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Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P

IgG4-related diseases (IgG-RDs) are a group of fibroinflammatory diseases that affect a variety of tissues, resulting in tumour-like effects and/or organ dysfunction. Monoclonal gammopathies (MGPs) are a group of disorders characterized by clonal proliferation of plasma cells or lymphoid cells resulting in the secretion of a monoclonal immunoglobulin. Cases of MGPs in IgG4-RDs coexisting with plasma cell dyscrasias and lymphoid neoplasms have been reported over the past few years. Therefore, the results of examinations of M protein in IgG4-RD patients should be interpreted with caution. Herein, we report the case of a 58-year-old male with a history of type 2 diabetes who presented with submandibular masses, anosmia, swollen lymph nodes, proteinuria, and renal impairment. Laboratory tests revealed hyperglobulinemia and elevated levels of IgG4 (124 g/L) and serum-free light chains (sFLCs). Serum protein electrophoresis (SPEP) revealed an M spike of 5.6 g/dL, and immunofixation electrophoresis (IPE) revealed biclonal IgG-κ and IgG-λ. The patient underwent bone marrow, lymph node, and kidney biopsy, which ruled out plasma cell disorders and lymphoma. He was finally diagnosed with an IgG4-RD comorbid with diabetic nephropathy. The findings in this case highlight that significant activation of B cells in IgG4-RD patients, especially those with multiorgan involvement can lead to significant hyperglobulinemia and high sFLC and IgG4 levels, which are more pronounced in the setting of renal impairment. Relatively high concentrations of polyclonal IgG4 can give rise to a focal band bridging the β and γ fractions, which may mimic the appearance of a monoclonal band on SPEP and monoclonal gammaglobulinemia in IFE. The patient experienced considerable improvement in his symptoms after rituximab combined with glucocorticoid therapy, and a monoclonal immunoglobulin was not detected. [ABSTRACT FROM AUTHOR]

Background: Chronic kidney disease (CKD) is associated with an increased risk of adverse pregnancy outcomes, but the risk at different stages of CKD (defined by estimated glomerular filtration rate, eGFR) compared with women without CKD has not been quantified in large cohorts. Objectives: To quantify the association between CKD and adverse pregnancy outcomes according to CKD definition, CKD stage and presence or absence of diabetes. Search strategy: A systematic search of EMBASE and MEDLINE from inception to 5 January 2023. Selection criteria: English‐language randomised controlled trials as well as cohort and case–control studies investigating adverse pregnancy outcomes in pregnant women with CKD. Data collection and analysis: Two reviewers conducted independent data extractions. A random‐effects model was used to estimate risk. Main results: We included 19 studies with 3 251 902 women. Defining CKD using eGFR or serum creatinine produced results with greater effect size but wider confidence intervals. Compared with CKD stages 1–2, women with CKD stages 3–5 have a greater risk, but also greater imprecision in the risk estimate, of the following outcomes: pre‐eclampsia (OR 55.18, 95% CI 2.63–1157.68, vs OR 24.74, 95% CI 1.75–348.70), preterm birth (OR 20.24, 95% CI 2.85–143.75, vs OR 8.18, 95% CI 1.54–43.46) and neonatal intensive care unit admission (OR 19.32, 95% CI 3.07–121.68, vs OR 9.77, 95% CI 2.49–38.39). Women with diabetic kidney disease, compared with women without diabetic kidney disease, have higher risks of maternal mortality, small‐for‐gestational‐age neonates, pre‐eclampsia and gestational hypertension. Conclusions: There is heterogeneity in the definition of CKD in pregnancy. Future studies should consider ways to standardise its definition and measurement in pregnancy. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the impact of denosumab on (i) the incidence of type 2 diabetes (T2D), and (ii) long‐term health outcomes (microvascular [neuropathy, retinopathy, nephropathy] and macrovascular [cardiovascular disease, cerebrovascular accident] complications, and all‐cause mortality) in patients with T2D, before (iii) combining results with prior studies using meta‐analysis. Methods: A retrospective analysis of data in a large global federated database (TriNetX; Cambridge, MA) was conducted from 331 375 patients, without baseline T2D or cancer, prescribed either denosumab (treatment, n = 45 854) or bisphosphonates (control, n = 285 521), across 83 healthcare organizations. Propensity score matching (1:1) of confounders was undertaken that resulted in 45 851 in each cohort. Secondary analysis further evaluated the impact of denosumab on long‐term health outcomes in patients with T2D. Additionally, we systematically searched prior literature that assessed the association between denosumab and T2D. Estimates were pooled using random‐effects meta‐analysis. Risk of bias and evidence quality were assessed using Cochrane‐endorsed tools. Results: Denosumab (vs. bisphosphonates) was associated with a lower risk of incident T2D over 5 years (hazard ratio 0.83 [95% confidence interval {CI} 0.78‐0.88]). Secondary analysis showed significant risk reduction in all‐cause mortality (0.79 [0.72‐0.87]) and foot ulceration (0.67 [0.53‐0.86]). Also, pooled results from four studies (three observational, one randomized controlled trial) following meta‐analysis showed a reduced relative risk (RR [95% CI]) for incident T2D in patients prescribed denosumab (0.83 [0.79‐0.87]) (I2 = 10.76%). Conclusions: This is the largest cohort study to show that denosumab treatment is associated with a reduced RR of incident T2D, as well as an associated reduced RR of all‐cause mortality and microvascular complications, findings that may influence guideline development in the treatment of osteoporosis, particularly in patients who are at a high risk of T2D. [ABSTRACT FROM AUTHOR]

