The Impact of Dopamine on Insulin Secretion in Healthy Controls.

OBJECTIVE: Dopamine is very commonly used in the critical care setting and impacts glucose homeostasis. In some studies, it is noted to increase insulin resistance or decrease insulin secretion. The role of insulin secretion in response to dopamine is incompletely understood. METHODS: Eight individuals underwent a hyperglycemic clamp with a dopamine infusion, and eight controls underwent hyperglycemic clamp alone. Insulin, C-peptide, glucagon, cortisol, and norepinephrine (NE) concentrations were measured at various time points. An index of insulin sensitivity (M/I) was calculated. Statistical comparison between the control and treatment arm was done using repeated measures ANOVA. The data is expressed as mean ± standard deviation. Paired t-test was used to compare pre- and post-dopamine infusion time points in the study individuals only. Data was considered to be statistically significant at P < 0.05. RESULTS: On assessing the treatment group before and during dopamine infusion, insulin and C-peptide concentrations were higher at the time of the infusion (P = 0.02 and P = 0.003, respectively). The index of insulin sensitivity was not statistically different. There was a significant decrease in insulin (P = 0.002), C-peptide (P = 0.005), and NE (P < 0.0001) concentrations in the treatment group, compared to the controls. Glucagon concentration was higher in the treatment group (P = 0.02). CONCLUSION: In this study, dopamine infusion did not adversely impact insulin secretion.

Developing a Personal and Social Identity With Type 1 Diabetes During Adolescence: A Hypothesis Generative Study.

This study explored the incorporation of type 1 diabetes mellitus (T1DM) into self-identity among adolescents. Guided interviews explored 40 adolescents' views of T1DM in relation to their sense of self and relationships with others. Responses were analyzed using thematic analysis. Results revealed that the entire sample described T1DM as a significant burden; many described how T1DM made them feel less "normal." Adolescents described both positive and negative aspects of self-management in social relationships, though most reported benefits in sharing T1DM with friends. Females were more likely to share information about T1DM and to describe positive changes in self-perception as a result of T1DM. The psychosocial processes related to integration of T1DM into self-identity described in these qualitative data provide hypothesis-generating findings that can guide future quantitative research examining incorporation of T1DM into adolescent self-identity in relation to measures of self-esteem, peer orientation, self-management, and glycemic control.

Foster care and type 1 diabetes in the Bronx: a case series.

OBJECTIVE: The objective of this retrospective study was to describe the health status of children with type 1 diabetes mellitus (T1DM) in foster care. RESEARCH DESIGN AND METHODS: A retrospective chart review of children with T1DM in foster care at the Children's Hospital at Montefiore (CHAM) in Bronx, NY, USA, was performed. RESULTS: All patients were either African American or Hispanic and raised by single mothers. The majority of referrals were for medical neglect. The time spent in foster care ranged from 1 to 7 years, with 1-12 placements. Only two children were reunified with their biological mothers. Extensive financial burdens on the health-care system for children with diabetes including prolonged hospitalizations awaiting placement, frequent hospital admissions, and support services were noted. CONCLUSIONS: To our knowledge, this is the first report on children with T1DM in foster care. Poor glycemic control and suboptimal social outcomes were noted in the children we report in our case series. Programs geared to improve and reform foster care for children with diabetes are needed.

Insulin sensitivity and obstructive sleep apnea in adolescents with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) in adults is linked with insulin resistance (IR) and obstructive sleep apnea (OSA). However, less is known about these associations in adolescents. METHODS: We studied 3 groups of adolescents: 27 obese PCOS (OPCOS) (ages 13-21)11 normal-weight PCOS (NPCOS) (ages 13-21 years), and 8 healthy controls (ages 18-21 years). A hyperinsulinemic euglycemic clamp study was performed in all groups to determine IR by insulin sensitivity (M/I). Polysomnography was performed to assess for OSA in OPCOS and NPCOS groups. We compared indices of IR among all groups and OSA among OPCOS, and NPCOS. RESULTS: We noted that OPCOS and NPCOS and controls differed significantly in their IR. M/I was significantly lower in OPCOS vs. controls (p=0.0061), and also lower for NPCOS vs control but this approached but did not reach statistical significance (p=0.084). In addition, none of the NPCOS subjects had OSA compared to 42% of OPCOS (p=0.03). CONCLUSIONS: Our study suggests OPCOS adolescents have increased IR compared to controls and NPCOS subjects. Higher IR for NPCOS vs controls approached but did not reach statistical significance. Larger studies are needed. In addition, adolescents with OPCOS are at a high risk for OSA.

