Future diabetes risk can be predicted by the number of abnormal oral glucose tolerance test values during pregnancy.

AIM: To quantify the future risk of type 2 diabetes (T2D) in women with gestational diabetes (GD) based on baseline metabolic characteristics and the number of abnormal values during a 3-hour 100-g oral glucose tolerance test (OGTT). MATERIALS AND METHODS: We conducted a population-based retrospective cohort study of 10 023 pregnant women who underwent testing for GD in a large health maintenance organization in Israel using a 100-g OGTT. Glucose values were obtained at four time points, 0, 60, 120 and 180 minutes. RESULTS: We identified 9939 women who met the study criteria. Median follow-up was 3.25 (interquartile range 1.5-5.1; maximum 10.1) years. Using women without GD as reference, women with GD were at an increased risk of future T2D (hazard ratio [HR] 5.33 [95% confidence interval {CI} 3.86-7.34]). This risk increased with a greater number of abnormal OGTT values, with the highest risk seen in women with four abnormal values (HR 16.67 [95% CI 7.94-35.01]). In a multivariate model, a higher number of abnormal values, Arab ethnicity, higher body mass index, triglycerides and prepregnancy glucose were significantly associated with increased risk. Future T2D risk was also affected by the type of OGTT abnormality; an abnormal fasting value had the greatest risk, whereas an abnormal 3-hour value had the lowest risk (HR 3.61 [95% CI 2.42-5.38] vs. 1.50 [95% CI 0.93-2.43], respectively). CONCLUSIONS: GD is a heterogenous disease, with varying degrees of glucose intolerance and subsequent T2D risk. Targeting interventions to women at the highest risk may help to improve postpartum adherence and effective long-term follow-up strategies.

Flash Glucose Monitoring in Israel: Understanding Real-World Associations between Self-Monitoring Frequency and Metrics of Glycemic Control.

OBJECTIVE: Flash glucose monitoring has been widely used in Israel for diabetes treatment and since 2018, the cost is reimbursed for all people with type 1 diabetes nationally. In the current study, we present the daily scanning behavior for FreeStyle Libre users in Israel and how this was associated with a range of metrics for glycemic assessment. METHODS: Deidentified data from FreeStyle Libre readers were collected between September 2014 and October 2020. Scan-rate data from Israel was extracted and sorted into 10 equal-sized groups based on scan frequency. The glucose parameters derived for each group were: estimated HbA1c (eA1c), time in range (TIR) between 70 and 180 mg/dL, and time with glucose levels of <70 mg/dL, <54 mg/dL, and >180 mg/dL. RESULTS: The data set for Israel included 12 370 readers, with data from 131 639 separate glucose sensors representing 152 million automatically recorded individual glucose readings. Users performed an average of 15 daily glucose scans, ranging from a mean of 4.1 scans per day (lowest, 10%), rising to a mean of 38.7 scans/day (highest, 10%) (median, 12; IQR, 8-18 for all readers). As the scan rates increased, the eA1c decreased from 7.6% to 6.7% (P < .001). Mean TIR increased from 56.9% to 70.0% with increasing scan rates (P < .001). Concordantly, time with glucose levels of >180 mg/dL and <54 mg/dL decreased from 37.2% to 23.6% (P < .001) and from 2.23% to 1.99%, respectively, as scan frequency increased. CONCLUSION: In Israel, people with diabetes under real-world conditions record higher rates of FreeStyle Libre scanning. These are associated with improvements in TIR, eA1c, and reduced time with glucose levels of >180 mg/dL or <54 mg/dL.

Impact of flash glucose monitoring on glucose control and hospitalization in type 1 diabetes: A nationwide cohort study.

