Association between sexual dysfunction and vitamin D in Swedish primary health care patients born in the Middle East and Sweden.

The present study investigated primary care patients and compared self-reported sexual health in Swedes and Middle Easterners; analysed differences within and between the groups and analysed differences in 25-hydroxyvitamin D [25(OH)D] levels between the groups. 522 patients responded to a health questionnaire that included items on sexual health: 225 Middle Easterners from Iran, Iraq, and Turkey and 297 Swedes. Logistic regression was used to calculate the odds ratio (OR). Middle Easterners reported less sexual dysfunction than Swedes, and 75.8% of them and 18.9% of Swedes presented a 25(OH)D of < 50 nmol/L. The crude OR for reporting sexual dysfunction was 70% higher in Swedes compared to Middle Easterners (OR 1.70, 95% CI 1.15-2.50). This OR remained significant after adjustment for age, gender, waist circumference, and reported sexual desire. However, the significance disappeared after additional adjustment for 25(OH)D. In both groups, more females than males reported insufficient sexual desire. More female Middle Easterners reported sex life dissatisfaction. More female Swedes reported sexual dysfunction. Vitamin D could explain an association between gender and sex life dissatisfaction in Middle Easterners, and age could explain an association between gender and sexual dysfunction in Swedes. Age, waist circumference, and 25(OH)D levels were significant covariates in the logistic regression models. Results from the present study suggest that 25(OH)D variation partly explains differences in sexual dysfunction between the groups and between genders within the groups. Vitamin D therapy should be investigated to determine if these results are clinically useful.

Observational study of selective screening for prediabetes and diabetes in a real-world setting: an interprofessional collaboration method between public dental services and primary health care in Sweden.

OBJECTIVE: Describe a method in a real-world setting to identify persons with undiagnosed prediabetes and type 2 diabetes through an interprofessional collaboration between Public Dental Services and Primary Health Care in Regions Stockholm. DESIGN: A descriptive observational study. SETTING: The study was conducted at seven sites in the region of Stockholm, Sweden. Each collaborating site consisted of a primary health clinic and dental clinic. SUBJECTS: Study participants included adults over 18 years of age who visited the Public Dental Services and did not have a medical history of prediabetes or type 2 diabetes. MAIN OUTCOME MEASURES: Selective screening is conducted in accordance with a risk assessment protocol at the Public Dental Services. In the investigated method, DentDi (Dental and Diabetes), adults diagnosed with caries and/or periodontitis over a cut-off value are referred to the Primary Health Care clinic for screening of prediabetes and type 2 diabetes. RESULTS: DentDi, introduced at seven sites, between the years 2017 and 2020, all of which continue to use the method today. A total of 863 participants from the Public Dental Services were referred to the Primary Health Care. Of those 396 accepted the invitation to undergo screening at the primary health care centre. Twenty-four individuals did not meet the inclusion criteria, resulting in a total of 372 persons being included in the study. Among the 372 participants, 27% (101) had elevated glucose levels, of which 12 were diagnosed with type 2 diabetes and 89 with prediabetes according to the study classification. CONCLUSIONS: DentDi is a feasible method of interprofessional collaboration where each profession contributes with the competence included in everyday clinical practice for early identification of persons with prediabetes and type 2 diabetes with a complete chain of care. The goal is to disseminate this method throughout Stockholm County and even other regions in Sweden.

Type 2 diabetes and poor oral health have a bidirectional association. The number of persons with undetected prediabetes and type 2 diabetes is high and rising globally.Through collaboration between Public Dental Services and Primary Health Care we have developed a feasible and novel method of selectively screening for prediabetes and type 2 diabetes in a real-world setting.By utilizing everyday practice within each discipline, this method has been implemented at seven sites in Region Stockholm.From the original number of 863 participants referred from the Public Dental Services to Primary Health Care 396 attended the medical screening. After excluding 24 participants, a total of 372 participants underwent screening for prediabetes and type 2 diabetes.The results of this study showed that almost 30% who were screened for prediabetes and type 2 diabetes had elevated blood glucose levels.

