Tumors, IGF-2, and hypoglycemia: insights from the clinic, the laboratory, and the historical archive.

Tumors of mesenchymal and epithelial origin produce IGF-2, which activates pathways in the tumors. In a minority of patients, the tumors (hepatomas, fibromas, and fibrosarcomas are the most common among many) release into the circulation enough IGF-2-related peptides to mimic the fasting hypoglycemia characteristic of patients with insulin-producing islet-cell tumors. Rarely, markedly elevated IGF-2 levels produce somatic changes suggestive of acromegaly. Typically, the elevated IGF-2 levels are associated with suppressed plasma levels of insulin, IGF-1, and GH. Complicating the pathophysiology are the IGF binding proteins (IGFBPs) that can bind IGF-2 and IGF-1, modifying hormone metabolism and action. IGFBP concentrations are often altered in the presence of these tumors. At the cellular level, the 3 hormone-related ligands, IGF-2, IGF-1, and insulin, all bind to 4 (or more) types of IGF-1 receptor (IGF-1R) and insulin receptor (IR). Each receptor has its own characteristic affinity for each ligand, a tyrosine kinase, and overlapping profiles of action in the target cells. The IGF-2R, in addition to binding mannose-6-phosphate-containing proteins, provides an IGF-2 degradation pathway. Recent evidence suggests IGF-2R involvement also in signal transduction. Surgery, the treatment of choice, can produce a cure. For patients not cured by surgery, multiple therapies exist, for the tumor and for hypoglycemia. Potential future therapeutic approaches are sketched. From 1910 to 1930, hypoglycemia, insulin, insulinomas, and non-islet-cell tumors were recognized. The latter third of the century witnessed the emergence of the immunoassay for insulin; the IGFs, their binding proteins, and assays to measure them; and receptors for the insulin-related peptides as well as the intracellular pathways beyond the receptor. In closing, we replace non-islet-cell tumor hypoglycemia, an outdated and misleading label, with IGF-2-oma, self-explanatory and consistent with names of other hormone-secreting tumors.

Durability of the effect of online diabetes training for medical residents on knowledge, confidence, and inpatient glycemia.

BACKGROUND: Inpatient dysglycemia is associated with increased morbidity, mortality and cost. Medical education must not only address knowledge gaps, but also improve clinical care. METHODS: All 129 medicine residents at a large academic medical center were offered a case-based online curriculum on the management of inpatient dysglycemia in the fall of 2009. First-year residents took a 3-h course with 10 modules. Second and third-year residents, who had been educated the prior year, underwent abbreviated training. All residents were offered a 20-min refresher course in the spring of 2009. We assessed resident knowledge, resident confidence, and patient glycemia on two teaching wards before and after the initial intervention, as well as after the refresher course. RESULTS: A total of 117 residents (91%) completed the initial training; 299 analyzed admissions generated 11, 089 blood glucose values and 4799 event blood glucose values. Admissions with target glycemia increased from 19.4% to 33.0% (P = 0.035) by the end of the curriculum. There was a strong downward trend in hyperglycemia from 22.4% to 11.3% (P = 0.055) without increased hypoglycemia. Confidence and knowledge increased significantly among first-time and repeat participants. Residents rated the intervention as highly relevant to their practice and technologically well implemented. CONCLUSION: Optimization of an online curriculum covering the management of inpatient glycemia over the course of 2 years led to significantly more admissions in the target glycemia range. Given its scalability, modularity and applicability, this web-based educational intervention may become the standard curriculum for the management of inpatient glycemia.

Effect of case-based training for medical residents on inpatient glycemia.

OBJECTIVE: To determine whether an educational intervention for medical house staff improves blood glucose (BG) in hospitalized patients. RESEARCH DESIGN AND METHODS: All 116 medicine residents at an academic medical center were assigned to online or classroom training on inpatient dysglycemia in fall 2008. Both groups were offered an online refresher course in spring 2009 addressing gaps in clinical practice identified on chart review. We assessed event BG, the first BG of any 3-h period, on two teaching wards. RESULTS: A total of 108 residents (93.1%) completed the initial training. The primary outcome, median event BG, decreased from 152 mg/dL in August 2008 to 139 mg/dL in December 2008 (P < 0.0001). Prevalence of event BG >200 mg/dL decreased from 25.5 to 22.7% (P = 0.0207), at the expense of more event BGs <70 mg/dL (2.0-3.9%, P = 0.0124). CONCLUSIONS: A curriculum for medicine residents on inpatient glycemia led to lower inpatient BG.