Hyperglycemia and diabetes mellitus in children with pancreatitis.

OBJECTIVE: To assess the risk factors for developing hyperglycemia and diabetes mellitus (DM) in children with pancreatitis. STUDY DESIGN: Patients (from infants to age 21 years) hospitalized with acute pancreatitis (AP), acute recurrent pancreatitis (ARP), and chronic pancreatitis were studied retrospectively. Subjects with known DM or cystic fibrosis before presentation with pancreatitis were excluded. RESULTS: A total of 176 patients met the study criteria. Of these, 140 had AP, 29 had ARP, and 7 had chronic pancreatitis. Severe pancreatitis was associated with hyperglycemia; 41% of the patients with hyperglycemia required insulin, and 8 patients (4.5%) developed DM requiring insulin by the time of discharge. These 8 patients with postpancreatitis DM were more likely to be overweight. Five of the 8 patients had a seizure disorder, and 4 had another comorbidity, such as mental retardation or cerebral palsy. Seven of the 8 patients who developed DM had a single episode of AP, and one patient had ARP. CONCLUSIONS: Our findings indicate that hyperglycemia and DM can occur with pancreatitis. In some cases, postpancreatitis DM was associated with mental retardation, seizure disorder, and use of antiseizure medication. As opposed to adults who develop DM after chronic pancreatitis, children can develop DM due to a single episode of AP.

Predictors of direct costs of diabetes care in pediatric patients with type 1 diabetes.

OBJECTIVE: This study examines factors that predict elevated direct costs of pediatric patients with type 1 diabetes. METHODS: A cohort of 784 children with type 1 diabetes at least 6 months postdiagnosis and managed by pediatric endocrinologists at Texas Children's Hospital were included in this study. Actual reimbursed costs from January 2004 to December 2005 were obtained. Medication and supply costs were based on estimates from insulin dosage and type of insulin regimen prescribed, respectively. We examined utilization of care, total diabetes-related direct medical costs, and predictors of direct costs and hospitalization. RESULTS: Annually, 7% (58/784) of patients (excluding initial hospitalization at diagnosis) had a diabetes-related hospitalization and median length of stay was days. Mean total diabetes-related direct cost per person-year was $4730 [95% confidence interval (CI), 4516-4944]. Supplies accounted for 38% and medications 33% of costs, respectively. Older age, hemoglobin A(1C) (HbA(1C) ) > 8.5%, use of a multi-injection or pump regimen, living in a non-married household, and female gender were associated with higher annual costs. HbA(1C) > 8.5%, living in a non-married household, and female gender increased the odds of a diabetes-related hospitalization. DISCUSSION: Better metabolic control in patients with type 1 diabetes was associated with lower direct medical costs and lower odds of hospitalization. Marital status of the primary caregiver, irrespective of type of insurance, impacts the patient's healthcare costs and risk of hospitalization. This large single-center US study analyzes cost distribution in children with diabetes and is informative for payers and providers focused on effective management and improving healthcare costs.

Health-related quality of life and cognitive functioning in pediatric short stature: comparison of growth-hormone-naïve, growth-hormone-treated, and healthy samples.

