Effect of sodium-glucose cotransporter-2 inhibitors on continuous glucose monitoring metrics, as adjunctive to insulin in adults with type 1 diabetes mellitus: a meta-analysis of randomized controlled trials.

AIMS: This meta-analysis of randomized controlled trials (RCTs) aimed to evaluate the effect of sodium-glucose cotransporter-2 inhibitors (SGLT2is) on continuous glucose monitoring metrics as adjunctive to insulin in adults with type 1 diabetes mellitus (T1D). METHODS: A systematic literature search was conducted through Medline (via PubMed), Cochrane Library and Google Scholar until October 25, 2023. Dual-independent study selection, data extraction and quality assessment were conducted. Results were summarized with random effects meta-analysis. RESULTS: Eight RCTs were identified, involving a total of 2310 T1D patients. The use of SGLT2is on top of standard insulin therapy was associated with a significantly higher time in range (TIR) compared to placebo (mean difference (MD) 9.7 %; 95 % confidence interval (CI) [8.3, 1.11]; P < 0.001). The time above range was significantly lower in patients receiving SGLT2is (MD -8.71 %; 95 % CI [-11.62, -5.79]; P < 0.001), whereas no difference was observed regarding the time below range (TBR) (MD 0.34 %; 95 % CI [-0.17, 0.85]; P = 0.19). A significantly lower sensor-recorded mean daily glucose was noted in the group receiving SGLT2is (MD -16.55 mg/dL; 95 % CI [-19.82, -13.29]; P < 0.001). When considering the metrics of glucose variability, SGLT2is demonstrated a significant favorable effect on the mean amplitude of glucose excursions (MD -16.92 mg/dL; 95 % CI [-25.31, -8.13]; P < 0.001) and the mean standard deviation of weekly glucose levels (MD -7.67 mg/dL; 95 % CI [-11, -4.35]; P < 0.001). No significant effect was observed concerning the coefficient of variation (MD -1 %; 95 % CI [-2.39, 0.4]; P = 0.16). Regarding safety outcomes, SGLT2is were significantly linked to higher odds of diabetic ketoacidosis compared to insulin alone (OR 3.18; 95 % CI [1.79, 5.66]; P < 0.001), with no significant impact on severe hypoglycemia events (OR 1; 95 % CI [0.54, 1.85]; P = 0.1). CONCLUSION: Our findings suggest that in individuals with T1D, adjunct therapy with SGLT2is provides a significant benefit in terms of TIR and reduced glucose variability, without an increase in TBR.

Molecular Insights in Uterine Leiomyosarcoma: A Systematic Review.

Uterine fibroids (UFs) are the most common benign tumors of female genital diseases, unlike uterine leiomyosarcoma (LMS), a rare and aggressive uterine cancer. This narrative review aims to discuss the biology and diagnosis of LMS and, at the same time, their differential diagnosis, in order to distinguish the biological and molecular origins. The authors performed a Medline and PubMed search for the years 1990-2022 using a combination of keywords on the topics to highlight the many genes and proteins involved in the pathogenesis of LMS. The mutation of these genes, in addition to the altered expression and functions of their enzymes, are potentially biomarkers of uterine LMS. Thus, the use of this molecular and protein information could favor differential diagnosis and personalized therapy based on the molecular characteristics of LMS tissue, leading to timely diagnoses and potential better outcomes for patients.

Diffusion-weighted imaging in the assessment of renal function in patients with diabetes mellitus type 2.

