Pancreatic beta-cell function dynamics in youth with GCK, HNF1A, and KCNJ11 genes mutations during mixed meal tolerance test.

OBJECTIVE: The aims were (1) to assess beta-cell function in GCK diabetes patients over 2-year period; (2) to evaluate the dynamics of beta-cell function in HNF1A and KCNJ11 patients after treatment optimization; using mixed meal tolerance test (MMTT) as a gold standard for non-invasive beta-cell function assessment. RESEARCH DESIGN AND METHODS: Twenty-two GCK diabetes patients, 22 healthy subjects, 4 patients with HNF1A and 2 with KCNJ11 were recruited. Firstly, beta-cell function was compared between GCK patients versus controls; the dynamics of beta-cell function were assessed in GCK patients with two MMTTs in 2-year period. Secondly, the change of beta-cell function was evaluated in HNF1A and KCNJ11 patients after successful treatment optimization in 2-year period. RESULTS: GCK diabetes patients had lower area under the curve (AUC) of C-peptide (CP), average CP and peak CP compared to controls. Also, higher levels of fasting, average, peak and AUC of glycemia during MMTT were found in GCK patients compared to healthy controls. No significant changes in either CP or glycemia dynamics were observed in GCK diabetes group comparing 1st and 2nd MMTTs. Patients with HNF1A and KCNJ11 diabetes had significantly improved diabetes control 2 years after the treatment was optimized (HbA1c 7.1% vs. 5.9% [54 mmol/mol vs. 41 mmol/mol], respectively, p = 0.028). Higher peak CP and lower HbA1c were found during 2nd MMTT in patients with targeted treatment compared to the 1st MMTT before the treatment change. CONCLUSION: In short-term perspective, GCK diabetes group revealed no deterioration of beta-cell function. Individualized treatment in monogenic diabetes showed improved beta-cell function.

Serum Cystatin C as a Biomarker for Early Diabetic Kidney Disease and Dyslipidemia in Young Type 1 Diabetes Patients.

Background and objectives: This study aimed to assess the clinical significance of serum cystatin C in the early diagnosis of renal injury and its association with dyslipidemia in young T1D patients. Materials and Methods: A total of 779 subjects were evaluated for kidney function by estimating glomerular filtration rate (eGFR) based on serum creatinine (eGFRcreat) and cystatin C (eGFRcys). Results: The median age of study subjects was 16.2 years (2.1;26.4), diabetes duration-5.3 years (0.51;24.0). The median of HbA1c was 8% (5.2;19.9) (64 mmol/mol (33.3;194)); 24.2% of participants had HbA1c < 7% (53 mmol/mol). Elevated albumin excretion rate was found in 13.5% of subjects. The median of cystatin C was 0.8 mg/L (0.33;1.71), the median of creatinine-63 µmol/L (6;126). The median of eGFRcys was lower than eGFRcreat (92 mL/min/1.73 m2 vs. 101 mL/min/1.73 m2, p < 0.001). A total of 30.2% of all patients were classified as having worse kidney function when using cystatin C vs. creatinine for eGFR calculation. Linear correlations were found between cystatin C and HbA1c, r = -0.088, p < 0.05, as well as cystatin C and HDL, r = -0.097, p < 0.01. Conclusions: This study showed that cystatin C might be used as an additional biomarker of early kidney injury in young patients with T1D.

Kinetics of C-peptide during mixed meal test and its value for treatment optimization in monogenic diabetes patients.

AIM: The mixed meal tolerance test (MMTT) is a gold standard for evaluating beta-cell function. There is limited data on MMTT in monogenic diabetes (MD). Therefore, we aimed to analyze plasma C-peptide (CP) kinetics during MMTT in young MODY and neonatal diabetes patients as a biomarker for beta-cell function. METHODS: We included 41 patients with MD diagnosis (22 GCK, 8 HNF1A, 3 HNF4A, 4 KCNJ11, 2 ABCC8, 1 INS, 1 KLF11). Standardized 3-hour MMTT with glycemia and plasma CP measurements were performed for all individuals. Pancreatic beta-cell response was assessed by the area under the curve CP (AUCCP), the baseline CP (CPBase) and the peak CP (CPmax). Threshold points of CPBase, CP90, CPmax and CPAUC were determined from analysis of ROC curves. RESULTS: GCK diabetes patients had significantly higher AUCCP, CPBase and CPmax compared to HNF4A and KCNJ11 patients. In HNF4A, KCNJ11 and ABCC8 patients with all CP levels < 200 pmol/L, the treatment change attempt to sulfonylurea agent was unsuccessful. The ROC analysis showed that CP baseline threshold equal or higher to 133.5 pmol/L could be used to predict successful switch to oral agents. CONCLUSION: A pretreatment challenge with MMTT might be used to guide the optimal treatment after molecular diagnosis of MD.

