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).

Bacterial supernatants elevate glucose-dependent insulin secretion in rat pancreatic INS-1 line and islet ß-cells via PI3K/AKT signaling.

Diabetes and periodontitis are considered associated chronic diseases, and hyperinsulinemia in prediabetes has been shown to be present in normoglycemic animals with periodontitis. As periodontal bacterial species are significant sources of endotoxemia and may directly stimulate insulin secretion, we hypothesized that increased bacterial virulence may exert an adverse effect on rat pancreatic ß-cell function via PI3K/AKT signaling. INS-1 cells and isolated pancreatic islets were cultured separately with the following supernatants: Streptococcus anginosus, Streptococcus mutans, Fusobacterium nucleatum, Prevotella intermedia, Porphyromonas gingivalis (P.g), and Treponema denticola (T.d). Supernatants were purified from single bacterial cultures and prepared at different dilutions (100 pg/ml, 50 ng/ml, 200 ng/ml, and 500 ng/ml) to challenge INS-1 and islets. Gene expression (IL-1ß, TNFα, IL-6, TLR2, TLR4, Ins1, and Ins2) and insulin secretion were measured. The results showed upregulation of gene expression up to 5.5-fold, not only as a result of the different dilutions used, but also due to bacterial virulence (p < 0.05). P.g and T.d supernatants demonstrated an increase in insulin secretion to fivefold at hypo- and hyperglycemia, yet stimulation from hypo- to hyperglycemia stays in the same ratio. Activation of TLR4/PI3K/AKT signaling by supernatants in INS-1 cells resulted in increased IL-1ß, TNFα, IL-6 gene expression levels, and AKT phosphorylation, which were abolished by TLR4 and PI3K/AKT signaling inhibitor. We demonstrated that bacterial supernatants derived from gram-negative species increasingly stimulate insulin secretion in ß-cells and TLR4 may promote inflammation by activating the PI3K/AKT signaling pathway to induce pro-inflammatory molecules. Bacterial species, depending on their virulence, appear to play a role in the relationship between periodontitis and prediabetes by promoting insulin resistance and ß-cell compensatory response.

Unrecognised cardiovascular disease in type 2 diabetes: is it time to act earlier?

Cardiovascular disease (CVD) is the most significant prognostic factor in individuals with type 2 diabetes (T2D). However, a significant number of individuals may develop CVD that does not present with the classic angina-related or heart failure symptoms. In these cases, CVD may seem to be 'silent' or 'asymptomatic', but may be more accurately characterised as unrecognised diabetic cardiac impairment. An initial step to raise awareness of unrecognised CVD in individuals with T2D would be to reach a consensus regarding the terminology used to describe this phenomenon. By standardising the terminologies, and agreeing on the implementation of an efficient screening program, it is anticipated that patients will receive an earlier diagnosis and appropriate and timely treatment. Given the availability of anti-diabetic medications that have been shown to concomitantly reduce CV risk and mortality, it is imperative to improve early identification and initiate treatment as soon as possible in order to enable as many patients with T2D as possible to benefit.

Growth of Epithelial Organoids in a Defined Hydrogel.

Epithelial organoids are simplified models of organs grown in vitro from embryonic and adult stem cells. They are widely used to study organ development and disease, and enable drug screening in patient-derived primary tissues. Current protocols, however, rely on animal- and tumor-derived basement membrane extract (BME) as a 3D scaffold, which limits possible applications in regenerative medicine. This prompted us to study how organoids interact with their matrix, and to develop a well-defined hydrogel that supports organoid generation and growth. It is found that soft fibrin matrices provide suitable physical support, and that naturally occurring Arg-Gly-Asp (RGD) adhesion domains on the scaffold, as well as supplementation with laminin-111, are key parameters required for robust organoid formation and expansion. The possibility to functionalize fibrin via factor XIII-mediated anchoring also allows to covalently link fluorescent nanoparticles to the matrix for 3D traction force microscopy. These measurements suggest that the morphogenesis of budding intestinal organoids results from internal pressure combined with higher cell contractility in the regions containing differentiated cells compared to the regions containing stem cells. Since the fibrin/laminin matrix supports long-term expansion of all tested murine and human epithelial organoids, this hydrogel can be widely used as a defined equivalent to BME.

