Increasing evidence shows that maternal hyperglycemia inhibits cardiomyocyte (CM) proliferation and promotes cell apoptosis during fetal heart development, which leads to cardiac dysplasia. Accumulating evidence suggests that the overexpression of miR-21 in CMs has a protective role in cardiac function. Therefore, we investigated whether miR-21 can rescue CM injury caused by high glucose. First, we performed biological function analysis of miR-21-5p overexpression in H9c2 cells treated with high glucose. We found that the proliferation of H9c2 cells treated with high glucose decreased significantly and was rescued after overexpression of miR-21-5p. CCK-8 and EdU incorporation assays were performed to assess cell proliferation. The cell proliferation of the miR-21-5p mimic transfection group was improved compared with that of the NC mimic group (*p < 0.05, miR-21-5p mimics vs. NC mimics) when the proliferation of H9c2 cells was reduced by high glucose (****p < 0.0001, high glucose (HG) vs. normal glucose (NG)). Then, we verified the targeted and negative regulation of miR-21-5p on Rhob using a dual-luciferase activity assay and RT-qPCR, respectively. We further demonstrated that miR-21-5p regulates Rhob to rescue the inhibition of CM proliferation induced by high glucose. The CCK-8 results showed that the cell proliferation of the siRNA-Rhob group was higher than that of the NC mimic group (***p < 0.001) and that of the cotransfection group with Up-Rhob plasmids and miR-21-5p mimics was lower than that of the miR-21-5p mimic group (*p < 0.05). Conclusion: Overexpression of miR-21-5p rescues the inhibition of high glucose-induced CM proliferation through regulation of Rhob.

This study aimed to explore the association between hyperglycemia in pregnancy (type 2 diabetes (T2D) and gestational diabetes mellitus (GDM)) and child developmental risk in Europid and Aboriginal women.

PANDORA is a longitudinal birth cohort recruited from a hyperglycemia in pregnancy register, and from normoglycemic women in antenatal clinics. The Wave 1 substudy included 308 children who completed developmental and behavioral screening between age 18 and 60 months. Developmental risk was assessed using the Ages and Stages Questionnaire (ASQ) or equivalent modified ASQ for use with Aboriginal children. Emotional and behavioral risk was assessed using the Strengths and Difficulties Questionnaire. Multivariable logistic regression was used to assess the association between developmental scores and explanatory variables, including maternal T2D in pregnancy or GDM.

After adjustment for ethnicity, maternal and child variables, and socioeconomic measures, maternal hyperglycemia was associated with increased developmental “concern” (defined as score ≥1 SD below mean) in the fine motor (T2D odds ratio (OR) 5.30, 95% CI 1.77–15.80; GDM OR 3.96, 95% CI 1.55–10.11) and problem-solving (T2D OR 2.71, 95% CI 1.05–6.98; GDM OR 2.54, 95% CI 1.17–5.54) domains, as well as increased “risk” (score ≥2 SD below mean) in at least one domain (T2D OR 5.33, 95% CI 1.85–15.39; GDM OR 4.86, 95% CI 1.95–12.10). Higher maternal education was associated with reduced concern in the problem-solving domain (OR 0.27, 95% CI 0.11–0.69) after adjustment for maternal hyperglycemia.

Maternal hyperglycemia is associated with increased developmental concern and may be a potential target for intervention so as to optimize developmental trajectories.

Hyperglycemia is reported to predict worse outcome in patients with stroke, including intracerebral hemorrhage (ICH). In 83 consecutive cases of ICH at a tertiary stroke center, hyperglycemia (serum glucose >7 mmol/L) compared to normoglycemia at presentation was associated with higher rates of in-hospital mortality (51.2% vs. 26.2%, OR 2.3, CI 1.2–7.6, p = 0.02). The association with in-hospital mortality withstood adjustment for age, ICH volume, intraventricular hemorrhage, and infratentorial ICH location, but not baseline Glasgow Coma Scale. Acute hyperglycemia is associated with in-hospital mortality in spontaneous ICH patients, though this may be an indirect, rather than a causal relationship.

