Yoon Hi Cho

Puberty as an accelerator for diabetes complications.

Much is written about how difficult it is to deal with diabetes during adolescence, and rightly so. Less is understood as to how puberty may be an accelerator of vascular complications. With the increase in childhood diabetes, complication risks need to be revisited in relation to puberty and the secular increase in adiposity. Recent data suggest greater risk for severe vascular complications in those with diabetes during puberty, compared with young people who develop diabetes after puberty. It is also widely recognized that higher hemoglobin A1c (HbA1c) results are often seen during the pubertal period. This article will review complication outcomes in relation to puberty and examine mechanisms by which puberty may modify risk above glycemic exposure, and possible gender disparities in the risk of complications in the adolescent period.

Severe Short Stature Caused by Novel Compound Heterozygous Mutations of the Insulin-Like Growth Factor 1 Receptor (IGF1R)

CONTEXT IGF-I, essential for normal human growth in utero and postnatally, mediates its effects through the IGF-I receptor (IGF1R). More than nine heterozygous mutations, including one compound heterozygous mutation, of the IGF1R gene have been reported in patients with varying degrees of intrauterine and postnatal growth retardation. OBJECTIVE The objective of the study was the analysis of the IGF1R gene in a short-statured patient. PATIENT The male patient, with a height of -5.91 sd score (aged 20.3 yr), had consistently elevated circulating serum concentrations of IGF-I. A diagnosis of antibody-negative insulin-requiring diabetes was made at age 14 yr. His deceased sister was also severely short statured (-3.75 sd score). RESULTS The patient and his sister carried novel, compound heterozygous IGF1R missense mutations, E121K (exon 2) and E234K (exon 3), inherited from the mother and father, respectively. In vitro reconstitution studies demonstrated that neither the E121K nor E234K mutation affected IGF1R prepeptide expression, but levels of the proteolytically cleaved α- and β-subunit were consistently low. As a consequence, each IGF1R variant exhibited significantly reduced IGF-I-induced signal transduction. Correlating to these studies, expression of functional IGF1R and the IGF-I-induced activation of the IGF1R pathway were markedly reduced in the primary dermal fibroblasts established from the patient. CONCLUSIONS Only the second compound heterozygous IGF1R mutations to be identified, the p.E121K/E234K variant is the cause of intrauterine growth retardation and the most severe postnatal growth failure described to date in a patient with IGF1R defects. Whether the mutant IGF1R also contributes to the diabetic phenotype, however, remains to be determined.

Microvascular complications assessment in adolescents with 2- to 5-yr duration of type 1 diabetes from 1990 to 2006

Cho YH, Craig ME, Hing S, Gallego PH, Poon M, Chan A, Donaghue KC. Microvascular complications assessment in adolescents with 2‐ to 5‐yr duration of type 1 diabetes from 1990 to 2006.

Association Between HbA1c Variability and Risk of Microvascular Complications in Adolescents With Type 1 Diabetes

CONTEXT There is a paucity of data regarding the association between glycosylated hemoglobin (HbA1c) variability and risk of microvascular complications in adolescents with type 1 diabetes (T1D). OBJECTIVE To investigate the association between HbA1c variability and risk of microvascular complications in adolescents with T1D. DESIGN Prospective cohort study from 1990 to 2014 (median follow-up, 8.1 y). SETTING Tertiary pediatric hospital. PARTICIPANTS A total of 1706 adolescents (aged 12-20 minimum diabetes duration 5 y) with median age of 15.9 years (interquartile range, 14.3-17.5) and diabetes duration of 8.1 years (6.3-10.8). MAIN OUTCOME MEASURES Glycemic variability was computed as the SD of all HbA1c measurements (SD-HbA1c) after diagnosis. Retinopathy was detected using 7-field fundal photography, renal function assessed using albumin excretion rate, peripheral neuropathy detected using thermal and vibration threshold testing, and cardiac autonomic neuropathy (CAN) detected using time- and frequency-domain analyses of electrocardiogram recordings. Generalized estimating equations were used to examine the relationship between complications outcomes and HbA1c variability, after adjusting for known risk factors, including HbA1c, diabetes duration, blood pressure, and lipids. RESULTS In multivariable analysis, SD-HbA1c was associated with early retinopathy (odds ratio [OR] 1.32; 95% confidence interval, 1.00-1.73), albuminuria (OR 1.81; 1.04-3.14), increased log10 albumin excretion rate (OR 1.10; 1.05-1.15) and CAN (OR 2.28; 1.23-4.21) but not peripheral neuropathy. CONCLUSIONS Greater HbA1c variability predicts retinopathy, early nephropathy, and CAN, in addition to established risk factors, in adolescents with T1D. Minimizing long term fluctuations in glycemia may provide additional protection against the development of microvascular complications.

Autonomic neuropathy in young people with type 1 diabetes: a systematic review

Autonomic neuropathy is an under-recognized complication of diabetes, although it affects multiple organ systems and has widespread clinical manifestations including orthostatic hypotension, exercise intolerance, gastroparesis, diarrhea, constipation, and urinary incontinence. The most severe consequences include hypoglycemia unawareness and cardiovascular dysfunction. Autonomic neuropathy is also implicated in sudden unexplained deaths in otherwise healthy young people--the ‘dead in bed syndrome’. In adults, cardiovascular autonomic neuropathy is an independent predictor of mortality, predominantly due to cardiovascular disease, nephropathy, and hypoglycemia. While overt autonomic neuropathy is rare in childhood and adolescence, subclinical signs of autonomic dysfunction are common, and can be found soon after diabetes diagnosis. Risk factors for autonomic neuropathy in young people include diabetes duration, poor glycemic control, and presence of aldose reductase gene (AKR1B1) polymorphisms, specifically the Z-2/Z-2 genotype. Autonomic dysfunction is accelerated by puberty.

