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1.  Changes in human brain glutamate concentration during hypoglycemia: insights into cerebral adaptations in hypoglycemia-associated autonomic failure in type 1 diabetes 
Hypoglycemia-associated autonomic failure (HAAF) is a condition in which patients with type 1 diabetes (T1D) who experience frequent hypoglycemia develop defective glucose counter-regulation and become unable to sense hypoglycemia. Brain glutamate may be involved in the mechanism of HAAF. The goal of this study was to follow the human brain glutamate concentration during experimentally induced hypoglycemia in subjects with and without HAAF. 1H magnetic resonance spectroscopy was used to track the occipital cortex glutamate concentration throughout a euglycemic clamp followed immediately by a hypoglycemic clamp. T1D patients with HAAF were studied in comparison to two control groups, i.e., T1D patients without HAAF and healthy controls (n=5 per group). Human brain glutamate concentration decreased (P⩽0.01) after the initiation of hypoglycemia in the two control groups, but a smaller trend toward a decrease in patients with HAAF did not reach significance (P>0.05). These findings are consistent with a metabolic adaptation in HAAF to provide higher glucose and/or alternative fuel to the brain, eliminating the need to oxidize glutamate. In an exploratory analysis, we detected additional metabolite changes in response to hypoglycemia in the T1D patient without HAAF control group, namely, increased aspartate and decreased lactate.
PMCID: PMC4013769  PMID: 24549182
brain; diabetes; glutamate; hypoglycemia; unawareness
2.  Hypoglycemia as a driver of cardiovascular risk in diabetes 
Severe hypoglycemia in patients with diabetes is associated with increased risk of adverse cardiovascular events and death. Recent large randomized clinical trials in individuals with type 2 diabetes have shown that intensive glycemic control may result in increased mortality and hypoglycemia has been investigated as a possible cause. Acute hypoglycemia is a pro-arrhythmic, pro-inflammatory and pro-thrombotic state and several mechanisms have been proposed to explain how hypoglycemia might increase cardiovascular morbidity and mortality. However, data from large clinical trials do not provide strong evidence to establish hypoglycemia as cause of increase mortality. Severe hypoglycemia is also a marker of frailty and predictor of adverse outcomes in patients with diabetes. Individualized therapy should be the goal in patients with diabetes to avoid severe hypoglycemia and any related adverse outcomes.
PMCID: PMC3743541  PMID: 23881546
Hypoglycemia; diabetes mellitus; cardiovascular risk; HAAF; mortality; type 2 diabetes mellitus; type 1 diabetes mellitus; severe hypoglycemia
3.  Hypoglycemia mediated by paraneoplastic production of Insulin like growth factor–2 from a malignant renal solitary fibrous tumor – clinical case and literature review 
Hypoglycemic episodes are infrequent in individuals without a history of diabetes mellitus or bariatric surgery. When hypoglycemia does occur in such individuals, an uncommon but important diagnosis to consider is non-islet cell tumor hypoglycemia (NICTH). We report a case of NICTH associated with paraneoplastic insulin-like growth factor-2 (IGF-2) production and review current relevant medical literature.
Case presentation
A 60 year old male with no relevant past medical history was referred to the endocrinology clinic with 18 month history of episodic hypoglycemic symptoms and, on one occasion was noted to have a fingerstick glucose of 36 mg/dL while having symptoms of hypoglycemia. Basic laboratory evaluation was unrevealing. Further evaluation however showed an elevated serum IGF-2 level at 2215 ng/mL (reference range 411–1248 ng/mL). Imaging demonstrated a large right suprarenal mass. A right nephrectomy with resection of the mass demonstrated a malignant solitary fibrous tumor. Post resection, the patient’s IGF-2 levels normalized and hypoglycemic symptoms resolved.
Due to the structural and biochemical homology between IGF-2 and insulin, elevated levels of IGF-2 can result in hypoglycemia. A posttranslational precursor to IGF-2 known as “big IGF” also possesses biologic activity. Review of recent reported cases of NICTH identified widespread anatomic locations and varied pathologic diagnoses of tumors associated with paraneoplastic production of IGF-2 causing hypoglycemia. Definitive management of hypoglycemia associated with paraneoplastic production of IGF-2 consists of resection of the tumor responsible for IGF-2 production. Accumulating literature provides a firm basis for routine IGF-2 laboratory evaluation in patients presenting with spontaneous hypoglycemia with no readily apparent cause.
