Maternal and Perinatal Outcomes During the COVID-19 Epidemic in Pregnancies Complicated by Gestational Diabetes.

Introduction: Gestational diabetes (GDM) is one of the most common complications in pregnancy, with a prevalence that continues to rise. At the time of the COVID-19 epidemic, immediate reorganisation and adjustment of the system was needed. Telemedicine support was offered in order to provide high-quality treatment to pregnant women. However, the success of the treatment is unknown. We therefore aimed to evaluate COVID-19 epidemic effects on pregnancy outcomes in GDM. Methods: The maternal outcomes (insulin treatment, gestational weight gain, caesarean section, hypertensive disorders) and perinatal outcomes (rates of large and small for gestational age, preterm birth and a composite child outcome) of women visiting a university hospital diabetes clinic from March to December 2020 were compared with those treated in the same period in 2019. Results: Women diagnosed with GDM during the COVID-19 epidemic (n=417), were diagnosed earlier (23.9 [11.7-26.0] vs. 25.1 [21.8-26.7] gestational week), had higher fasting glucose (5.2 [5.0-5.4] vs. 5.1 [4.8-5.3] mmol/l) and earlier pharmacological therapy initiation, and had achieved lower HbA1c by the end of followup (5.1% (32.2 mmol/mol) [4.9% (30.1 mmol/mol)-5.4% (35.0 mmol/mol)] vs. 5.2% (33.3 mmol/mol) [5.0% (31.1 mmol/mol) - 5.4%·(35.5 mmol/mol)], p<0.001) compared to a year before (n=430). No significant differences in perinatal outcomes were found. Conclusions: Although GDM was diagnosed at an earlier gestational age and higher fasting glucose concentration was present at the time of diagnosis, the COVID-19 epidemic did not result in worse glucose control during pregnancy or worse pregnancy outcomes in Slovenia.

Presence and Determinants of Cardiovascular Disease and Mortality in Individuals With Type 1 Diabetes of Long Duration: The FinnDiane 50 Years of Diabetes Study.

OBJECTIVE: The aim of this study was to determine the incidence of cardiovascular disease (CVD) and mortality as well as their risk factors in type 1 diabetes (T1D) of >50 years' duration. RESEARCH DESIGN AND METHODS: From 5,396 individuals included in the Finnish Diabetic Nephropathy Study (FinnDiane), 729 diagnosed in 1967 or earlier survived with T1D for >50 years. In this FinnDiane 50-year cohort, cumulative incidence of CVD events was assessed from the diagnosis of diabetes, and the excess CVD risk, compared with 12,710 matched individuals without diabetes. In addition, risk factors for different types of CVD (both nonfatal and fatal) and mortality were analyzed, and cause-specific hazard ratios were estimated during a median follow-up of 16.6 years from the baseline visit (median duration of diabetes 39 years at baseline). RESULTS: In individuals with diabetes duration of >50 years, the 60-year cumulative incidence of CVD from the diagnosis of diabetes was 64.3% (95% CI 62.5-66.0). Compared with individuals without diabetes, the standardized incidence ratio for CVD was 7.4 (6.5-8.3); in those with normoalbuminuria, it was 4.9 (4.0-5.9). Mean HbA1c and HbA1c variability, dyslipidemia, BMI, kidney disease, age, and diabetes duration were the variables associated with incident CVD. In particular, HbA1c was associated with peripheral artery disease (PAD). The standardized mortality ratio compared with the Finnish background population was 3.2 (2.8-3.7). The factors associated with mortality were diabetes duration, increased HbA1c variability, inflammation, insulin resistance, kidney disease, and PAD. CONCLUSIONS: Individuals with T1D of very long duration are at a high risk of CVD. In addition, throughout the lifespan, optimal glycemic control remains central to CVD and excess mortality prevention.

Non-proteinuric pathways in loss of renal function in patients with type 2 diabetes.

