Time-updated Fibroblast Growth Factor 23 Is Predictive for Posttransplant Diabetes Mellitus in Kidney Transplant Recipients.

Objective: This work aimed to study whether fibroblast growth factor 23 (FGF23) is predictive for incident posttransplant diabetes mellitus (PTDM) in kidney transplant recipients (KTRs). Methods: We repeatedly analyzed plasma C-terminal FGF23 concentrations in 170 KTRs enrolled in the TransplantLines Biobank and Cohort Study. Associations of time-updated plasma FGF23 with incident PTDM were studied by Cox regression. Results: A total of 170 KTRs (46% female, aged 54.4 ± 12.4 years) with 540 FGF23 measurements were included. Plasma FGF23 concentrations at transplantation were 31.1 (0.76-2576) pmol/L. During a follow-up of 24 (12-24) months, 38 patients developed PTDM. The highest FGF23 tertile (compared to the lowest) was associated with an increased risk for PTDM (fully adjusted hazard ratio 20.9; 95% CI, 3.4-130.0; P < .001). Conclusion: In KTRs without diabetes at baseline, the highest tertile of FGF23, compared to the lowest, is predictive for development of PTDM.

Balancing Risks and Benefits: Sodium-Glucose Cotransporter 2 Inhibitors and the Risk of Diabetic Ketoacidosis.

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a new class of drugs that have been proven beneficial in the management of diabetes, chronic kidney disease, and heart failure and in the mitigation of cardiovascular risk. The benefits of SGLT2i therapy have led to the rapid adoption of these drugs in clinical guidelines. Since the introduction of these drugs, concerns have arisen, as diabetic ketoacidosis (DKA) unexpectedly occurred in patients treated with SGLT2i. DKA is an infrequent but serious complication of SGLT2i therapy, and is potentially preventable. The risk factors for the development of SGLT2i-associated DKA are inappropriate dose reductions of insulin, the dietary restriction of carbohydrates, and factors that may increase insulin demand such as excessive alcohol intake and major surgery. Moreover, the risk of SGLT2i-associated DKA is higher in persons with type 1 diabetes. It is crucial that both patients and healthcare providers are aware of the risks of SGLT2i-associated DKA. In an effort to encourage safe prescribing of this effective class of drugs, we present two cases that illustrate the risks of SGLT2i therapy with regard to the development of DKA.

The impact of socioeconomic factors, social determinants, and ethnicity on the utilization of glucose sensor technology among persons with diabetes mellitus: a narrative review.

Continuous glucose monitoring (CGM) usage has been shown to improve disease outcomes in people living with diabetes by facilitating better glycemic management. However, previous research has suggested that access to these devices can be influenced by nonmedical factors such as socioeconomic status and ethnicity. It is critical that equitable access to CGM devices is ensured as people from those groups experience poorer diabetes-related health outcomes. In this narrative review, we provide an overview of the various healthcare systems worldwide and how socioeconomic status, social context, and ethnicity shape device usage and the associated health outcomes. In general, we found that having a lower socioeconomic status and belonging to an ethnic minority group negatively impact CGM usage. While financial means proved to be an important mediator in this process, it was not the sole driver as disparities persisted even after adjustment for factors such as income and insurance status. Recommendations to increase CGM usage for people of a lower socioeconomic status and ethnic minorities include increasing the availability of financial, administrative, and educational support, for both patients and healthcare providers. However, recommendations will vary due to local country-specific circumstances, such as reimbursement criteria and healthcare ecosystems.

The effects of income, education, social factors and ethnicity on the use of glucose sensors by people with diabetes mellitus: a narrative review Over the recent years, glucose sensors have transformed the monitoring of glucose levels in people with diabetes. However, access to these devices has been determined by the healthcare systems and the associated rules and regulations, as well as perceptions from providers and patients about who would benefit most from these devices. In this narrative review, we performed an expansive literature search into what is known about factors that negatively impact the access to glucose sensors, and how these factors might be addressed. From this, we learn that, depending on the healthcare system, financial means form a major driver behind the disparities in glucose sensor use. However, factors such as ethnicity and provider and patient perceptions also can negatively affect one's chances to obtain a glucose sensor. Furthermore, we found that a successful program aimed at resolving the found disparities in glucose sensor use must be multi-faceted, and must include measures aimed at financial support, the use of objective and simple criteria for sensor eligibility, as well as educational support for both patients and providers.