BACKGROUND: We evaluated the impact of flash continuous glucose monitoring (FCGM) on glycemic control and healthcare burden in a large real-world cohort of patients with type 1 diabetes (T1D) initiating FCGM technology. METHODS: In this retrospective cohort study, we included adults (age ≥18 years) with T1D from a large Health Maintenance Organization in Israel, who initiated FCGM during 2018. Primary outcomes included change in HbA1c ≥3 months following FCGM commencement and change in rate of internal-medicine hospitalization. Additional outcomes included changes in glucose test strip purchases, diabetes related outpatient health care visits and hospitalization for diabetic ketoacidosis (DKA) and/or severe hypoglycemia. RESULTS: The study included 3490 patients, followed for a median of 14 (inter-quartile range 11-15) months after FCGM commencement. Among 2682 patients with an HbA1c measured both at baseline and ≥3 months after FCGM initiation, average HbA1c declined from 8.1% ± 1.46% to 7.9% ± 1.31% (P < .001) at first measurement and was maintained during follow up. Specifically, in those with HbA1c ≥8%, a mean decline of 0.5% (P < .001) was observed. A clinically significant HbA1c reduction of ≥0.5% was experienced by 25.5% of the patients. The rate of internal medicine hospitalization, visits to primary care, or visits to endocrine/diabetes specialists in the period following FCGM commencement vs the 6 months prior was significantly reduced (P < .001). Hospitalization for DKA and/or hypoglycemia declined as well (P = .004). CONCLUSIONS: FCGM was associated with significant and durable improvement in glycemic control as well as reduced consumption of healthcare services.

Role of Cannulated Prolactin Test in Evaluation of Hyperprolactinemia - A Retrospective Study.

OBJECTIVE: While guidelines propose a single elevated prolactin measurement drawn without excess venipuncture stress as sufficient for diagnosing hyperprolactinemia, this may lead to unnecessary evaluation in the setting of stress-induced hyperprolactinemia. In this study, we aimed to define the role of the cannulated prolactin test in confirming hyperprolactinemia. METHODS: We conducted a retrospective review of 757 patients with unexplained hyperprolactinemia who performed a cannulated prolactin test in a community-based referral endocrine clinic between 2000-2015. The prolactin test consisted of "test-baseline" levels taken at rest (T0), and cannulated measurements at 60 and 90 minutes (T60 and T90) without repeated venipuncture. The most recent prolactin level performed prior to the test (referral-prolactin) was collected. RESULTS: Referral-prolactin was available for 621 (82%) patients, of whom 324 (52.2%) normalized at T0. The probability of normoprolactinemia at T0 was 50% if referral-prolactin was 2.0-fold the upper-limit-of-normal (ULN), yet only 5% if referral-prolactin was 5.0-fold the ULN. Of the 359 patients with hyperprolactinemia at T0, prolactin normalized at T60 and/or T90 in 99 (27.6%) patients. The probability of normoprolactinemia was low (<5%) in those with T0 prolactin levels >2.4-fold ULN. Overall, of 757 prolactin tests performed, only 260 (34.3%) patients had persistent hyperprolactinemia. CONCLUSION: Patients with referral-prolactin levels >5.0-fold the ULN, or a rested-prolactin (T0) >2.4-fold the ULN are unlikely to normalize during the cannulated test and consideration should be made to proceed directly with pituitary imaging. In patients with prolactin levels below these thresholds, the cannulated prolactin test may considerably reduce unnecessary investigations, treatment, and cost.

Clinical and Molecular Characteristics of Eight Israeli Families with Thyroid Hormone Receptor Beta Mutations.

BACKGROUND: Reduced sensitivity to thyroid hormone (RSTH) syndrome describes a group of rare heterogeneous genetic disorders. Precise diagnosis is essential to avoid unnecessary treatment. OBJECTIVES: To identify and characterize previously undiagnosed patients with RSTH in Israel. METHODS: Patients with suspected RSTH throughout Israel were referred for study. After clinical evaluation, genomic DNA was obtained and all coding exons of the thyroid hormone receptor beta (THRB) gene were sequenced. If mutations were found, all available blood relatives were evaluated. The common polymorphism rs2596623, a putative intronic regulatory variant, was also genotyped. Genotype/phenotype correlations were sought, and the effect of mutation status on pregnancy outcome was determined. RESULTS: Eight mutations (one novel; two de-novo, six dominant) were identified in eight probands and 13 family members. Clinical and genetic features were similar to those reported in other populations. Previous suggestions that rs2596623 predicts clinical features were not confirmed. There was no evidence of increased risk of miscarriage or fetal viability. Mothers carrying a THRB mutation tended to have increased gestational hypertension and low weight gain during pregnancy. Their affected offspring had increased risk of small-for-gestational age and poor postnatal weight gain. CONCLUSIONS: Clinical heterogeneity due to THRB mutations cannot be explained by the variant rs2596623. Mothers and newborns with THRB mutations seem to be at increased risk of certain complications, such as gestational hypertension and poor intrauterine and postnatal growth. However, these issues are usually mild, suggesting that routine intervention to regulate thyroid hormone levels may not be warranted in these patients.

