The number of nephroprotection targets attained is associated with cardiorenal outcomes and mortality in patients with diabetic kidney disease. The CKD-REIN cohort study.

AIM: The risk of cardiorenal events remains high among patients with diabetes and chronic kidney disease (CKD), despite the prescription of recommended treatments. We aimed to determine whether the attainment of a combination of nephroprotection targets at baseline (glycated haemoglobin <7.0%, urinary albumin-creatinine ratio <300 mg/g, blood pressure <130/80 mmHg, renin-angiotensin system inhibition) was associated with better cardiorenal outcomes and lower mortality. MATERIALS AND METHODS: From the prospective French CKD-REIN cohort, we studied 1260 patients with diabetes and CKD stages 3-4 (estimated glomerular filtration rate: 15-60 ml/min/1.73 m2); 69% were men, and at inclusion, mean ± SD age: 70 ± 10 years; estimated glomerular filtration rate: 33 ± 11 ml/min/1.73 m2. The median follow-up was 4.9 years. RESULTS: In adjusted Cox regression models, the attainment of two nephroprotection targets was consistently associated with a lower risk of cardiorenal events [hazard ratio 0.70 (95% confidence interval 0.57-0.85)], incident kidney failure with replacement therapy [0.58 (0.43-0.77)], four major adverse cardiovascular events (cardiovascular death, myocardial infarction, stroke, hospitalization for heart failure) [0.75 (0.57-0.99)] and all-cause mortality [0.59 (0.42-0.82)] when compared with the attainment of zero or one target. For patients with a urinary albumin-creatinine ratio ≥300 mg/g, those who attained at least two targets had lower hazard ratios for cardiorenal events [0.61 (0.39-0.96)], four major adverse cardiovascular events [0.53 (0.28-0.98)] and all-cause mortality [0.35 (0.17-0.70)] compared with those who failed to attain any targets. CONCLUSIONS: These findings suggest that the attainment of a combination of nephroprotection targets is associated with better cardiorenal outcomes and a lower mortality rate in people with diabetic kidney disease.

Penile prosthesis for erectile dysfunction in France: A six-year nationwide database analysis.

INTRODUCTION: Urological consultations for erectile dysfunction (ED) are increasing worldwide. Penile prosthesis (PP) implantations are performed when other treatments are unsuccessful. However, there is no data regarding PP implantations in France beyond the year 2016. OBJECTIVES: This study aimed to describe the changes in the number and type of PP implants used for the treatment of ED in France from 2016 to 2021 and the hospitalization rates following implantation using French national data from the Program for the Medicalization of Information Systems (PMSI). MATERIALS AND METHODS: We analyzed data on PP implantations in all France hospitals. PPs were coded into three types according to the Common Classification of Medical Procedures (CCAM). The number of patients admitted to hospital with complications twelve months after implantation was also recorded. RESULTS: During the study period, 3675 men received 3868 PPs in France. A gradual increase in the total number of implanted PPs was observed, with an overall increase of 33.8%. In 2020, there was a sharp decline in the number of implanted PPs, primarily owing to the COVID-19 pandemic. The most commonly used implant was PPs with an extracavernous compartment, comprising 85% of all PPs. Twelve months after implantation, only 1-2% of the patients were rehospitalized. CONCLUSION: PP implantation surgeries are highly reproducible and have a low incidence of complications, in terms of rehospitalization after one year of placement (1.8%). Moreover, there was an increase in the demand for penile prosthesis implantations in France between 2016 and 2021. LEVEL OF EVIDENCE: 4: Descriptive epidemiological study.

Pathogenic, Total Loss-of-Function DYRK1B Variants Cause Monogenic Obesity Associated With Type 2 Diabetes.