Serum T50 predicts cardiovascular mortality in individuals with type 2 diabetes: A prospective cohort study.

BACKGROUND AND AIMS: Individuals with type 2 diabetes (T2D) have a higher risk of cardiovascular disease, compared with those without T2D. The serum T50 test captures the transformation time of calciprotein particles in serum. We aimed to assess whether serum T50 predicts cardiovascular mortality in T2D patients, independent of traditional risk factors. METHODS: We analyzed 621 individuals with T2D in this prospective cohort study. Cox regression models were performed to test the association between serum T50 and cardiovascular and all-cause mortality. Causes of death were categorized according to ICD-10 codes. Risk prediction improvement was assessed by comparing Harrell's C for models without and with T50. RESULTS: The mean age was 64.2 ± 9.8 years, and 61% were male. The average serum T50 time was 323 ± 63 min. Higher age, alcohol use, high-sensitive C-reactive protein, and plasma phosphate were associated with lower serum T50 levels. Higher plasma triglycerides, venous bicarbonate, sodium, magnesium, and alanine aminotransferase were associated with higher serum T50 levels. After a follow-up of 7.5[5.4-10.7] years, each 60 min decrease in serum T50 was associated with an increased risk of cardiovascular (fully adjusted HR 1.32, 95% CI 1.08-1.50, and p = 0.01) and all-cause mortality (HR 1.15, 95%CI 1.00-1.38, and p = 0.04). Results were consistent in sensitivity analyses after exclusion of individuals with estimated glomerular filtration rate <45 or <60 mL/min/1.73 m2 and higher plasma phosphate levels. CONCLUSIONS: Serum T50 improves prediction of cardiovascular and all-cause mortality risk in individuals with T2D. Serum T50 may be useful for risk stratification and to guide therapeutic strategies aiming to reduce cardiovascular mortality in T2D.

HbA1c and fasting plasma glucose levels are equally related to incident cardiovascular risk in a high CVD risk population without known diabetes.

OBJECTIVES: Type 2 diabetes (T2DM) is associated with increased risk for cardiovascular disease (CVD). Whether screen-detected T2DM, based on fasting plasma glucose (FPG) or on HbA1c, are associated with different risks of incident CVD in high-risk populations and which one is preferable for diabetes screening in these populations, remains unclear. METHODS: 8,274 high-risk CVD participants were included from the UCC-SMART cohort. Participants were divided into groups based on prior T2DM diagnosis, and combinations of elevated/non-elevated FPG and HbA1c (cut-offs at 7 mmol/L and 48 mmol/mol, respectively): Group 0: known T2DM; group 1: elevated FPG/HbA1c; group 2: elevated FPG, non-elevated HbA1c; group 3: non-elevated FPG, elevated HbA1c; group 1 + 2: elevated FPG, regardless of HbA1c; group 1 + 3: elevated HbA1c, regardless of FPG; and group 4 (reference), non-elevated FPG/HbA1c. RESULTS: During a median follow-up of 6.3 years (IQR 3.3-9.8), 712 cardiovascular events occurred. Compared to the reference (group 4), group 0 was at increased risk (HR 1.40; 95 % CI 1.16-1.68), but group 1 (HR 1.16; 95 % CI 0.62-2.18), 2 (HR 1.18; 95 % CI 0.84-1.67), 3 (HR 0.61; 95 % CI 0.15-2.44), 1 + 2 (HR 1.17; 95 % CI 0.86-1.59) and 1 + 3 (HR 1.01; 95 % CI 0.57-1.79) were not. However, spline interpolation showed a linearly increasing risk with increasing HbA1c/FPG, but did not allow for identification of other cut-off points. CONCLUSIONS: Based on current cut-offs, FPG and HbA1c at screening were equally related to incident CVD in high-risk populations without known T2DM. Hence, neither FPG, nor HbA1c, is preferential for diabetes screening in this population with respect to risk of incident CVD.

Effect of high in comparison to low dairy intake intervention on markers of bone and cartilage remodeling and phosphate metabolism in healthy adults with overweight.