Fasting plasma glucose and serum 25-hydroxy vitamin D levels in individuals with Middle Eastern and Swedish descent.

Purpose: To determine fasting plasma glucose and serum 25-hydroxyvitamin D (s-25(OH)D) levels and associations between abnormal fasting plasma glucose levels and inadequate s-25(OH)D levels in individuals of Middle Eastern and Swedish descent. Methods: Observational study with individuals without a diabetes diagnosis, 54.5% of Swedish descent and 45.5% of Middle Eastern descent. In total, 830 participants from two primary healthcare centres in Flemingsberg and Jakobsberg, which are southern and northern suburbs, respectively, of Stockholm, Sweden were included in the study. Results: Prevalence of inadequate s-25(OH)D levels (at or below 50 nmol/L) was 67.2% among those of Middle Eastern descent and 20.5% among those of Swedish descent (P < 0.001). S-25(OH)D levels correlated weakly positively with fasting plasma glucose levels (ρ = 0.20, P = 0.002) in individuals of Middle Eastern descent. Being of Middle Eastern descent (OR 6.7, 95% CI 4.3-10.4) and having abnormal fasting plasma glucose (OR 1.8, 95% CI 1.2-2.9) were independent predictors of having inadequate s-25(OH)D levels. Conclusions: Healthcare in Sweden should consider testing fasting plasma glucose and s-25(OH)D levels, particularly in individuals of Middle Eastern descent. The unclear relationship between vitamin D and glucose levels warrants investigation. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-023-01226-0.

Comparison of Framingham 10-year cardiovascular risks in Sweden- and foreign-born primary health care patients in Sweden.

BACKGROUND: The prevalence of cardiovascular disease around the world varies by ethnicity and region of birth. Immigrants living in Sweden may have a higher prevalence of cardiovascular diseases than native-born Swedes, but little is known about their actual cardiovascular risk. This study aimed to examine the relationship in Sweden between 10-year cardiovascular risk and birthplace. METHOD: This cross-sectional study was based on cardiovascular risk factor data obtained from the 4D Diabetes Project, a Programme 4D subproject in Sweden. Participants were recruited from two primary healthcare centres in Stockholm without a history of diabetes or pre-diabetes. The outcome variable was 10-year cardiovascular risk based on the calculation of a Framingham Risk Score with six risk factors: age, sex, LDL, HDL, BP, diabetes and smoking for each participant. Multiple linear regression was performed to generate ß-coefficients for the outcome. RESULTS: There was an average of 8.86% cardiovascular risk over 10 years in Sweden-born participants and a 5.45% 10-year risk in foreign-born, (P < 0.0001). Foreign-born participants were about 10 years younger (mean age 46 years vs. 56 years, P < 0.001), with a significantly higher proportion of smokers (23.9% vs. 13.7%; P = 0.001). To be born in Sweden (with parents born in Sweden) was significantly associated with a 10-year cardiovascular risk in the crude model (ß- coefficient = 3.40, 95% CI 2.59-4.22; P < 0.0001) and when adjusted for education and alcohol consumption (ß- coefficient = 2.70 95% CI 1.86-3.54; P < 0.0001). Regardless of the birthplace, 10-year cardiovascular risk was lower for those with higher education compared to those with less than 10 years of education. CONCLUSION: This study found a relationship between 10-year calculated cardiovascular risk and place of birth. Sweden-born participants had a higher association with 10-year cardiovascular risk than foreign-born participants. These results contradict previous reports of higher rates of CVD in residents of Middle-Eastern countries and Middle-Eastern immigrants living in Sweden.

Characterization of data-driven clusters in diabetes-free adults and their utility for risk stratification of type 2 diabetes.