OBJECTIVE: Rare variants in DYRK1B have been described in some patients with central obesity, type 2 diabetes, and early-onset coronary disease. Owing to the limited number of conducted studies, the broader impact of DYRK1B variants on a larger scale has yet to be investigated. RESEARCH DESIGN AND METHODS: DYRK1B was sequenced in 9,353 participants from a case-control study for obesity and type 2 diabetes. Each DYRK1B variant was functionally assessed in vitro. Variant pathogenicity was determined using criteria from the American College of Medical Genetics and Genomics (ACMG). The effect of pathogenic or likely pathogenic (P/LP) variants on metabolic traits was assessed using adjusted mixed-effects score tests. RESULTS: Sixty-five rare, heterozygous DYRK1B variants were identified and were not associated with obesity or type 2 diabetes. Following functional analyses, 20 P/LP variants were pinpointed, including 6 variants that exhibited a fully inhibitory effect (P/LP-null) on DYRK1B activity. P/LP and P/LP-null DYRK1B variants were associated with increased BMI and obesity risk; however, the impact was notably more pronounced for the P/LP-null variants (effect of 8.0 ± 3.2 and odds ratio of 7.9 [95% CI 1.2-155]). Furthermore, P/LP-null variants were associated with higher fasting glucose and type 2 diabetes risk (effect of 2.9 ± 1.0 and odds ratio of 4.8 [95% CI 0.85-37]), while P/LP variants had no effect on glucose homeostasis. CONCLUSIONS: P/LP, total loss-of-function DYRK1B variants cause monogenic obesity associated with type 2 diabetes. This study underscores the significance of conducting functional assessments in order to accurately ascertain the tangible effects of P/LP DYRK1B variants.

Exploring the role of purinergic receptor P2RY1 in type 2 diabetes risk and pathophysiology: Insights from human functional genomics.

OBJECTIVE: Human functional genomics has proven powerful in discovering drug targets for common metabolic disorders. Through this approach, we investigated the involvement of the purinergic receptor P2RY1 in type 2 diabetes (T2D). METHODS: P2RY1 was sequenced in 9,266 participants including 4,177 patients with T2D. In vitro analyses were then performed to assess the functional effect of each variant. Expression quantitative trait loci (eQTL) analysis was performed in pancreatic islets from 103 pancreatectomized individuals. The effect of P2RY1 on glucose-stimulated insulin secretion was finally assessed in human pancreatic beta cells (EndoCßH5), and RNA sequencing was performed on these cells. RESULTS: Sequencing P2YR1 in 9,266 participants revealed 22 rare variants, seven of which were loss-of-function according to our in vitro analyses. Carriers, except one, exhibited impaired glucose control. Our eQTL analysis of human islets identified P2RY1 variants, in a beta-cell enhancer, linked to increased P2RY1 expression and reduced T2D risk, contrasting with variants located in a silent region associated with decreased P2RY1 expression and increased T2D risk. Additionally, a P2RY1-specific agonist increased insulin secretion upon glucose stimulation, while the antagonist led to decreased insulin secretion. RNA-seq highlighted TXNIP as one of the main transcriptomic markers of insulin secretion triggered by P2RY1 agonist. CONCLUSION: Our findings suggest that P2RY1 inherited or acquired dysfunction increases T2D risk and that P2RY1 activation stimulates insulin secretion. Selective P2RY1 agonists, impermeable to the blood-brain barrier, could serve as potential insulin secretagogues.

Functional genetics reveals the contribution of delta opioid receptor to type 2 diabetes and beta-cell function.

Functional genetics has identified drug targets for metabolic disorders. Opioid use impacts metabolic homeostasis, although mechanisms remain elusive. Here, we explore the OPRD1 gene (encoding delta opioid receptor, DOP) to understand its impact on type 2 diabetes. Large-scale sequencing of OPRD1 and in vitro analysis reveal that loss-of-function variants are associated with higher adiposity and lower hyperglycemia risk, whereas gain-of-function variants are associated with lower adiposity and higher type 2 diabetes risk. These findings align with studies of opium addicts. OPRD1 is expressed in human islets and beta cells, with decreased expression under type 2 diabetes conditions. DOP inhibition by an antagonist enhances insulin secretion from human beta cells and islets. RNA-sequencing identifies pathways regulated by DOP antagonism, including nerve growth factor, circadian clock, and nuclear receptor pathways. Our study highlights DOP as a key player between opioids and metabolic homeostasis, suggesting its potential as a therapeutic target for type 2 diabetes.

