Publications by authors named "Simon J Fisher"

43 Publications

Understanding the Prevalence of Prediabetes and Diabetes in Patients With Cancer in Clinical Practice: A Real-World Cohort Study.

J Natl Compr Canc Netw 2021 Mar 10;19(6):709-718. Epub 2021 Mar 10.

2Huntsman Cancer Institute, and.

Background: This study aimed to understand the prevalence of prediabetes (preDM) and diabetes mellitus (DM) in patients with cancer overall and by tumor site, cancer treatment, and time point in the cancer continuum.

Methods: This cohort study was conducted at Huntsman Cancer Institute at the University of Utah. Patients with a first primary invasive cancer enrolled in the Total Cancer Care protocol between July 2016 and July 2018 were eligible. Prevalence of preDM and DM was based on ICD code, laboratory tests for hemoglobin A1c, fasting plasma glucose, nonfasting blood glucose, or insulin prescription.

Results: The final cohort comprised 3,512 patients with cancer, with a mean age of 57.8 years at cancer diagnosis. Of all patients, 49.1% (n=1,724) were female. At cancer diagnosis, the prevalence of preDM and DM was 6.0% (95% CI, 5.3%-6.8%) and 12.2% (95% CI, 11.2%-13.3%), respectively. One year after diagnosis the prevalence was 16.6% (95% CI, 15.4%-17.9%) and 25.0% (95% CI, 23.6%-26.4%), respectively. At the end of the observation period, the prevalence of preDM and DM was 21.2% (95% CI, 19.9%-22.6%) and 32.6% (95% CI, 31.1%-34.2%), respectively. Patients with myeloma (39.2%; 95% CI, 32.6%-46.2%) had the highest prevalence of preDM, and those with pancreatic cancer had the highest prevalence of DM (65.1%; 95% CI, 57.0%-72.3%). Patients who underwent chemotherapy, radiotherapy, or immunotherapy had a higher prevalence of preDM and DM compared with those who did not undergo these therapies.

Conclusions: Every second patient with cancer experiences preDM or DM. It is essential to foster interprofessional collaboration and to develop evidence-based practice guidelines. A better understanding of the impact of cancer treatment on the development of preDM and DM remains critical.
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http://dx.doi.org/10.6004/jnccn.2020.7653DOI Listing
March 2021

Insulin action in the brain regulates both central and peripheral functions.

Am J Physiol Endocrinol Metab 2021 07 31;321(1):E156-E163. Epub 2021 May 31.

Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah.

The brain has been traditionally thought to be insensitive to insulin, primarily because insulin does not stimulate glucose uptake/metabolism in the brain (as it does in classic insulin-sensitive tissues such as muscle, liver, and fat). However, over the past 20 years, research in this field has identified unique actions of insulin in the brain. There is accumulating evidence that insulin crosses into the brain and regulates central nervous system functions such as feeding, depression, and cognitive behavior. In addition, insulin acts in the brain to regulate systemic functions such as hepatic glucose production, lipolysis, lipogenesis, reproductive competence, and the sympathoadrenal response to hypoglycemia. Decrements in brain insulin action (or brain insulin resistance) can be observed in obesity, type 2 diabetes (T2DM), aging, and Alzheimer's disease (AD), indicating a possible link between metabolic and cognitive health. Here, we describe recent findings on the pleiotropic actions of insulin in the brain and highlight the precise sites, specific neuronal population, and roles for supportive astrocytic cells through which insulin acts in the brain. In addition, we also discuss how boosting brain insulin action could be a therapeutic option for people at an increased risk of developing metabolic and cognitive diseases such as AD and T2DM. Overall, this perspective article serves to highlight some of these key scientific findings, identify unresolved issues, and indicate future directions of research in this field that would serve to improve the lives of people with metabolic and cognitive dysfunctions.
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http://dx.doi.org/10.1152/ajpendo.00642.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321819PMC
July 2021

A structurally minimized yet fully active insulin based on cone-snail venom insulin principles.

Nat Struct Mol Biol 2020 07 1;27(7):615-624. Epub 2020 Jun 1.

Department of Biochemistry, University of Utah, Salt Lake City, UT, USA.