Cardiac Autonomic Dysfunction Is Associated With High-Risk Albumin-to-Creatinine Ratio in Young Adolescents With Type 1 Diabetes in AdDIT (Adolescent Type 1 Diabetes Cardio-Renal Interventional Trial)

OBJECTIVE This study examined the association between cardiac autonomic dysfunction and high albumin-to-creatinine ratio (ACR) in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS Adolescents recruited as part of a multicenter screening study (n = 445, 49% female, aged 10–17 years, mean duration 6.9 years; mean HbA1c 8.4%, 68 mmol/mol) underwent a 10-min continuous electrocardiogram recording for heart rate variability analysis. Time-domain heart rate variability measures included baseline heart rate, SD of the R-R interval (SDNN), and root mean squared difference of successive R-R intervals (RMSSD). Spectral analysis included sympathetic (low-frequency) and parasympathetic (high-frequency) components. Standardized ACR were calculated from six early morning urine collections using an established algorithm, reflecting age, sex, and duration, and stratified into ACR tertiles, where the upper tertile reflects higher nephropathy risk. RESULTS The upper-tertile ACR group had a faster heart rate (76 vs. 73 bpm; P < 0.01) and less heart rate variability (SDNN 68 vs. 76 ms, P = 0.02; RMSSD 63 vs. 71 ms, P = 0.04). HbA1c was 8.5% (69 mmol/mmol) in the upper tertile vs. 8.3% (67 mmol/mol) in the lower tertiles (P = 0.07). In multivariable analysis, upper-tertile ACR was associated with faster heart rate (β = 2.5, 95% CI 0.2–4.8, P = 0.03) and lower RMSSD (β = −9.5, 95% CI −18.2 to −0.8, P = 0.03), independent of age and HbA1c. CONCLUSIONS Adolescents at potentially higher risk for nephropathy show an adverse cardiac autonomic profile, indicating sympathetic overdrive, compared with the lower-risk group. Longitudinal follow-up of this cohort will further characterize the relationship between autonomic and renal dysfunction and the effect of interventions in this population.

Insulin Pump Therapy Is Associated with Lower Rates of Retinopathy and Peripheral Nerve Abnormality

Objective To compare rates of microvascular complications in adolescents with type 1 diabetes treated with continuous subcutaneous insulin infusion (CSII) versus multiple daily injections (MDI). Research Design and Methods Prospective cohort of 989 patients (aged 12–20 years; diabetes duration >5 years) treated with CSII or MDI for >12 months. Microvascular complications were assessed from 2000–14: early retinopathy (seven-field fundal photography), peripheral nerve function (thermal and vibration threshold testing), autonomic nerve abnormality (heart rate variability analysis of electrocardiogram recordings) and albuminuria (albumin creatinine ratio/timed overnight albumin excretion). Generalized estimating equations (GEE) were used to examine the relationship between treatment and complications rates, adjusting for socio-economic status (SES) and known risk factors including HbA1c and diabetes duration. Results Comparing CSII with MDI: HbA1C was 8.6% [70mmol/mol] vs. 8.7% [72 mmol/mol]) (p = 0.7), retinopathy 17% vs. 22% (p = 0.06); microalbuminuria 1% vs. 4% (p = 0.07), peripheral nerve abnormality 27% vs. 33% (p = 0.108) and autonomic nerve abnormality 24% vs. 28% (p = 0.401). In multivariable GEE, CSII use was associated with lower rates of retinopathy (OR 0.66, 95% CI 0.45–0.95, p = 0.029) and peripheral nerve abnormality (OR 0.63, 95% CI 0.42–0.95, p = 0.026), but not albuminuria (OR 0.46, 95% CI 0.10–2.17, p = 0.33). SES was not associated with any of the complication outcomes. Conclusions In adolescents, CSII use is associated with lower rates of retinopathy and peripheral nerve abnormality, suggesting an apparent benefit of CSII over MDI independent of glycemic control or SES.

Long-Term Outcomes in a Family with Nephrogenic Syndrome of Inappropriate Antidiuresis

We report a familial case of the nephrogenic syndrome of inappropriate antidiuresis (NSIAD), including 30-year followup data on two patients. The proband and one maternal uncle presented in their infancy with severe recurrent hyponatremia, and clinical pictures consistent with the syndrome of inappropriate antidiuretic hormone (SIADH) in the absence of an elevated ADH level. They were both confirmed to be hemizygous for the R137C mutation on the V2R gene (AVPR2), the same locus of the gain of function mutation demonstrated in the original reports of this condition. The probands mother was identified as an asymptomatic carrier of this X-linked condition. Our case describes a favourable long-term outcome for NSIAD, in particular, successful treatment with oral urea during the infancy period, and with self-regulated precautions on fluid intake into adult life.

Case report: consumptive hypothyroidism consequent to multiple infantile hepatic haemangiomas.

A 10-month-old infant with multiple infantile hepatic hemangiomas and developmental delay is reported. He was found to be profoundly hypothyroid. Evaluation and management issues are discussed. This case emphasizes the importance of screening for hypothyroidism in patients with hemangiomas and the potential therapeutic benefit of prednisolone therapy in this condition.

Heart rate variability in pubertal girls with type 1 diabetes: its relationship with glycaemic control, insulin resistance and hyperandrogenism

To examine the association between glycaemic control, insulin resistance and hyperandrogenism on cardiac autonomic function in peripubertal girls with type 1 diabetes.