Sick genes, sick individuals, or sick populations with chronic disease? An international example from a standardized study of glucose tolerance and high blood pressure

Intensive searches for genes predisposing to or "causing" chronic disease are based on familial patterns indicating gene based inheritance. Rose's paradigm, less popular with clinical scientist thinking in individuals, is that populations give rise to their extreme values who become patients. For diabetes (NIDDM), population-based twin registers (e.g. Denmark) show little mono-to-di-zygotic difference, a suggesting major hospital ascertainment bias in ascribing a genetic basis to NIDDM. Here we examined geographically dispersed populations of West African origin, or similar genetic background within Cameroon, then between Jamaica and African-Caribbean (AfC) migrants to Britain (70 percent from Jamaica). Carefully representive samples were drawn from local population registers in rural and urban Cameroon, Jamaica and Manchester, UK. Results, on similar genetic backgrounds in the Cameroon, and between Jamaica and Manchester, suggest factors affecting energy balance (intake versus expenditure) rather than gene differences determine diabetes and, probably, hypertension rates in these and, probably, most populations.(AU)

Assessing dietary intakes in relation to diabetes mellitus and hypertension in Afro-origin population samples in Cameroon, Jamaica and Caribbean migrants to Europe - abstract

This international study examines nutritional influences on emerging diabetes mellitus and hypertension in Afro-origin populations, in random samples aged 25 - 79 years. The aim is to assess habitual food and nutrient intake from food frequency questionnaires (FFQ) built up, piloted, used and recalibrated with 24 hr recalls and food diaries and to relate these results of 75 g WHO glucose tolerance tests (GTT), blood pressure (BP) and anthropometric measurements. Method standardizing is essential so as to compare between as well as within sites. The paper emphasizes nutritional methods. In Jamaica, FFQs were developed from 104 Kingston residents, then applied in Spanish Town enumeration districts; in Manchester, from 40 Caribbean (84 percent Jamaican origin) and in Cameroon from 76 randomly sampled city, and 79 rural, households, with 76 - 79 percent response rates. Items contributing > 90 percent to macronutrient and total energy intake were included on FFQs, totalling 69 foods in Jamaica, 108 in Manchester and 76 m Cameroon. These were administered during and after the GTTs, taking some 40 minutes. For 350 subjects per site (response 65 - 88 percent), mean age-stratified body mass indices (BMI) ranged from 23.4 - 26.4 kg/mý in younger Cameroonian, Jamaican and Manchester men; respective female BMIs were higher at 26-28, 26-27 and 25 - 31. Manchester FFQ results for 101 subjects, generally low incomes, showed that almost all diets contain typical West Indian foods despite greater cost. Portion sizes are different for the same food compared with both the national UK and Jamaican populations (e.g. medium serving rice - 260 g vs 150 g), illustrating the importance of portion size data specific to each population. Percent energy from fat is lower and from carbohydrates much higher than in the national UK population, as are fruit and vegetable intakes and alcohol intakes in men. Jamaican values were intermediate between those in Britain and Cameroon where food habits and same-dish composition differed substantially, with a wider variety consumed in the city. Village diets from 200 FFQs consisted mainly of green leafy vegetables. These results show that standardised methods of building up instruments to assess nutritional intakes cross-culturally are feasible and can be applied in population studies of chronic disease (AU)

Standardized comparison of glucose intolerance in West African-origin populations of rural and urban Cameroon, Jamaica, and Caribbean migrants to Britain