Largely on the basis of data from patients with type 1 diabetes, the natural history of diabetic renal disease has been classified as a sequence of three stages: normoalbuminuria, microalbuminuria, and macroalbuminuria. Progressive decline of glomerular filtration rate (GFR) was thought to parallel the onset of macroalbuminuria (overt nephropathy), whereas glomerular hyperfiltration was deemed a hallmark of early disease. However, researchers have since shown that albuminuria is a continuum and that GFR can start to decline before progression to overt nephropathy. In addition to proteinuria, other risk factors might contribute to GFR deterioration including female sex, obesity, dyslipidaemia (in particular hypertriglyceridaemia), hypertension, and glomerular hyperfiltration, at least in a subgroup of patients. This phenomenon could explain why patients with type 2 diabetes can have renal insufficiency even before the onset of overt nephropathy, and might also suggest why the heterogeneous phenotype of type 2 diabetic renal disease does not necessarily associate with typical histological lesions of diabetic renal disease, unlike in type 1 diabetic renal disease. Patients with renal insufficiency but without albuminuria are usually excluded from randomised clinical trials in overt nephropathy, thus optimum treatment for this group of patients is unknown. The wide inter-patient variability of the disease probably needs individually tailored intervention.

Effects of manidipine and delapril in hypertensive patients with type 2 diabetes mellitus: the delapril and manidipine for nephroprotection in diabetes (DEMAND) randomized clinical trial.

To assess whether angiotensin-converting enzyme inhibitors and third-generation dihydropyridine calcium channel blockers ameliorate diabetic complications, we compared glomerular filtration rate (GFR; primary outcome), cardiovascular events, retinopathy, and neuropathy in 380 hypertensive type 2 diabetics with albuminuria <200 mg/min included in a multicenter, double-blind, placebo-controlled trial (DEMAND [Delapril and Manidipine for Nephroprotection in Diabetes]) and randomized to 3-year treatment with manidipine/delapril combination (10/30 mg/d; n=126), delapril (30 mg/d; n=127), or placebo (n=127). GFR was centrally measured by iohexol plasma clearance. Median monthly GFR decline (interquartile range [IQR]) was 0.32 mL/min per 1.73 m(2) (IQR: 0.16-0.50 mL/min per 1.73 m(2)) on combined therapy, 0.36 mL/min per 1.73 m(2) (IQR: 0.18-0.53 mL/min per 1.73 m(2)) on delapril, and 0.30 mL/min per 1.73 m(2) (IQR: 0.12-0.50 mL/min per 1.73 m(2)) on placebo (P=0.87 and P=0.53 versus combined therapy or delapril, respectively). Similar findings were observed when baseline GFR values were not considered for slope analyses. Albuminuria was stable in the 3 treatment groups. The hazard ratio (95% CI) for major cardiovascular events between combined therapy and placebo was 0.17 (0.04-0.78; P=0.023). Among 192 subjects without retinopathy at inclusion, the hazard ratio for developing retinopathy between combined therapy and placebo was 0.27 (0.07-0.99; P=0.048). Among 200 subjects with centralized neurological evaluation, the odds ratios for peripheral neuropathy at 3 years between combined therapy or delapril and placebo were 0.45 (0.24-0.87; P=0.017) and 0.52 (0.27-0.99; P=0.048), respectively. Glucose disposal rate decreased from 5.8±2.4 to 5.3±1.9 mg/kg per min on placebo (P=0.03) but did not change on combined or delapril therapy. Treatment was well tolerated. In hypertensive type 2 diabetic patients, combined manidipine and delapril therapy failed to slow GFR decline but safely ameliorated cardiovascular disease, retinopathy, and neuropathy and stabilized insulin sensitivity.

RAGE biology, atherosclerosis and diabetes.