OBJECTIVE: Investigation of functional magnetic resonance (MR) imaging role in early diagnosis of diabetic nephropathy (DN) in patients with diabetes mellitus (DM) type 2, by quantification of the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values. MATERIAL AND METHODS: 10 healthy volunteers and 91 DM type 2 patients were scanned using diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI) sequences. Patients were divided into four groups based on the estimated glomerular filtration value (eGFR). ADC and FA values, calculated in six regions of interest in each kidney (cortex and medulla), were compared to eGFR and laboratory parameters of renal function. RESULTS: ADC values of DM patients were higher in the cortex than in the medulla (p < 0.01), while FA values were higher in the medulla (p = 0.284). Creatinine, cystatin C negatively correlated with ADC (cortex, medulla, parenchyma). Medullary FA were lower in DM patients and positively correlated with the eGFR (p = 0.049). Tractography showed disturbed structure in patients with impaired renal function. DISCUSSION: Medullary FA value is a more sensitive parameter than parenchymal ADC in the early detection of renal damage in DM patients. ADC and FA values are significant in the diagnosis of DN; further research is needed for the update and refinement of the established recommendations.

Fecal pancreatic elastase-1 and erythrocyte magnesium levels in diabetes type 1 and type 2.

In both types of diabetes mellitus (DM), type 1 and type 2 (T1DM and T2DM), there are both endocrine and exocrine dysfunctions of the pancreas (PED), as well as disturbances in serum magnesium levels. The aim of this study was to examine the frequency of PED according to the level of fecal elastase-1 (FE-1) in patients with T1DM and T2DM, determining the correlation of the level of FE-1 with certain anthropometric parameters, certain indicators of metabolic regulation of diabetes, and certain nutritive markers of PED. MATERIALS AND METHODS: In the examinees, (56 with T1DM (F = 35 and M = 21), 62 with T2DM (F = 30 and M = 32), and 40 in the control group (F = 19 and M = 21)), we examined anthropometric parameters, and using standard biochemical methods, we measured the level of FE-1, magnesium concentration in blood and erythrocytes, and selected blood parameters. RESULTS: FE-1 concentration < 200 µg/g was present in 14.2% of the examinees with T1DM, 20.9% with T2DM, and 2.5% in the control group. In all examinees with DM, there was a statistically significant correlation (P < 0.05) between the level of FE-1 and Mg concentration in the erythrocytes (R = 0.40). CONCLUSIONS: Prevalence of pancreatic exocrine insufficiency (PEI), according to the level of FE-1, is significantly higher in patients with DM than in the control group, while it is a bit higher in patients with T2DM than the ones with T1DM. In both types of DM, Mg concentration in erythrocytes is in a significant correlation with the level of FE-1.

1h Post-load Blood Glucose in the Identification of Proatherogenic Cardiometabolic Profile in Obesity.

BACKGROUND AND AIM: Current data show that 1h oral glucose tolerance test (OGTT) blood glucose (1h-BG) might identify persons at increased risk of developing type 2 diabetes and cardiovascular diseases more precisely than fasting blood glucose (FBG) and 2h OGTT blood glucose (2h-BG). The aim of study was to determine whether is justified to use 1h-BG over traditional blood glucose measurements, in cardiometabolic profiling of obese individuals. METHOD: Cross-sectional study enrolled 60 obese individuals without previous history of diabetes and other cardiometabolic disorders. Anthropometrical, ultrasound and laboratory examinations were conducted. RESULTS: All three parameters significantly directly correlated with age, body mass index, waist circumference, erythrocyte sedimentation rate, C-reactive protein, triglycerides and glycated hemoglobin. FBG and 1h-BG significantly directly correlated with alanine transaminase, gammaglutamyltransferase and total cholesterol. FBG significantly directly correlated with fibrinogen and aspartate transaminase, 1h-BG with systolic blood pressure and 2h-BG with diastolic blood pressure. None of parameters significantly correlated with gender, total white blood cell count, uric acid, 25-hydroxyvitamin D, high density lipoprotein cholesterol, low density lipoprotein cholesterol, serum adiponectin and albuminuria. Differences in correlation coefficients were not statistically significant. Individuals with 1h-BG >8.6 mmol/l had much more proatherogenic cardiometabolic profile, as well as higher incidence of dysglycemia, metabolic syndrome (MetS) and non-alcoholic fatty liver disease (NAFLD) than ones with 1h-BG <8.6 mmol/l, but all differences were driven by the average value of glycemia. There were no statistically significant differences in ability of predicting MetS, NAFLD and pathologically increased carotid artery intima media thickness among analyzed glucose metabolism parameters. CONCLUSION: 1h-BG is not superior to FBG and 2h-BG in the identification of proatherogenic cardiometabolic profile in obesity.