BACKGROUND: In the ageing population, issues with bone and joint health are highly prevalent. Both beneficial and potential risks of dairy products on bone and joint health are reported in epidemiological studies. Furthermore, the phosphorus (P) load from dairy could potentially lead to unfavorable changes in P metabolism. OBJECTIVE: To investigate the effect of dairy intake on markers of bone and joint metabolism and P metabolism in an intervention study with high and low dairy intake. METHODS: In a post hoc analysis of a randomized cross-over trial with overweight adults, the effect of a standardized high dairy intake [HDI (5-6 dairy portions per day) versus low dairy intake (LDI, ≤ 1 dairy portion/day)] for 6 weeks on markers of bone and joint health was assessed using enzyme-linked immunosorbent assays and electrochemiluminescence immunoassays. Markers indicative for cartilage breakdown, including urinary CTX-II, serum COMP and 4-hydroxyproline, and markers indicative for bone remodeling, such as serum CTX-I, PTH, 25(OH)D, osteocalcin, P1NP and FGF23, were investigated using linear mixed models. Furthermore, changes in P metabolism, including the main phosphate-regulating hormone FGF23 were explored. RESULTS: This study was completed by 46 adults (57% female, age 59 ± 4 years, BMI 28 ± 2 kg/m2). Following HDI, markers such as urinary CTX-II excretion, COMP, 25(OH)D, PTH and CTX-I were significantly lower after HDI, as compared to LDI. For example, CTX-II excretion was 1688 ng/24 h at HDI, while it was 2050 ng/24 h at LDI (p < 0.001). Concurrently, P intake was higher at HDI than at LDI (2090 vs 1313 mg/day, p < 0.001). While plasma P levels did not differ (1.03 vs 1.04 mmol/L in LDI, p = 0.36), urinary P excretion was higher at HDI than at LDI (31 vs 28 mmol/L, p = 0.04). FGF23 levels tended to be higher at HDI than at LDI (76.3 vs. 72.9 RU/mL, p = 0.07). CONCLUSIONS: HDI, as compared to LDI, reduced markers that are indicative for joint and bone resorption and bone turnover. No changes in P metabolism were observed. CLINICAL TRIAL REGISTRY: This trial was registered at https://trialsearch.who.int/Trial2.aspx?TrialID=NTR4899 as NTR4899.

Impact of Preoperative Diabetes Mellitus on Postoperative Outcomes in Elective Pancreatic Surgery and Its Implications for Prehabilitation Practice.

OBJECTIVES: Patients with pancreatic disease(s) have a high risk of developing diabetes mellitus (DM). Diabetes mellitus is associated with adverse postoperative outcomes. This study aimed to investigate the prevalence and effects of DM on postoperative outcomes in pancreatic surgery. METHODS: Subgroup analysis of a prospective cohort study conducted at an academic hospital. Patients undergoing pancreatoduodenectomy between January 2019 and November 2022 were included and screened for DM preoperatively using glycated hemoglobin (HbA1c). New-onset DM was diagnosed based on HbA1c ≥ 6.5% (48 mmol/mol). Postoperative outcomes were compared between patients with and without DM. RESULTS: From 117 patients, 29 (24.8%) were given a diagnosis of DM, and of those, 5 (17.2%) were diagnosed with new-onset DM, and 15 (51.8%) displayed poorly controlled preoperative DM (HbA 1c ≥ 7% [53 mmol/mol]). The incidence of surgical site infections (48.3% vs 27.3% in the non-DM group; P = 0.04) was higher for patients with DM. This association remained significant after adjusting for confounders (odds ratio, 2.60 [95% confidence interval, 1.03-6.66]; P = 0.04). CONCLUSIONS: One-quarter of the patients scheduled for pancreatoduodenectomy had DM; over half of them had poor glycemic control. The association between DM status and surgical site infections revealed in this study emphasizes the importance of adequate preoperative glycemic control.

Evaluation of Healthcare Utilisation and Expenditures in Persons with Type 2 Diabetes Undergoing Bariatric-Metabolic Surgery.