Systematic Genetic Study of Youth With Diabetes in a Single Country Reveals the Prevalence of Diabetes Subtypes, Novel Candidate Genes, and Response to Precision Therapy.

Identifying gene variants causing monogenic diabetes (MD) increases understanding of disease etiology and allows for implementation of precision therapy to improve metabolic control and quality of life. Here, we aimed to assess the prevalence of MD in youth with diabetes in Lithuania, uncover potential diabetes-related gene variants, and prospectively introduce precision treatment. First, we assessed all pediatric and most young-adult patients with diabetes in Lithuania (n = 1,209) for diabetes-related autoimmune antibodies. We then screened all antibody-negative patients (n = 153) using targeted high-throughput sequencing of >300 potential candidate genes. In this group, 40.7% had MD, with the highest percentage (100%) in infants (diagnosis at ages 0-12 months), followed by those diagnosed at ages >1-18 years (40.3%) and >18-25 years (22.2%). The overall prevalence of MD in youth with diabetes in Lithuania was 3.5% (1.9% for GCK diabetes, 0.7% for HNF1A, 0.2% for HNF4A and ABCC8, 0.3% for KCNJ11, and 0.1% for INS). Furthermore, we identified likely pathogenic variants in 11 additional genes. Microvascular complications were present in 26% of those with MD. Prospective treatment change was successful in >50% of eligible candidates, with C-peptide >252 pmol/L emerging as the best prognostic factor.

Factors Affecting Cardiovascular Risk in Children, Adolescents, and Young Adults with Type 1 Diabetes.

Cardiovascular risk and obesity are becoming major health issues among individuals with type 1 diabetes (T1D). The aim of this study was to evaluate cardiovascular risk factors and obesity in youth with T1D in Lithuania. Methods. 883 patients under 25 years of age with T1D for at least 6 months were investigated. Anthropometric parameters, blood pressure, and microvascular complications were evaluated, and the lipid profile and HbA1c were determined for all patients. Results. Study subjects' mean HbA1c was 8.5 ± 2%; 19.5% were overweight and 3.6% obese. Hypertension and dyslipidemia were diagnosed in 29.8% and 62.6% of participants, respectively. HbA1c concentration was directly related to levels of total cholesterol (r = 0.274, p < 0.001), LDL (r = 0.271, p < 0.001), and triglycerides (r = 0.407, p < 0.001) and inversely associated with levels of HDL (r = 0.117, p = 0.001). Prevalence of dyslipidemia increased with duration of diabetes (p < 0.05). Hypertension was more prevalent in overweight and obese compared to normal-weight patients (40.6 and 65.6 vs. 25.6%, respectively, p < 0.001). Frequency of microvascular complications was higher among patients with dyslipidemia (27.2 vs. 18.8%, p = 0.005) and among those with hypertension (25.9 vs. 23.2%, p < 0.001). Conclusion. The frequency of cardiovascular risk factors is high in youth with T1D and associated with diabetes duration, obesity, and metabolic control.

Can coefficient of variation of time-domain analysis be valuable for detecting cardiovascular autonomic neuropathy in young patients with type 1 diabetes: a case control study.