PMCID: PMC4067084  PMID: 24934576
Non islet cell tumor hypoglycemia (NICTH); Insulin like Growth Factor–2 (IGF-2); Big IGF-2; Hypoglycemia; Paraneoplastic production; Insulinoma; Solitary fibrous tumor
4.  Neurochemical profile of patients with type 1 diabetes measured by 1H-MRS at 4 T 
The impact of type 1 diabetes mellitus (T1DM) on a comprehensive neurochemical profile of the human brain has not been reported yet. Our previous proton magnetic resonance spectroscopy (1H-MRS) studies on T1DM were focused exclusively on the assessment of brain glucose levels. In this study, we reexamined our previously acquired data to investigate concentration differences of a broad range of neurochemicals in T1DM subjects relative to nondiabetic controls. We selected MRS data from 13 subjects (4 F/9 M, age=41±11 years, body mass index=26±3 kg/m2) with well-controlled T1DM (disease duration=22±12 years, A1C=7.5%±2.0%) and 32 nondiabetic controls (14 F/18 M, age=36±10 years, body mass index=27±6 kg/m2) acquired during a hyperglycemic clamp (target [Glc]plasma=300±15 mg/dL). The 1H-MR spectra were collected from two 15.6-mL voxels localized in gray-matter-rich occipital lobe and in white-matter-rich parieto-occipital region using ultra-short echo-time STEAM at 4 T. LCModel analysis allowed reliable quantification of 17 brain metabolites. Lower levels of N-acetylaspartate (by 6%, P=0.007) and glutamate (by 6%, P=0.045) were observed in the gray matter of T1DM patients as compared with controls, which might indicate a partial neuronal loss or dysfunction as a consequence of long-term T1DM. No other differences in metabolites were observed between subjects with T1DM and controls.
PMCID: PMC3652707  PMID: 23403373
diabetes; glutamate; MR spectroscopy; neurochemistry; neurotransmitters
5.  Hypoglycemia-induced increases in thalamic cerebral blood flow are blunted in subjects with type 1 diabetes and hypoglycemia unawareness 
The thalamus has been found to be activated during the early phase of moderate hypoglycemia. Here, we tested the hypothesis that this region is less activated during hypoglycemia in subjects with type 1 diabetes (T1DM) and hypoglycemia unawareness relative to controls. Twelve controls (5 F/7 M, age 40±14 years, body mass index 24.2±2.7 kg/m2) and eleven patients (7 F/4 M, age 39±13 years, body mass index 26.5±4.4 kg/m2) with well-controlled T1DM (A1c 6.8±0.4%) underwent a two-step hyperinsulinemic (2.0 mU/kg per minute) clamp. Cerebral blood flow (CBF) weighted images were acquired using arterial spin labeling to monitor cerebral activation in the midbrain regions. Blood glucose was first held at 95 mg/dL and then allowed to decrease to 50 mg/dL. The CBF image acquisition during euglycemia and hypoglycemia began within a few minutes of when the target blood glucose values were reached. Hypoglycemia unaware T1DM subjects displayed blunting of the physiologic CBF increase that occurs in the thalamus of healthy individuals during the early phase of moderate hypoglycemia. A positive correlation was observed between thalamic response and epinephrine response to hypoglycemia, suggesting that this region may be involved in the coordination of the counter regulatory response to hypoglycemia.
PMCID: PMC3494000  PMID: 22892724
diabetes; glucose; hypoglycemia; imaging
6.  Support for and aspects of use of educational games in family medicine and internal medicine residency programs in the US: a survey 
BMC Medical Education  2010;10:26.
The evidence supporting the effectiveness of educational games in graduate medical education is limited. Anecdotal reports suggest their popularity in that setting. The objective of this study was to explore the support for and the different aspects of use of educational games in family medicine and internal medicine residency programs in the United States.
We conducted a survey of family medicine and internal medicine residency program directors in the United States. The questionnaire asked the program directors whether they supported the use of educational games, their actual use of games, and the type of games being used and the purpose of that use.
Of 434 responding program directors (52% response rate), 92% were in support of the use of games as an educational strategy, and 80% reported already using them in their programs. Jeopardy like games were the most frequently used games (78%). The use of games was equally popular in family medicine and internal medicine residency programs and popularity was inversely associated with more than 75% of residents in the program being International Medical Graduates. The percentage of program directors who reported using educational games as teaching tools, review tools, and evaluation tools were 62%, 47%, and 4% respectively.
Given a widespread use of educational games in the training of medical residents, in spite of limited evidence for efficacy, further evaluation of the best approaches to education games should be explored.
PMCID: PMC2851700  PMID: 20338034
7.  Curricula for teaching the content of clinical practice guidelines to family medicine and internal medicine residents in the US: a survey study 
Teaching the content of clinical practice guidelines (CPGs) is important to both clinical care and graduate medical education. The objective of this study was to determine the characteristics of curricula for teaching the content of CPGs in family medicine and internal medicine residency programs in the United States.
We surveyed the directors of family medicine and internal medicine residency programs in the United States. The questionnaire included questions about the characteristics of the teaching of CPGs: goals and objectives, educational activities, evaluation, aspects of CPGs that the program teaches, the methods of making texts of CPGs available to residents, and the major barriers to teaching CPGs.
Of 434 programs responding (out of 839, 52%), 14% percent reported having written goals and objectives related to teaching CPGs. The most frequently taught aspect was the content of specific CPGs (76%). The top two educational strategies used were didactic sessions (76%) and journal clubs (64%). Auditing for adherence by residents was the primary evaluation strategy (44%), although 36% of program directors conducted no evaluation. Programs made texts of CPGs available to residents most commonly in the form of paper copies (54%) while the most important barrier was time constraints on faculty (56%).
Residency programs teach different aspects of CPGs to varying degrees, and the majority uses educational strategies not supported by research evidence.
PMCID: PMC2753632  PMID: 19772570

Results 1-7 (7)