Swiss recommendations of the Society for Endocrinology and Diabetes (SGED/SSED) for the treatment of type 2 diabetes mellitus (2023).

As a first step, the authors emphasise lifestyle changes (increased physical activity, stopping smoking), blood pressure control, and lowering cholesterol). The initial medical treatment should always be a combination treatment with metformin and a sodium-glucose transporter 2 (SGLT-2) inhibitor or a glucagon-like 1 peptide (GLP-1) receptor agonist. Metformin is given first and up-titrated, followed by SGLT-2 inhibitors or GLP-1 receptor agonists. In persons with type 2 diabetes, if the initial double combination is not sufficient, a triple combination (SGLT-2 inhibitor, GLP-1 receptor agonist, and metformin) is recommended. This triple combination has not been officially tested in cardiovascular outcome trials, but there is more and more real-world experience in Europe and in the USA that proves that the triple combination with metformin, SGLT-2 inhibitor, and GLP-1 receptor agonist is the best treatment to reduce 3-point MACE, total mortality, and heart failure as compared to other combinations. The treatment with sulfonylurea is no longer recommended because of its side effects and higher mortality compared to the modern treatment with SGLT-2 inhibitors and GLP-1 receptor agonists. If the triple combination is not sufficient to reduce the HbA1c to the desired target, insulin treatment is necessary. A quarter of all patients with type 2 diabetes (sometimes misdiagnosed) require insulin treatment. If insulin deficiency is the predominant factor at the outset of type 2 diabetes, the order of medications has to be reversed: insulin first and then cardio-renal protective medications (SGLT-2 inhibitors, GLP-1 receptor agonists).

Current Management and Outcome of Pregnancies in Women With Adrenal Insufficiency: Experience from a Multicenter Survey.

CONTEXT: Appropriate management of adrenal insufficiency (AI) in pregnancy can be challenging due to the rarity of the disease and lack of evidence-based recommendations to guide glucocorticoid and mineralocorticoid dosage adjustment. OBJECTIVE: Multicenter survey on current clinical approaches in managing AI during pregnancy. DESIGN: Retrospective anonymized data collection from 19 international centers from 2013 to 2019. SETTING AND PATIENTS: 128 pregnancies in 113 women with different causes of AI: Addison disease (44%), secondary AI (25%), congenital adrenal hyperplasia (25%), and acquired AI due to bilateral adrenalectomy (6%). RESULTS: Hydrocortisone (HC) was the most commonly used glucocorticoid in 83% (97/117) of pregnancies. Glucocorticoid dosage was increased at any time during pregnancy in 73/128 (57%) of cases. In these cases, the difference in the daily dose of HC equivalent between baseline and the third trimester was 8.6 ± 5.4 (range 1-30) mg. Fludrocortisone dosage was increased in fewer cases (7/54 during the first trimester, 9/64 during the second trimester, and 9/62 cases during the third trimester). Overall, an adrenal crisis was reported in 9/128 (7%) pregnancies. Cesarean section was the most frequent mode of delivery at 58% (69/118). Fetal complications were reported in 3/120 (3%) and minor maternal complications in 15/120 (13%) pregnancies without fatal outcomes. CONCLUSIONS: This survey confirms good maternal and fetal outcome in women with AI managed in specialized endocrine centers. An emphasis on careful endocrine follow-up and repeated patient education is likely to have reduced the risk of adrenal crisis and resulted in positive outcomes.

[Amiodarone and thyroid]. / Schilddrüse und Amiodarone--wenn das Antiarrhythmikum die Schilddrüse aus dem Takt bringt.

Amiodarone is a widely used antiarrythmic drug and can lead either to hypothyroidism or hyperthyroidism due to its molecular structure which is similar to levothyroxin. Amiodarone induced hypothyroidism can be treated easely with hormonal subsitution. Hyperthyroidism is more challenging. There exist two forms of amiodarone-induced Hyperthyroidism (AIT): AIT type 1 is directly related to the iodine compound of amiodarone and responds to thyreostatic therapy. Type 2 is a consequence of the direct toxicity of amiodarone to the thyroid gland and is treated primarily with glucocorticoids. However, this differentiation often is impossible in clinical settings and a pragmatic approach is needed.

