Mechanismen und Nutzen der Prädiabetes-Remission durch Lebensstilintervention

Eine Lebensstilintervention bei Menschen mit Prädiabetes kann das Risiko einer Progression zum Diabetes mellitus Typ 2 verringern, was am effektivsten durch eine Rückkehr zu normaler Glukoseregulation erreicht wird. Die Effekte der Lebensstilintervention sind im Kontext eines Gewichtsverlusts hauptsächlich durch eine Verbesserung der Insulinsensitivität vermittelt. Innerhalb der heterogenen Subcluster des Prädiabetes gibt es jedoch einen Anteil an Patienten mit besonders hohem metabolischem Risiko, die im Rahmen ihrer umfassenden Reduktion des Leberfettanteils auch ihre Insulinsekretion verbessern können. Diese Erkenntnis ist ein wichtiger Schritt in Richtung Präzisionsdiabetologie, mit deren Hilfe in Zukunft maßgeschneiderte Therapien und Interventionen im Kontrast zum jetzigen one size fits all-Ansatz dabei helfen wird, die Last durch Diabetes mellitus Typ 2 und assoziierte Folgeerkrankungen zu reduzieren. Die besondere Bedeutung des ektopen Fettgewebes in der Pathogenese des Diabetes mellitus Typ 2 im Stadium des Prädiabetes verdeutlicht, dass eine präferentielle Reduktion des viszeralen Fettgewebes im Rahmen eines Körpergewichtsverlustes Vorteile bietet, was durch konkrete Zielwerte monitoriert werden kann. Interessanterweise unterscheidet sich der Mechanismus der Remission des Prädiabetes deutlich von der Remission des Diabetes mellitus Typ 2, insbesondere hinsichtlich der Rolle der Insulinsekretion. Auch hier öffnet sich ein Fenster für maßgeschneiderte präventive Interventionen. Wir definieren in der vorliegenden Arbeit das Konzept der Prädiabetes-Remission und zeigen deren präventives Potential hinsichtlich der Reduktion des Risikos, einen Diabetes mellitus Typ 2 zu entwickeln und potenziellen Vermeidung von Typ 2 Diabetes assoziierten Komplikationen. Unsere Ergebnisse sowohl hinsichtlich der Mechanismen der Prädiabetes-Remission als auch seine protektiven Effekte konnten wir in der bislang größten Diabetes-Präventionsstudie in der westlichen Welt (DPP) reproduzieren. Wir schlagen daher vor, das glykämische Ziel einer Normalisierung des Glukosestoffwechsels neben der bereits empfohlenen Reduktion des Körpergewichts als Primärziel für das Management von Patienten mit Prädiabetes in aktuelle Leitlinien aufzunehmen

Prediabetes remission to reduce the global burden of type 2 diabetes

Prediabetes is a highly prevalent and increasingly common condition affecting a significant proportion of the global population. The heterogeneous nature of prediabetes presents a challenge in identifying individuals who particularly benefit from lifestyle or other therapeutic interventions aiming at preventing type 2 diabetes (T2D) and associated comorbidities. The phenotypic characteristics of individuals at risk for diabetes are associated with both specific risk profiles for progression and a differential potential to facilitate prediabetes remission and reduce the risk of future T2D. This review examines the current definition and global prevalence of prediabetes and evaluates the potential of prediabetes remission to reduce the alarming increase in the global burden of T2D.</p

Spironolactone is associated with reduced mitotane levels in adrenocortical carcinoma patients

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Mitotane, a derivative of the pesticide dichlorodiphenyltrichloroethane, has been used successfully as first line chemotherapy since the 1960s, if maintained within a narrow therapeutic window. Spironolactone (SPL) is frequently used to treat glucocorticoid excess-associated adverse effects such as severe hypokalemia. Although data of a previous case report indicate a link, valid data regarding SPL use and mitotane plasma concentrations in a human cohort are lacking.This retrospective analysis includes data from 54 mitotane-receiving ACC patients (14 co-administered with SPL) treated between January 2005 and April 2020 (20 male, mean age 54.1 ± 2.2 years). All available mitotane concentrations, treatment doses, tumor stage and evidence of hormone activity were collected. Primary outcomes included mitotane levels and concentration/dose ratios as well as time-in-range (TR) in patients with and without additional SPL treatment. The SPL group was characterized by higher glucocorticoid secretion. Other features such as tumor stage, size and anthropometrics were similar between groups. Interestingly, the SPL group had significantly lower mitotane levels despite higher doses. Mitotane TR was significantly reduced in the SPL group, as was time-in-range to progression. These data provide first evidence in a human cohort for potential SPL-mitotane interactions (beyond mentioned case report), which affect dose response and may modulate treatment outcomes. This should caution clinicians to carefully adjust mitotane doses during SPL treatment in ACC patients or choose alternative therapeutic options.</jats:p

58-OR: Remission of Prediabetes upon Weight Loss Depends on Insulin Sensitivity

The Prediabetes Lifestyle Intervention Study (PLIS) - a multicenter study conducted by the German Center for Diabetes Research - showed that intensified compared to conventional lifestyle intervention led to higher probability to normalize glucose regulation. Here, we examined clinical traits determining remission of prediabetes in PLIS participants with a clinically relevant weight loss of ≥5% of their initial body weight after 12 months of lifestyle intervention. Of 11participants, 298 achieved a weight loss of ≥5 %. We classified individuals as responders, who returned to normal glucose regulation by fasting glucose, 2h OGTT plasma glucose and HbA1c (n=128) and compared them to non-responders (n =170) . There were no differences in BMI change (-3.43 ±2.02 kg/m2 in responders, -2.83 ±1.37 in non-responders, p = 0.68) , whole body fat mass loss (6.7 ± 4.9 l vs. 5.9 ±4.5, p = 0.25) or reduction in liver fat (6.1 ±6.3 percentage points vs. 6.6 ±6.4, p = 0.59) . Similarly, there was no difference in change of insulin secretion between responders and non-responders. In contrast, responders improved insulin sensitivity significantly more than non-responders (Insulin Sensitivity Index +4.5 ±4.7, vs. +2.3 ±3.1, p &amp;lt; 0.01) . We conclude that, in prediabetes, weight loss induced return to normal glucose regulation primarily depends on improvements in insulin sensitivity, contrasting recently reported mechanisms of diabetes remission. Disclosure A.Sandforth: None. K.D.Lange: None. R.Wagner: Advisory Panel; Akcea Therapeutics, Daiichi Sankyo, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Lilly, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. German center for diabetes research: n/a. A.F.Pfeiffer: None. M.Roden: Advisory Panel; Eli Lilly and Company, Research Support; Boehringer Ingelheim International GmbH, Nutricia, Speaker's Bureau; Novo Nordisk. A.Fritsche: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. R.Jumpertz von schwartzenberg: None. A.L.Birkenfeld: None. </jats:sec