The objective of this study was to evaluate the impact of short stature on generic health-related quality of life (HRQOL) and cognitive functioning in pediatric patients. Eighty-nine youth, 48 who were initially seen with short stature (SS group) and 41 with a history of short stature being treated with growth hormone (GHT group) and one of their legal guardians participated in the study. HRQOL and cognitive functioning were assessed using the PedsQL™ 4.0 Generic Core Scales and PedsQL™ Cognitive Functioning Scale. Comparisons were made between the study groups and with a previously obtained matched healthy sample. For the GHT group, height Z score was found to be a positive predictor of overall HRQOL while duration of GHT was found to be a predictor of physical functioning. For the SS group, the difference between midparental height Z score and height Z score was found to be a negative predictor of overall HRQOL and cognitive functioning. Comparison with the healthy sample demonstrated significant negative impact on HRQOL for child self-report and on HRQOL and cognitive functioning for parent proxy-report in both study groups. The GHT group had a significantly higher child self-reported Physical Functioning score than the SS group (effect size (ES) = 0.52, p < 0.05). In conclusion, the GHT group had slightly better HRQOL scores than the SS group, but the difference was not statistically significant. Both groups had significantly lower HRQOL and cognitive functioning scores than healthy sample. Predictors of HRQOL and cognitive functioning found in this study lend support to the use of the PedsQL™ 4.0 Generic Score Scales and PedsQL™ Cognitive Functioning Scale in routine assessment of children with short stature in order to identify children at increased risk for impaired HRQOL and cognitive functioning.

Total parenteral nutrition associated with severe insulin resistance following hematopoietic stem cell transplantation in patients with hemophagocytic syndrome: report on two cases.

Hyperglycemia secondary to total parenteral nutrition (TPN) is reported in adults. In addition, insulin resistance and type 2 diabetes as late consequences of hematopoietic stem cell transplantation (HSCT) are well described. Both situations are generally manageable with traditional insulin dosing. We present two children who developed severe insulin resistance requiring intravenous insulin therapy at doses up to 13 units/kg/h. Both children were on TPN after undergoing HSCT for hemophagocytic syndrome. We believe that our report will alert physicians to such a condition and help with early recognition that is a key to successful intervention. These cases aim to increase awareness and stimulate research to unravel the associated underling mechanisms.

New potential adjuncts to treatment of children with type 1 diabetes mellitus.

Insulin administration is the primary therapy for type 1 diabetes mellitus (T1DM). Current available insulin therapies do not successfully enable children with T1DM to reach glycemic goals without side effects such as hypoglycemia and weight gain. Pramlintide is a synthetic analog of human amylin that acts in conjunction with insulin to delay gastric emptying and inhibit the release of glucagon and is indicated for use in patients with type 1 and type 2 diabetes. Recent studies in adult patients have examined the role of glucagon-like peptide 1 (GLP-1) and agents that bind to its receptor in type 1 diabetes. It is hypothesized that a major component of the glycemic effect is attributable to the known action of GLP-1 to delay gastric emptying and to inhibit glucagon secretion. Further studies with the use of amylin analogs and long-acting GLP-1 agonists as congeners with insulin in T1DM are indicated in children. In recent years, our better understanding of the pathophysiology of diabetes has led to the development of new therapies for diabetes. This article reviews the potential use of these newer pharmacologic agents as adjunctive therapy in T1DM in children and adolescents.

Reducing postprandial hyperglycemia with adjuvant premeal pramlintide and postmeal insulin in children with type 1 diabetes mellitus.

OBJECTIVE: The purpose of this study was to determine the effect of adjuvant premeal pramlintide with postmeal insulin on postprandial hyperglycemia in children with type 1 diabetes mellitus (T1DM). METHODS: Eight adolescents with T1DM on intensive insulin therapy participated in an open-label, non-randomized, crossover study, comparing postprandial glucose excursions in study A (prescribed insulin regimen and given premeal) vs. study B (pramlintide + insulin). Prandial insulin dose for study B was decreased by 20% and given postmeal, while pramlintide was given just before the meal. Blood glucose (BG), glucagon, and pramlintide concentrations were measured basally and at timed intervals during a 300-min study period. RESULTS: Postprandial incremental BG for the duration of the study was reduced in study B vs. study A with AUC((-60 to 300 min)) (area under the curve) at 6600 +/- 2371 vs. 20 230 +/- 3126 mg/dL/min (367 +/- 132 vs. 1124 +/- 174 mmol/L/min) (p < 0.001). Glucagon concentration was suppressed for approximately 120 min following administration of 30 microg of pramlintide and postmeal insulin (p < 0.003). No severe hypoglycemic episodes were experienced in this study. CONCLUSIONS: Postprandial hyperglycemia is considerably reduced in adolescents with T1DM when treated with fixed-dose premeal pramlintide, and precisely calculated postmeal insulin, without significant side effects.

Hyperlipidemia in children.

Vandana S. Raman, MD, and Rubina A. Heptulla, MD, explain the clinical assessment and management strategies for childhood hyperlipidemia.