BACKGROUND: The prevention of type 2 diabetes is challenging due to the variable effects of risk factors at an individual level. Data-driven methods could be useful to detect more homogeneous groups based on risk factor variability. The aim of this study was to derive characteristic phenotypes using cluster analysis of common risk factors and to assess their utility to stratify the risk of type 2 diabetes. METHODS: Data on 7317 diabetes-free adults from Sweden were used in the main analysis and on 2332 diabetes-free adults from Mexico for external validation. Clusters were based on sex, family history of diabetes, educational attainment, fasting blood glucose and insulin levels, estimated insulin resistance and ß-cell function, systolic and diastolic blood pressure, and BMI. The risk of type 2 diabetes was assessed using Cox proportional hazards models. The predictive accuracy and long-term stability of the clusters were then compared to different definitions of prediabetes. RESULTS: Six risk phenotypes were identified independently in both cohorts: very low-risk (VLR), low-risk low ß-cell function (LRLB), low-risk high ß-cell function (LRHB), high-risk high blood pressure (HRHBP), high-risk ß-cell failure (HRBF), and high-risk insulin-resistant (HRIR). Compared to the LRHB cluster, the VLR and LRLB clusters showed a lower risk, while the HRHBP, HRBF, and HRIR clusters showed a higher risk of developing type 2 diabetes. The high-risk clusters, as a group, had a better predictive accuracy than prediabetes and adequate stability after 20 years. CONCLUSIONS: Phenotypes derived using cluster analysis were useful in stratifying the risk of type 2 diabetes among diabetes-free adults in two independent cohorts. These results could be used to develop more precise public health interventions.

Diabetes downregulates the antimicrobial peptide psoriasin and increases E. coli burden in the urinary bladder.

Diabetes is known to increase susceptibility to infections, partly due to impaired granulocyte function and changes in the innate immunity. Here, we investigate the effect of diabetes, and high glucose on the expression of the antimicrobial peptide, psoriasin and the putative consequences for E. coli urinary tract infection. Blood, urine, and urine exfoliated cells from patients are studied. The influence of glucose and insulin is examined during hyperglycemic clamps in individuals with prediabetes and in euglycemic hyperinsulinemic clamped patients with type 1 diabetes. Important findings are confirmed in vivo in type 2 diabetic mice and verified in human uroepithelial cell lines. High glucose concentrations induce lower psoriasin levels and impair epithelial barrier function together with altering cell membrane proteins and cytoskeletal elements, resulting in increasing bacterial burden. Estradiol treatment restores the cellular function with increasing psoriasin and bacterial killing in uroepithelial cells, confirming its importance during urinary tract infection in hyperglycemia. In conclusion, our findings present the effects and underlying mechanisms of high glucose compromising innate immunity.

Process evaluation of a pragmatic implementation trial to support self-management for the prevention and management of type 2 diabetes in Uganda, South Africa and Sweden in the SMART2D project.

INTRODUCTION: Type 2 diabetes (T2D) and its complications are increasing rapidly. Support for healthy lifestyle and self-management is paramount, but not adequately implemented in health systems. Process evaluations facilitate understanding why and how interventions work through analyzing the interaction between intervention theory, implementation and context. The Self-Management and Reciprocal Learning for Type 2 Diabetes project implemented and evaluated community-based interventions (peer support program; care companion; and link between facility care and community support) for persons at high risk of or having T2D in a rural community in Uganda, an urban township in South Africa, and socioeconomically disadvantaged urban communities in Sweden. RESEARCH DESIGN AND METHODS: This paper reports implementation process outcomes across the three sites, guided by the Medical Research Council framework for complex intervention process evaluations. Data were collected through observations of peer support group meetings using a structured guide, and semistructured interviews with project managers, implementers, and participants. RESULTS: The countries aligned implementation in accordance with the feasibility and relevance in the local context. In Uganda and Sweden, the implementation focused on peer support; in South Africa, it focused on the care companion part. The community-facility link received the least attention. Continuous capacity building received a lot of attention, but intervention reach, dose delivered, and fidelity varied substantially. Intervention-related and context-related barriers affected participation. CONCLUSIONS: Identification of the key uncertainties and conditions facilitates focus and efficient use of resources in process evaluations, and context relevant findings. The use of an overarching framework allows to collect cross-contextual evidence and flexibility in evaluation design to adapt to the complex nature of the intervention. When designing interventions, it is crucial to consider aspects of the implementing organization or structure, its absorptive capacity, and to thoroughly assess and discuss implementation feasibility, capacity and organizational context with the implementation team and recipients. These recommendations are important for implementation and scale-up of complex interventions. TRIAL REGISTRATION NUMBER: ISRCTN11913581.

