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1.
Diabetes Care ; 45(1): 23-27, 2022 01 01.
Article in English | MEDLINE | ID: mdl-34986255

ABSTRACT

Since diabetes was first described over 3,000 years ago, clinicians and scientists alike have sought ever improving treatments en route to a cure. As we approach the 100th anniversary of insulin's first therapeutic use, this article will recount the glorious history associated with research surrounding insulin's isolation, purification, cloning, and subsequent modification. The discovery path we will relate tells the story of many relentless and passionate investigators pursuing ground-breaking research. The fruits of their labor include several Nobel Prizes, new technology, and, more importantly, ever improving treatments for one of humankind's greatest medical scourges.


Subject(s)
Diabetes Mellitus , Insulin , Diabetes Mellitus/drug therapy , History, 20th Century , Humans , Insulin/therapeutic use , Insulin, Regular, Human/therapeutic use , Nobel Prize , Research Personnel
2.
Pediatr Res ; 89(3): 653-659, 2021 02.
Article in English | MEDLINE | ID: mdl-32386398

ABSTRACT

BACKGROUND: Despite improved health, shorter stature is common in cystic fibrosis (CF). We aimed to describe height velocity (HV) and contribution of height-related genetic variants to height (HT) in CF. METHODS: HV cohort: standard deviation scores (-Z) for HT, mid-parental height-adjusted HT (MPAH), and HV were generated using our Pediatric Center's CF Foundation registry data. HV-Z was compared with population means at each age (5-17 y), the relationship of HV-Z with HT-Z assessed, and HT-Z compared with MPAH-Z. GRS cohort: HT genetic risk-Z (HT-GRS-Z) were determined for pancreatic exocrine sufficient (PS) and insufficient (PI) youth and adults from our CF center and their relationships with HT-Z assessed. RESULTS: HV cohort: average HV-Z was normal across ages in our cohort but was 1.5× lower (p < 0.01) for each SD decrease in HT-Z. MPAH-Z was lower than HT-Z (p < 0.001). GRS cohort: HT-GRS-Z more strongly correlated with HT-Z and better explained height variance in PS (rho = 0.42; R2= 0.25) vs. PI (rho = 0.27; R2 = 0.11). CONCLUSIONS: Despite shorter stature compared with peers and mid-parental height, youth with CF generally have normal linear growth in mid- and late childhood. PI tempered the heritability of height. These results suggest that, in CF, final height is determined early in life in CF and genetic potential is attenuated by other factors. IMPACT: Children with CF remain shorter than their healthy peers despite advances in care. Our study demonstrates that children with CF have persistent shorter stature from an early age and fail to reach their genetic potential despite height velocities comparable to those of average maturing healthy peers and similar enrichment in known height increasing single-nucleotide polymorphisms (SNPs). Genetic risk scores better explained variability in pancreatic sufficient than in pancreatic insufficient individuals, suggesting that other modifying factors are in play for pancreatic insufficient individuals with CF. Given the CF Foundation's recommendation to target not only normal body mass index, but normal height percentiles as well, this study adds valuable insight to this discussion.


Subject(s)
Body Height , Cystic Fibrosis/physiopathology , Exocrine Pancreatic Insufficiency/genetics , Adolescent , Child , Child, Preschool , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Electronic Health Records , Female , Genotype , Humans , Male , Pediatrics , Puberty , Registries , Risk
3.
Epilepsia ; 58 Suppl 2: 50-59, 2017 06.
Article in English | MEDLINE | ID: mdl-28591479