PURPOSE: Changes in healthcare utilisation and expenditures after bariatric-metabolic surgery (BMS) for people with type 2 diabetes mellitus (T2DM) are unclear. We used the Dutch national all-payer claims database (APCD) to evaluate utilisation and expenditures in people with T2DM who underwent BMS. METHODS: In this cohort study, patients with T2DM who had BMS in 2016 were identified in the APCD. This group was matched 1:2 to a control group with T2DM who did not undergo BMS based on age, gender and healthcare expenditures. Data on healthcare expenditures and utilisation were collected for 2013-2019. RESULTS: In total, 1751 patients were included in the surgery group and 3502 in the control group. After BMS, total median expenditures in the surgery group stabilised (€ 3156 to € 3120) and increased in the control group (€ 3174 to € 3434). Total pharmaceutical expenditures decreased 28% in the surgery group (€957 to €494) and increased 55% in the control group (€605 to €936). In the surgery group, 67.1% did not use medication for T2DM in 2019 compared to 13.3% in the control group. Healthcare use for microvascular complications increased in the control group, but not in the surgery group. CONCLUSION: BMS in people with T2DM stabilises healthcare expenditures and decreases medication use and care use for microvascular complications. In contrast, healthcare use and expenditures in T2DM patients who do not undergo surgery gradually increase over time. Due to the progressive nature of T2DM, it is expected that these differences will become larger in the long-term.

Serum peroxiredoxin-4, a biomarker of oxidative stress, is associated with the development of nephropathy in patients with type 2 diabetes (Zodiac-65).

Oxidative stress is implicated in the development and progression of type 2 diabetes (T2D). Peroxiredoxin-4 is an antioxidant protein, which may serve as biomarker of oxidative stress, and has previously been associated with new-onset T2D. In this study, we investigated associations between circulating peroxiredoxin-4 and the risk of developing new-onset microvascular complications in T2D patients. Serum peroxiredoxin-4 was measured in 536 patients with T2D with (n = 257) and without (n = 279) baseline microvascular complications who participated in a primary-care based cohort study (Zwolle Outpatient Diabetes project Integrating Available Care [ZODIAC] study). Over a median follow-up of 3.4 years, 38 (13.6%) developed nephropathy, defined as albuminuria in two consecutive urine samples. In multivariable Cox proportional hazards regression analyses, peroxiredoxin-4 was associated with new-onset nephropathy (hazard ratio [HR] per doubling 1.78 [95% CI: 1.27-2.49], P < 0.001) after adjustment for potential confounding factors, including age, sex, disease duration, HbA1c levels, macrovascular complications, systolic blood pressure, and even high-sensitive C-reactive protein. There was no interaction of peroxiredoxin-4 with hs-CRP impacting on new-onset nephropathy. No significant associations were found with new-onset retinopathy or neuropathy. In conclusion, circulating peroxiredoxin-4 associates positively with an increased risk of developing nephropathy in T2D independent and irrespective of low-grade inflammation.

Triglyceride/HDL cholesterol ratio and lipoprotein insulin resistance Score: Associations with subclinical atherosclerosis and incident cardiovascular disease.

BACKGROUND: The triglyceride/HDL cholesterol (TG/HDL-C) ratio and the Lipoprotein Insulin Resistance (LP-IR) score are lipid markers of insulin resistance. Their associations with carotid intima media thickness (cIMT; subclinical atherosclerosis) and incident cardiovascular disease (CVD) have not been thoroughly investigated. METHODS: In a cross-sectional cohort (89 subjects without type 2 diabetes (T2D) and 81 subjects with T2D we determined cIMT (ultrasound), homeostasis model assessment of insulin resistance (HOMA-IR) and the TG/HDL-C ratio. The LP-IR score, based on 6 lipoprotein characteristics determined by nuclear magnetic resonance spectroscopy, was measured in 123 participants. A prospective study was carried out among 6232 participants (Prevention of REnal and Vascular ENd-stage Disease study). RESULTS: Cross-sectionally, the adjusted associations of HOMA-IR, the TG/HDL-C ratio and the LP-IR score with cIMT were approximately similar (standardized ß = 0.34 (95 % CI 0.19-0.48), 0.24 (95 % CI 0.09-039) and 0.41 (95 % CI 0.23--0.59), respectively). Prospectively, 507 new cases of CVD were observed after a median follow-up of 8.2 (interquartile range 7.5-8.8) years. HOMA-IR, the TG/HDL-C ratio and LP-IR were each associated with incident CVD independent of potential confounders (HR 1.12, 95 % CI 1.02-1.24;1.22, 95 % CI 1.11-1.35 and 1.15. 95 % CI 1.01-1.31, respectively). The association of the TG/HDL-C ratio with incident CVD was somewhat stronger than that of HOMA-IR. CONCLUSION: Lipoprotein-based markers of insulin resistance are at least as strongly associated with subclinical atherosclerosis and clinical atherosclerosis development as HOMA-IR, obviating the need to measure insulin to determine the impact of insulin resistance. For practical purposes, the easily obtainable TG/HDL-C ratio may suffice.