Therapeutic Potential of Sunitinib in Ameliorating Endothelial Dysfunction in Type 2 Diabetic Rats.

INTRODUCTION: Sunitinib, a multi-targeted tyrosine kinase receptor inhibitor used to treat renal-cell carcinoma and gastrointestinal stromal tumor, was recently shown to have a beneficial effect on metabolism in type 2 diabetes (T2D). Endothelial dysfunction is a key factor behind macro- and microvascular complications in T2D. The effect of sunitinib on endothelial function in T2D remains, however, unclear. We therefore tested the hypothesis that sunitinib ameliorates endothelial dysfunction in T2D. METHODS: Sunitinib (2 mg/kg/day, by gavage) was administered to T2D Goto-Kakizaki (GK) rats for 6 weeks, while water was given to GK and Wistar rats as controls. Hemodynamic, inflammatory, and metabolic parameters as well as endothelial function were measured. RESULTS: Systolic, mean arterial blood pressures, plasma tumor necrosis factor α levels, kidney weight to body weight (BW) ratio, and glucose levels were higher, while BW was lower in GK rats than in Wistar rats. Six-week treatment with sunitinib in GK rats did not affect these parameters but suppressed the increase in glucose levels. Endothelium-dependent relaxations were reduced in both aortas and mesenteric arteries isolated from GK as compared to Wistar rats, which was markedly reversed in both types of arteries from GK rats treated with sunitinib. CONCLUSIONS: This study demonstrates that sunitinib has a glucose-lowering effect and ameliorates endothelial dysfunction in both conduit and resistance arteries of GK rats.

HIF-1 mediated activation of antimicrobial peptide LL-37 in type 2 diabetic patients.

Infections are common in patients with diabetes, but increasing antibiotic resistance hampers successful bacterial clearance and calls for alternative treatment strategies. Hypoxia-inducible factor 1 (HIF-1) is known to influence the innate immune defense and could therefore serve as a possible target. However, the impact of high glucose on HIF-1 has received little attention and merits closer investigation. Here, we show that higher levels of proinflammatory cytokines and CAMP, encoding for the antimicrobial peptide cathelicidin, LL-37, correlate with HIF-1 in type 2 diabetic patients. Chemical activation of HIF-1 further enhanced LL-37, IL-1ß, and IL-8 in human uroepithelial cells exposed to high glucose. Moreover, HIF-1 activation of transurethrally infected diabetic mice resulted in lower bacterial load. Drugs activating HIF-1 could therefore in the future potentially have a therapeutic role in clearing bacteria in diabetic patients with infections where antibiotic treatment failed. KEY MESSAGES: • Mohanty et al. "HIF-1 mediated activation of antimicrobial peptide LL-37 in type 2 diabetic patients." • Our study highlights induction of the antimicrobial peptide, LL-37, and strengthening of the innate immunity through hypoxia-inducible factor 1 (HIF-1) in diabetes. • Our key observations are: 1. HIF-1 activation increased LL-37 expression in human urothelial cells treated with high glucose. In line with that, we demonstrated that patients with type 2 diabetes living at high altitude had increased levels of the LL-37. 2. HIF-1 activation increased IL-1ß and IL-8 in human uroepithelial cells treated with high glucose concentration. 3. Pharmacological activation of HIF-1 decreased bacterial load in the urinary bladder of mice with hereditary diabetes. • We conclude that enhancing HIF-1 may along with antibiotics in the future contribute to the treatment in selected patient groups where traditional therapy is not possible.

Adiponectin, IGFBP-1 and -2 are independent predictors in forecasting prediabetes and type 2 diabetes.