Green tea is a popular drink used for therapeutic purposes to mitigate the consequences of diabetes. In this study, we aimed at evaluating the potential of green tea infusion to ameliorate structural and enzymatic damages caused by hyperglycemia in the testis and epididymis of Wistar rats. For that, nondiabetic and streptozotocin-induced diabetic rats (negative control and diabetes control, respectively) received 0.6 mL of water by gavage. Another set of diabetic animals received 100 mg/kg of green tea infusion diluted in 0.6 mL of water/gavage (diabetes + green tea) daily. After 42 days of treatment, the testes and epididymides were removed and processed for histopathological analysis, micromineral determination, and enzymatic assays. The results showed that treatment with green tea infusion preserved the testicular and epididymal histoarchitecture, improving the seminiferous epithelium and the sperm production previously affected by diabetes. Treatment with green tea reduced tissue damages caused by this metabolic condition. Given the severity of hyperglycemia, there was no efficacy of the green tea infusion in maintaining the testosterone levels, antioxidant enzyme activity, and microminerals content. Thus, our findings indicate a protective effect of this infusion on histological parameters, with possible use as a complementary therapy for diabetes.

Diabetic pregnancies are cleary associated with maternal type 2 diabetes and metabolic syndrome as well as atherosclerotic diseases in the offspring. The global prevalence of hyperglycemia in pregnancy was estimated as 15.8% of live births to women in 2019, with an upward trend. Numerous parental risk factors as well as trans-generational mechanisms targeting the utero-placental system, leading to diabetes, dysmetabolic and atherosclerotic conditions in the next generation, seem to be involved within this pathophysiological context. To focus on the predictable impact of trans-generational diabetic programming, we studied age- and gender-matched offspring of diabetic and nondiabetic mothers. The offspring generation consists of three groups: C57BL/6-J-Ins2Akita (positive control group), wild-type C57BL/6-J-Ins2Akita (experimental group), and C57BL/6-J mice (negative control group). We undertook intraperitoneal glucose tolerance tests at 3 and 11 weeks of age. Moreover, this in vivo model was complemented by a corresponding in silico model. Although at 3 weeks of age, no significant effects could be observed, we could demonstrate at 11 weeks of age characteristic and significant differences in relation to maternal diabetic imprinting based on the in silico model-based predictors. These predictors allow the generation of a concise classification tree assigning maternal diabetic imprinting correctly in 91% of study cases. Our data show that hyperglycemic in utero milieu contributes to trans-generational diabetic programming leading to impaired glucose tolerance in the offspring of diabetic mothers early on. These observations can be clearly and early distinguished from genetically determined diabetes, for example, type 1 diabetes, in which basal glucose values are significantly raised.

Introduction: Patients with poorly-controlled diabetes often visit the emergency department (ED) for treatment of hyperglycemia. While previous qualitative studies have examined the patient experience of diabetes as a chronic illness, there are no studies describing patients’ perceptions of ED care for hyperglycemia. The objective of this study was to explore the patient experience regarding ED hyperglycemia visits, and to characterize perceived barriers to adequate glycemic control post-discharge. Methods: This study was conducted at a tertiary care academic centre in London, Ontario. A qualitative constructivist grounded theory methodology was used to understand the experience of adult patient partners who have had an ED hyperglycemia visit. Patient partners, purposively sampled to capture a breadth of age, sex, disease and presentation frequency were invited to participate in a semi-structured individual interview to probe their experiences. Sampling continued until a theoretical framework representing key experiences and expectations reached sufficiency. Data were collected and analyzed iteratively using a constant comparative approach. Results: 22 patients with type 1 or 2 diabetes were interviewed. Participants sought care in the ED over other options because of their concern of having a potentially life-threatening condition, advice from a healthcare provider or family member, or a perceived lack of convenient alternatives to the ED based on time and location. Participants’ care expectations centred around symptom relief, glycemic control, reassurance and education, and seeking referral to specialist diabetes care post-discharge. Finally, perceived system barriers that challenged participants’ glycemic control included affordability of medical supplies and medications, access to follow-up and, in some cases, the transition from pediatric to adult diabetes care. Conclusion: Patients with diabetes utilize the ED for a variety of urgent and emergent hyperglycemic concerns. In addition to providing excellent medical treatment, ED healthcare providers should consider patients’ expectations when caring for those presenting with hyperglycemia. Future studies will focus on developing strategies to help patients navigate some of the barriers that exist within our current limited healthcare system, enhance follow-up care, and improve short- and long-term health outcomes.

A 21-year-old male with known type 1 diabetes mellitus presented to the emergency department (ED) with two days of vomiting, polyuria, and polydipsia after several days of viral upper respiratory tract infection symptoms. Since his symptom onset, his home capillary blood glucose readings have been higher than usual. On the day of presentation, his glucometer read “high,” and he could not tolerate oral fluids. On examination, his pulse was 110 beats/minute, and his respiratory rate was 24 breaths/minute. He was afebrile, and the remaining vital signs were normal. Other than dry mucous membranes, his cardiopulmonary, abdominal, and neurologic exams were unremarkable. Venous blood gas demonstrated a pH of 7.25 mm Hg, pCO2 of 31 mm Hg, HCO3 of 13 mm Hg, anion gap of 18 mmol/L, and laboratory blood glucose of 40 mmol/L, as well as serum ketones measuring “large.”