ABSTRACT

The most common, and usually the only, endocrine disturbance in patients with hypothalamic hamartoma (HH) and epilepsy is central precocious puberty (CPP). The mechanism for CPP associated with HH may relate to ectopic generation and pulsatile release of gonadotropin-releasing hormone (GnRH) from the HH, but this remains an unproven hypothesis. Possible regulators of GnRH release that are intrinsic to HH tissue include the following: (1) glial factors (such as transforming growth factor α[TGFα) and (2) γ-aminobutyric acid (GABA)-mediated excitation. Both are known to be present in surgically-resected HH tissue, but are present in patients with and without a history of CPP, suggesting the possibility that symptoms related to HH are directly associated with the region of anatomic attachment of the HH to the hypothalamus, which determines functional network connections, rather than to differences in HH tissue expression or pathophysiology. CPP associated with HH presents with isosexual development prior to the age of 8 years in girls and 9 years in boys. It is not uncommon for CPP with HH to present in children at an earlier age in comparison to other causes of CPP, including in infancy. Surgical resection of the HH can be effective for treating CPP, but is reserved for patients with intractable epilepsy, since GnRH agonists are widely available and effective treatment. Other endocrine disturbances with HH are rare, but can include growth hormone deficiency, hypothyroidism, and adrenal insufficiency. Diabetes insipidus is commonly encountered postoperatively, but is not observed with HH prior to surgical intervention.


Subject(s)
Drug Resistant Epilepsy/physiopathology , Epilepsies, Partial/physiopathology , Hamartoma/physiopathology , Hypothalamic Diseases/physiopathology , Puberty, Precocious/physiopathology , Child , Child, Preschool , Comorbidity , Drug Resistant Epilepsy/diagnosis , Drug Resistant Epilepsy/therapy , Endocrine System Diseases/diagnosis , Endocrine System Diseases/physiopathology , Endocrine System Diseases/therapy , Epilepsies, Partial/diagnosis , Epilepsies, Partial/therapy , Female , Gonadotropin-Releasing Hormone/blood , Hamartoma/diagnosis , Hamartoma/therapy , Hormones, Ectopic/blood , Humans , Hypothalamic Diseases/diagnosis , Hypothalamic Diseases/therapy , Hypothalamus/physiopathology , Infant , Male , Nerve Net/physiopathology , Puberty, Precocious/diagnosis , Puberty, Precocious/therapy , Transforming Growth Factor alpha/physiology , gamma-Aminobutyric Acid/physiology
4.
Pediatrics ; 137(2): e20150169, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26746406

ABSTRACT

Previous studies have shown that thyroid hormone directly stimulates bone resorption in in vitro organ culture, and in adults excess thyroid hormone is associated with decreased bone mineral density. There are limited data in children regarding the effect of hyperthyroidism on bone metabolism and even fewer instances in the literature of hyperthyroidism presenting with bone demineralization and fracture. We report a case of an 11-year-old boy with undiagnosed hyperthyroidism presenting with fractures and osteoporosis. This case emphasizes the importance of maintaining a broad differential diagnosis when a patient presents with a pathologic fracture.


Subject(s)
Graves Disease/diagnosis , Osteoporosis/etiology , Osteoporotic Fractures/etiology , Radius Fractures/etiology , Spinal Fractures/etiology , Thoracic Vertebrae/injuries , Child , Graves Disease/complications , Humans , Male , Osteoporosis/diagnosis , Osteoporotic Fractures/diagnostic imaging , Radiography , Radius Fractures/diagnostic imaging , Spinal Fractures/diagnostic imaging , Thoracic Vertebrae/diagnostic imaging
5.
PLoS One ; 4(3): e4827, 2009.
Article in English | MEDLINE | ID: mdl-19287497