OBJECTIVE: To compare the prevalence of glucose intolerance in genetically similar African-origin populations within Cameroon and from Jamaica and Britain. RESEARCH DESIGN AND METHODS: Subjects studied were from rural and urban Cameroon or from Jamaica, or were Caribbean migrants, mainly Jamaican, living in Manchester, England. Sampling bases included a local census of adults aged 25-74 years in Cameroon, districts statistically representative in Jamaica, and population registers in Manchester. African-Caribbean ethnicity required three grandparents of this ethnicity. Diabetes was defined by the World Health Organization (WHO) 1985 criteria using a 75-g oral glucose tolerance test (2-h > or = 11.1 mmol/l or hypoglycemic treatment) and by the new American Diabetes Association criteria (fasting glucose > or = 7.0 mmol/l or hypoglycemic treatment). RESULTS: For men, mean BMIs were greatest in urban Cameroon and Manchester (25-27 kg/m2); in women, these were similarly high in urban Cameroon and Jamaica and highest in Manchester (27-28 kg/m2). The age-standardized diabetes prevalence using WHO criteria was 0.8 percent in rural Cameroon, 2.0 percent in urban Cameroon, 8.5 percent in Jamaica, and 14.6 percent in Manchester, with no difference between sexes (men: 1.1 percent, 1.0 percent, 6.5 percent, 15.3 percent, women: 0.5 percent, 2.8 percent, 10.6 percent, 14.0 percent), all tests for trend P < 0.001. Impaired glucose tolerance was more frequent in Jamaica. CONCLUSIONS: The transition in glucose intolerance from Cameroon to Jamaica and Britain suggests that environment determines diabetes prevalence in these populations of similar genetic origin.(Au)

Development of food frequency questionaires in three population samples of African origin from Cameroon, Jamaica and Caribbean

OBJECTIVES: To develop the methods of assessment of food and nutrient intake using standardized food frequency questionnaires (FFQ) in three African origin population from Cameroon, Jamaica and Caribbean migrants to the United Kingdom. DESIGN: Cross-sectional assessment of diet from a representative sample in each site, using either a 2-day food diary or a 24-h recall method to determine foods for inclusion on the food frequency questionnaire. SETTING: A rural and urban site in Cameroon, Evodoula and Cite Verte in Yaounde, respectively; a district in Kingston Jamaica; African-Caribbeans living in central Manchester, UK. SUBJECTS: Aged 25-79 years, 61 from the Cameroonian urban site, 62 from the village site, 102 subjects from Jamaica (additional analysis on a subsample of 20): 29 subjects from Manchester, UK. MAIN OUTCOME MEASURES: Foods contributing to nutrients in each site to allow the development of a FFQ. RESULTS: A high response rate was obtained in each site. Comparison of macronutrient intakes between the sites showed that carbohydrates was important contributor to energy intake in Jamaica (55 percent) and the least in rural Cameroon. In rural Cameroon, fat (mainly palm oil) was the most important contributor to energy intake (44 percent). Manchester had the highest contribution of protein to energy (17 percent). Food contributing to total energy, protein, fat and carbohydrate were determined. In rural Cameroon, the top of 10 food items contributed 66 percent of the total energy intake compared to 37 percent for the top 10 foods in Manchester. Foods contributing to energy were similar in Jamaica and Manchester. Cassava contributed 44 percent of the carbohydrate intake in rural Cameroon and only 6 percent in urban Cameroon. One FFQ had been developed for use in both sites in Cameroon containing 76 food items. The FFQ for Jamaica contains 69 foods and for Manchester 108 food items. CONCLUSION: Considerable variations exist within sites (Cameroon) and between sites in foods which are important contributors to nutrients intakes. With careful exploration of eating habits it has been possible to develop standardized, but locally appropriate FFQs for the use in African population in different countres.(AU)

Nutritional influences on the emergence of diabetes mellitus and high blood pressure in Afro-origin populations in Cameroon, Jamaica, and Caribbean migrants to Europe - abstract