Introduction: Hyperglycemic emergencies, including diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS), often recur in patients who have poorly controlled diabetes. Identification of those at risk for recurrent hyperglycemia visits may improve health care delivery and reduce ED utilization for these patients. The objective of this study was to prospectively characterize patients re-presenting to the emergency department (ED) for hyperglycemia within 30 days of an initial ED visit. Methods: This is a prospective cohort study of patients ≥18 years presenting to two tertiary care EDs (combined annual census 150,000 visits) with a discharge diagnosis of hyperglycemia, DKA or HHS from Jul 2016-Nov 2018. Trained research personnel collected data from medical records, telephoned patients at 10-14 days after the ED visit for follow-up, and completed an electronic review to determine if patients had a recurrent hyperglycemia visit to any of 11 EDs within our local health integration network within 30 days of the initial visit. Descriptive statistics were used where appropriate to summarize the data. Results: 240 patients were enrolled with a mean (SD) age of 53.9 (18.6) years and 126 (52.5%) were male. 77 (32.1%) patients were admitted from their initial ED visit. Of the 237 patients (98.8%) with 30-day data available, 55 (23.2%) had a recurrent ED visit for hyperglycemia within this time period. 21 (8.9%) were admitted on this subsequent visit, with one admission to intensive care and one death within 30 days. For all patients who had a recurrent 30-day hyperglycemia visit, 22/55 (40.0%) reported having outpatient follow-up with a physician for diabetes management within 10-14 days of their index ED visit. 7/21 (33.3%) patients who were admitted on the subsequent visit had received follow-up within the same 10-14 day period. Conclusion: This prospective study builds on our previous retrospective work and describes patients who present recurrently for hyperglycemia within 30 days of an index ED visit. Further research will attempt to determine if access to prompt follow-up after discharge can reduce recurrent hyperglycemia visits in patients presenting to the ED.

Impaired β-cell development and insulin secretion are characteristic of intrauterine growth-restricted (IUGR) fetuses. In normally grown late gestation fetal sheep pancreatic β-cell numbers and insulin secretion are increased by 7–10 days of pulsatile hyperglycemia (PHG). Our objective was to determine if IUGR fetal sheep β-cell numbers and insulin secretion could also be increased by PHG or if IUGR fetal β-cells do not have the capacity to respond to PHG. Following chronic placental insufficiency producing IUGR in twin gestation pregnancies (n=7), fetuses were administered a PHG infusion, consisting of 60 min, high rate, pulsed infusions of dextrose three times a day with an additional continuous, low-rate infusion of dextrose to prevent a decrease in glucose concentrations between the pulses or a control saline infusion. PHG fetuses were compared with their twin IUGR fetus, which received a saline infusion for 7 days. The pulsed glucose infusion increased fetal arterial glucose concentrations an average of 83% during the infusion. Following the 7-day infusion, a square-wave fetal hyperglycemic clamp was performed in both groups to measure insulin secretion. The rate of increase in fetal insulin concentrations during the first 20 min of a square-wave hyperglycemic clamp was 44% faster in the PHG fetuses compared with saline fetuses (P<0.05). There were no differences in islet size, the insulin+ area of the pancreas and of the islets, and β-cell mass between groups (P>0.23). Chronic PHG increases early phase insulin secretion in response to acute hyperglycemia, indicating that IUGR fetal β-cells are functionally responsive to chronic PHG.

Introduction: Patients with diabetes who are in emerging adulthood, defined as the life stage between 18-29 years, have unique challenges in managing their illness and are at risk of acute complications and loss to follow-up. The studys objective was to describe emergency department (ED) utilization for hyperglycemia in emerging adults with diabetes and to characterize 30-day outcomes including return visits and admission for hyperglycemia. Methods: This was a health records review of emerging adults presenting over a one-year period to four tertiary care EDs with a diagnosis of hyperglycemia, diabetic ketoacidosis or hyperosmolar hyperglycemic state. Research personnel collected data on patient characteristics, treatment, disposition, and determined if patients returned to the ED for hyperglycemia within 30 days. Descriptive statistics were used to summarize the data where appropriate. Results: There were 185 ED encounters for hyperglycemia, representing 116 unique emerging adult patients. Mean (SD) age was 23 (3.5) years and 50.9% were female. 80 (69.0%) had known type 1 diabetes, 11 (9.5%) had type 2, and 25 (21.5%) were newly diagnosed in the ED. Of 185 visits, 98 (53.0%) resulted in hospital admission. 56 (30.3%) returned to the ED for hyperglycemia within 30 days of their initial encounter, and 21 (11.4%) resulted in admission on this subsequent visit. Conclusion: We characterized ED utilization and 30-day outcomes of emerging adults with diabetes for hyperglycemia. Future research should focus on earlier identification of those at higher risk for recurrent ED visits or admission and the efficacy of interventions to prevent these adverse outcomes.

