salicylates and Hyperinsulinism

Although the conditions that cause hypoglycemia in adults may also be present in infants and children, there are many entities unique to the pediatric age group. This reflects the delicate balance that exists in the newborn and young child between glucose production and utilization. During fasting in infants and children, hepatic glucose production is normally two to three times that of adults when expressed on the basis of weight. In the newborn and young infants, hypoglycemia usually presents with irritability, feeding difficulties, lethargy, cyanosis, tachypnea, and/or hypothermia rather than the typical adrenergic or neuroglucopenic symptoms seen in the adult. The hypoglycemia may be due to abnormalities in hormone secretion, substrate interconversion, or mobilization of metabolic fuels. The hypoglycemia associated with hyperinsulinemia may be transient neonatal, sustained, or drug-induced. Inborn errors of metabolism caused by enzymatic defects are responsible for hypoglycemia associated with abnormalities of production and utilization of metabolic fuels. These can involve carbohydrate, protein, and fat metabolism. In addition, there may be acquired or transient defects in carbohydrate metabolism secondary to other diseases or ingestion of certain substances. Finally ketotic hypoglycemia appears to be due to abnormalities in substrate availability. A variety of tests are useful for establishing the etiologic basis of the hypoglycemia, and the appropriate treatment depends upon the underlying cause.

Topics: Child; Endocrine System Diseases; Ethanol; Fatty Acids; Glucose; Heart Defects, Congenital; Homeostasis; Humans; Hyperinsulinism; Hypoglycemia; Infant; Infant, Newborn; Infant, Small for Gestational Age; Ketosis; Metabolism, Inborn Errors; Reye Syndrome; Salicylates

Low-grade inflammation may contribute to obesity-related insulin resistance and has been associated with increased risk of type 2 diabetes mellitus. The present study evaluated whether treatment with salsalate, a traditional anti-inflammatory medication, would improve insulin action in obese non-diabetic individuals.. The study was a randomised, double-blind, placebo-controlled, parallel trial conducted at the inpatient clinical research unit of the NIDKK (Phoenix, AZ, USA). Participants were 54 adults (18 to 45 years of age) with BMI >or= 30 kg/m(2). The intervention was salsalate (3 g/day, n = 28) or identical placebo (n = 26) for 7 days. The allocation was kept concealed by giving the investigator only a number corresponding to a vial of placebo or salsalate sequentially randomised in blocks by sex. Main outcomes were changes in insulin action assessed as rate of glucose disposal (R (d)) by euglycaemic-hyperinsulinaemic clamp (insulin infusion rate 40 mU m(-2) min(-1)) and glucose tolerance by 75 g OGTT.. The study was completed by 47 participants, of which 40 were analysed (salsalate n = 22, placebo n = 18). Salsalate treatment resulted in decreased fasting plasma glucose concentration (mean [SD]; 4.83 [0.28] vs 5.11 [0.33] mmol/l, p = 0.001) and glucose AUC during the OGTT (p = 0.01), and in increased R (d) (20 [8] vs 18 [6] micromol [kg estimated metabolic body size](-1) min(-1), p = 0.002), while there was no significant change in these variables with placebo (p > 0.3 for all). The effect of salsalate on R (d) disappeared (p = 0.9) after normalising to increased insulin concentrations (701 [285] vs 535 [201] pmol/l, p < 0.0001) measured during the clamp. No side effects of salsalate were observed during the study.. The glucose-lowering potential of salicylates appears to be due to effects on insulin concentration rather than improved insulin action. Salicylate-based compounds may be useful for the treatment and prevention of type 2 diabetes.

Topics: Adiponectin; Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; Body Mass Index; C-Reactive Protein; Double-Blind Method; Fatty Acids, Nonesterified; Female; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Male; Middle Aged; Obesity; Placebos; Salicylates; Sample Size; Young Adult

Chronic subacute inflammation is implicated in the pathogenesis of insulin resistance and type 2 diabetes. Salicylates were shown years ago to lower glucose and more recently to inhibit NF-kappaB activity. Salsalate, a prodrug form of salicylate, has seen extensive clinical use and has a favorable safety profile. We studied the efficacy of salsalate in reducing glycemia and insulin resistance and potential mechanisms of action to validate NF-kappaB as a potential pharmacologic target in diabetes.. In open label studies, both high (4.5 g/d) and standard (3.0 g/d) doses of salsalate reduced fasting and postchallenge glucose levels after 2 weeks of treatment. Salsalate increased glucose utilization during euglycemic hyperinsulinemic clamps, by approximately 50% and 15% at the high and standard doses, respectively, and insulin clearance was decreased. Dose-limiting tinnitus occurred only at the higher dose. In a third, double-masked, placebo-controlled trial, 1 month of salsalate at maximum tolerable dose (no tinnitus) improved fasting and postchallenge glucose levels. Circulating free fatty acids were reduced and adiponectin increased in all treated subjects.. These data demonstrate that salsalate improves in vivo glucose and lipid homeostasis, and support targeting of inflammation and NF-kappaB as a therapeutic approach in type 2 diabetes.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; Calorimetry; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Hyperinsulinism; Inflammation; Insulin; Insulin Resistance; Male; NF-kappa B; Placebos; Salicylates