Aim: To explore the effect of canagliflozin on kidney and cardiovascular events and safety outcomes in individuals with type 2 diabetes and chronic kidney disease across geographic regions and racial groups. Materials and Methods: A stratified Cox proportional hazards model was used to assess efficacy and safety outcomes by geographic region and racial group. The primary composite outcome was a composite of end‐stage kidney disease (ESKD), doubling of the serum creatinine (SCr) level, or death from kidney or cardiovascular causes. Secondary outcomes included: (i) cardiovascular death or heart failure (HF) hospitalization; (ii) cardiovascular death, myocardial infarction (MI) or stroke; (iii) HF hospitalization; (iv) doubling of the SCr level, ESKD or kidney death; (v) cardiovascular death; (vi) all‐cause death; and (vii) cardiovascular death, MI, stroke, or hospitalization for HF or for unstable angina. Results: The 4401 patients were divided into six geographic region subgroups: North America (n = 1182, 27%), Central and South America (n = 941, 21%), Eastern Europe (n = 947, 21%), Western Europe (n = 421, 10%), Asia (n = 749, 17%) and Other (n = 161, 4%). The analyses included four racial groups: White (n = 2931, 67%), Black or African American (n = 224, 5%), Asian (n = 877, 20%) and Other (n = 369, 8%). Canagliflozin reduced the relative risk of the primary composite outcome in the overall trial by 30% (hazard ratio 0.70, 95% confidence interval 0.59‐0.82; P = 0.00001). Across geographic regions and racial groups, canagliflozin consistently reduced the primary composite endpoint without evidence of heterogeneity (interaction P values of 0.39 and 0.91, respectively) or significant safety outcome differences. Conclusions: Canagliflozin reduces the risk of kidney and cardiovascular events similarly across geographic regions and racial groups. [ABSTRACT FROM AUTHOR]

Objective(s): This study aimed to investigate the effects of Warm Water Immersion (WWI) on inflammation, kidney function, and kidney tissue damage in rats with diabetes mellitus (DM). Materials and Methods: Forty male rats were divided into four groups: Healthy Control (HC), Diabetic Control (DC), Diabetic Rats treated with WWI (DW), and Healthy Rats treated with WWI (HW). Daily 15-minute WWI sessions at 43 °C were administered for eight weeks. Various parameters including lipids, fasting blood sugar (FBS), HbA1C, insulin, advanced glycation end products (AGEs), HSP70, glomerular filtration rate (GFR), urinary albumin excretion, creatinine, blood urea nitrogen (BUN), oxidative stress, anti-oxidant parameters, and gene expression of RAGE, VEGF, and TGFß1 were assessed. Histological examination of kidney tissue was also conducted. Results: Significant reductions in FBS, AGEs, glutathione, superoxide dismutase (SOD), and nitric oxide (NO) levels were observed in the DW group compared to DC. Expression of RAGE, VEGF, and TGFß1 genes decreased in DW. Triglycerides, total cholesterol, and LDL cholesterol were lower in DW. Insulin, HDL cholesterol, catalase, total anti-oxidant capacity (TAC), and tissue HSP70 were higher in DW. Histological assessment revealed reduced kidney damage in DW compared to DC. Conclusion: WWI for eight weeks shows promise in mitigating diabetic nephropathy in rats, suggesting its potential as a non-invasive adjunctive therapy for managing diabetes complications. [ABSTRACT FROM AUTHOR]