NT-proBNP Mediates the Association Between FGF23 and All-Cause Mortality in Individuals With Type 2 Diabetes.

BACKGROUND: FGF23 (fibroblast growth factor 23) is associated with a higher mortality risk in type 2 diabetes, but the mechanism is unclear. We aimed to study whether NT-proBNP (N-terminal pro-brain natriuretic peptide) mediates the association between FGF23 and mortality. METHODS AND RESULTS: We analyzed C-terminal FGF23 and NT-proBNP levels in 399 patients with type 2 diabetes. Cox regression analyses were performed, followed by mediation analyses using Structural Equation Modeling. During follow-up of 9.2 [7.6-11.3] years, 117 individuals died. FGF23 was associated with all-cause mortality, independent of potential confounders (fully adjusted hazard ratio [HR], 2.32 [95% CI, 1.21-4.43], P=0.01). The association was lost upon further adjustment for NT-proBNP (HR, 1.84; 95% CI, 0.91-3.73). NT-proBNP accounted for 26% of the mediation effect between FGF23 and all-cause mortality. CONCLUSIONS: These findings suggest that a higher FGF23 level is associated with increased mortality in individuals with type 2 diabetes through an effect on volume homeostasis.

Plasma Citrate Levels Are Associated with an Increased Risk of Cardiovascular Mortality in Patients with Type 2 Diabetes (Zodiac-64).

Circulating citrate may represent a proxy of mitochondrial dysfunction which plays a role in the development of vascular complications in type 2 diabetes (T2D). Here, we determined the associations between plasma citrate levels and cardiovascular (CV) mortality in T2D patients. In this prospective cohort study, 601 patients were included who participated in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC). Plasma citrate levels were measured by nuclear magnetic resonance spectroscopy. Cox proportional hazards regression models were used to evaluate the associations between plasma citrate and the risk of CV mortality. Over a median follow-up of 11.4 years, 119 (19.8%) of the 601 patients died from a CV cause. In multivariable Cox proportional hazards regression models, adjusting for conventional risk factors, plasma citrate was associated with an increased risk of CV mortality (the hazard ratio (HR) per 1-SD increment was 1.19 (95%CI: 1.00-1.40), p = 0.048). This association was prominent in males (n = 49 with CV mortality) (HR 1.52 (95%CI: 1.14-2.03), p = 0.005), but not in females (n = 70 with CV mortality) (HR 1.11 (95%CI: 0.90-1.37), p = 0.319) (age-adjusted Pinteraction = 0.044). In conclusion, higher plasma citrate levels are associated with an increased risk of CV mortality in patients with established T2D. Future studies are warranted to unravel the potential role of citrate-related pathways in the pathogenesis of T2D-related vascular complications.

Both LDL and HDL particle concentrations associate positively with an increased risk of developing microvascular complications in patients with type 2 diabetes: lost protection by HDL (Zodiac-63).

