BACKGROUND. Postreceptor insulin resistance (IR) is associated with hyperglycemia and hepatic steatosis. However, receptorlevel IR (e.g., insulin receptor pathogenic variants, INSR) causes hyperglycemia without steatosis. We examined 4 pathologic conditions of IR in humans to examine pathways controlling lipid metabolism and gluconeogenesis. METHODS.Cross-sectional study of severe receptor IR (INSR, n = 7) versus postreceptor IR that was severe (lipodystrophy, n = 14), moderate (type 2 diabetes, n = 9), or mild (obesity, n = 8). Lipolysis (glycerol turnover), hepatic glucose production (HGP), gluconeogenesis (deuterium incorporation from body water into glucose), hepatic triglyceride (magnetic resonance spectroscopy), and hepatic fat oxidation (plasma β-hydroxybutyrate) were measured. RESULTS.Lipolysis was 2-to 3-fold higher in INSR versus all other groups, and HGP was 2-fold higher in INSR and lipodystrophy versus type 2 diabetes and obesity (P < 0.001), suggesting severe adipose and hepatic IR. INSR subjects had a higher contribution of gluconeogenesis to HGP, approximately 77%, versus 52% to 59% in other groups (P = 0.0001). Despite high lipolysis, INSR subjects had low hepatic triglycerides (0.5% [interquartile range 0.1%-0.5%]), in contrast to lipodystrophy (10.6% [interquartile range 2.8%-17.1%], P < 0.0001). β-hydroxybutyrate was 2-to 7-fold higher in INSR versus all other groups (P < 0.0001), consistent with higher hepatic fat oxidation. CONCLUSION.These data support a key pathogenic role of adipose tissue IR to increase glycerol and FFA availability to the liver in both receptor and postreceptor IR. However, the fate of FFA diverges in these populations. In receptor-level IR, FFA oxidation drives gluconeogenesis rather than being reesterified to triglyceride. In contrast, in postreceptor IR, FFA contributes to both gluconeogenesis and hepatic steatosis. TRIAL REGISTRATION. ClinicalTrials.gov NCT01778556, NCT00001987, and NCT02457897. FUNDING.
IntroductionIdiopathic ketotic hypoglycemia (KH) is the most common cause of hypoglycemia in non-diabetic children ages 0.5–6 years old and typically occurs after a period of poor food intake. There are no large studies looking at the value of common laboratory testing in children presenting with KH or how often other diagnoses are made.ObjectivesTo examine the clinical presentations and the value of laboratory testing done in a cohort of children clinically diagnosed with KH.MethodsBilling records were searched from 2008 to 2017 for patients seen by the endocrine service for “hypoglycemia, not otherwise specified”. Charts were reviewed to determine age, sex, presenting symptoms and testing ordered at the time of the consult. Through chart reviews after the event and parent phone calls, diagnoses other than idiopathic KH were searched.ResultsOf 150 charts reviewed, 62 had sufficient information to make a clinical diagnosis of KH (32 males 30 females, mean age 2.9 years). Most had a history of gastrointestinal illness or prolonged fasting but 29% had no apparent precipitating event. Laboratory testing was quite variable and while low serum CO2 was seen in over half, no routine hormone testing, metabolic testing or supervised fasting resulted in a relevant diagnosis. We identified 4 out of 62 (6.5%) with relevant diagnoses which explained KH, including one child with failure to thrive found to have growth hormone (GH) deficiency and 3 by genetic testing, including one case of GSD type 9α, but all had atypical presentations.ConclusionsIn the typical setting of a healthy 0.5–6 year-old child with an uncomplicated episode of KH following poor food intake and a normal exam including growth, hormonal and metabolic testing can safely be deferred. However, frequent recurrences and atypical features should prompt further investigation.Trial registrationNot needed for a retrospective chart review study.
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