Objective: Adiponectin and insulin-like growth factor (IGF) binding proteins IGFBP-1 and IGFBP-2 are biomarkers of insulin sensitivity. IGFBP-1 reflects insulin sensitivity in the liver, adiponectin in adipose tissue and IGFBP-2 in both tissues. Here, we study the power of the biomarkers adiponectin, IGFBP-1, IGFBP-2, and also included IGF-I and IGF-II, in predicting prediabetes and type 2 diabetes (T2D) in men and women with normal oral glucose tolerance (NGT). Design: Subjects with NGT (35-56 years) recruited during 1992-1998 were re-investigated 8-10 years later. In a nested case control study, subjects progressing to prediabetes (133 women, 164 men) or to T2D (55 women, 98 men) were compared with age and sex matched NGT controls (200 women and 277 men). Methods: The evaluation included questionnaires, health status, anthropometry, biochemistry and oral glucose tolerance test. Results: After adjustment, the lowest quartile of adiponectin, IGFBP-1 and IGFBP-2 associated independently with future abnormal glucose tolerance (AGT) in both genders in multivariate analyses. High IGFs predicted weakly AGT in women. In women, low IGFBP-2 was the strongest predictor for prediabetes (OR:7.5), and low adiponectin for T2D (OR:29.4). In men, low IGFBP-1 was the strongest predictor for both prediabetes (OR:13.4) and T2D (OR:14.9). When adiponectin, IGFBP-1 and IGFBP-2 were combined, the ROC-AUC reached 0.87 for women and 0.79 for men, higher than for BMI alone. Conclusion: Differences were observed comparing adipocyte- and hepatocyte-derived biomarkers in forecasting AGT in NGT subjects. In women the strongest predictor for T2D was adiponectin and in men IGFBP-1, and for prediabetes IGFBP-2 in women and IGFBP-1 in men.

Prevention and management of type 2 diabetes mellitus in Uganda and South Africa: Findings from the SMART2D pragmatic implementation trial.

Health systems in many low- and middle-income countries are struggling to manage type 2 diabetes (T2D). Management of glycaemia via well-organized care can reduce T2D incidence, and associated morbidity and mortality. The primary aim of this study was to evaluate the effectiveness of facility plus community care interventions (integrated care), compared to facility only care interventions (facility care) towards improvement of T2D outcomes in Uganda and South Africa. A pragmatic cluster randomized trial design was used to compare outcomes among participants with T2D and those at high risk. The trial had two study arms; the integrated care arm, and the facility care arm; and in Uganda only, an additional usual care arm. Participants were enrolled at nine primary health facilities in Uganda, and two in South Africa. Participants were adults aged 30 to 75 years, and followed for up to 12 months. Primary outcomes were glycaemic control among participants with T2D, and reduction in HbA1c > = 3 mmol/mol among participants at high risk. Secondary outcomes were retention into care and incident T2D. Adjusted analysis revealed significantly higher retention into care comparing integrated care and facility care versus usual care in Uganda and integrated care versus facility care in South Africa. The effect was particularly high among participants at high risk in Uganda with an incident rate ratio of 2.46 [1.33-4.53] for the facility care arm and 3.52 [2.13-5.80] for the integrated care arm. No improvement in glycaemic control or reduction in HbA1c was found in either country. However, considerable and unbalanced loss to follow-up compromised assessment of the intervention effect on HbA1c. Study interventions significantly improved retention into care, especially compared to usual care in Uganda. This highlights the need for adequate primary care for T2D and suggest a role for the community in T2D prevention. Trial registration number: ISRCTN11913581.

Machine learning for prediction of diabetes risk in middle-aged Swedish people.

AIMS: To study if machine learning methodology can be used to detect persons with increased type 2 diabetes or prediabetes risk among people without known abnormal glucose regulation. METHODS: Machine learning and interpretable machine learning models were applied on research data from Stockholm Diabetes Preventive Program, including more than 8000 people initially with normal glucose tolerance or prediabetes to determine high and low risk features for further impairment in glucose tolerance at follow-up 10 and 20 years later. RESULTS: The features with the highest importance on the outcome were body mass index, waist-hip ratio, age, systolic and diastolic blood pressure, and diabetes heredity. High values of these features as well as diabetes heredity conferred increased risk of type 2 diabetes. . The machine learning model was used to generate individual, comprehensible risk profiles, where the diabetes risk was obtained for each person in the data set. Features with the largest increasing or decreasing effects on the risk were determined. CONCLUSIONS: The primary application of this machine learning model is to predict individual type 2 diabetes risk in people without diagnosed diabetes, and to which features the risk relates. However, since most features affecting diabetes risk also play a role for metabolic control in diabetes, e.g. body mass index, diet composition, tobacco use, and stress, the tool can possibly also be used in diabetes care to develop more individualized, easily accessible health care plans to be utilized when encountering the patients.