ABSTRACT

BACKGROUND: Type 1 diabetes mellitus is caused by immune-mediated destruction of pancreatic beta-cells leading to insulin deficiency, impaired intermediary metabolism, and elevated blood glucose concentrations. While at autoimmune diabetes onset a limited number of beta-cells persist, the cells' regenerative potential and its regulation have remained largely unexplored. Using two mouse autoimmune diabetes models, this study examined the proliferation of pancreatic islet ss-cells and other endocrine and non-endocrine subsets, and the factors regulating that proliferation. METHODOLOGY AND PRINCIPAL FINDINGS: We adapted multi-parameter flow cytometry techniques (including DNA-content measurements and 5'-bromo-2'-deoxyuridine [BrdU] incorporation) to study pancreatic islet single cell suspensions. These studies demonstrate that beta-cell proliferation rapidly increases at diabetes onset, and that this proliferation is closely correlated with the diabetic animals' elevated blood glucose levels. For instance, we show that when normoglycemia is restored by exogenous insulin or islet transplantation, the beta-cell proliferation rate returns towards low levels found in control animals, yet surges when hyperglycemia recurs. In contrast, other-than-ss endocrine islet cells did not exhibit the same glucose-dependent proliferative responses. Rather, disease-associated alterations of BrdU-incorporation rates of delta-cells (minor decrease), and non-endocrine islet cells (slight increase) were not affected by blood glucose levels, or were inversely related to glycemia control after diabetes onset (alpha-cells). CONCLUSION: We conclude that murine beta-cells' ability to proliferate in response to metabolic need (i.e. rising blood glucose concentrations) is remarkably well preserved during severe, chronic beta-cell autoimmunity. These data suggest that timely control of the destructive immune response after disease manifestation could allow spontaneous regeneration of sufficient beta-cell mass to restore normal glucose homeostasis.


Subject(s)
Blood Glucose/metabolism , Cell Proliferation , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Type 1/pathology , Islets of Langerhans/cytology , Animals , Bromodeoxyuridine , DNA/metabolism , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/immunology , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/immunology , Flow Cytometry , Insulin/metabolism , Mice , Mice, Inbred C57BL , Mice, Inbred NOD
6.
Diabetes ; 58(5): 1175-84, 2009 May.
Article in English | MEDLINE | ID: mdl-19228810

ABSTRACT

OBJECTIVE: Insulin deficiency in type 1 diabetes and in rodent autoimmune diabetes models is caused by beta-cell-specific killing by autoreactive T-cells. Less is known about beta-cell numbers and phenotype remaining at diabetes onset and the fate of other pancreatic endocrine cellular constituents. RESEARCH DESIGN AND METHODS: We applied multicolor flow cytometry, confocal microscopy, and immunohistochemistry, supported by quantitative RT-PCR, to simultaneously track pancreatic endocrine cell frequencies and phenotypes during a T-cell-mediated beta-cell-destructive process using two independent autoimmune diabetes models, an inducible autoantigen-specific model and the spontaneously diabetic NOD mouse. RESULTS: The proportion of pancreatic insulin-positive beta-cells to glucagon-positive alpha-cells was about 4:1 in nondiabetic mice. Islets isolated from newly diabetic mice exhibited the expected severe beta-cell depletion accompanied by phenotypic beta-cell changes (i.e., hypertrophy and degranulation), but they also revealed a substantial loss of alpha-cells, which was further confirmed by quantitative immunohistochemisty. While maintaining normal randomly timed serum glucagon levels, newly diabetic mice displayed an impaired glucagon secretory response to non-insulin-induced hypoglycemia. CONCLUSIONS: Systematically applying multicolor flow cytometry and immunohistochemistry to track declining beta-cell numbers in recently diabetic mice revealed an altered endocrine cell composition that is consistent with a prominent and unexpected islet alpha-cell loss. These alterations were observed in induced and spontaneous autoimmune diabetes models, became apparent at diabetes onset, and differed markedly within islets compared with sub-islet-sized endocrine cell clusters and among pancreatic lobes. We propose that these changes are adaptive in nature, possibly fueled by worsening glycemia and regenerative processes.


Subject(s)
Diabetes Mellitus, Type 1/pathology , Diabetes Mellitus, Type 1/physiopathology , Islets of Langerhans/cytology , Islets of Langerhans/pathology , T-Lymphocytes/immunology , Animals , B-Lymphocytes/immunology , Diabetes Mellitus, Type 1/immunology , Disease Models, Animal , Flow Cytometry , Insulin/genetics , Insulin-Secreting Cells/cytology , Insulin-Secreting Cells/immunology , Insulin-Secreting Cells/pathology , Islets of Langerhans/immunology , Islets of Langerhans/physiopathology , Lymphocyte Activation , Mice , Mice, Inbred NOD , Mice, Transgenic , Promoter Regions, Genetic , Rats , Receptors, Antigen, T-Cell/genetics
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