BACKGROUND: Triglyceride-rich lipoproteins (TRL) and low-density lipoproteins (LDL) are associated positively whereas high-density lipoproteins (HDL) are associated inversely with the development of new-onset type 2 diabetes (T2D). Here we studied potential associations between these lipoprotein particle concentrations and the risk of developing microvascular complications in patients with established T2D. METHODS: Lipoprotein particle concentrations (TRLP, LDLP, and HDLP) were determined in 278 patients with T2D participating in a primary care-based longitudinal cohort study (Zwolle Outpatient Diabetes project Integrating Available Care [ZODIAC] study) leveraging the Vantera nuclear magnetic resonance (NMR) platform using the LP4 algorithm. Associations between lipoprotein particles and incident microvascular complications (nephropathy, neuropathy, and retinopathy) were assessed using Cox proportional hazards regression models. RESULTS: In total, 136 patients had microvascular complications at baseline. During a median follow-up of 3.2 years, 49 (34.5%) of 142 patients without microvascular complications at baseline developed new-onset microvascular complications. In multivariable Cox proportional hazards regression analyses, both total LDLP and HDLP concentrations, but not total TRLP concentrations, were positively associated with an increased risk of developing any microvascular complications after adjustment for potential confounding factors, including age, sex, disease duration, HbA1c levels, history of macrovascular complications, and statin use (adjusted hazard ratio [HR] per 1 SD increment: 1.70 [95% CI 1.24-2.34], P < 0.001 and 1.63 [95% CI 1.19-2.23], P = 0.002, respectively). When analyzing each microvascular complication individually, total LDLP concentrations were positively associated with retinopathy (adjusted HR 3.35, 95% CI 1.35-8.30, P = 0.009) and nephropathy (adjusted HR 2.13, 95% CI 1.27-3.35, P = 0.004), and total HDLP concentrations with neuropathy (adjusted HR 1.77, 95% CI 1.15-2.70, P = 0.009). No significant associations were observed for lipoprotein particle subfractions. CONCLUSIONS: Total lipoprotein particle concentrations of both LDL and HDL associate positively with an increased risk of developing microvascular complications in T2D. We propose that the protective role of HDL on the development of microvascular complications may be lost in established T2D.

Real-life 24-week changes in glycemic parameters among European users of flash glucose monitoring with type 1 and 2 diabetes and different levels of glycemic control.

AIM: To evaluate real-life changes of glycemic parameters among flash glucose monitoring (FLASH) users who do not meet glycemic targets. METHODS: De-identified data were obtained between 2014 and 2021 from patients using FLASH uninterrupted for a 24-week period. Glycemic parameters during first and last sensor use were examined in four identifiable groups: type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM) on basal-bolus insulin, T2DM on basal insulin, and T2DM without insulin treatment. Within each group, subgroup analyses were performed in persons with initial suboptimal glycemic regulation (time in range (TIR; 3.9-10 mmol/L) < 70%, time above range (TAR; >10 mmol/L) > 25%, or time below range (TBR; <3.9 mmol/L) > 4%). RESULTS: Data were obtained from 1,909 persons with T1DM and 1,813 persons with T2DM (1,499 basal-bolus insulin, 189 basal insulin, and 125 non-insulin users). In most of the performed analyses, both overall and in the various subgroups, significant improvements were observed in virtually all predefined primary (TIR) and secondary endpoints (eHbA1c, TAR, TBR and glucose variability). CONCLUSIONS: 24-weeks FLASH use in real life by persons with T1DM and T2DM with suboptimal glycemic regulation is associated with improvement of glycemic parameters, irrespective of pre-use regulation or treatment modality.

Determinants of excessive weight gain after the initiation of insulin therapy in type 2 diabetes mellitus: Retrospective inception cohort study (ZODIAC 60).

AIMS: To explore determinants of excessive weight gain after initiation of insulin therapy in type 2 diabetes mellitus (T2DM), in particular variables identified in the pre-insulin phase. METHODS: We performed a retrospective observational intervention cohort study, by means of a new user design/ inception cohort concerning n = 5086 patients. We studied determinants of excessive weight gain (5 kg or more) in the first year after initiation of insulin therapy, using both visualization and logistic regression analysis with subsequent receiver operation characteristic (ROC) analyses. Potential determinants pre-, at- and post-insulin initiation were included. RESULTS: One out of 10 patients (10.0%) gained 5 kg weight or more. The earliest determinants of excessive weight gain were weight change (inversely) and HbA1c change in the two years prior to insulin therapy (p < 0.001). Patients that lost weight parallel with HbA1c rise in the two-years pre-insulin, showed the most pronounced weight gain. Of these patients, roughly one out of five (20.3%) gained 5 kg weight or more. CONCLUSIONS: Clinicians and patients should be alert for excessive weight gain after initiation of insulin, in the case of weight loss prior to insulin therapy initiation, particularly with increasing and prolonged high HbA1c at (and after) insulin initiation.

Fibroblast Growth Factor 23, Glucose Homeostasis, and Incident Diabetes: Findings of 2 Cohort Studies.

