The nitric oxide (NO) signaling pathway in hypothalamic neurons plays a key role in the regulation of the secretion of gonadotropin-releasing hormone (GnRH), which is crucial for reproduction. We hypothesized that a disruption of neuronal NO synthase (NOS1) activity underlies some forms of hypogonadotropic hypogonadism. Whole-exome sequencing was performed on a cohort of 341 probands with congenital hypogonadotropic hypogonadism to identify ultrarare variants in NOS1 . The activity of the identified NOS1 mutant proteins was assessed by their ability to promote nitrite and cGMP production in vitro. In addition, physiological and pharmacological characterization was carried out in a Nos1 -deficient mouse model. We identified five heterozygous NOS1 loss-of-function mutations in six probands with congenital hypogonadotropic hypogonadism (2%), who displayed additional phenotypes including anosmia, hearing loss, and intellectual disability. NOS1 was found to be transiently expressed by GnRH neurons in the nose of both humans and mice, and Nos1 deficiency in mice resulted in dose-dependent defects in sexual maturation as well as in olfaction, hearing, and cognition. The pharmacological inhibition of NO production in postnatal mice revealed a critical time window during which Nos1 activity shaped minipuberty and sexual maturation. Inhaled NO treatment at minipuberty rescued both reproductive and behavioral phenotypes in Nos1 -deficient mice. In summary, lack of NOS1 activity led to GnRH deficiency associated with sensory and intellectual comorbidities in humans and mice. NO treatment during minipuberty reversed deficits in sexual maturation, olfaction, and cognition in Nos1 mutant mice, suggesting a potential therapy for humans with NO deficiency.

Although the benefits of regular exercise on cardiovascular risk factors are well established for people with type 1 diabetes (T1D), glycemic control remains a challenge during exercise. Carbohydrate consumption to fuel the exercise bout and/or for hypoglycemia prevention is an important cornerstone to maintain performance and avoid hypoglycemia. The main strategies pertinent to carbohydrate supplementation in the context of exercise cover three aspects: the amount of carbohydrates ingested (i.e., quantity in relation to demands to fuel exercise and avoid hypoglycemia), the timing of the intake (before, during and after the exercise, as well as circadian factors), and the quality of the carbohydrates (encompassing differing carbohydrate types, as well as the context within a meal and the associated macronutrients). The aim of this review is to comprehensively summarize the literature on carbohydrate intake in the context of exercise in people with T1D.

SUMMARY:The prevalence of obesity is increasing world-wide. Obesity is associated with a plethora of metabolic and clinical constraints, which result in a higher risk for the development of cardiovascular complications and metabolic disease, particularly insulin resistance and type 2 diabetes. Obesity is an acknowledged determinant of glycemic control in patients with type 1 diabetes and accounts for the majority of premature death due to cardiovascular events. Physical exercise is generally recommended in patients with diabetes in order to prevent the development of or reduce existing obesity, as adopted by every international treatment guideline so far. Regular physical exercise has a beneficial impact on body composition, cardiovascular integrity, insulin sensitivity and quality of life. However, only a minority of patients participates in regular physical exercise, due to individual or disease-related barriers. In type 2 diabetes, there is robust evidence for beneficial effects of physical exercise on glycemic control, cardiovascular health and the development of diabetes-related long-term complications. In type 1 diabetes and patients treated with insulin, a higher risk for exercise-related hypoglycemia has to be considered, which requires certain prerequisites and adequate adaptions of insulin dosing. Current treatment guidelines do only incompletely address the development of exercise-related hypoglycemia. However, every patient with diabetes should participate in regular physical exercise in order to support and enable sufficient treatment and optimal glycemic control.

We investigated the short-term effects of dapagliflozin as adjunct to insulin on insulin sensitivity, postprandial glucose excursions and ketone body production in type 1 diabetes mellitus (T1DM). A total of seven male patients completed the randomized, double-blind, placebo-controlled cross-over trial, receiving 10 mg of dapagliflozin daily for 3 days, followed by placebo, or the reverse. At Day 3, hyperinsulinaemic, euglycaemic clamps and oral glucose tolerance test clamps with repeated blood sampling were performed. Required glucose infusion and blood glucose excursions did not differ significantly between dapagliflozin treatment and placebo (P = 0.491; P = 0.342). Prior to oral glucose, total ketone bodies showed a higher trend following dapagliflozin treatment (P = 0.051). Following oral glucose, total ketone bodies decreased while concentrations of total GLP-1 were higher following dapagliflozin (P = 0.009). Non-esterified free fatty acids did not differ between dapagliflozin treatment and placebo and ketonuria was absent under both conditions. In T1DM, short-term addition of dapagliflozin to insulin influenced neither postprandial glucose excursions nor insulin sensitivity. Following oral glucose, total ketone bodies decreased in parallel with an increase in GLP-1 concentrations, which were higher under dapagliflozin treatment as compared with placebo.

