No abstract

Although assessment of counterregulatory hormone responses to hypoglycemia relies upon insulin to lower the glucose level, it is not known if the exogenous insulin does used itself influences the magnitude of the hormone response. To assess this, 12 normal subjects randomly received 2 hypoglycemic clamp studies in which the only variable was the insulin dose (0.6 or 5.0 mU/kg-min). Despite 10-fold differences in circulating insulin (265 +/- 29 vs 2576 +/- 222 pmol/L respectively), the hypoglycemic stimulus did not vary. Glucose levels fell over one hour, and then were maintained for two hours at the same hypoglycemic plateau (approximately 3.1 mmol/L for each study) by a variable glucose infusion. Although basal counterregulatory hormone levels in low and high dose studies were indistinguishable, during hypoglycemia the response of epinephrine, growth hormone, and glucagon was significantly suppressed when the degree of hyperinsulinemia was increased. We conclude that raising the magnitude of hyperinsulinemia suppresses the magnitude of the counterregulatory hormone response to hypoglycemia in normal subjects. This modulating effect of insulin per se is yet another variable in the interpretation of hypoglycemic counterregulation.

Objectives: To document diagnosis rates of type 2 diabetes mellitus in children and adolescents in Western Australia over the past 12 years, the clinical characteristics of these patients and any comorbidities. Design: Review of a prospectively recorded diabetes database. Setting: Tertiary paediatric referral centre (the only such centre in WA). Patients: All children and adolescents aged < 17 years diagnosed with type 2 diabetes between 1990 and 2002 and managed by Princess Margaret Hospital Diabetes Unit. Main outcome measures: Anthropometric and demographic data; glycohaemoglobin (HbA1c) level; blood pressure; lipid levels; presence of acanthosis nigricans. Results: 43 patients (15 males and 28 females) were diagnosed with type 2 diabetes. Age (SD) at diagnosis was 13.6 (1.8) years. The rate of diagnosis has been progressively increasing (average annual increase in the unadjusted overall rates of type 2 diabetes was 27%). Twenty‐three patients (53%) were of Indigenous origin and 18 (42%) resided in rural areas. The mean (SD) HbA1c level at diagnosis was 10.0% (3.2%). Seventy‐two per cent of patients had acanthosis nigricans, 59% had hypertension, and 24% had hyperlipidaemia. Conclusions: There has been an increase in the diagnosis rate of type 2 diabetes in children and adolescents in WA. Comorbidities are frequent.

No abstract

In patients treated with CSII, interruption of the basal insulin infusion in the middle of the night does not result in more rapid metabolic decompensation in patients treated with lispro compared with those treated with regular human insulin. Lispro insulin is effective in treating mild ketosis and hyperglycemia, and its rapid action may be advantageous in the "sick day" management at home of patients with IDDM.