The Wnt/ß-catenin Signalling Pathway Inhibitor Sclerostin is a Biomarker for Early Atherosclerosis in Obesity.

BACKGROUND: Sclerostin is an inhibitor of the wingless-type mouse mammary tumor virus integration site family/ß-catenin signalling pathway (WßcSP), which plays an important role in bone metabolism and in vascular biology. It could act protective regarding atherosclerosis development through its effect on WßcSP in vascular cells. Nevertheless, results of studies analyzing association between circulating sclerostin level (CSL) and atherosclerotic diseases (AD) are showing conflicting results. The aim of this study is to test the value of CSL as a biomarker of subclinical carotid atherosclerosis (SCA) in obese persons. METHODS: The cross-sectional study included 50 obese persons without previous history of diabetes and AD. Participants underwent adequate anthropometrical, ultrasound and laboratory examinations, including 2h 75 g oral glucose tolerance test (OGTT). RESULTS: Only the presence of SCA significantly indirectly correlated with CSL (p<0.05). Based on the median value of CSL, we formed two groups: low CSL (CSL<7.9 pmol/l) and high CSL (CSL>7.9 pmol/l). There were no statistically significant differences in general (gender, age and current smoking) and anthropometrical characteristics (body mass index, waist circumference, systolic and diastolic blood pressure), inflammatory (total white blood cell count, erythrocyte sedimentation rate, fibrinogen, C-reactive protein and uric acid), glucose metabolism (fasting and 2h OGTT blood glucose, glycated hemoglobin and presence of dysglycemia) and lipid metabolism (low density lipoprotein cholesterol, high density lipoprotein cholesterol, triglycerides, apolipoprotein A-I, apolipoprotein B and lipoprotein (a)) parameters between low and high CSL groups. Low CSL group had significantly higher incidence of SCA (p<0.05). CONCLUSION: CSL could serve as a useful biomarker of early atherosclerosis in obese persons without previous history of cardiometabolic disorders but the final conclusion requires further testing.

Surrogates of Insulin Sensitivity and Indices of Cardiometabolic Profile in Obesity.

BACKGROUND AND OBJECTIVES: Obesity is often associated with insulin resistance (IR). We considered different IR indexes: the Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) index, the two specimen (0 and 120 min) oral glucose tolerance test Matsuda Index (MI) and the Homeostasis Model Assessment-Adiponectin (HOMA-AD) index. These IR indexes were compared with indicators of the cardiometabolic profile. METHOD: This cross-sectional study enrolled 60 obese individuals without previous history of diabetes. Anthropometrical, ultrasound and laboratory examinations were conducted. RESULTS: All 3 indexes significantly correlated with indicators of central obesity, systolic and diastolic blood pressure, inflammation parameters, liver enzymes, HbA1c and some lipid parameters. The majority of correlation coefficients were the highest for HOMA-AD, but only the difference in correlation with waist circumference comparing with MI was statistically significant. HOMA-IR directly, and MI indirectly, significantly correlated with age, while HOMA-AD significantly directly correlated with the mean carotid artery intima media thickness (CAIMT). MI showed the best performances in predicting non-alcoholic fatty liver disease and pathologically increased CAIMT; HOMA-AD was the best in predicting metabolic syndrome, while HOMA-IR demonstrated the poorest performances in the prediction of all 3 conditions. There were no statistically significant differences in predicting performances of the analysed indexes. CONCLUSION: The HOMA-AD and MI are not superior compared with the HOMA-IR, in the identification of obese individuals with a proatherogenic cardiometabolic profile.

Intravitreal bevacizumab injection alone or combined with macular photocoagulation compared to macular photocoagulation as primary treatment of diabetic macular edema.