Burning sensation in the feet and glycosylated haemoglobin levels in Swedish- and non-Swedish-born primary healthcare patients.

BACKGROUND: A painful burning sensation in the feet is a common problem. The most common cause is small fibre neuropathy, a type of peripheral neuropathy that is often a consequence of diabetes and prediabetes. AIM: To examine the association between a self-reported burning sensation in the feet and HbA1c levels in primary healthcare patients. METHODS: This study used data from patients in the 4D diabetes project in Swedish primary healthcare. The study population included 824 patients. Logistic regression was performed to study the association between the outcome and explanatory variables. RESULTS: A total of 24% of patients reported a burning sensation in the feet. This sensation was not associated with HbA1c levels. However, the probability of reporting a burning sensation was two times higher in non-Swedish-born than Swedish-born patients (OR, 2.31; 95% CI, 1.55-3.44) and higher in smokers than those who had never smoked, regardless of region of birth (OR, 1.69; 95% CI, 1.07-2.65). CONCLUSIONS: Our results do not support the hypothesis that a self-reported burning sensation in the feet is associated with HbA1c levels. Rather, they indicate a strong relationship between a burning sensation and region of birth, as well as between a burning sensation and smoking.

Early detection of type 2 diabetes in socioeconomically disadvantaged areas in Stockholm - comparing reach of community and facility-based screening.

BACKGROUND: Type 2 diabetes and its high-risk stage, prediabetes, are often undiagnosed. Early detection of these conditions is of importance to avoid organ complications due to the metabolic disturbances associated with diabetes. Diabetes screening can detect persons unaware of diabetes risk and the elevated glucose levels can potentially be reversed through lifestyle modification and medication. There are mainly two approaches to diabetes screening: opportunistic facility-based screening at health facilities and community screening. OBJECTIVE: To determine the difference in population reach and participant characteristics between community- and facility-based screening for detection of type 2 diabetes and persons at high risk of developing diabetes. METHODS: Finnish diabetes risk score (FINDRISC) is a risk assessment tool used by two diabetes projects to conduct community- and facility-based screenings in disadvantaged suburbs of Stockholm. In this study, descriptive and limited inferential statistics were carried out analyzing data from 2,564 FINDRISC forms from four study areas. Community- and facility-based screening was compared in terms of participant characteristics and with population data from the respective areas to determine their reach. RESULTS: Our study found that persons born in Africa and Asia were reached through community screening to a higher extent than with facility-based screening, while persons born in Sweden and other European countries were reached more often by facility-based screening. Also, younger persons were reached more frequently through community screening compared with facility-based screening. Both types of screening reached more women than men. CONCLUSION: Community-based screening and facility-based screening were complementary methods in reaching different population groups at high risk of developing type 2 diabetes. Community screening in particular reached more hard-to-reach groups with unfavorable risk profiles, making it a critical strategy for T2D prevention. More men should be recruited to intervention studies and screening initiatives to achieve a gender balance.

Treatment with a ß-2-adrenoceptor agonist stimulates glucose uptake in skeletal muscle and improves glucose homeostasis, insulin resistance and hepatic steatosis in mice with diet-induced obesity.