Increased emphasis on strict glycaemic control of insulin dependent diabetes mellitus (IDDM) in young patients may be expected to cause increases in rates of significant hypoglycaemia. To evaluate whether this is the case for a large population based sample of IDDM children and adolescents rates of severe (coma, convulsion) and moderate (requiring assistance for treatment) hypoglycaemia were studied prospectively over a four year period.A total of 709 patients were studied yielding 2027 patient years of data (mean (SD) age: 12.3 (4.4); range 0-18 years, duration IDDM: 4.9 (3.8) years). Details of hypoglycaemia were recorded at clinic visits every three months when glycated haemoglobin (HbA1 c ) was also measured.Overall the incidence of severe hypoglycaemia was 7.8 and moderate was 15.4 episodes/100 patient years. Over the four years mean (SD) clinic HbA1 c steadily fell from 10.2 (1.6)% in 1992 to 8.8 (1.5)% in 1995. In parallel with this there was a dramatic increase in the rate of hypoglycaemia, especially in the fourth year of the study, when severe hypoglycaemia increased from 4.8 to 15.6 episodes/100 patient years. This increase was particularly marked in younger children (<6 years) in whom severe hypoglycaemia increased from 14.9 to 42.1 episodes/100 patient years in 1995.It is concluded that attempts to achieve improved metabolic control must be accompanied by eVorts to minimise the eVects of significant hypoglycaemia, particularly in the younger age group. (Arch Dis Child 1998;78:111-115) Keywords: hypoglycaemia; insulin dependent diabetes mellitus; glycaemic control Hypoglycaemia is the most common acute complication of the treatment of insulin dependent diabetes mellitus (IDDM) and its occurrence often restricts attempts to improve glycaemic control. This is particularly critical for younger patients who may be even more susceptible to severe hypoglycaemia 1 as a result of the interaction of both physiological and behavioural factors. A number of reports have described the incidence and clinical factors associated with significant hypoglycaemia in childhood but many of these have become outdated with recent changes to management goals and practices.2-5 For example, the greater emphasis on improved metabolic control and intensified treatment after the release of the Diabetes Control and Complications Trial (DCCT) results is likely to have altered the epidemiology of this acute complication of treatment. 6 We have recently reported results of a study performed over a three year period in which we found a high incidence of significant hypoglycaemia in children and adolescents. 7 Episodes were rare in the first year from diagnosis but were more frequent in children aged <6 years and in those with lower glycated haemoglobin (HbA1 c ). We now report a continuation of the same study, now completed over four years, and analysed to determine the relationship between glycaemic control and rates of hypoglycaemia. Although the association between lower HbA1 c and the incidence of severe hypoglycaemia h...

To evaluate the effects of childhood and poorly controlled insulin-dependent diabetes mellitus (IDDM) on counterregulatory hormone and symptomatic responses to hypoglycemia, we studied 16 nondiabetic children (13 +/- 2 yr), 19 nondiabetic adults (26 +/- 3 yr), and 13 children with IDDM (14 +/- 2 yr, HbA, 15.1 +/- 3.3%) during a gradual reduction in plasma glucose with the glucose-clamp technique. Plasma glucose was reduced from approximately 5 to approximately 2.8 mM over 240 min with serial assessment of counterregulatory hormone levels and symptom awareness. The plasma glucose level that triggered a sustained rise in plasma epinephrine was consistently higher in nondiabetic children than in adults (3.9 +/- 0.06 vs. 3.2 +/- 0.06 mM, P less than 0.001). Poorly controlled IDDM further elevated the glucose threshold for epinephrine release to normoglycemic levels (4.9 +/- 0.2 mM, P less than 0.001 vs. both control groups). Age and IDDM also produced an upward shift in the glucose level at which growth hormone release and symptom awareness were initiated. In contrast to the effect on glucose thresholds, maximal epinephrine responses and symptom scores were increased only by age and not IDDM (2-fold higher in children). We conclude that childhood and poor diabetes control independently contribute to an upward shift in glucose thresholds for counterregulatory hormone release and symptom awareness during mild hypoglycemia. Normoglycemic counterregulation may interfere with efforts to control diabetes in young patients.

The enormous library of pharmaceutical compounds presents endless research avenues. However, several factors limit the therapeutic potential of these drugs, such as drug resistance, stability, off-target toxicity, and inadequate delivery to the site of action. Extracellular vesicles (EVs) are lipid bilayer-delimited particles and are naturally released from cells. Growing evidence shows that EVs have great potential to serve as effective drug carriers. Since EVs can not only transfer biological information, but also effectively deliver hydrophobic drugs into cells, the application of EVs as a novel drug delivery system has attracted considerable scientific interest. Recently, EVs loaded with siRNA, miRNA, mRNA, CRISPR/Cas9, proteins, or therapeutic drugs show improved delivery efficiency and drug effect. In this review, we summarize the methods used for the cargo loading into EVs, including siRNA, miRNA, mRNA, CRISPR/Cas9, proteins, and therapeutic drugs. Furthermore, we also include the recent advance in engineered EVs for drug delivery. Finally, both advantages and challenges of EVs as a new drug delivery system are discussed. Here, we encourage researchers to further develop convenient and reliable loading methods for the potential clinical applications of EVs as drug carriers in the future.