Islet transplantation as safe and efficacious method to restore glycemic control and to avoid severe hypoglycemia after donor organ failure in pancreas transplantation.

The aim of this study was to assess safety and efficacy of islet transplantation after initial pancreas transplantation with subsequent organ failure. Patients undergoing islet transplantation at our institution after pancreas organ failure were compared to a control group of patients with pancreas graft failure, but without islet transplantation and to a group receiving pancreas retransplantation. Ten patients underwent islet transplantation after initial pancreas transplantation failed and were followed for a median of 51 months. The primary end point of HbA1c <7.0% and freedom of severe hypoglycemia was met by nine of 10 patients after follow-up after islet transplantation and in all three patients in the pancreas retransplantation group, but by none of the patients in the group without retransplantation (n = 7). Insulin requirement was reduced by 50% after islet transplantation. Kidney function (eGFR) declined with a rate of -1.0 mL ± 1.2 mL/min/1.73 m2 per year during follow-up after islet transplantation, which tended to be slower than in the group without retransplantation (P = .07). Islet transplantation after deceased donor pancreas transplant failure is a method that can safely improve glycemic control and reduce the incidence of severe hypoglycemia and thus establish similar glycemic control as after initial pancreas transplantation, despite the need of additional exogenous insulin.

Specific and redundant roles of PKBα/AKT1 and PKBß/AKT2 in human pancreatic islets.

Protein kinase Bα (PKBα)/AKT1 and PKBß/AKT2 are required for normal peripheral insulin action but their role in pancreatic ß cells remains enigmatic as indicated by the relatively mild islet phenotype of mice with deficiency for either one of these two isoforms. In this study we have analysed proliferation, apoptosis, ß cell size and glucose-stimulated insulin secretion in human islets overexpressing either PKBα or PKBß. Our results reveal redundant and specific functions. Overexpression of either isoform resulted in increased ß cell size, but insulin production and secretion remained unchanged. Proliferation and apoptosis of ß cells were only significantly stimulated and inhibited, respectively, by PKBα/AKT1. Importantly, overexpression of PKBα/AKT1 in dissociated islets increased the ratio of ß cells to non-ß cells. These results confirm our previous findings obtained with rodent islets and strongly indicate that PKBα/AKT1 can regulate ß cell mass also in human islets.

Mitochondrial capacity is affected by glycemic status in young untrained women with type 1 diabetes but is not impaired relative to healthy untrained women.

In this study, we examined whether glycemic status influences aerobic function in women with type 1 diabetes and whether aerobic function is reduced relative to healthy women. To this end, we compared several factors determining aerobic function of 29 young sedentary asymptomatic women (CON) with 9 women of similar age and activity level with type 1 diabetes [DIA, HbA1c range = 6.9-8.2%]. Calf muscle mitochondrial capacity was estimated by (31)P-magnetic resonance spectroscopy. Capillarization and muscle fiber oxidative enzyme activity were assessed from vastus lateralis and soleus muscle biopsies. Oxygen uptake and cardiac output were evaluated by ergospirometry and N(2)O/SF(6) rebreathing. Calf muscle mitochondrial capacity was not different between CON and DIA, as indicated by the identical calculated maximal rates of oxidative ATP synthesis [0.0307 (0.0070) vs. 0.0309 (0.0058) s(-1), P = 0.930]. Notably, HbA1c was negatively correlated with mitochondrial capacity in DIA (R(2) = 0.475, P = 0.040). Although HbA1c was negatively correlated with cardiac output (R(2) = 0.742, P = 0.013) in DIA, there was no difference between CON and DIA in maximal oxygen consumption [2.17 (0.34) vs. 2.21 (0.32) l/min, P = 0.764], cardiac output [12.1 (1.9) vs. 12.3 (1.8) l/min, P = 0.783], and endurance capacity [532 (212) vs. 471 (119) s, P = 0.475]. There was also no difference between the two groups either in the oxidative enzyme activity or capillary-to-fiber ratio. We conclude that mitochondrial capacity depends on HbA1c in untrained women with type 1 diabetes but is not reduced relative to untrained healthy women.