Pulmonary and systemic vascular dysfunction in young offspring of mothers with preeclampsia.

BACKGROUND: Adverse events in utero may predispose to cardiovascular disease in adulthood. The underlying mechanisms are unknown. During preeclampsia, vasculotoxic factors are released into the maternal circulation by the diseased placenta. We speculated that these factors pass the placental barrier and leave a defect in the circulation of the offspring that predisposes to a pathological response later in life. The hypoxia associated with high-altitude exposure is expected to facilitate the detection of this problem. METHODS AND RESULTS: We assessed pulmonary artery pressure (by Doppler echocardiography) and flow-mediated dilation of the brachial artery in 48 offspring of women with preeclampsia and 90 offspring of women with normal pregnancies born and permanently living at the same high-altitude location (3600 m). Pulmonary artery pressure was roughly 30% higher (mean+/-SD, 32.1+/-5.6 versus 25.3+/-4.7 mm Hg; P<0.001) and flow-mediated dilation was 30% smaller (6.3+/-1.2% versus 8.3+/-1.4%; P<0.0001) in offspring of mothers with preeclampsia than in control subjects. A strong inverse relationship existed between flow-mediated dilation and pulmonary artery pressure (r=-0.61, P<0.001). The vascular dysfunction was related to preeclampsia itself because siblings of offspring of mothers with preeclampsia who were born after a normal pregnancy had normal vascular function. Augmented oxidative stress may represent an underlying mechanism because thiobarbituric acid-reactive substances plasma concentration was increased in offspring of mothers with preeclampsia. CONCLUSIONS: Preeclampsia leaves a persistent defect in the systemic and the pulmonary circulation of the offspring. This defect predisposes to exaggerated hypoxic pulmonary hypertension already during childhood and may contribute to premature cardiovascular disease in the systemic circulation later in life.

Exaggerated pulmonary hypertension during mild exercise in chronic mountain sickness.

BACKGROUND: Chronic mountain sickness (CMS) is an important public health problem and is characterized by exaggerated hypoxemia, erythrocytosis, and pulmonary hypertension. While pulmonary hypertension is a leading cause of morbidity and mortality in patients with CMS, it is relatively mild and its underlying mechanisms are not known. We speculated that during mild exercise associated with daily activities, pulmonary hypertension in CMS is much more pronounced. METHODS: We estimated pulmonary artery pressure by using echocardiography at rest and during mild bicycle exercise at 50 W in 30 male patients with CMS and 32 age-matched, healthy control subjects who were born and living at an altitude of 3,600 m. RESULTS: The modest, albeit significant difference of the systolic right-ventricular-to-right-atrial pressure gradient between patients with CMS and controls at rest (30.3 +/- 8.0 vs 25.4 +/- 4.5 mm Hg, P 5 .002) became more than three times larger during mild bicycle exercise (56.4 +/- 19.0 vs 39.8 +/- 8.0 mm Hg, P < .001). CONCLUSIONS: Measurements of pulmonary artery pressure at rest greatly underestimate pulmonary artery pressure during daily activity in patients with CMS. The marked pulmonary hypertension during mild exercise associated with daily activity may explain why this problem is a leading cause of morbidity and mortality in patients with CMS.

Human follicular fluid heparan sulfate contains abundant 3-O-sulfated chains with anticoagulant activity.

Anticoagulant heparan sulfate proteoglycans bind and activate antithrombin by virtue of a specific 3-O-sulfated pentasaccharide. They not only occur in the vascular wall but also in extravascular tissues, such as the ovary, where their functions remain unknown. The rupture of the ovarian follicle at ovulation is one of the most striking examples of tissue remodeling in adult mammals. It involves tightly controlled inflammation, proteolysis, and fibrin deposition. We hypothesized that ovarian heparan sulfates may modulate these processes through interactions with effector proteins. Our previous work has shown that anticoagulant heparan sulfates are synthesized by rodent ovarian granulosa cells, and we now have set out to characterize heparan sulfates from human follicular fluid. Here we report the first anticoagulant heparan sulfate purified from a natural human extravascular source. Heparan sulfate chains were fractionated according to their affinity for antithrombin, and their structure was analyzed by 1H NMR and MS/MS. We find that human follicular fluid is a rich source of anticoagulant heparan sulfate, comprising 50.4% of total heparan sulfate. These antithrombin-binding chains contain more than 6% 3-O-sulfated glucosamine residues, convey an anticoagulant activity of 2.5 IU/ml to human follicular fluid, and have an anti-Factor Xa specific activity of 167 IU/mg. The heparan sulfate chains that do not bind antithrombin surprisingly exhibit an extremely high content in 3-O-sulfated glucosamine residues, which suggest that they may exhibit biological activities through interactions with other proteins.