CONTEXT: The phosphate-regulating hormone fibroblast growth factor 23 (FGF23) has been linked to deregulations in glucose metabolism, but its role is insufficiently understood. OBJECTIVE: This study investigates potential crosstalk between FGF23 and glucose homeostasis. METHODS: First, we investigated the effect of glucose loading on plasma C-terminal FGF23 levels and its temporal relationship with changes in plasma phosphate in 45 overweight (body mass index [BMI] 25-30) individuals using time-lag analyses. Second, we studied cross-sectional associations of plasma C-terminal FGF23 levels with glucose homeostasis using multivariable linear regression in a population-based cohort. We also investigated associations of FGF23 with incident diabetes and obesity (BMI > 30) in individuals without diabetes or obesity at baseline, respectively, using multivariable Cox regression analyses. Finally, we explored whether the association between FGF23 and diabetes depends on BMI. RESULTS: After glucose loading, changes in FGF23 preceded changes in plasma phosphate (Ptime-lag = .04). In the population-based cohort (N = 5482; mean age 52 years, 52% women, median FGF23 69 RU/mL), FGF23 was associated with plasma glucose (ß = .13 [.03-.23]; P = .01), insulin (ß = .10 [.03-.17]; P < .001), and proinsulin (ß = .06 [0.02-0.10]; P = .01) at baseline. On longitudinal analyses, a higher baseline FGF23 was independently associated with development of diabetes (199 events [4%]; fully adjusted hazard ratio [HR] 1.66 [95% CI, 1.06-2.60]; P = .03) and development of obesity (241 events [6%]; fully adjusted HR 1.84 [95% CI, 1.34-2.50]; P < .001). The association between FGF23 and incident diabetes lost significance after additional adjustment for BMI. CONCLUSION: Glucose loading has phosphate-independent effects on FGF23 and, vice versa, FGF23 is associated with glucose, insulin and proinsulin levels, and obesity. These findings suggest crosstalk between FGF23 and glucose homeostasis, which may promote susceptibility to incident diabetes.

Lower Extremity Amputation Rates in People With Diabetes Mellitus: A Retrospective Population Based Cohort Study in Zwolle Region, The Netherlands.

OBJECTIVE: Lower extremity amputations are a major complication of diabetes mellitus (DM). In a previous Dutch study, the incident rate of major amputations was 89.2 per 100 000 person years. The primary aim of this study was to describe the lower extremity amputation rates in people with DM in the Zwolle region, where preventive and curative footcare is organised according to the guidelines of the International Working Group of the Diabetic Foot (IWGDF). The secondary aim was to evaluate outcomes and underlying characteristics of these people. METHODS: This was a retrospective regional population based cohort study. Data from all people with DM treated in primary and secondary care, living in the region Zwolle were collected. All amputations in the period 2017 to 2019 were analysed. Comparisons were made between those with and without an amputation. RESULTS: In the analysis 5 915 people with DM were included, with a mean age of 67.8 (IQR 57.9, 75.9) years. Of those people, 47% were women and the median HbA1c was 53 (IQR 47, 62) mmol/mol. Over the three year study period 68 amputations were performed in 59 people: 46 minor, 22 major. This translated into an average annual crude amputation incidence rate of non-traumatic major and minor amputations of 41.5 and 86.9 per 100 000 person years among people with diabetes. Compared with those not undergoing amputations, those who underwent an amputation were more often men, older, mainly had T2DM, were treated in secondary care, had higher diastolic blood pressure, worse diabetic footcare profile, longer DM duration and higher HbA1c. At the end of the follow up, 111 people died: 96 (1.6%) without and 15 (25.4%) with amputations (p < .001). CONCLUSIONS: This retrospective study provides detailed insight into the rate of amputations in Dutch people with diabetes in the region Zwolle. Compared with previous Dutch estimates, these data suggest a considerable decrease in the major amputation incidence rate.

Plasma levels of GlycA, a pro-inflammatory glycoprotein biomarker, associate with an increased risk of microvascular complications in patients with type 2 diabetes (Zodiac-62).