Diet determines features of the metabolic syndrome in 6- to 14-year-old children.

BACKGROUND/OBJECTIVES: Insulin resistance (IR) and hypertension are common in overweight children, and the adipocyte-derived hormones resistin, adiponectin, and leptin may modulate IR and blood pressure (BP). Few data exist in children on dietary determinants of IR, BP, or leptin, and no data exist on dietary determinants of resistin and adiponectin. Therefore, the objective of this study was to investigate dietary determinants of IR, BP, resistin, adiponectin, and leptin concentrations, as well as the interrelationship among these variables, in normal and overweight children. SUBJECTS/METHODS: In 6- to 14-year-old Swiss children (n=79), nutritional intake was assessed using two 24-hour-recalls and a one-day dietary record. Body mass index (BMI), body fat percentage (BF%), waist/hip ratio (W/H ratio), BP, glucose, insulin, resistin, adiponectin, and leptin were determined. IR was calculated using the quantitative insulin sensitivity check index (QUICKI). RESULTS: BMI, BF%, and W/H ratio were significant predictors of leptin and insulin, QUICKI, and systolic BP, but not resistin or adiponectin. Of the overweight and obese children, 40% were diagnosed pre-hypertensive or hypertensive. Total energy, fat, saturated fat, and protein intakes were significant predictors of fasting insulin and QUICKI, and total fat, saturated fat, and monounsaturated fat intakes were significant predictors of systolic BP, independent of BMI standard deviation score (BMI-SDS) and age. There were no associations between these dietary factors and leptin, adiponectin, or resistin. CONCLUSION: In children, dietary macronutrient composition is a predictor of IR and systolic BP, but not resistin, adiponectin, or leptin concentrations. Resistin and adiponectin concentrations are not correlated with IR or BP in this age range.

Dietary intakes of fat and antioxidant vitamins are predictors of subclinical inflammation in overweight Swiss children.

BACKGROUND: In obese children, subclinical inflammation is often present and is correlated with the metabolic syndrome. Dietary factors, such as fatty acids and antioxidants, potentially modulate the association between adiposity and subclinical inflammation, but few data are available in children. OBJECTIVE: The aim of the study was to determine whether dietary fat or antioxidant intakes influence circulating tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), C-reactive protein (CRP), and leptin concentrations in overweight children. DESIGN: In a cross-sectional study of 6-14-y-old normal-weight (n = 33), overweight (n = 19), and obese (n = 27) Swiss children, nutritional intakes were assessed from two 24-h dietary recalls and a 1-d dietary record. Percentage body fat from skinfold thicknesses, waist-hip ratio, and blood pressure were measured. Fasting blood samples were collected for the measurement of insulin, glucose, HDL-cholesterol, triacylglycerol, CRP, IL-6, TNF-alpha, and leptin concentrations. RESULTS: CRP, IL-6, and leptin increased significantly (P < 0.02) with increasing adiposity, independent of age; TNF-alpha did not increase. Total dietary fat and the percentage of energy from fat were significant predictors of CRP concentration, independent of body mass index (P < 0.05). Meat intake was a significant predictor of IL-6 and leptin, independent of body mass index (P < 0.05). Intakes of antioxidant vitamins (vitamins E and C and beta-carotene) were significant predictors of leptin (P < 0.05) but not of CRP, IL-6, or TNF-alpha. CONCLUSIONS: Overweight Swiss children as young as 6 y have elevated concentrations of inflammatory markers. Intakes of total fat and antioxidant vitamins are determinants of subclinical inflammation in this age group.

Central necrosis in isolated hypoxic human pancreatic islets: evidence for postisolation ischemia.