Effect of case-based training for medical residents on confidence, knowledge, and management of inpatient glycemia.

OBJECTIVE: To determine whether a brief, case-based educational intervention improves resident confidence, knowledge, and management of glycemia in hospitalized patients. RESEARCH DESIGN AND METHODS: All 116 medical residents at a large academic medical center were offered a case-based curriculum on the management of inpatient glycemia in fall 2008. Residents on ambulatory and elective rotations were taught in small groups, whereas all others underwent online training. All participants were offered a brief online refresher course in spring 2009. We assessed resident confidence across 9 domains of treating inpatient dysglycemia, knowledge based on 4 questions before the course, a 23-part questionnaire after the intervention, and changes in resident behavior as documented in chart abstractions. RESULTS: One hundred eight (93.1%) residents completed initial training, and 102 (87.9%) completed the refresher course. The share of scores indicating that residents felt "somewhat comfortable" or "completely comfortable" treating inpatient dysglycemia increased from 62.5% before the course to 94.3% (P<0.001) after the initial intervention and 92.8% (P<0.001) after the refresher. Knowledge scores improved from 72.2% correct answers to 88.9% (P<0.001) for the 4 questions asked before and after the course. Across all 23 questions posed after the initial course, residents answered 86.1% correctly and maintained a score of 85.5% after the refresher course. Online-trained residents, at 89.7%, outscored their classroom-trained peers (82.3%; P<0.001) after the initial course. Chart abstractions did not show any significant changes in managing glycemia. CONCLUSION: A curriculum on the management of inpatient glycemia was broadly adopted by medical residents at a large academic medical center and led to greater confidence and knowledge among residents. Further expansion to other health care providers and hospitals using a Web-based format and incorporation of updated guidelines is needed to confirm and build on these encouraging results.

Kwashiorkor and an acrodermatitis enteropathica-like eruption after a distal gastric bypass surgical procedure.

OBJECTIVE: To describe a case of kwashiorkor and an acrodermatitis enteropathica-like eruption associated with zinc deficiency after a distal gastric bypass surgical procedure. METHODS: A case report of a morbidly obese patient who underwent a gastric bypass operation is presented, including clinical, laboratory, and radiologic findings. In addition, the literature on potential nutritional deficiencies after bariatric surgical intervention is reviewed. RESULTS: A 43-year-old woman with a history of morbid obesity underwent a distal Roux-en-Y gastric bypass procedure at an outside institution. Six months later, she presented to our clinic because of abdominal pain, lower extremity edema, and a patchy maculopapular scaling rash. She had not adhered to a vitamin supplementation regimen prescribed postoperatively. Her symptoms progressively worsened, and she was hospitalized for management of severe malnutrition and dehydration. Laboratory tests revealed low levels of albumin, hemoglobin, vitamin A, vitamin D, copper, and zinc and elevated levels of liver enzymes. Anasarca and bowel wall edema were seen on an abdominal computed tomographic scan, and an upper endoscopy revealed a stomal ulcer and a stricture at the site of the gastrojejunal anastomosis. The patient was diagnosed as having kwashiorkor, zinc deficiency, and an acrodermatitis enteropathica-like eruption. Treatment was begun with total parenteral nutrition, which led to alleviation of her symptoms. Approximately 3 months later, she underwent gastric bypass revision but had numerous postoperative complications. CONCLUSION: Kwashiorkor and severe nutritional deficiencies were noted in this patient after a distal gastric bypass surgical procedure. This clinical presentation is uncommon and can be attributed to the increased malabsorption that occurs with distal gastric bypass, the development of mechanical complications, and the inadequacy of nutritional supplementation. After a bariatric operation, careful adherence to follow-up regimens and the involvement of a multidisciplinary team can improve the chances of a successful outcome.

Effects of fasting, leptin, and insulin on AGRP and POMC peptide release in the hypothalamus.