Respiratory nitric oxide and pulmonary artery pressure in children of aymara and European ancestry at high altitude.

Invasive studies suggest that healthy children living at high altitude display pulmonary hypertension, but the data to support this assumption are sparse. Nitric oxide (NO) synthesized by the respiratory epithelium regulates pulmonary artery pressure, and its synthesis was reported to be increased in Aymara high-altitude dwellers. We hypothesized that pulmonary artery pressure will be lower in Aymara children than in children of European ancestry at high altitude, and that this will be related to increased respiratory NO. We therefore compared pulmonary artery pressure and exhaled NO (a marker of respiratory epithelial NO synthesis) between large groups of healthy children of Aymara (n = 200; mean +/- SD age, 9.5 +/- 3.6 years) and European ancestry (n = 77) living at high altitude (3,600 to 4,000 m). We also studied a group of European children (n = 29) living at low altitude. The systolic right ventricular to right atrial pressure gradient in the Aymara children was normal, even though significantly higher than the gradient measured in European children at low altitude (22.5 +/- 6.1 mm Hg vs 17.7 +/- 3.1 mm Hg, p < 0.001). In children of European ancestry studied at high altitude, the pressure gradient was 33% higher than in the Aymara children (30.0 +/- 5.3 mm Hg vs 22.5 +/- 6.1 mm Hg, p < 0.0001). In contrast to what was expected, exhaled NO tended to be lower in Aymara children than in European children living at the same altitude (12.4 +/- 8.8 parts per billion [ppb] vs 16.1 +/- 11.1 ppb, p = 0.06) and was not related to pulmonary artery pressure in either group. Aymara children are protected from hypoxic pulmonary hypertension at high altitude. This protection does not appear to be related to increased respiratory NO synthesis.

Explant cultures of white adipose tissue.

Obesity is characterized by increased adiposity of visceral and subcutaneous depots as well as other organs, including the vasculature. These fat depots secrete various hormone-like proteins implicated in metabolic homeostasis (e.g., adiponectin, resistin), the central control of appetite (e.g., leptin) and the increased production of cytokines. These molecules act either in a paracrine or endocrine manner, contributing to the metabolic and cardiovascular complications of obesity. Explant cultures of white adipose tissue are an important step in analyzing the secretory mechanisms of adipose tissue by preserving the physiological in vivo cross-talk between the various types of cells.

Endothelial nitric oxide synthase (eNOS) knockout mice have defective mitochondrial beta-oxidation.

OBJECTIVE: Recent observations indicate that the delivery of nitric oxide by endothelial nitric oxide synthase (eNOS) is not only critical for metabolic homeostasis, but could also be important for mitochondrial biogenesis, a key organelle for free fatty acid (FFA) oxidation and energy production. Because mice deficient for the gene of eNOS (eNOS(-/-)) have increased triglycerides and FFA levels, in addition to hypertension and insulin resistance, we hypothesized that these knockout mice may have decreased energy expenditure and defective beta-oxidation. RESEARCH DESIGN AND METHODS: Several markers of mitochondrial activity were assessed in C57BL/6J wild-type or eNOS(-/-) mice including the energy expenditure and oxygen consumption by indirect calorimetry, in vitro beta-oxidation in isolated mitochondria from skeletal muscle, and expression of genes involved in fatty acid oxidation. RESULTS: eNOS(-/-) mice had markedly lower energy expenditure (-10%, P < 0.05) and oxygen consumption (-15%, P < 0.05) than control mice. This was associated with a roughly 30% decrease of the mitochondria content (P < 0.05) and, most importantly, with mitochondrial dysfunction, as evidenced by a markedly lower beta-oxidation of subsarcolemmal mitochondria in skeletal muscle (-30%, P < 0.05). Finally, impaired mitochondrial beta-oxidation was associated with a significant increase of the intramyocellular lipid content (30%, P < 0.05) in gastrocnemius muscle. CONCLUSIONS: These data indicate that elevated FFA and triglyceride in eNOS(-/-) mice result in defective mitochondrial beta-oxidation in muscle cells.