Our four nation study is establishing the role of nutrition in evolving diabetes mellitus (DM) and high blood pressure (BP) in these Afro-origin populations. Using highly standardized methods, we are testing whether increasing energy (particularly fat) and Na+ intakes, and decreased K+, Ca+ and antioxidant intakes, are associated with decreasing glucose tolerance (GT) and increasing BP within and between centres. Random community samples, aged 25 - 74 years, are stratified by sex up to 1,500/centre to generate sufficient index cases of impaired (I) GT and `high' BP (> 140 and/or 90 mm Hg but < 160 to 95 mm Hg) for an intervention trial and incident phase. During a 2-hr 759 glucose tolerance test (GTT), a food frequency questionnaire (FQQ), built up from food dairies and 24-hr recalls, and repeat 24-hr urines are supplying mean energy, fat, carbohydrate, fibre, protein and cation intakes. To date, 894 Jamaicans have been seen at the Spanish Town site, some 780 people (360 Afro-Caribbean) in Manchester, with 180 GT tested, 416 Cameroonians (246 urban) and a pilot study completed in Paris. Rates of IGT and DM run at approximately 8 percent and 14 percent in Jamaica, 15 percent of each in Manchester, and 4-8 percent in Cameroon through Jamaica to Manchester. Those at risk of hypertension (> 140 and/or 90 mm Hg) are similarly distributed. As baseline prevalence rates are established, the nutritionally-based intervention programme will be piloted as a randomized trial. Such efforts offer the chance for primary prevention of high BP, diabetes mellitus and their complications in these populations, before or as they face an epidemic from them (AU)

Development of food frequency questionnaires in three population samples of African origin from Cameroon, Jamaica and Caribbean migrants to the UK

OBJECTIVES: To develop the methods for assessment of food and nutrient intake using standardized food frequency questionnaires (FFQ) in three African origin populations from Cameroon, Jamaica and Caribbean migrants to the United Kingdom. DESIGN: Cross-sectional assessment of diet from a representative sample in each site, using either a 2-day food dairy or a 24-h recall method to determine food for inclusion on the food frequency questionnaire. SETTING: A rural and urban site in Cameroon, Evodoula and Cite Verte in Yaounde, respectively; a district in Kingston, Jamaica; Afro-Caribbeans living in central Manchester, UK. SUBJECTS: Aged 25-79 years, 61 from the Cameroonian urban site, 62 from village site; 102 subjects from Jamaica (additional analysis on a subsample of 20): 29 subjects from Manchester, UK. MAIN OUTCOME MEASURES: Food contributing to nutrients in each site to allow the development of a FFQ. RESULTS: A high response rate was obtained in each site. Comparison of macronutrient intakes between the sites showed that carbohydrate was the most important contributor to energy intake in Jamaica (55 percent) and the least in the rural Cameroon. In rural Cameroon, fat (mainly palm oil) was the most important contributor to energy intake (44 percent). Manchester had the highest contribution of protein energy (17 percent). Food contributing to toal energy, protein, fat and carbohydrate were determined. In rural Cameroon, the top 10 food items contributed 66 percent of the total energy intake compared to 37 percent for the top 10 foods in Manchester. Food contributing to energy were similar in Jamaica and Manchester. Cassava contributed 40 percent of the carbohydrate intake in rural Cameroon and only 6 percent in urban Cameroon. One FFQ has been developed for use in both sites in Cameroon containing 76 food items. The FFQ for Jamaica contains 69 foods and for Manchester 108 food items. CONCLUSION: Considerable variations exist within sites (Cameroon) and between sites in foods which are important contributors to nutrient intakes. With careful exploration of eating habits it has been possible to develop standardized, but locally appropriate FFQs for use in African populations in different countries.(AU)

Standardised comparison of glucose tolerance and diabetes prevalence in four African/African-Caribbean populations in Britain, Jamaica and Cameroon

To study factors promoting the emergence of diabetes in African-Caribbean (AfC) as the second largest ethnic minority in Britain and how these compare with genetically similar populations in Jamaica (origin of 80 percent AfC) and Cameroon, using the same protocol we carried out 75g glucose tolerance tests in representative community samples aged 25-74 years, by WHO criteria. As results were similar by gender, sexes are combined here. [See table] Diabetes prevalence (age-standardised) increased from Africa to the Caribbean to Europe and was highest in Manchester men. Body mass index showed a striking increase from rural to younger urban Cameroonians. Increasing NIDDM prevalence is paralleled across site by changes in nutritional and lifestyle factors, also measured using standardised methods. Even in Cameroon, prevalence approaches rates in whites in Europe.(AU)