Agouti-related protein (AGRP) and proopiomelanocortin (POMC) have opposing effects on melanocortin receptor (MC-R) signaling and energy balance, and are important targets for leptin and insulin in the hypothalamus. While food intake and leptin have documented effects on POMC and AGRP gene expression, and insulin has effects on POMC gene expression, little is known about their effects on POMC or AGRP peptide release. Here we have examined the effects of fasting, leptin, and insulin on the release of AGRP and the POMC-derived peptide gamma(3)-MSH from the perifused rat hypothalamus in vitro. In the first experiment, fasting (48 h) resulted in a significant overall decrease in gamma(3)-MSH release measured every 20 min during a 3-h baseline perifusion period and after depolarization with 56 mM KCl (p = 0.02); there was a trend towards an overall increase in the release of AGRP but this was not significant. When the ratio of gamma(3)-MSH/AGRP release was calculated at each time point, there was an overall decrease in gamma(3)-MSH/AGRP with fasting (p < 0.01). Further examination of the ratio of gamma(3)-MSH/AGRP revealed a 34% reduction (p < 0.05) in the basal area under the curve (AUC) and a 33% reduction (p < 0.01) in the post-KCl stimulated AUC in fasted vs. fed animals. In the second experiment, perifusion of hypothalamic slices with 10(-8) or 10(-7) M leptin for 2 h resulted in a significant decrease in the release of AGRP noted primarily after depolarization with KCl (p < 0.01); no effect was seen on gamma(3)-MSH release. Similarly, in a third experiment, perifusion with 10(-7) M insulin caused a significant decrease in AGRP release (p < 0.001) without affecting gamma(3)-MSH release. Thus, there is a significant decrease in gamma(3)-MSH and the ratio of gamma(3)-MSH to AGRP released during fasting, consistent with a net inhibition of hypothalamic MC-R signaling. In contrast, short-term treatment with leptin and insulin may inhibit MC-R signaling primarily by decreasing the release of AGRP.

Oxyphil parathyroid adenoma: a malignant presentation of a benign disease.

Functioning parathyroid adenomas of the oxyphil cell type are rare, and the clinical characteristics of patients with these tumors have not been well defined. We describe two cases of severe primary hyperparathyroidism (PHPT) caused by benign oxyphil parathyroid adenomas. The patients' clinical presentations mimicked parathyroid carcinoma. Both had very large tumors associated with marked elevations in PTH and serum calcium levels. Skeletal manifestations were also atypical for benign PHPT, with severe osteoporosis in one patient and osteitis fibrosa cystica in the other. These cases also highlight the remarkable capacity of the skeleton to recover after successful parathyroidectomy, previously reported in other forms of severe PHPT. Bone mineral density improved dramatically 1 yr after parathyroidectomy, with increases of 51% at the lumbar spine, 36% at the total hip, and 11% at the distal one third radius. Most of the increases occurred in the first postoperative months. Consistent with this early and accelerated skeletal response, markers of bone turnover were increased 2 months after surgery and normalized by 8 months postoperatively. In patients with PHPT who present with severe or atypical clinical features, oxyphil adenoma should be considered.

Metabolic effects of transgenic melanocyte-stimulating hormone overexpression in lean and obese mice.

The proopiomelanocortin-derived peptide, alpha-MSH, inhibits feeding via melanocortin receptors in the hypothalamus and genetic defects inactivating the melanocortin system have been shown to lead to obesity in experimental animals and humans. To determine whether long-term melanocortinergic activation has significant effects on body weight and composition and insulin sensitivity, transgenic mice overexpressing N-terminal proopiomelanocortin, including alpha- and gamma(3)-MSH, under the control of the cytomegalovirus-promoter were generated. The transgene was expressed in multiple tissues including the hypothalamus, in which both alpha-MSH and gamma(3)-MSH levels were increased approximately 2-fold, compared with wild-type controls. Transgene homozygous mice were also crossed with obese leptin receptor-deficient db(3J) and obese yellow A(y) mice. MSH overexpression led to uniform, dose- dependent darkening of coat color. MSH overexpression reduced weight gain and adiposity and improved glucose tolerance in lean male mice. In female transgenic mice, there was no significant effect on body weight, but there was a significant decrease in insulin levels. Obesity was attenuated in obese db(3J)/db(3J) male and female mice, but there was no improvement in glucose metabolism. In contrast, the MSH transgene improved glucose tolerance in male A(y) mice. These results support the hypothesis that long-term melanocortinergic activation could serve as a potential strategy for anti-obesity and/or antidiabetic therapy.