Targeting blood glucose management in school improves glycemic control in children with poorly controlled type 1 diabetes mellitus.

We hypothesized that school nurse supervision of glucose and insulin-dose adjustment significantly improves the hemoglobinA(1c) (HbA(1c)) level in pediatric patients with poorly controlled type 1 diabetes mellitus (HbA(1c) > or = 9%). A total of 36 subjects were enrolled and 18 subjects were randomized to receive the 3-month intervention. Their average HbA(1c) was lowered by 1.6%, suggesting that this intervention helps this difficult group of patients.

Gastric emptying and postprandial glucose excursions in adolescents with type 1 diabetes.

Because amylin is co-secreted with insulin from beta cells, patients with type 1 diabetes (T1DM) are deficient in both insulin and amylin. Amylin delays gastric emptying and suppresses glucagon in the postprandial period. Hence, we hypothesized that children with complication-naive T1DM have accelerated gastric emptying in response to a mixed meal because of amylin deficiency. Amylin, glucagon, insulin, glucose, and gastric emptying were measured in seven T1DM and in eight control subjects without diabetes. Subjects with T1DM had markedly elevated glucose concentrations when compared with controls (p < 0.0001). Amylin concentrations as predicted were lower in T1DM compared with those in controls (p < 0.0001). Insulin did not peak in the immediate postprandial period in T1DM when compared with controls (p < 0.0001). Glucagon concentrations did not significantly differ between groups. Interestingly, gastric velocity was delayed in patients with T1DM compared with controls (p < 0.01). In conclusion, subjects with T1DM do have amylin deficiency but this is not associated with accelerated gastric emptying as we had hypothesized but rather with delayed gastric emptying. Factors other than amylin play a role in control of gastric motility in T1DM. Subcutaneous insulin delivery fails to reach adequate concentrations in the postprandial period to curtail peak glucose concentration in T1DM.

Effect of Marijuana Use on Thyroid Function and Autoimmunity.

BACKGROUND: Marijuana is legalized for medical use in 24 states and for recreational use in 5. However, effects of marijuana use on thyroid function and autoimmunity are unknown. METHODS: We performed a cross-sectional analysis of data from the National Health and Nutrition Examination Survey (NHANES) conducted between 2007 and 2012 to assess the effects of marijuana on thyroid function and autoimmunity in users. We included 5280 adults ages 18 to 69 years, who responded to questions related to marijuana use and had laboratory results related to thyroid parameters. Subjects were categorized as nonusers (never used), past users (used prior to 30 days ago), and recent users (used within last 30 days). Using NHANES normative cut offs for thyroid parameters, we compared recent users with nonusers and past users and calculated the odds ratios for the relative rate of clinically significant thyroid dysfunction in those groups. Multivariate logistic regression was then performed to control for confounders. RESULTS: Fifty-four percent of subjects reported lifetime cannabis use, with 15% using it recently. Univariate regression analysis showed that recent marijuana users had significantly lower frequency of elevated thyrotropin (TSH) and positive anti-thyroperoxidase antibody (TPOAb) versus nonusers/past users. After controlling for confounders, recent marijuana use remained an independent predictor for TSH <5.6 µIU/mL (odds ratio of 0.344 with 95% CI of 0.127-0.928; p = 0.04) but not for negative TPOAb. CONCLUSION: Recent marijuana use was not associated with thyroid dysfunction but was significantly associated with lower levels of TSH.

Use of Sitagliptin With Closed-Loop Technology to Decrease Postprandial Blood Glucose in Type 1 Diabetes.