This paper aims to compare the metabolic effects of glucose-fructose co-ingestion (GLUFRU) with glucose alone (GLU) in exercising individuals with type 1 diabetes mellitus. Fifteen male individuals with type 1 diabetes (HbA1c 7.0% ± 0.6% (53 ± 7 mmol/mol)) underwent a 90 min iso-energetic continuous cycling session at 50% VO2max while ingesting combined glucose-fructose (GLUFRU) or glucose alone (GLU) to maintain stable glycaemia without insulin adjustment. GLUFRU and GLU were labelled with 13C-fructose and 13C-glucose, respectively. Metabolic assessments included measurements of hormones and metabolites, substrate oxidation, and stable isotopes. Exogenous carbohydrate requirements to maintain stable glycaemia were comparable between GLUFRU and GLU (p = 0.46). Fat oxidation was significantly higher (5.2 ± 0.2 vs. 2.6 ± 1.2 mg·kg−1·min−1, p < 0.001) and carbohydrate oxidation lower (18.1 ± 0.8 vs. 24.5 ± 0.8 mg·kg−1·min−1 p < 0.001) in GLUFRU compared to GLU, with decreased muscle glycogen oxidation in GLUFRU (10.2 ± 0.9 vs. 17.5 ± 1.0 mg·kg−1·min−1, p < 0.001). Lactate levels were higher (2.2 ± 0.2 vs. 1.8 ± 0.1 mmol/L, p = 0.012) in GLUFRU, with comparable counter-regulatory hormones between GLUFRU and GLU (p > 0.05 for all). Glucose and insulin levels, and total glucose appearance and disappearance were comparable between interventions. Glucose-fructose co-ingestion may have a beneficial impact on fuel metabolism in exercising individuals with type 1 diabetes without insulin adjustment, by increasing fat oxidation whilst sparing glycogen.

Zusammenfassung. Körperliche Aktivität und Training sind wichtige Bausteine eines gesunden Lebensstils, auch oder vor allem bei Personen mit Diabetes mellitus. Eine Reduktion des kardiovaskulären Risikos sowie eine Verbesserung zahlreicher weiterer Parameter durch Bewegung konnte sowohl bei Personen ohne Diabetes als auch bei Patientinnen und Patienten mit Diabetes in Studien gezeigt werden. Beim Typ-2-Diabetes wird daher – zum Teil auch noch bei Vorhandensein von Spätkomplikationen – ein mehrmals wöchentlich durchgeführtes Ausdauer- als auch Krafttraining zur Verbesserung der glykämischen Kontrolle und Reduktion des kardiovaskulären Risikos empfohlen. Bereits kurze Trainingseinheiten haben einen nachhaltig positiven Effekt auf den Organismus, die Überwindung der Inaktivität und Ausübung von Sport ist aber im Alltag häufig mit gewissen Schwierigkeiten verbunden. Unterschiedliche Trainingstypen haben differierende Auswirkungen auf den Blutzuckerspiegel, dies ist vor allem bei Patientinnen und Patienten mit Insulintherapie zu beachten. Bei Patientinnen und Patienten mit Typ-1-Diabetes gelten per se dieselben Aktivitätsziele. Sport birgt bei diesen Patienten nebst den günstigen Effekten aber auch die Gefahr einer Destabilisierung der glykämischen Kontrolle, insbesondere ist das während des Sports erhöhte Hypoglykämierisiko relevant. Durch adäquate blutzuckeradaptierte Therapiemodifikationen und unter Einsatz moderner technologischer Hilfsmittel kann dem aber wirksam entgegengewirkt werden.

Physical activity and exercise are important components of a healthy lifestyle, especially in patients with diabetes mellitus. It has been shown that physical activity generally reduces cardiovascular risk and improves glycaemic control as well as additional parameters such as blood pressure, cholesterol levels, and body composition. Therefore, frequent aerobic exercise and moderate resistance training are currently recommended for diabetic patients. While even short activities may have a positive metabolic effect for up to one day, overcoming the obstacle of inactivity and implementing regular exercise is often difficult in daily life. Depending on the type of the activity, blood glucose levels may not only decrease during exercise, but even increase in case of higher exercise intensity. This is of particular importance for patients with insulin therapy and, specifically, in type 1 diabetes. While exercise has been shown to have similarly beneficial effects on cardiovascular risk in patients with type 1 diabetes, physical activity is associated with an increased risk of exercise-associated hypoglycaemia. As a consequence, appropriate measures (e.g. adaptation of insulin doses and/or ingestion of additional carbohydrates) are usually recommended in these patients. Modern technical devices such as insulin pumps and/or continuous glucose monitoring systems are important in supporting active patients with diabetes to optimize glucose control during and after exercise.

Zusammenfassung. Verschiedenste Erkrankungen des exokrinen Pankreas können auch Störungen des endokrinen Pankreasanteils verursachen. Der resultierende Diabetes mellitus wird als pankreatopriver (Typ-3c-Diabetes) bezeichnet. Mangel an funktionierendem Pankreasgewebe heisst nicht nur Insulinmangel sondern insbesondere auch Mangel an Glukagon, womit die Zuckereinstellung erschwert wird und die Gefahr schwerer Hypoglykämien unter Insulintherapie steigt. Obwohl es sich beim Typ 3c Diabetes um eine relativ seltenere Diabetesform handelt, ist er in der Häufigkeit dennoch nicht zu unterschätzen. Bedingt durch seine metabolische Komplexizität mit hoher Glukosevariabilität stellt er eine schwierig einzustellende Diabetesform dar. Eine frühzeitige und gute Therapie ist bei den oftmals schwer kranken Patienten mit pankreatoprivem Diabetes dafür umso wichtiger, um ein gutes kurz-, mittel- und langfristiges Outcome zu erreichen.