Diabetes is characterized by accelerated atherosclerosis with widely distributed vascular lesions. An important mechanism by which hyperglycaemia contributes to vascular injury is through the extensive intracellular and extracellular formation of AGEs (advanced glycation end products). AGEs represent a heterogeneous group of proteins, lipids and nucleic acids, irreversibly cross-linked with reducing sugars. AGEs are implicated in the atherosclerotic process, either directly or via receptor-mediated mechanisms, the most extensively studied receptor being RAGE (receptor for AGEs). The AGE-RAGE interaction alters cellular signalling, promotes gene expression and enhances the release of pro-inflammatory molecules. It elicits the generation of oxidative stress in numerous cell types. The importance of the AGE-RAGE interaction and downstream pathways leading to injurious effects as a result of chronic hyperglycaemia in the development, progression and instability of diabetic atherosclerotic lesions has been amply demonstrated in animal studies. Moreover, the deleterious link of AGEs with diabetic vascular complications has been suggested in many human studies. In the present review, our current understanding of their role as an important mediator of vascular injury through the various stages of atherosclerosis in diabetes will be reviewed and critically assessed.

Association between adiponectin and low-grade albuminuria is BMI-dependent in type 2 diabetes.

AIM: Low-grade albuminuria is a marker of increased risk for both cardiovascular and renal disease. Adiponectin, with its insulin-sensitizing, anti-inflammatory and antiatherogenic properties, is associated with cardiovascular as well as renal disease. Limited and conflicting data exist on the association of adiponectin with low-grade albuminuria. Our aim was to explore the association of plasma adiponectin and low-grade albuminuria in patients with type 2 diabetes. Furthermore, we were interested whether this association is dependent upon insulin sensitivity. METHODS: In this cross-sectional study, plasma adiponectin and urinary albumin excretion rate (UAER) were determined in 71 patients by radioimmunoassay. Insulin sensitivity was measured by hyperinsulinemic euglycemic clamp and expressed as the M value. The relationship between variables was described using univariate and multiple linear regression. RESULTS: Adiponectin and UAER were negatively associated (R = -0.285, p < 0.05) only in patients with BMI >25. The association was independent of the clamp-derived M value, gender, BMI, arterial pressure or cholesterol. CONCLUSION: In obese patients with type 2 diabetes, there is an inverse association between adiponectin and low-grade albuminuria, the association being independent of insulin resistance. The consequences of such a relationship in terms of renal disease progression and cardiovascular survival remain to be evaluated.

Adipocytokines are associated with renal function in patients with normal range glomerular filtration rate and type 2 diabetes.

INTRODUCTION: Adipocytokines represent a molecular link between metabolic factors and vascular function. The purpose of our study was to investigate the relationship between adiponectin, leptin and renal function parameters in patients with glomerular filtration rate (GFR) above 90 ml/min/m(2) and type 2 diabetes. MATERIALS AND METHODS: In 52 patients, plasma (P-) and urinary (U-) adiponectin and leptin were determined by radioimmunoassay and ELISA, respectively. Kidney function was assessed with GFR (plasma iohexol clearance) and albuminuria (radioimmunoassay). RESULTS: The patients were aged 58+/-8 years and had a mean BMI value of 31.2+/-5.2 kg/m(2). Our measurements yielded the following values, expressed as median (25th percentile, 75th percentile): P-adiponectin 11.0 (7.1, 14.5) microg/ml, P-leptin 20.7 (9.6, 35.9)ng/ml, U-adiponectin 0.8 (0.3, 1.2) microg/mg creatinine, and U-leptin 1.0 (0.4, 1.9) microg/mg creatinine. Albuminuria correlated with P-adiponectin (R=-0.31, p=0.03), and GFR correlated with U-leptin (R=-0.32, p=0.04). CONCLUSIONS: Adiponectin and leptin are associated with parameters of renal function already at the stage of apparently normal kidney function in type 2 diabetes. The exact mechanisms of the adipocyte-vasculature axis still remain to be elucidated.