Local adipose tissue depots as cardiovascular risk factors.

Obesity is associated with increased cardiovascular morbidity and mortality. Although obesity-associated hypertension, dyslipidemia and insulin resistance account in part for this association, it becomes increasingly apparent that a systemic and local pro-inflammatory response of adipose tissue might also be a contributing factor. White adipose tissue (WAT) is a highly active organ secreting various peptides such as cytokines, chemokines and hormone-like proteins. Besides the visceral and subcutaneous depots, WAT is also found in the close vicinity of blood vessels (perivascular adipose tissue), where it secretes cytokines such as interleukin-1, tumor necrosis factor alpha, pro-atherogenic chemokines, and pro-angiogenic peptides. These factors appear to contribute directly to alterations of the function and structure of the vascular wall, including chronic inflammation, alterations of vascular tone, proliferation of smooth muscle cells, neo-angiogenesis and hence to the development of atherosclerosis and cardiovascular complications.

[White adipose tissue, inflammation and atherosclerosis]. / Tissu adipeux, inflammation et athérome.

Our view of white adipose tissue (WAT) has changed over the last decade, from an inert triglyceride storage tissue to a highly active metabolic organ. Indeed, WAT secretes proinflammatory cytokines such TNF-a, interleukin-1 (IL-1), interleukin-1 receptor antagonist (IL-1Ra), and interleukin-6 (IL-6), and chemokines such as monocyte chemoattractant protein-1 (MCP-1), interferon gamma inducible protein 10 (IP-10), interleukin-8 (IL-8), RANTES, and peptides with hormone-like actions such as adiponectin, leptin and resistin. Through their paracrine actions these factors contribute to local WAT inflammation, neoangiogenesis and differentiation. On entering the systemic circulation they can contribute to creating or maintaining a systemic inflammatory state, hypertension and insulin resistance, and can also affect central control of food intake. When located around organs such as the kidney, heart and blood vessels, WAT can adversely affect organ function by secreting cytokines and chemokines. For example, perivascular WAT which secretes proatherogenic cytokines and chemokines and which is present around large and medium-sized arteries, could contribute to the development of atherosclerotic lesions by attracting inflammatory cells and stimulating neoangiogenesis, thereby amplifying the chronic vascular inflammation which is the hallmark of atherosclerosis.

Pulmonary hypertension in high-altitude dwellers: novel mechanisms, unsuspected predisposing factors.

Studies of high-altitude populations, and in particular of maladapted subgroups, may provide important insight into underlying mechanisms involved in the pathogenesis of hypoxemia-related disease states in general. Over the past decade, studies involving short-term hypoxic exposure have greatly advanced our knowledge regarding underlying mechanisms and predisposing events of hypoxic pulmonary hypertension. Studies in high altitude pulmonary edema (HAPE)-prone subjects, a condition characterized by exaggerated hypoxic pulmonary hypertension, have provided evidence for the central role of pulmonary vascular endothelial and respiratory epithelial nitric oxide (NO) for pulmonary artery pressure homeostasis. More recently, it has been shown that pathological events during the perinatal period (possibly by impairing pulmonary NO synthesis), predispose to exaggerated hypoxic pulmonary hypertension later in life. In an attempt to translate some of this new knowledge to the understanding of underlying mechanisms and predisposing events of chronic hypoxic pulmonary hypertension, we have recently initiated a series of studies among high-risk subpopulations (experiments of nature) of high-altitude dwellers. These studies have allowed to identify novel risk factors and underlying mechanisms that may predispose to sustained hypoxic pulmonary hypertension. The aim of this article is to briefly review this new data, and demonstrate that insufficient NO synthesis/bioavailability, possibly related in part to augmented oxidative stress, may represent an important underlying mechanism predisposing to pulmonary hypertension in high-altitude dwellers.