BACKGROUND: Cardiovascular autonomic neuropathy (CAN) increases morbidity and mortality in diabetes through association with a high risk of cardiac arrhythmias and sudden death, possibly related to silent myocardial ischemia. During the sub-clinical stage, CAN can be detected through reduction in heart rate variability (HRV). The aim of our study was to estimate if the time and frequency-domain analysis can be valuable for detecting CAN in young patients with type 1 diabetes mellitus (T1DM). METHODS: For this case control study of evaluation of cardiovascular autonomic function the 15-25 years age group of patients with duration of T1DM more than 9 years (n = 208, 89 males and 119 females) were selected. 67 patients with confirmed CAN were assigned to the "case group" and 141 patients without CAN served as a control group, the duration of T1DM was similar (15.07 ± 4.89 years vs.13.66 ± 4.02 years; p = 0.06) in both groups. Cardiovascular autonomic reflex tests and time and frequency domains analysis of HRV were performed for all subjects. RESULTS: Time domain measures were significantly lower in CAN group compared with control (p < 0.05). R-R max / R-R min ratio and coefficient of variation (CV) were the lowest during deep breathing among T1DM patients with CAN. Receivers operating characteristic (ROC) curves were constructed to compare the accuracies of the parameters of time-domain analysis for diagnosing CAN. We estimated a more reliable cut-off value of parameters of time-domain. The CV values in supine position <1.65, reflected sensitivity 94.3%, specificity 91.5%. The CV values during deep breathing <1.45 reflected sensitivity 97.3%, specificity 96.2%. The CV values in standing position <1.50 reflected sensitivity 96.2%, specificity 93.0%. The most valuable CV was during deep breathing (AUC 0.899). The results of frequency-domain (spectral analysis) analysis showed significant decrease in LF power and LFPA, HF Power and HFPA, total power among subjects with CAN than compared with subjects without CAN (p < 0.05). CONCLUSIONS: Time and frequency domain analysis of HRV permits a more accurate evaluation of cardiovascular autonomic function, providing more information about sympathetic and parasympathetic activity. The coefficient of variation (time-domain analysis) especially during deep breathing could be valuable for detecting CAN.

The course of diabetes in children, adolescents and young adults: does the autoimmunity status matter?

BACKGROUND: Initial classification of diabetes of young may require revision to improve diagnostic accuracy of different forms of diabetes. The aim of our study was to examine markers of beta-cell autoimmunity in a cohort of young (0-25 years) patients with type 1 diabetes and compare the presentation and course of the disease according to the presence of pancreatic antibodies. METHODS: Cross-sectional population-based study was performed covering 100% of pediatric (n = 860) and 70% of 18-25 years old adult patients (n = 349) with type 1 diabetes in Lithuania. RESULTS: No antibodies (GAD65, IA-2, IAA and ICA) were found in 87 (7.5%) cases. Familial history of diabetes was more frequent in those with antibodies-negative diabetes (24.1 vs. 9.4%, p < 0.001). Gestational age, birth weight and age at diagnosis was similar in both groups. Ketosis at presentation was more frequent in patients with autoimmune diabetes (88.1 vs. 73.5%, p < 0.05). HbA1c at the moment of investigation was 8.6 (3) vs. 8.7 (2.2)% in antibodies-negative and antibodies-positive diabetes groups, respectively, p > 0.05. In the whole cohort, neuropathy was found in 8.8% and nephropathy - in 8.1% of cases, not depending on autoimmunity status. Adjusted for age at onset, disease duration and HbA1c, retinopathy was more frequent in antibodies-negative subjects (13.8 vs. 7.8%, p < 0.05). CONCLUSION: Antibodies-negative pediatric and young adult patients with type 1 diabetes in this study had higher incidence of family history of diabetes, higher frequency of retinopathy, less frequent ketosis at presentation, but similar age at onset, HbA1c, incidence of nephropathy and neuropathy compared to antibodies-positive patients.

Diabetes distress in males and females with type 1 diabetes in adolescence and emerging adulthood.

BACKGROUND: Age and gender are important factors in the adjustment and psychological well-being of patients with chronic physical illness. AIM: To explore the gender and age differences in diabetes distress between adolescents and emerging adults with type 1 diabetes (T1D). SUBJECTS AND METHODS: Diabetes distress was compared in 255 adolescents and 283 emerging adults with T1D using Problem Areas in Diabetes scale. RESULTS: High diabetes distress level was found in 22.8% of participants. Lack of confidence in self-care (6.0 vs 3.0, p=0.002), negative emotional consequences (10.0 vs 6.0, p=0.004), and overall score (18.75 vs 11.25, p=0.002) were higher in adult than in adolescent males, when adjusted for age at T1D onset. Negative emotional consequences (13.0 vs 10.0, p=0.005) and overall score (25.0 vs 20.0, p=0.016) were higher in adult compared to adolescent females, when adjusted for age at T1D onset. Lack of confidence in self-care (6.0 vs 3.0, p=0.002), negative emotional consequences (10.0 vs 6.0, p=0.015), and overall score (20.0 vs 11.2, p=0.005) were higher in adolescent females compared to males, when adjusted for age at T1D onset. Negative emotional consequences score was higher in adult females compared to males (13.0 vs 10.0, p=0.029), when adjusted for age at T1D onset. In conclusion, our findings show that patients with T1D have greater burden of diabetes distress in emerging adulthood than in adolescence and add to evidence suggesting the importance of addressing diabetes distress in clinical care and the necessity of wider picture beyond the physical manifestation of diabetes to be taken into consideration.