Overcrowding in Psychiatric Wards is Associated With Increased Risk of Adverse Incidents.

OBJECTIVE: To study the association between bed occupancy in psychiatric wards and rate of adverse incidents (AIs) including aggressive behavior and falls. METHODS: This is a retrospective study analyzing bed occupancy and AIs' data in 4 closed wards in a state psychiatric hospital in Israel over a 20-month period. Ward-level daily records were extracted from the hospital's electronic admission-discharge and AI registries, creating a log of 609 days for each of the 4 wards. Relationships between gross and net bed occupancy and AIs rate were calculated, in general and for each ward and type of incidents. RESULTS: Average gross occupancy was 106±14.8% and net occupancy was 96.4±15.6%. Gross occupancy >100% was recorded in 51% of days. Net occupancy was higher on days with at least 1 incident than on no-incident days (98.6±14.8% vs. 95.7±15.7%, P<0.0001). AIs occurred in 18.6% of days in the lowest occupancy quadrant (up to 85% occupancy), compared with 26.7% of days in the highest occupancy quadrant (106% and above). Moreover, aggressive behavior-type incidents were significantly lower in the lowest occupancy quadrant days compared with the highest occupancy quadrant (8.3% vs. 14.1%, P<0.01). Evidence of a dose-response effect of bed occupancy on AIs rate was found. CONCLUSIONS: Overoccupancy is prevalent in psychiatric wards and is associated with an increased rate of aggressive AIs and falls. Policy makers should be convinced about the necessity to reduce overcrowding in psychiatric wards and to improve safety of inpatient facilities.

Gestational diabetes and risk of future diabetes in a multi-ethnic population.

AIM: To investigate ethnic disparities in risk of gestational diabetes-mellitus (GDM) and future diabetes. METHODS: A population-based retrospective cohort study of women who underwent a 100-g oral glucose-tolerance-test (oGTT) during pregnancy between 2007 and 2017 in Clalit-Health-Services of the Jerusalem district. Univariate and multivariate logistic regression analyses were used to compare the risk of GDM in Arab versus Jewish women. Further, Cox-regression analysis was used to establish the risk of future diabetes. RESULTS: A total of 9875 women, 71 % of Jewish ethnicity and 29 % of Arab ethnicity were included. Arab women had a higher incidence of GDM compared to Jewish women (17.3 % vs. 10.6 %, p < 0.001), which persisted after adjusting for age, BMI, and metabolic profile (aOR 1.7; CI 1.48-2.0, P < 0.001). Additionally, Arab ethnicity was associated with an increased risk of future diabetes, even after adjusting for GDM status (aHR 5.9; 95 % CI 3.7-9.4, P < 0.001). CONCLUSIONS: Women of Arab ethnicity have a higher risk for both GDM and future diabetes, a risk that is beyond the initial increased risk associated with GDM. These findings highlight the need for increased focus on preventing diabetes in women of Arab ethnicity, especially those with a history of GDM.

CARMELINA: An important piece of the DPP-4 inhibitor CVOT puzzle.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of glucose-lowering agent for type 2 diabetes (T2D) that are commonly used in clinical practice. With the recent disclosure of data from the CARMELINA cardiovascular outcomes trial (CVOT), which investigated linagliptin, CV and renal outcomes data are now available for four agents in the DPP-4 inhibitor class that are approved in most markets. To consider how the CARMELINA study may be interpreted, and the relevance for our clinical practice, we convened as an expert group of diabetes specialists from the Central and Eastern Europe region to discuss the new disclosures. Our discussions revealed a general confidence in safety across the class that is further supported by CARMELINA. However, we also concluded that there are important differences in the available evidence level between agents in the setting of heart failure and data on renal outcomes. Here, we noted the clinical relevance to our practice of the study population in CARMELINA, which is unique among CVOTs in including a majority of patients with chronic kidney disease (CKD). Given the risk for future development of renal impairment that is associated with T2D even in patients without current overt CKD, we believe that the CARMELINA study provides important new insights that are clinically relevant for a broad range of patients. Finally, we discuss how these insights can be integrated into the approach to the pharmacotherapeutic management of hyperglycaemia that is recommended in newly updated guidelines.

