglykämie eine unmittelbare Hormonanalytik erfolgt. Durch das Verhältnis von Insulin, C-Peptid sowie Proinsulin zum Blutzucker und anhand der Konstellation der kontrainsulinären Hormone wie Cortisol, ACTH, Wachstumshormon, Insulin-like growth factor 1 (IGF-1) sowie der Katecholamine kann eine Aussage über die Ätiologie der Hypoglykämie getroffen werden.

Effects of mixed meal tolerance test on gastric emptying, glucose and lipid homeostasis in obese nonhuman primates

Meal ingestion elicits a variety of neuronal, physiological and hormonal responses that differ in healthy, obese or diabetic individuals. The mixed meal tolerance test (MMTT) is a well-established method to evaluate pancreatic β-cell reserve and glucose homeostasis in both preclinical and clinical research in response to calorically defined meal. Nonhuman primates (NHPs) are highly valuable for diabetic research as they can naturally develop type 2 diabetes mellitus (T2DM) in a way similar to the onset and progression of human T2DM. The purpose of this study was to investigate the reproducibility and effects of a MMTT containing acetaminophen on plasma glucose, insulin, C-peptide, incretin hormones, lipids, acetaminophen appearance (a surrogate marker for gastric emptying) in 16 conscious obese cynomolgus monkeys (Macaca fascicularis). Plasma insulin, C-peptide, TG, aGLP-1, tGIP, PYY and acetaminophen significantly increased after meal/acetaminophen administration. A subsequent study in 6 animals showed that the changes of plasma glucose, insulin, C-peptide, lipids and acetaminophen were reproducible. There were no significant differences in responses to the MMTT among the obese NHPs with (n = 11) or without (n = 5) hyperglycemia. Our results demonstrate that mixed meal administration induces significant secretion of several incretins which are critical for maintaining glucose homeostasis. In addition, the responses to the MMTTs are reproducible in NHPs, which is important when the MMTT is used for evaluating post-meal glucose homeostasis in research.

Post-load glucose subgroups and associated metabolic traits in individuals with type 2 diabetes: An IMI-DIRECT study

Aim Subclasses of different glycaemic disturbances could explain the variation in characteristics of individuals with type 2 diabetes (T2D). We aimed to examine the association between subgroups based on their glucose curves during a five-point mixed-meal tolerance test (MMT) and metabolic traits at baseline and glycaemic deterioration in individuals with T2D. Methods The study included 787 individuals with newly diagnosed T2D from the Diabetes Research on Patient Stratification (IMI-DIRECT) Study. Latent class trajectory analysis (LCTA) was used to identify distinct glucose curve subgroups during a five-point MMT. Using general linear models, these subgroups were associated with metabolic traits at baseline and after 18 months of follow up, adjusted for potential confounders. Results At baseline, we identified three glucose curve subgroups, labelled in order of increasing glucose peak levels as subgroup 1–3. Individuals in subgroup 2 and 3 were more likely to have higher levels of HbA1c, triglycerides and BMI at baseline, compared to those in subgroup 1. At 18 months (n = 651), the beta coefficients (95% CI) for change in HbA1c (mmol/mol) increased across subgroups with 0.37 (-0.18–1.92) for subgroup 2 and 1.88 (-0.08–3.85) for subgroup 3, relative to subgroup 1. The same trend was observed for change in levels of triglycerides and fasting glucose. Conclusions Different glycaemic profiles with different metabolic traits and different degrees of subsequent glycaemic deterioration can be identified using data from a frequently sampled mixed-meal tolerance test in individuals with T2D. Subgroups with the highest peaks had greater metabolic risk.

OR30-07 Mixed Meal Tolerance Test (MMTT) Results from Revita-2, the First Randomized, Sham-Controlled, Double-Blind, Prospective, Multicenter Study of Duodenal Mucosal Resurfacing (DMR) Safety and Efficacy in Patients with Sub-Optimally Controlled Type 2 Diabetes (T2D)

BACKGROUND: The duodenum is a key metabolic signaling center and regulator of metabolic homeostasis. Duodenal mucosal hyperplasia is therefore a potential therapeutic target for metabolic diseases related to insulin-resistance. Previous reports demonstrated that DMR, a minimally invasive, endoscopic mucosal ablative procedure, safely improves hepatic and glycemic parameters. Primary endpoints from REVITA-2, the first randomized, sham-controlled, double-blind, prospective, multicenter study of DMR safety and efficacy in patients with T2D, were met and previously reported. Here we further explore mechanisms underlying the beneficial effects of DMR on hepatic and glucose metabolism by analyzing mixed meal tolerance test (MMTT) data from the REVITA-2 study. Methods: Eligible patients (HbA1c 7.5–10%, BMI ≥ 24 to ≤ 40 kg/m2, on stable treatment with ≥1 oral anti-diabetic medication) received DMR or sham procedure (1:1). Exploratory endpoints included median change in fasting plasma glucose (FPG), MMTT glucose area under the curve (AUC) over 2 hours, and change in MMTT C-peptide and glucagon over 2 hours, from baseline to 12 weeks post-DMR. One-sided P value based on ANCOVA model on ranks without imputation assessed treatment difference at the 0.05 significance level. The modified intent to treat primary analysis population included randomized patients in whom study procedure was attempted. Results: A total of 70 patients (DMR, N = 35; sham, N = 35) were included in the analysis, of which 57% and 54% (DMR, n = 20; sham, n = 19) had baseline FPG ≥ 180 mg/dL. Median MMTT AUC for glucose was significantly reduced post-DMR (-36.38 mg/dL) compared with sham (-4.94 mg/dL; P = 0.009), driven by a significant decrease in FPG (DMR, -41.0 mg/dL; sham, -15.0 mg/dL; P = 0.003) rather than median MMTT postprandial glucose excursion (DMR, -4.63 mg/dL; sham, 5.34 mg/dL; P = 0.209). AUC glucose reductions were more pronounced in patients with baseline FPG ≥ 180 (DMR, -63.03 mg/dL; sham, -20.31 mg/dL; P = 0.007) compared with baseline FPG < 180 (DMR, -26.81 mg/dL; sham, 13.81 mg/dL; P = 0.271). In patients with baseline FPG ≥ 180, postprandial C-peptide excursion was significantly increased (DMR, 0.41 ng/mL; sham, 0.02 ng/mL; P = 0.012) and postprandial glucagon excursion was significantly decreased (DMR, -8.03 pg/mL; sham, 2.13 pg/mL; P = 0.027). Conclusion: DMR markedly improves glucose responses to a mixed meal challenge, primarily driven by a decrease in FPG, suggesting a primary effect on insulin resistance. Increases in C-peptide and reductions in glucagon levels suggest improvement in beta cell function in addition to improvements in hepatic insulin sensitivity, and ratifies the position of the duodenum as both a culprit endocrine organ and therapeutic target for patients with T2D.