[Insulin, nitric oxide and the sympathetic nervous system: from crossroads to metabolic and cardiovascular homeostasis]. / Insuline, monoxyde d'azote et système nerveux sympathique: au carrefour de l'homéostasie métabolique et cardiovasculaire.

Epidemiological studies demonstrate an association between insulin resistance, hypertension and cardiovascular morbidity. Over the past decade, evidence has accumulated indicating that short-term insulin administration, in addition to its metabolic effects, also has important cardiovascular actions. The sympathetic nervous system and the L-arginine-nitric oxide pathway have emerged as central players in the mediation of insulin's cardiovascular actions. The underlying mechanisms and the factors that may govern the interaction between insulin and these two major cardiovascular regulatory systems have been studied extensively in healthy people and insulin-resistant subjects. Here we summarize the current understanding and gaps in knowledge on insulin's cardiovascular actions in humans, and discuss possible pathophysiological consequences of their alteration. Based on recent new insight, we propose that a genetic and/or acquired defect of nitric oxide synthesis could represent a central defect triggering many of the metabolic, vascular and sympathetic abnormalities characteristic of insulin-resistant states, all of which may predispose to cardiovascular disease.

[NO, a major regulator of metabolic and cardiovascular homeostasis]. / Le NO, un régulateur majeur de l'homéostasie glucidique et cardio-vasculaire.

Obesity and insulin resistance are reaching epidemic proportions worldwide. Over the past decade, nitric oxide (NO) has emerged as a key player in the regulation of the metabolic and cardiovascular homeostasis. Here we will review recent data obtained in mice with disruption of the genes encoding for each of the three nitric oxide synthase isoforms. These data demonstrate that both defective and augmented NO synthesis have detrimental effects on the regulation of the metabolic and cardiovascular system. These observations provide the rationale for the use of NO-donors and/or inhibitors of NO overproduction in the treatment of insulin resistance.

[Nitric oxide donors, a new treatment for insulin resistance, metabolic syndrome and diabetes?]. / Les donneurs de NO, un nouveau traitement de la résistance a l'insuline, du syndrome métabolique et du diabète?

Obesity/insulin resistance ("diabesity") and the associated long term complications are reaching epidemic proportions worldwide. Recent evidence in experimental animals and humans shows that nitric oxide (NO) plays a key role in glucose and cardiovascular homeostasis. Pharmaceutical drugs releasing small and physiological amounts of NO may represent potential new treatments for insulin resistance.

Partial gene deletion of endothelial nitric oxide synthase predisposes to exaggerated high-fat diet-induced insulin resistance and arterial hypertension.

Nitric oxide (NO) plays a major role in the regulation of cardiovascular and metabolic homeostasis, as evidenced by insulin resistance and arterial hypertension in endothelial NO synthase (eNOS) null mice. Extrapolation of these findings to humans is difficult, however, because eNOS gene deficiency has not been reported. eNOS gene polymorphism and impaired NO synthesis, however, have been reported in several cardiovascular disease states and could predispose to insulin resistance. High-fat diet induces insulin resistance and arterial hypertension in normal mice. To test whether partial eNOS deficiency facilitates the development of insulin resistance and arterial hypertension during metabolic stress, we examined effects of an 8-week high-fat diet on insulin sensitivity (euglycemic clamp) and arterial pressure in eNOS(+/-) mice. When fed a normal diet, these mice had normal insulin sensitivity and were normotensive. When fed a high-fat diet, however, eNOS(+/-) mice developed exaggerated arterial hypertension and had fasting hyperinsulinemia and a 35% lower insulin-stimulated glucose utilization than control mice. The partial deletion of the eNOS gene does not alter insulin sensitivity or blood pressure in mice. When challenged with nutritional stress, however, partial eNOS deficiency facilitates the development of insulin resistance and arterial hypertension, providing further evidence for the importance of this gene in linking metabolic and cardiovascular disease.