Low thyroid-stimulating hormone and its persistence beyond the first trimester of pregnancy.

OBJECTIVE: To investigate predictors of low thyroid-stimulating hormone (TSH) persisting beyond the first trimester and associated pregnancy outcomes. METHODS: We retrospectively assessed the association between low first-trimester TSH and obstetric outcomes of singleton pregnancies in southern Israel between 2001 and 2011. We included women with first-trimester TSH and at least one other THS measurement. Clinical data were from maternity and community medical records. RESULTS: Among 3761 women, 185 (4.9%) had a TSH of 0.10 mIU/L or less in the first trimester. Multiple of the median human chorionic gonadotropin was higher in women with TSH of 0.40 mIU/L or less versus 0.41-4.0 mIU/L, but was not associated with higher rates of persistent low TSH. Maternal age (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.00-1.16; per yearly increment), free thyroxine (FT4; OR 1.11, 95% CI 1.03-1.20; per ng/dL increment), and TSH of 0.10 mIU/L or less (OR 3.06, 95% CI 1.38-6.80 vs 0.21-0.40 mIU/L) were independent predictors of persistent low TSH. No adverse pregnancy outcomes occurred in women with low first-trimester TSH. CONCLUSIONS: Low TSH persisting beyond the first trimester was more common with increasing maternal age, elevated FT4, and TSH below 0.10 mIU/L, but was not associated with obstetric complications.

Stepwise CaSR, AP2S1, and GNA11 sequencing in patients with suspected familial hypocalciuric hypercalcemia.

PURPOSE: Patients with familial hyperparathyroidism and low urinary calcium excretion may have familial hypocalciuric hypercalcemia (FHH) with mutations in one of three genes: the calcium-sensing receptor (CaSR) defining FHH-type 1, the adaptor-related protein complex 2 (AP2S1) related to FHH-type 3 or the G-protein subunit alpha11 (GNA11) associated with FHH-type 2. We aimed to evaluate the presence of mutations in these genes and to identify phenotypic specificities and differences in these patients. SUBJECTS AND METHODS: Selected patients were recruited for genetic evaluation. After informed consent was signed, blood for DNA extraction was obtained and genetic sequencing of CaSR was done. In negative cases, we further performed sequencing of AP2S1 and GNA11. RESULTS: A total of 10 index cases were recruited. CaSR sequencing yielded three missense heterozygous mutations (30%): c.554G > A (p.I32V) previously characterized by our team, c.1394 G > A (p.R465Q) and a novel expected disease-causing mutation c.2479 A > C (p.S827R). We identified 2 additional patients (20%) carrying the deleterious recurrent mutation c.44G > T (p.R15L) in the AP2S1 gene. No GNA11 mutation was found. Clinically, patients with AP2S1 mutations had significant cognitive and behavioral disorders, and higher blood calcium and magnesium levels than patients with FHH1. CONCLUSION: CaSR and AP2S1 sequencing is worthwhile in patients with familial hyperparathyroidism and phenotype suggesting FHH as it can diagnose up to 50% of cases. GNA11 mutations seem much rarer. Learning disabilities in these patients, associated with higher serum calcium and magnesium levels may suggest the presence of AP2S1 rather than CaSR mutation and may guide the first step in the genetic evaluation.

[The guidelines for the diagnosis prevention and treatment of type 2 diabetes mellitus--2005].