BACKGROUND: Postprandial hyperglycemia poses a challenge to closed-loop systems. Dipeptidyl peptidase-4 (DPP-4) inhibitors, like sitagliptin, reduce postprandial glucose concentrations in patients with type 2 diabetes. The objective of this study was to assess sitagliptin's role in type 1 diabetes (T1DM) as an adjunct therapy in reducing postprandial blood glucose with an insulin-only closed-loop system. METHODS: This was a randomized, double-blinded, placebo controlled, crossover design trial. The participants were18-35 years old, had T1DM, and an HbA1c of ≤ 8.5%. A dose determination study included eight subjects with T1DM. There were three study visits. Four hours after receiving study drug (placebo, sitagliptin 50 mg, sitagliptin 100 mg), subjects underwent a mixed meal tolerance test with assessment of hormone concentrations. In a second study, 15 subjects underwent two visits receiving either placebo or 100 mg of sitagliptin plus an insulin only closed-loop system for 25 hours with timed meals. Blood glucose and other hormone concentrations were analyzed using repeated measures ANOVA. RESULTS: For the dose determination study, sitagliptin 100 mg resulted in reduced postprandial blood glucose ( P = .006). For the closed-loop study, glucose concentrations were lower in the treatment group, most prominently during the first two study meals ( P = .03). There was no difference in glucagon concentrations, but insulin concentrations and insulin delivery were lower in the treatment group. CONCLUSIONS: Sitagliptin may be considered as an adjunct therapy in a closed-loop setting. Larger studies are needed to determine the role of oral agents like sitagliptin to lower postprandial hyperglycemia with closed loop.

Predictors of Loss to Follow-Up among Children with Type 2 Diabetes.

BACKGROUND/AIMS: Youth with type 2 diabetes (T2D) have poor compliance with medical care. This study aimed to determine which demographic and clinical factors differ between youth with T2D who receive care in a pediatric diabetes center versus youth lost to follow-up for >18 months. METHODS: Data were analyzed from 496 subjects in the Pe-diatric Diabetes Consortium registry. Enrollment variables were selected a priori and analyzed with univariable and multivariable logistic regression models. RESULTS: After a median of 1.3 years from enrollment, 55% of patients were lost to follow-up. The final model included age, race/ethnicity, parent education, and estimated distance to study site. The odds ratio (99% confidence interval) of loss to follow-up was 2.87 (1.34, 6.16) for those aged 15 to <18 years versus those aged 10 to <13 years and 6.57 (2.67, 16.15) for those aged ≥18 years versus those aged 10 to <13 years. Among patients living more than 50 miles from the clinic, the odds ra tio of loss to follow-up was 3.11 (1.14, 8.49) versus those living within 5 miles of the site. CONCLUSION: Older adolescents with T2D are more likely to be lost to follow-up, but other socioeconomic factors were not significant predictors of clinic follow-up.

The role of amylin and glucagon in the dampening of glycemic excursions in children with type 1 diabetes.

Postprandial hyperglycemia and preprandial hypoglycemia contribute to poor glycemic control in type 1 diabetes. We hypothesized that postprandial glycemic excursions could be normalized in type 1 diabetes by suppressing glucagon with pramlintide acetate in the immediate postprandial period and supplementing glucagon in the late postprandial period. A total of 11 control subjects were compared with 8 type 1 diabetic subjects on insulin pump therapy, using the usual insulin bolus-to-carbohydrate ratio during a standard liquid meal. Type 1 diabetic subjects were then randomized to two open-labeled studies. On one occasion, type 1 diabetic subjects received a 60% increase in the insulin bolus-to-carbohydrate ratio with minidose glucagon rescue injections, and on the other occasion type 1 diabetic subjects received 30-45 microg pramlintide with their usual insulin bolus-to-carbohydrate ratio. Glucose, glucagon, amylin (pramlintide), and insulin concentrations were measured for 420 min. The plasma glucose area under the curve (AUC) for 0-420 min was lower in control versus type 1 diabetic subjects (316 +/- 5 vs. 929 +/- 18 mg x h(-1) x dl(-1), P < 0.0001). Pramlintide, but not an increase in insulin, reduced immediate postprandial hyperglycemia (AUC(0-180 min) 470 +/- 43 vs. 434 +/- 48 mg x h(-1) x dl(-1), P < 0.01). Pramlintide administration suppressed glucagon (P < 0.02), and glucagon injections prevented late hypoglycemia with increased insulin. In summary, in type 1 diabetes, glucagon modulation with pramlintide as an adjunct to insulin therapy may prove beneficial in controlling postmeal glycemic swings.

Effects of hypoglycemia on human brain activation measured with fMRI.