PURPOSE: GlycA, a pro-inflammatory glycoprotein biomarker, associates with newly developed type 2 diabetes (T2D). We determined the association of plasma GlycA with the development of microvascular complications in patients with established T2D. METHODS: Plasma GlycA was measured by nuclear magnetic resonance spectrometry in T2D patients without microvascular complications at baseline (n = 145) participating in a longitudinal cohort study of primary care-treated T2D patients (Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) study). Associations of GlycA with incident microvascular complications including nephropathy, retinopathy, and neuropathy, were determined by Cox proportional hazards regression analyses. RESULTS: After a median follow-up of 3.2 (interquartile range [IQR]: 2.9-3.4) years, 49 patients (33.8%) developed one or more microvascular complications. Median GlycA levels were 453.5 (IQR: 402.0-512.8) µmol/l. GlycA was associated with incident microvascular complications (hazard ratio [HR] per 1-SD increment: 1.28 [95% confidence interval [CI]:1.00-1.63], P = 0.048]), even after adjustment for potential confounders and high-sensitive C-reactive protein (hs-CRP), HR 1.79 [95%CI:1.25-2.57], P = 0.001). In contrast, hs-CRP levels were not significantly associated with the risk of developing microvascular complications (P = 0.792). CONCLUSION: Higher plasma GlycA is associated with an increased risk of developing microvascular complications in T2D patients. Altered N-glycan branching associated with acute-phase reactive proteins may represent a preferred biomarker of systemic low-grade inflammation in predicting diabetic complications.

Type 1 diabetes management: Room for improvement.

AIMS/HYPOTHESIS: Optimal diabetes care and risk factor management are important to delay micro- and macrovascular complications in individuals with type 1 diabetes (T1D). Ongoing improvement of management strategies requires the evaluation of target achievement and identification of risk factors in individuals who do (or do not) achieve these targets. METHODS: Cross-sectional data were collected from adults with T1D visiting six diabetes centers in the Netherlands in 2018. Targets were defined as glycated hemoglobin (HbA1c) <53 mmol/mol, low-density lipoprotein-cholesterol (LDL-c) <2.6 mmoL/L (no cardiovascular disease [CVD] present) or <1.8 mmoL/L (CVD present), or blood pressure (BP) <140/90 mm Hg. Target achievement was compared for individuals with and without CVD. RESULTS: Data from 1737 individuals were included. Mean HbA1c was 63 mmol/mol (7.9%), LDL-c was 2.67 mmoL/L, and BP 131/76 mm Hg. In individuals with CVD, 24%, 33%, and 46% achieved HbA1c, LDL-c, and BP targets respectively. In individuals without CVD these percentages were 29%, 54%, and 77%, respectively. Individuals with CVD did not have any significant risk factors for HbA1c, LDL-c, and BP target achievement. In comparison, individuals without CVD were more likely to achieve glycemic targets if they were men and insulin pump users. Smoking, microvascular complications, and the prescription of lipid-lowering and antihypertensive medication were negatively associated with glycemic target achievement. No characteristics were associated with LDL-c target achievement. Microvascular complications and antihypertensive medication prescription were negatively associated with BP target attainment. CONCLUSION: Opportunities for improvement of diabetes management exist for the achievement of glycemic, lipid, and BP targets but may differ between individuals with and without CVD.

The association of low muscle mass with prevalence and incidence of type 2 diabetes in different BMI classes.

OBJECTIVE: The aim of this study is to investigate whether muscle mass is associated with the prevalence and incidence of type 2 diabetes and whether this association differs within men and women of normal weight, overweight or obesity. METHODS: Adult participants were included from the Lifelines cohort study. Low muscle mass was defined as < -1SD of the gender-stratified creatinine excretion rate (CER). Multivariate logistic regression analysis was used to assess the association between muscle mass and the prevalence and incidence of type 2 diabetes. RESULTS: Muscle mass was associated with the prevalence of type 2 diabetes both in men and in women (OR 1.51 [95 %CI 1.32-1.72]; P < 0.001 and OR 1.53 [1.36 - 1.73]; P < 0.001). Incident type 2 diabetes was associated with a decreased muscle mass for both men and women (male; OR 1.22 [1.05 - 1.43]; P = 0.01 and female; OR 1.36 [1.17 - 1.59]; P < 0.001), and remained significant after adjustments in normal weight women (OR 1.77 [1.16-2.70]; P = 0.008). CONCLUSIONS: Both a low muscle mass and loss of muscle mass are associated with the prevalence and incidence of diabetes in the general population. This association is strongest in people with normal weight, and weakens in people within higher BMI subgroups.