Introduction: Hyperglycemia is a significant cause of morbidity and mortality, often resulting in adverse outcomes such as recurrent ED visits, hospitalization or death. The objective of this study was to perform a systematic review to identify predictors of these adverse outcomes among patients who present to the ED with hyperglycemia. Methods: Electronic searches of Medline and EMBASE were conducted for studies published in English between the years 1946 and June 2017. Studies with patients presenting to the ED with hyperglycemia were eligible for inclusion. Both adult and pediatric populations were included, as were diabetic and non-diabetic patients. Two reviewers independently screened all titles and abstracts for relevance to the research question. If consensus could not be reached, full-length manuscripts were reviewed. For any discrepancy, a third reviewer was consulted, and disagreement was resolved through discussion. Study quality was assessed using the Newcastle-Ottawa Quality Assessment Scale. Study- and patient-specific data were then extracted and presented descriptively in the systematic review. Results: Thirteen observational studies were included, with a combined total of 664,829 patients. The studies scored between 5 to 8 on the Quality Assessment Scale out of a possible total of 8. Predictors of adverse outcomes included patients in both older and younger (< 25) age groups, history of diabetes, multiple comorbidities, patients requiring insulin, sepsis and hyperlactatemia, access to a family physician, a sentinel hyperglycemia visit in the past month, and triage glucose level > 20 mmol/L. Protective factors included no admissions in the past year, care from a diabetes team while in hospital, systolic blood pressure between 90-150 mmHg and heart rate > 110 bpm. Conclusion: This systematic review found eight predictors and four protective factors for adverse outcomes in patients presenting to the ED with hyperglycemia. These factors should be considered for easier identification of higher-risk patients for adverse outcomes in order to guide management and follow-up.

Introduction: Hyperglycemic emergencies, including diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS), carry significant morbidity for individuals even after discharge. The objective of this study was to describe the patient-important outcomes and burden of disease for emergency department (ED) patients with hyperglycemia after discharge from hospital. Methods: This was a prospective cohort study of patients 18 years presenting to two tertiary care EDs (combined annual census 150,000 visits) with a discharge diagnosis of hyperglycemia, DKA or HHS over a 15-month period (Jul 2016-Oct 2017). During the ED visit, consent was obtained for a telephone follow-up call to determine patient-important outcomes. Trained research personnel collected data from medical records and completed a 14 day telephone follow-up using a standardized questionnaire to determine medication changes, missed days of school or work, and repeat admissions or visits to a healthcare provider. Descriptive statistics were used where appropriate to summarize the data. Results: Thus far, 172 patients have been enrolled in our study. Mean (SD) age is 53.9 (19.3) years and 97 (56.4%) are male. 65 (37.8%) patients were admitted from their initial ED visit. Of the 125 patients (72.7%) providing post-discharge outcomes, 75 (60.0%) required an adjustment to their diabetes medications or insulin. 21 (16.8%) patients missed days of school or work for a median (IQR) duration of 3.5 (1.3, 7.0) days. 85 (68.0%) saw another healthcare provider within a 14 day period, 45 (36.0%) saw their family physician, and 34 (27.2%) saw an internist or endocrinologist. 9 (7.2%) were seen again in the ED, 5 of these patients required admission to hospital. There was one death that occurred within the follow-up period. Conclusion: This prospective study builds on our previous retrospective work and demonstrates that visits for hyperglycemia carry a significant burden of disease beyond what may be seen in a single ED encounter. Further research will attempt to identify the factors that may be predictive of adverse outcomes in hyperglycemic patients presenting to the ED.