Functional magnetic resonance imaging (fMRI) was used to measure the effects of acute hypoglycemia caused by passive sensory stimulation on brain activation. Visual stimulation was used to generate blood-oxygen-level-dependent (BOLD) contrast, which was monitored during hyperinsulinemic hypoglycemic and euglycemic clamp studies. Hypoglycemia (50 +/- 1 mg glucose/dl) decreased the fMRI signal relative to euglycemia in 10 healthy human subjects: the fractional signal change was reduced by 28 +/- 12% (P < .05). These changes were reversed when euglycemia was restored. These data provide a basis of comparison for studies that quantify hypoglycemia-related changes in fMRI activity during cognitive tasks based on visual stimuli and demonstrate that variations in blood glucose levels may modulate BOLD signals in the healthy brain.

Adjuvant Liraglutide and Insulin Versus Insulin Monotherapy in the Closed-Loop System in Type 1 Diabetes: A Randomized Open-Labeled Crossover Design Trial.

BACKGROUND: The closed-loop (CL) system delivers insulin in a glucose-responsive manner and optimal postprandial glycemic control is difficult to achieve with the algorithm and insulin available. We hypothesized that adjunctive therapy with liraglutide, a once-daily glucagon-like peptide-1 agonist, would be more effective in normalizing postprandial hyperglycemia versus insulin monotherapy in the CL system, in patients with type 1 diabetes. METHODS: This was a randomized, controlled, open-label, crossover design trial comparing insulin monotherapy versus adjuvant subcutaneous liraglutide 1.2 mg and insulin, using the CL system in 15 patients. Blood glucose (BG), insulin, and glucagon concentrations were analyzed. RESULTS: The liraglutide arm was associated with overall decreased mean BG levels (P = .0002). The average BG levels from 8:00 pm (day 1) to 9:00 pm (day 2) were lower in the liraglutide arm (144.6 ± 36.31 vs 159.7 ± 50.88 mg/dl respectively; P = .0002). Two-hour postbreakfast and lunch BG profiles were better in the liraglutide arm (P < .05) and the insulin and glucagon assay values were lower (P < .0001). Postprandially, the area under the curve (AUC) for 2-hour postbreakfast and lunch BG levels were significant (P = .01, P = .03) and the AUC for glucagon, postbreakfast (P < .0001) and lunch (P < .05), was also significant. The incidence of hypoglycemia did not differ between arms (P = .83, Fisher's exact test). Overall, adjunct liraglutide therapy plus CL was well tolerated even with expected side effects. CONCLUSION: This is a proof-of-concept study showing liraglutide can be a potential adjunctive therapy in addition to CL with insulin to reduce postprandial hyperglycemia in type 1 diabetes.

Evaluating emergency preparedness and impact of a hurricane sandy in pediatric patients with diabetes.

BACKGROUND: Natural disasters have always been associated with significant adverse events including medical and mental health problems. Children with chronic disease such has diabetes have also been believed to be affected to a greater extent by any natural disaster. The purpose of this study was to assess and compare emergency preparedness post-disaster and post-traumatic stress effects of Hurricane Sandy in affected and relatively unaffected populations. METHODS: The study was conducted between February and July 2013. A total of 142 families caring for children with Type 1 Diabetes Mellitus (T1DM) who attended clinics were recruited from hospitals in Bronx, NY (control) and in NJ (affected) by Hurricane Sandy. Subjects were recruited to participate in a survey 3-6 months after the hurricane. Data on demographics, glycemic control and insulin regimens were collected. Families were surveyed for socio-economic status (SES), using Hollingshead questionnaire, general and diabetes preparedness and the Hurricane Related Traumatic Experiences (HURTE) questionnaire was used to evaluate for symptoms of post-traumatic stress. RESULTS: Ninety-five percent of families reported to be generally well to moderately prepared for the hurricane and 83 % reported to be very well prepared with regards to their child's diabetes during the disaster. There was no difference between the sites for preparedness for the disaster, age or gender. There was a trend toward significance (p < 0.06) in New Jersey subjects as to a greater psychological impact from the hurricane. Poor glycemic control was significantly associated with lower SES (p < 0.008). Most importantly, SES was unrelated to preparedness for diabetes management during the hurricane. CONCLUSIONS: Despite low SES, families were generally well to moderately prepared for hurricane. In children with diabetes, interventional studies should be designed and implemented so that glycemic control remains unaffected, following any major disaster.