AIMS/HYPOTHESIS: Chronic stimulation of ß2-adrenoceptors, opposite to acute treatment, was reported to reduce blood glucose levels, as well as to improve glucose and insulin tolerance in rodent models of diabetes by essentially unknown mechanisms. We recently described a novel pathway that mediates glucose uptake in skeletal muscle cells via stimulation of ß2-adrenoceptors. In the current study we further explored the potential therapeutic relevance of ß2-adrenoceptor stimulation to improve glucose homeostasis and the mechanisms responsible for the effect. METHODS: C57Bl/6N mice with diet-induced obesity were treated both acutely and for up to 42 days with a wide range of clenbuterol dosages and treatment durations. Glucose homeostasis was assessed by glucose tolerance test. We also measured in vivo glucose uptake in skeletal muscle, insulin sensitivity by insulin tolerance test, plasma insulin levels, hepatic lipids and glycogen. RESULTS: Consistent with previous findings, acute clenbuterol administration increased blood glucose and insulin levels. However, already after 4 days of treatment, beneficial effects of clenbuterol were manifested in glucose homeostasis (32% improvement of glucose tolerance after 4 days of treatment, p < 0.01) and these effects persisted up to 42 days of treatment. These favourable metabolic effects could be achieved with doses as low as 0.025 mg kg-1 day-1 (40 times lower than previously studied). Mechanistically, these effects were not due to increased insulin levels, but clenbuterol enhanced glucose uptake in skeletal muscle in vivo both acutely in lean mice (by 64%, p < 0.001) as well as during chronic treatment in diet-induced obese mice (by 74%, p < 0.001). Notably, prolonged treatment with low-dose clenbuterol improved whole-body insulin sensitivity (glucose disposal rate after insulin injection increased up to 1.38 ± 0.31%/min in comparison with 0.15 ± 0.36%/min in control mice, p < 0.05) and drastically reduced hepatic steatosis (by 40%, p < 0.01) and glycogen (by 23%, p < 0.05). CONCLUSIONS/INTERPRETATION: Clenbuterol improved glucose tolerance after 4 days of treatment and these effects were maintained for up to 42 days. Effects were achieved with doses in a clinically relevant microgram range. Mechanistically, prolonged treatment with a low dose of clenbuterol improved glucose homeostasis in insulin resistant mice, most likely by stimulating glucose uptake in skeletal muscle and improving whole-body insulin sensitivity as well as by reducing hepatic lipids and glycogen. We conclude that selective ß2-adrenergic agonists might be an attractive potential treatment for type 2 diabetes. This remains to be confirmed in humans. Graphical abstract.

Improvement of Islet Allograft Function Using Cibinetide, an Innate Repair Receptor Ligand.

BACKGROUND: During intraportal pancreatic islet transplantation (PITx), early inflammatory reactions cause an immediate loss of more than half of the transplanted graft and potentiate subsequent allograft rejection. Previous findings suggest that cibinetide, a selective innate repair receptor agonist, exerts islet protective and antiinflammatory properties and improved transplant efficacy in syngeneic mouse PITx model. In a stepwise approach toward a clinical application, we have here investigated the short- and long-term effects of cibinetide in an allogeneic mouse PITx model. METHODS: Streptozotocin-induced diabetic C57BL/6N (H-2) mice were transplanted with 320 (marginal) or 450 (standard) islets from BALB/c (H-2) mice via the portal vein. Recipients were treated perioperative and thereafter daily during 14 d with cibinetide (120 µg/kg), with or without tacrolimus injection (0.4 mg/kg/d) during days 4-14 after transplantation. Graft function was assessed using nonfasting glucose measurements. Relative gene expressions of proinflammatory cytokines and proinsulin of the graft-bearing liver were assessed by quantitative polymerase chain reaction. Cibinetide's effects on dendritic cell maturation were investigated in vitro. RESULTS: Cibinetide ameliorated the local inflammatory responses in the liver and improved glycemic control immediately after allogeneic PITx and significantly delayed the onset of allograft loss. Combination treatment with cibinetide and low-dose tacrolimus significantly improved long-term graft survival following allogeneic PITx. In vitro experiments indicated that cibinetide lowered bone-marrow-derived-immature-dendritic cell maturation and subsequently reduced allogeneic T-cell response. CONCLUSIONS: Cibinetide reduced the initial transplantation-related severe inflammation and delayed the subsequent alloreactivity. Cibinetide, in combination with low-dose tacrolimus, could significantly improve long-term graft survival in allogeneic PITx.