A variety of explanations have been provided to elucidate the requirement of the large islet mass that is essential for a successful treatment of patients with type I diabetes by intrahepatic transplantation. The purpose of this study was to investigate islet cell survival under the effect of prolonged hypoxia and/or nutrient withdrawal, which mimics posttransplantation environment of transplanted islets in the liver. We studied the influence of 24 h of hypoxia (1% O2) in intact isolated human and rat islets as well as the effect of combined oxygen/nutrient deprivation in a mouse insulinoma cell line (MIN6). In intact human islets, 24 h of hypoxia led to central necrosis combined with apoptotic features such as nuclear pyknosis and DNA fragmentation. In the course of hypoxic treatment, ultrastructural analysis demonstrated a gradual transition from an apoptotic to a necrotic morphology particularly pronounced in central areas of large islets. In MIN6 cells, on the other hand, hypoxia led to a twofold (p < 0.01) increase in caspase-3 activity, an indicator of apoptosis, but not to necrosis, as determined by release of lactate dehydrogenase (LDH). Only in combination with nutrient/serum deprivation was a marked increase in LDH release observed (sixfold vs. control, p < 0.01). We therefore conclude that, similar to MIN6 cells, central necrosis in isolated hypoxic islets is the result of the combined effects of hypoxia and nutrient/serum deprivation, most likely due to limited diffusion. Provided that transplanted islets undergo a similar fate as shown in our in vitro study, future emphasis will require the development of strategies that protect the islet graft from early cell death and accelerate the revascularization process.

Successful simultaneous islet-kidney transplantation using a steroid-free immunosuppression: two-year follow-up.

We report on the feasibility of a glucocorticoid-free immunosuppression (sirolimus, low-dose tacrolimus, and daclizumab) in simultaneous islet-kidney transplantation in nine patients with type 1 diabetes. There was one renal primary nonfunction. Renal function (n = 8) as assessed by creatinine and creatinine clearance over time was 103 +/- 6 micromol/L and 64 +/- 6 mL/min/1.73 m(2), respectively. Five out of six patients with >or= 2 islet transplantations became insulin independent. The mean HbA(1c) during the follow-up period for all patients after transplantation is 6.2 +/- 0.9% as compared with 8.7 +/- 1.9% prior to transplant. These results in patients with a median follow-up of 2.3 years suggest that kidney transplantation under a glucocorticoid-free immunosuppression is feasible, and that the rate of insulin independence of 80% can be achieved not only in patients with no or minimal diabetes complications, but also in patients with more advanced late complications and in conjunction with kidney transplantation.

FLIP switches Fas-mediated glucose signaling in human pancreatic beta cells from apoptosis to cell replication.

Type 2 diabetes mellitus results from an inadequate adaptation of the functional pancreatic beta cell mass in the face of insulin resistance. Changes in the concentration of glucose play an essential role in the regulation of beta cell turnover. In human islets, elevated glucose concentrations impair beta cell proliferation and induce beta cell apoptosis via up-regulation of the Fas receptor. Recently, it has been shown that the caspase-8 inhibitor FLIP may divert Fas-mediated death signals into those for cell proliferation in lymphatic cells. We observed expression of FLIP in human pancreatic beta cells of nondiabetic individuals, which was decreased in tissue sections of type 2 diabetic patients. In vitro exposure of islets from nondiabetic organ donors to high glucose levels decreased FLIP expression and increased the percentage of apoptotic terminal deoxynucleotidyltransferase-mediated UTP end labeling (TUNEL)-positive beta cells; FLIP was no longer detectable in such TUNEL-positive beta cells. Up-regulation of FLIP, by incubation with transforming growth factor beta or by transfection with an expression vector coding for FLIP, protected beta cells from glucose-induced apoptosis, restored beta cell proliferation, and improved beta cell function. The beneficial effects of FLIP overexpression were blocked by an antagonistic anti-Fas antibody, indicating their dependence on Fas receptor activation. The present data provide evidence for expression of FLIP in the human beta cell and suggest a novel approach to prevent and treat diabetes by switching Fas signaling from apoptosis to proliferation.