BACKGROUND/AIM: Within diabetic retinopathy (DR), diabetic macular edema DIE) is one of the leading causes of the loss of visual acuity. The aim of this study was to determine the efficacy of the intravitreal vascular endothelial growth factor (VEGF) inhibitor application alone or combined with macular focal/grid lasephotocoagulation compared with laser treatment alone. METHODS: This prospective randomized clinical trial included 72 patients (120 treated eyes) with varying degrees of DR and DME. The DME treatment included intravitreal VEGF inhibitor bevacizumab (Avasting) application, with and without laser treatment. Bevacizumab (1.25 mg/0.05 mL) was administered intravitreally in 4-6-week intervals. Laser is applied 4-6 weeks after last dose of the drug as a part of combined treatment, or as the primary treatment. RESULTS: The mean reduction in central macular thickness (CMT) for the eyes (n = 31) treated with bevacizumab alone was 162.23 .rm, for the eyes (n = 53) treated with combined treatment the mean reduction in CMT was 124.24 pm, both statistically significant at p < 0.001. Laser macular photocolagulation as a part of combined treatment (in 53 eyes) significantly contributed to the CMT reduction, based on the paired t-test results (366.28 vs. 323.0 pLm at p < 0.05). In our study, the mean visual acuity improvement of 0.161 logMAR was achieved in the group of eyes treated with bevacizumab alone, and 0.093 logMAR in the group with combined treatment, both statistically significant atp < 0.05. The effect of laser photocolagulation alone on visual acuity and'CMT was not statistically significant. CONCLUSION: Treatment with bevacizumab alone or within combined treatment is more effective in treating DME than conventional macular laser treatment alone, both anatomically and functionally.

Obesity and vitamin D deficiency: trends to promote a more proatherogenic cardiometabolic risk profile.

Vitamin D deficiency is associated with cardiometabolic risk factors (eg, hypertension, insulin resistance, type 2 diabetes mellitus, obesity, and dyslipidemia). We studied 50 obese patients (body mass index [BMI]: 43.5 ± 9.2 kg/m(2)) and 36 normal weight participants (BMI: 22.6 ± 1.9 kg/m(2)). The prevalence of vitamin D deficiency (25-hydroxyvitamin D, 25(OH)D < 50 nmol/L) was 88% among obese patients and 31% among nonobese individuals; 25(OH)D levels were lower in the obese group (27.3 ± 13.7 vs 64.6 ± 21.3 nmol/L; P < .001). There was a negative correlation between vitamin D level and anthropometric indicators of obesity: BMI (r = -0.64; P < .001), waist circumference (r = -0.59; P < .001), and body fat percentage (r = -0.64; P < .001) as well as with fasting plasma insulin (r = -0.35; P < .001) and homeostasis model assessment of insulin resistance (r = -0.35; P < .001). In conclusion, we observed a higher prevalence of vitamin D deficiency among obese participants and this was associated with a proatherogenic cardiometabolic risk profile.

The impact of diabetes mellitus on the course and outcome of pregnancy during a 5-year follow-up.