Introduction: Diabetes mellitus is an increasingly prevalent chronic condition that is usually managed in an outpatient setting. However, the emergency department (ED) plays a crucial role in the management of diabetic patients, particularly for those who are presenting with newly diagnosed diabetes. Little research has been done to characterize the population of patients presenting to the ED with hyperglycemia with no previous diagnosis of diabetes. The objective of this study was to describe the epidemiology, treatment, and outcomes of patients who were newly diagnosed with diabetes in the ED and to compare those with newly diagnosed type I versus type II diabetes. Methods: A one-year health records review of newly diagnosed diabetes patients ≥18 years presenting to one of four tertiary care EDs was conducted. All patients with a discharge diagnosis of hyperglycemia, diabetic ketoacidosis or hyperosmolar hyperglycemic syndrome were screened, but only those who did not have a previous history of diabetes were included. Trained research personnel collected data on patient characteristics, management, disposition, and outcome. Descriptive statistics were used to summarize the data where appropriate. Results: Of 645 patients presenting with hyperglycemia in the study period, 112 (17.4%) were newly diagnosed diabetes patients. Of these patients, 30 (26.8%) were later diagnosed with type I diabetes and 82 (73.2%) were diagnosed with type II diabetes. For the newly diagnosed type I patients the mean (SD) age was 27.6 (9.9) and the mean (SD) age for type II patients was 52.4 (14.1). Of all the new onset patients, 26.8% were diagnosed with diabetic ketoacidosis. The percentage of patients diagnosed with diabetic ketoacidosis was higher in type I than type II (63.3% vs 13.4%; P<0.01). A total of 49 (43.8%) patients were admitted to the hospital, and more patients with type I were admitted compared to those with type II (66.7% vs 35.4 %; P<0.01). Conclusion: Limited research has been done to describe patients newly diagnosed with diabetes in the ED. Patients with type I were found to be more likely to present to the ED with serious symptoms requiring admission to hospital. Our findings demonstrate that the ED may have a strong potential role for improving diabetic care, by providing future opportunities for education and follow-up in the ED to reduce complications, particularly in type I.

Objectives: Decrements in cognitive function may already be evident in young children with type 1 diabetes (T1D). Here we report prospectively acquired cognitive results over 18 months in a large cohort of young children with and without T1D. Methods: A total of 144 children with T1D (mean HbA1c: 7.9%) and 70 age-matched healthy controls (mean age both groups 8.5 years; median diabetes duration 3.9 years; mean age of onset 4.1 years) underwent neuropsychological testing at baseline and after 18-months of follow-up. We hypothesized that group differences observed at baseline would be more pronounced after 18 months, particularly in those T1D patients with greatest exposure to glycemic extremes. Results: Cognitive domain scores did not differ between groups at the 18 month testing session and did not change differently between groups over the follow-up period. However, within the T1D group, a history of diabetic ketoacidosis (DKA) was correlated with lower Verbal IQ and greater hyperglycemia exposure (HbA1c area under the curve) was inversely correlated to executive functions test performance. In addition, those with a history of both types of exposure performed most poorly on measures of executive function. Conclusions: The subtle cognitive differences between T1D children and nondiabetic controls observed at baseline were not observed 18 months later. Within the T1D group, as at baseline, relationships between cognition (Verbal IQ and executive functions) and glycemic variables (chronic hyperglycemia and DKA history) were evident. Continued longitudinal study of this T1D cohort and their carefully matched healthy comparison group is planned. (JINS, 2016, 21, 293–302)

Placental lipoprotein lipase (LPL) is crucial for placental lipid transfer. Impaired LPL gene expression and activity were reported in pregnancies complicated by gestational diabetes mellitus (GDM) and intra-uterine growth restriction. We hypothesized that placental LPL DNA methylation is altered by maternal metabolic status and could contribute to fetal programming. The objective of this study was thus to assess whether placental LPL DNA methylation is associated with GDM and both maternal and newborn lipid profiles. Placenta biopsies were sampled at delivery from 126 women including 27 women with GDM diagnosed following a post 75 g-oral glucose tolerance test (OGTT) between weeks 24 and 28 of gestation. Placental LPL DNA methylation and expression levels were determined using bisulfite pyrosequencing and quantitative real-time PCR, respectively. DNA methylation levels within LPL proximal promoter region (CpG1) and intron 1 CpG island (CpGs 2 and 3) were lower in placenta of women with GDM. DNA methylation levels at LPL-CpG1 and CpG3 were also negatively correlated with maternal glucose (2-h post OGTT; r=–0.22; P=0.02) and HDL-cholesterol levels (third trimester of pregnancy; r=–0.20; p=0.03), respectively. Moreover, we report correlation between LPL-CpG2 DNA methylation and cord blood lipid profile. DNA methylation levels within intron 1 CpG island explained up to 26% (r⩽–0.51; P<0.001) of placental LPL mRNA expression variance. Overall, we showed that maternal metabolic profile is associated with placental LPL DNA methylation dysregulation. Our results suggest that site-specific LPL epipolymorphisms in the placenta are possibly functional and could potentially be involved in determining the future metabolic health of the newborn.