HLA-DRB1*03 as a risk factor for microalbuminuria in same duration of type 1 diabetes: a case control study.

BACKGROUND: Increased urinary albumin excretion rate is the earliest clinical manifestation of diabetic nephropathy. The development of microalbuminuria in patients with type 1 diabetes mellitus (T1D) usually begins 5 to 15 years after the onset of diabetes. The rate of progression of diabetic nephropathy varies considerably among patients and not always can be explained solely by glycaemic control. The evidence suggests that genetic susceptibility may play a role in the development of diabetes microvascular complications, besides the presence of such risk factors as hyperglycaemia, hypertension, dyslipidaemia and smoking. The aim of the study was to evaluate a link between known genetic risk factors for type 1 diabetes mellitus (HLA-DR3/DR4) and microalbuminuria among patients with the same durations of diabetes. METHODS: Ninety-nine patients with T1D at the age 18-35 years were recruited for the study. The urine albumin excretion rate was normal when <30 mg/24 h; microalbuminuria 30-300 mg/24 h. Genotypes were investigated in 39 patients with normal albumin excretion rate and duration of diabetes 13.46 ± 3.72 years and in 60 patients with microalbuminuria and duration of diabetes 15.28 ± 4.08 years (p = 0.11). Genetic typing of DR3 and DR4 antigens successfully was performed for 99 subjects. Statistical analysis was performed using SPSS v. 20.0. RESULTS: Genotyping of 99 patients with T1D was performed: no DR3 and DR4 risk alleles were found in 22 (22.22 %) cases, DR3 alleles were present in 47 (47.48 %) cases, DR4 alleles in 25 (25.25 %) cases, and DR3/DR4 alleles in 5 (5.05 %) cases. The highest 24 h albumin excretion rate was found in patients with DRB1 gene expressed DR3 risk alleles group, the lowest - in patients with DRB1 gene with no expression of both DR3 and DR4 antigen. We confirmed the 1.87 (p = 0.021) increased relative risk for microalbuminuria in patients with DR3/DR3 alleles and same duration of diabetes. The distribution of DR3 and DR4 risk alleles was not associated with cardiovascular autonomic neuropathy both in patients with normal albumin excretion rate and microalbuminuria (1.6 vs 2.1; p = 0.21). CONCLUSIONS: The 1.87 (p = 0.021) increased relative risk for microalbuminuria was found in patients with DR3/DR3 alleles and the same duration of diabetes.

Gestational diabetes, obesity, and metabolic syndrome diagnosed during pregnancy.

BACKGROUND: The aim was to analyze the impact of obesity on women with gestational diabetes mellitus (GDM) and the association of obesity and GDM with the metabolic syndrome. METHODS: In a retrospective study, the data of 233 obese women with GDM were compared with the data of 96 women with GDM and normal weight. RESULTS: Significantly higher fasting glycemia before the oral glucose tolerance test (5.2±1.1 mmol/L vs. 4.5±0.8 mmol/L, P<0.00001) and higher frequency of hypertensive disorders of pregnancy (26.2% vs. 9.4%, P=0.0003) were found in obese women with GDM than in GDM women of normal weight. These women needed insulin therapy more often (18.9% vs. 8.3%, P=0.007). Also 31 (13.3 %) of them had chronic hypertension as compared with 3.1% in women of normal weight (P=0.003). These 31 women had three components necessary for diagnosing of metabolic syndrome according to the World Health Organization-impaired glucose tolerance, obesity, and hypertension. No difference in gestational age and mean weight of their newborns was found, but newborns of obese GDM women with metabolic syndrome components more often were significantly macrosomic with features of diabetic fetopathy and had more often symptoms of hypoglycemia after birth. CONCLUSIONS: The presence of obesity and GDM has a significant impact on both maternal and fetal complications. The metabolic syndrome can be diagnosed not only after pregnancy but also during pregnancy.