BACKGROUND/AIM: Women with diabetes, especially diabetes type 1, have worse pregnancy outcomes, as well as increased incidence of spontaneous abortions, pre-eclampsia, fetal macrosomia, preterm delivery, congenital anomalies and perinatal mortality. The aim of this study was to analyze the course and outcome of pregnancy in the patients with diabetes in relation to the group of healthy women regarding preterm delivery, perinatal morbidity and mortality. Also, the aim was to compare pregnancy outcomes in the patients with pre-existing diabetes type 1 and the patients with gestational and diabetes type 2. METHODS: This retrospective study included 156 diabetic women treated at the Clinic of Endocrinology, Diabetes and Metabolic Diseases and Gynecology and Obstetrics Clinic of the Clinical Center of Vojvodina from 2006 to 2010. There were 94 patients with gestational diabetes, 48 with type 1 diabetes, and 14 patients with type 2 diabetes. The control group included 106 healthy women hospitalized at the Gynecology and Obstetrics Clinic. RESULTS: The women with type 1 diabetes presented with a statistically significantly higher incidence of cesarean section than those without diabetes, or with type 2 or gestational diabetes (p < 0.0001); the women with type 1 diabetes delivered at an earlier week of gestation (WG) in regard to women without diabetes, or with type 2 or gestational diabetes (p = 0.0017 and p = 0.02, respectively). The incidence of perinatal morbidity: hypoglycemia (p < 0.001), pathological jaundice (p = 0.0021), and other neonatal pathologies at birth (p = 0.0031), was statistically significantly higher and Apgar scores after 1 minute (p = 0.0142) and after 5 minutes (p = 0.0003) were statistically significantly lower in the patients with diabetes compared to the healthy women. The women with type 2 and gestational diabetes were statistically significantly older than those with type 1 diabetes (p = 0.001). A higher incidence of fetal macrosomia in the women with gestational and type 2 diabetes compared to those with type 1 diabetes was at the borderline of statistical significance (p = 0.07), whereas the incidence of hypoglycemia of newborn was statistically significantly higher in the patients with type 1 diabetes (p < 0.0001). Glycosylated hemoglobin (HbA1c) levels were statistically significantly higher in the diabetic women giving birth during and before the week of gestation 36 (p = 0.0087), but there were no differences in HbA1lc levels in regard to fetal macrosomia (p = 0.45) and congenital abnormalities (p = 0.32). CONCLUSION: The results of our study show a higher incidence of perinatal fetal morbidity (hypoglycemia, jaundice, respiratory distress syndrome) in the patients with type 1, type 2 and gestation diabetes than in the healthy controls. Also, we found a higher incidence of cesarean section in the patients with type 1 diabetes than in those with type 2, gestation diabetes and healthy controls. Although delivery in the patients with type 1, type 2 and gestational diabetes was completed approximately one to two weeks earlier compared to the healthy controls there was no statistically significant difference in the incidence of preterm delivery (≤ 36th week of gestation) between the women with diabetes and healthy controls. Preterm delivery associated with poorer glycaemic control reflected through higher values of HbA1c in third trimester. Risks from adverse pregnancy outcomes may be reduced to minimum by adequate preconception counseling of diabetic patients and early diagnosis of diabetes in pregnancy, in order to achieve glycemic control during organogenesis and within pregnancy and through the teamwork of endocrinologists, gynecologists and pediatricians.

Laparoscopic body-tail pancreatic resection for insulinoma.

INTRODUCTION: Insulinomas are the most common endocrine tumours of the pancreas. They are more frequent in females, and they are commonly less than 2 cm in diameter. If conservative treatment of typical clinical symptoms fails, detailed diagnostic procedures are necessary and surgical treatment is indicated.The aim of this report was to emphasize the need of pancreatic resection when insulinoma is poorly visualized during surgery and when it is not possible to perform intraoperative ultrasonography. CASE OUTLINE: A 27-year-old female patient suffered from hypoglycaemic episodes during physical efforts and fasting periods. After examination, diagnostic procedures and preoperative preparation, laparoscopic surgery was performed. The tumour was less than 10 mm in diameter, and it could not be visualized during laparoscopic exploration. The body and the tail of the pancreas were mobilized using ultrasound scissors and the resection was performed by two Endo GIA staplers. The surgical specimen was removed in an endo-bag. The postoperative course was without complications and the glycemic level was normalized. Macroscopic examination of the resected specimen showed a solitary, poorly demarcated, dark grey lesion, 0.8 cm in diameter, with a solid consistence in comparison with the surrounding gland tissue. Histological examination showed a poorly demarcated, subcapsular tissue in this area, consisting of uniform, irregular, cubic and short cylindrical cells, organized in clusters with pseudoglandular and "zellballen" formations. CONCLUSION: In case when the insulinoma is so small in size that it cannot be visualized during operation, pancreas resection is a surgical procedure of choice. Laparoscopic surgery is preferred because of less postoperative complications and faster recovery.