The incidence and prevalence of diabetes have reached epidemic proportions worldwide. The reasons for the pandemic are the sharp rise in obesity, decline in physical activity and the increase in life expectancy. There are some 400,000 people with diagnosed diabetes in Israel and they are at a markedly increased risk for cardiovascular disease, blindness, end-stage renal disease and lower limb amputation. To effectively lower this significantly increased burden of disease, a comprehensive multidisciplinary approach to chronic disease management is required. To facilitate such an approach, the Israel Diabetes Association published a guideline for the diagnosis, prevention and treatment of diabetes. The guideline, based on the ADA (American Diabetes Association) and IDF (International Diabetes Federation) guidelines, was approved by other national professional societies including hypertension, family practice, obesity, nephrology, atherosclerosis and internal medicine. The guidelines highlight the metabolic syndrome and prediabetic states, interventions for the prevention of diabetes, the new definitions of diabetes and impaired glucose metabolism and the newly defined targets for glucose, lipid, cholesterol and blood pressure control. In addition, the recommendations for periodic review and screening for complications are summarized. The need for patient education and empowerment are emphasized as is the need for the development and implementation of unique tools including computerized treatment flow-charts, prompts and quality measures, for the long term management of a complex metabolic disease.

Pancreatic Duodenal Homeobox (PDX-1) in health and disease.

Insulin is expressed exclusively in the adult beta-cells of the islets of Langerhans. Pancreatic Duodenum Homeobox-1 (PDX-1) is a major regulator of transcription in these cells. It transactivates the insulin gene by binding to a specific DNA motif in its promoter region. Glucose, the main physiological regulator of insulin secretion, also regulates insulin gene transcription through PDX-1. While acute exposure to high glucose concentrations causes an increase in PDX-1 binding, and consequently in insulin mRNA levels, chronic hyperglycemia (toxic to the beta-cell) leads to a decrease in PDX-1 and insulin levels. PDX-1 is absolutely required for pancreas development. In view of the selective expression in adult beta-cells, pancreatic agenesis in both the pdx-1 null mouse and a human carrying a homozygous mutation of PDX-1 was an unexpected and remarkable finding. The homozygous clinical phenotype was neonatal diabetes mellitus (DM) and exocrine insufficiency. Heterozygosity for PDX-1 mutations was found in some individuals with a newly characterized subtype of maturity-onset diabetes of the young (MODY4) and in others with type 2 DM. This review underlines the unique role of PDX-1 in maintaining adult beta-cell-specific functions in normal and disease-related states.

[Primary care for type 2 diabetes].

The prevalence of type 2 diabetes is dramatically increasing worldwide and expected to double over the next 25 years, reaching epidemic proportions and thus incurring a considerable financial burden on the health care system. In order to cure the epidemic and minimize expensive complications, a program aimed at optimizing metabolic control and improving surveillance and quality assessment needs to be developed and implemented nation-wide. Most diabetic patients should be treated within the primary care system. In order to meet treatment targets, improve metabolic control and avoid complications, the knowledge and skills needed to treat this chronic disease should be reinforced by dedicated multidisciplinary teams from centers specializing in diabetes care. The specialized diabetes clinics should be devoted to both the treatment of complicated cases of diabetes, that are not achieving treatment targets in the primary care setting, and to the education, updating and empowerment of all primary care teams involved in the treatment of patients with diabetes. A local framework for shared care should be developed through the combined efforts, of the staff of the diabetes center and the primary care physicians and nurses in order to secure the shared goals of optimal treatment and prevention of complications.

Disrupting mitochondrial-nuclear coevolution affects OXPHOS complex I integrity and impacts human health.

The mutation rate of the mitochondrial DNA (mtDNA), which is higher by an order of magnitude as compared with the nuclear genome, enforces tight mitonuclear coevolution to maintain mitochondrial activities. Interruption of such coevolution plays a role in interpopulation hybrid breakdown, speciation events, and disease susceptibility. Previously, we found an elevated amino acid replacement rate and positive selection in the nuclear DNA-encoded oxidative phosphorylation (OXPHOS) complex I subunit NDUFC2, a phenomenon important for the direct interaction of NDUFC2 with the mtDNA-encoded complex I subunit ND4. This finding underlines the importance of mitonuclear coevolution to physical interactions between mtDNA and nuclear DNA-encoded factors. Nevertheless, it remains unclear whether this interaction is important for the stability and activity of complex I. Here, we show that siRNA silencing of NDUFC2 reduced growth of human D-407 retinal pigment epithelial cells, significantly diminished mitochondrial membrane potential, and interfered with complex I integrity. Moreover, site-directed mutagenesis of a positively selected amino acid in NDUFC2 significantly interfered with the interaction of NDUFC2 with its mtDNA-encoded partner ND4. Finally, we show that a genotype combination involving this amino acid (NDUFC2 residue 46) and the mtDNA haplogroup HV likely altered susceptibility to type 2 diabetes mellitus in Ashkenazi Jews. Therefore, mitonuclear coevolution is important for maintaining mitonuclear factor interactions, OXPHOS, and for human health.