SNAP23 depletion enables more SNAP25/calcium channel excitosome formation to increase insulin exocytosis in type 2 diabetes.

SNAP23 is the ubiquitous SNAP25 isoform that mediates secretion in non-neuronal cells, similar to SNAP25 in neurons. However, some secretory cells like pancreatic islet ß cells contain an abundance of both SNAP25 and SNAP23, where SNAP23 is believed to play a redundant role to SNAP25. We show that SNAP23, when depleted in mouse ß cells in vivo and human ß cells (normal and type 2 diabetes [T2D] patients) in vitro, paradoxically increased biphasic glucose-stimulated insulin secretion corresponding to increased exocytosis of predocked and newcomer insulin granules. Such effects on T2D Goto-Kakizaki rats improved glucose homeostasis that was superior to conventional treatment with sulfonylurea glybenclamide. SNAP23, although fusion competent in slower secretory cells, in the context of ß cells acts as a weak partial fusion agonist or inhibitory SNARE. Here, SNAP23 depletion promotes SNAP25 to bind calcium channels more quickly and longer where granule fusion occurs to increase exocytosis efficiency. ß Cell SNAP23 antagonism is a strategy to treat diabetes.

Extent of the association between self-rated health and place of birth: a cross-sectional study among people at high risk of developing pre-diabetes and diabetes in Sweden.

OBJECTIVE: The first aim was to determine the extent of the relationship between place of birth and self-rated health (SRH) in primary healthcare patients born outside Sweden and those born in Sweden. The second aim was to investigate whether socioeconomic and lifestyle factors explained any differences. SETTING: Two academic primary healthcare centres in Stockholm County, Sweden. PARTICIPANTS: 825 patients at high risk of developing pre-diabetes and diabetes, aged 18-74 years, attending academic healthcare centres in areas with large numbers of immigrants, 56.8% born abroad and 43.2% born in Sweden. Patients with a diagnosis of diabetes were excluded. Inclusion criteria were based on previous research showing that people born in Middle Eastern and Asian countries who live in Sweden have a high prevalence of and risk for diabetes. OUTCOME: SRH was dichotomised as optimal (very good/good) and suboptimal (fair/bad/very bad) and compared in those born outside Sweden and in Sweden. RESULTS: There was a statistically significant difference in the SRH of the two groups (p=0.008). Logistic regression analysis showed a crude OR for reduced SRH of 1.46 (95% CI 1.10 to 1.92) in patients born outside Sweden. After controlling for education, employment and marital status, the OR increased to 1.50 (95% CI 1.11 to 2.02). After controlling for physical activity and smoking, it decreased to 1.36 (95% CI 1.00 to 1.85). CONCLUSION: Socioeconomic and lifestyle factors influenced SRH. It could therefore be useful for clinicians to consider these factors when providing care for patients born outside Sweden and resettled in areas with large numbers of immigrants.

"I Did Not Believe You Could Get Better"-Reversal of Diabetes Risk Through Dietary Changes in Older Persons with Prediabetes in Region Stockholm.

Diabetes risk can be controlled and even reversed by making dietary changes. The aim of this study was to improve the understanding of how older persons with a high risk of developing Type 2 diabetes manage and relate to information about diabetes risk over a ten-year period. Fifteen qualitative interviews were conducted among participants from the Stockholm Diabetes Prevention Program (SDPP). The participants were asked to recall the health examinations conducted by the SDPP related to their prediabetes and to describe their experiences and potential changes related to diet and physical activity. Data were analyzed using qualitative content analysis. The main theme found was that T2D (type 2 diabetes) risk is not perceived as concrete enough to motivate lifestyle modifications, such as changing dietary patterns, without other external triggers. Diagnosis was recognized as a reason to modify diet, and social interactions were found to be important for managing behavior change. Diagnosis was also a contributing factor to lifestyle modification, while prognosis of risk was not associated with efforts to change habits. The results from this study suggest that the potential of reversing prediabetes needs to be highlighted and more clearly defined for older persons to serve as motivators for lifestyle modification.