Influence of glucoregulation quality on C-reactive protein, interleukin-6 and tumor necrosis factor-alpha level in patients with diabetes type 1.

BACKGROUND/AIM: Results of studies which have proved an increased inflammatory activity in diabetes type 1, have been published over recent years. One of possible mechanisms that are used to explain chronic inflammation in diabetes is the state of hyperglycemia leading to the enhanced synthesis of glycosylation end products (AGEs) which activate macrophages, increase the oxidative stress and affect the synthesis of interleukins (IL-1, IL-6), tumor necrosis factor-alpha (TNF-alpha) and C-reactive protein (CRP). The aim of the study was to determine the inflammatory markers (CRP, IL-6, TNF-alpha) in patients with diabetes type 1 and to establish their correlation with glucoregulation parameters and other cardiovascular risk factors as well as to compare them with the healthy controls. METHODS: The study included 76 patients with diabetes type 1 and 30 healthy controls. We determined values of inflammatory markers (CRP, IL-6, TNF-alpha) and glucoregulation parameters (fasting glucose HbA(1c)). RESULTS: The values of CRP (p = 0.014), IL-6 (p = 0.020) and TNF-alpha (p = 0.037) were statistically significantly higher in the diabetic patients than in the healthy controls. There was a positive correlation between CRP with postprandial glycemia (p = 0.004); the multivariate regression analysis revealed a statistically significant correlation between CRP and age (p = 0.001), smoking (p = 0.055), fasting glucose (p = 0.021) and triglycerides (p = 0.048) as well as between IL-6 and LDL-cholesterol (p = 0.009). No statistically significant correlations were found between glycosilated hemoglobin (HbA(1c)) and the inflammatory markers (CRP, IL-6 and TNF-alpha). CONCLUSION: The patients with type 1 diabetes were found to have a low level of inflammatory activity manifested by the increased values of CRP, IL-6 and TNF-alpha.

[The role of insulin analogues in the current treatment of diabetes mellitus].

INTRODUCTION: Ever since insulin was discovered by Banting and Best in 1921, all further researches in this field had been conducted with one goal: to find new insulin molecules which would provide better glycemic control with fewer side effects i.e. to mimic endogenous physiological insulin secretion. NORMAL INSULIN SECRETION: In healthy individuals, endogenous insulin secretion can be classified as basal (which provides basal glucose homeostasis) and stimulated (as a response to a meal). Conventional insulin preparations--human insulin, have time-action profiles that cannot fully immitate endogenous insulin secretion, thus leading to postprandial hyperglicemia and high glycemic oscilations during the day. RAPID-ACTING ANALOGUES: Rapid acting analogues should have a time-action profile with onset of less than one hour, duration less than four hours, hypoglycemic potency equal or greater than that of human insulin, and similar effects in all patients. Two rapid action analogues, lispro and aspart are available. BASAL INSULIN ANALOGUES: The ideal basal insulin should provide slow and constant absorption, long half-life that would provide once daily dosing (or every other day), and peakless effect. Insulin glargine led to solubility at pH 4 and to slow absorption in neutral pH environment. Insulin detemir is a soluble insulin analogue with neutral pH and affinity to bind to serum albumin, thus gaining prolonged action. MITOGENIC INFLUENCE: The mitogenic influence of insulin is due to the affinity to bind to IGF-I receptors. Following two-year administration of glargine in mice and rats, systemic carcinogenic potential was not found, though there were reports of hepatocellular carcinomas, which are frequently found in these animals. CONCLUSION: In the last two decades, many trials have shown that unsatisfactory glycemic control leads to chronic complications in both types of diabetes. Using basal glucose level, postprandial glycemy and HbA1c as metabolic parameters, it has been proven that only strict glycemic control can lower the risk of developing complications. Discovery of insulin analogues (both rapid acting and basal) enables physicians to provide better glycoregulation and less hypoglycemic incidents to their patients.