Decreased serum concentrations of 25-hydroxycholecalciferol are associated with increased risk of progression to impaired fasting glucose and diabetes.

OBJECTIVE: To study the association between vitamin D status and the risk of incident impaired fasting glucose (IFG) and diabetes in a population-based cohort of diabetes-free subjects. RESEARCH DESIGN AND METHODS: In a historical prospective cohort study of subjects from the Clalit Health Services database, which includes information on nearly 4 million people, diabetes-free subjects aged 40-70 years with serum 25-hydroxycholecalciferol (25-OHD) measurements available were followed for 2 years to assess the development of IFG and diabetes in five 25-OHD subgroups: ≥25, 25.1-37.5, 37.6-50, 50.1-75, and >75 nmol/L. RESULTS: The baseline cohort included 117,960 adults: 83,526 normoglycemic subjects and 34,434 subjects with IFG. During follow-up, 8,629 subjects (10.3% of the normoglycemic group) developed IFG, and 2,162 subjects (1.8% of the total cohort) progressed to diabetes. A multivariable model adjusted for age, sex, population group, immigrant status, BMI, season of vitamin D measurement, LDL and HDL cholesterol, triglycerides, estimated glomerular filtration rate, history of hypertension or cardiovascular disease, Charlson comorbidity index, smoking, and socioeconomic status revealed an inverse association between 25-OHD and the risk of progression to IFG and diabetes. The odds of transitioning from normoglycemia to IFG, from normoglycemia to diabetes, and from IFG to diabetes in subjects with a 25-OHD level ≤25 nmol/L were greater than those of subjects with a 25-OHD level >75 nmol/L [odds ratio 1.13 (95% CI 1.03-1.24), 1.77 (1.11-2.83), and 1.43 (1.16-1.76), respectively]. CONCLUSIONS: Vitamin D deficiency appears to be an independent risk factor for the development of IFG and diabetes.

Clinical experience with insulin detemir in patients with type 2 diabetes from the near East countries.

INTRODUCTION: This study aimed at determining the clinical safety and efficacy of insulin detemir (IDet) in combination with oral anti-diabetic drugs (OADs) in type 2 diabetes (T2D) patients from four Near East Countries (Israel, Jordan, Pakistan and Lebanon). METHODS: This prospective observational study included T2D patients previously on OADs and newly diagnosed patients initiating IDet with or without OADs, at the discretion of physicians. Safety objectives included evaluation of hypoglycemia and adverse drug reactions (ADRs) from baseline to Week 24. Efficacy outcomes included baseline to Week 24 changes in glucose control parameters (glycated hemoglobin [HbA1c], fasting plasma glucose [FPG] and post-breakfast post-prandial plasma glucose [PPPG]). Change in body weight during this period was also assessed. RESULTS: A total of 2,155 patients (mean ± SD: age 57.1 ± 11.0 years, BMI 29.4 ± 5.1 kg/m(2), average diabetes duration 9.2 ± 5.4 years) were included. IDet dose at baseline was 0.20 ± 0.09 U/kg titrated up to 0.34 ± 0.14 U/kg by Week 24. From baseline to Week 24, the total number of hypoglycemic episodes increased from 1.30 to 1.37 events/patient-year, while major hypoglycemic episodes decreased from 0.15 to 0.02 events/patient-year. A total of 9 ADRs were reported, of which one event was a serious ADR. Statistically significant improvements in glucose control were reported from baseline to Week 24 (HbA1c: 9.6 ± 1.6% vs. 7.6 ± 1.1%; FPG: 201.5 ± 59.5 mg/dL vs. 124.9 ± 31.6 mg/dL; PPPG: 264.2 ± 65.7 mg/dL vs. 167.2 ± 36.8 mg/dL; all p < 0.0001). Body weight did not change significantly after 24 weeks of IDet therapy. CONCLUSION: IDet therapy in combination with OADs improved glycemic control without increasing the risk of hypoglycemia or weight gain.