Human insulin and its current therapeutic analogs all show propensity, albeit varyingly, to self-associate into dimers and hexamers, which delays their onset of action and makes blood glucose management difficult for people with diabetes. Recently, we described a monomeric, insulin-like peptide in cone-snail venom with moderate human insulin-like bioactivity. Here, with insights from structural biology studies, we report the development of mini-Ins-a human des-octapeptide insulin analog-as a structurally minimal, full-potency insulin. Mini-Ins is monomeric and, despite the lack of the canonical B-chain C-terminal octapeptide, has similar receptor binding affinity to human insulin. Four mutations compensate for the lack of contacts normally made by the octapeptide. Mini-Ins also has similar in vitro insulin signaling and in vivo bioactivities to human insulin. The full bioactivity of mini-Ins demonstrates the dispensability of the PheB24-PheB25-TyrB26 aromatic triplet and opens a new direction for therapeutic insulin development.
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http://dx.doi.org/10.1038/s41594-020-0430-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374640PMC
July 2020

Hypoglycemia unawareness and autonomic dysfunction in diabetes: Lessons learned and roles of diabetes technologies.

J Diabetes Investig 2020 Nov 7;11(6):1388-1402. Epub 2020 Jul 7.

Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.

Impaired awareness of hypoglycemia (IAH) is a reduction in the ability to recognize low blood glucose levels that would otherwise prompt an appropriate corrective therapy. Identified in approximately 25% of patients with type 1 diabetes, IAH has complex pathophysiology, and might lead to serious and potentially lethal consequences in patients with diabetes, particularly in those with more advanced disease and comorbidities. Continuous glucose monitoring systems can provide real-time glucose information and generate timely alerts on rapidly falling or low blood glucose levels. Given their improvements in accuracy, affordability and integration with insulin pump technology, continuous glucose monitoring systems are emerging as critical tools to help prevent serious hypoglycemia and mitigate its consequences in patients with diabetes. This review discusses the current knowledge on IAH and effective diagnostic methods, the relationship between hypoglycemia and cardiovascular autonomic neuropathy, a practical approach to evaluating cardiovascular autonomic neuropathy for clinicians, and recent evidence from clinical trials assessing the effects of the use of CGM technologies in patients with type 1 diabetes with IAH.
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http://dx.doi.org/10.1111/jdi.13290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610104PMC
November 2020

Associations Between the Time in Hypoglycemia and Hypoglycemia Awareness Status in Type 1 Diabetes Patients Using Continuous Glucose Monitoring Systems.

Diabetes Technol Ther 2020 11 13;22(11):787-793. Epub 2020 Oct 13.

Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.

Continuous glucose monitoring (CGM) systems help reduce hypoglycemia in patients with type 1 diabetes (T1D). It remains unclear whether T1D patients with impaired awareness of hypoglycemia (IAH) continue to develop more hypoglycemia than those with normal hypoglycemia awareness (NA) despite CGM use. For this cross-sectional observational study, 99 T1D patients using real-time CGMs for ≥86% of time were recruited. Fifty and 49 patients were found to have NA and IAH (based on the Clarke questionnaire), respectively. Two-week CGM hypoglycemia data were collected. IAH was associated with greater percentages of CGM values <70 and <54 mg/dL ( = 0.012,  = 0.004) compared to NA. Clarke scores correlated positively with the percentage of CGM values <70 and <54 mg/dL ( = 0.013,  = 0.004). IAH was also related to more events with glucose <70 and <54 mg/dL determined either with at ≥1 time point ( = 0.048,  = 0.003) or lasting ≥20 min ( = 0.016,  = 0.004). IAH patients presented with more day-time events with glucose <54 mg/dL ( = 0.015), nocturnal events with glucose levels <70 and <54 mg/dL ( = 0.009,  = 0.007) and longer day-time event duration with glucose levels <70 and <54 mg/dL ( < 0.001,  = 0.006), respectively. T1D patients with IAH continue to experience more hypoglycemia despite dedicated CGM use.
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http://dx.doi.org/10.1089/dia.2020.0016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699009PMC
November 2020

Alarm Settings of Continuous Glucose Monitoring Systems and Associations to Glucose Outcomes in Type 1 Diabetes.

J Endocr Soc 2020 Jan 19;4(1):bvz005. Epub 2019 Nov 19.

Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah.

Context: Little evidence exists regarding the positive and negative impacts of continuous glucose monitor system (CGM) alarm settings for diabetes control in patients with type 1 diabetes (T1D).

Objective: Evaluate the associations between CGM alarm settings and glucose outcomes.

Design And Setting: A cross-sectional observational study in a single academic institution.

Patients And Main Outcome Measures: CGM alarm settings and 2-week CGM glucose information were collected from 95 T1D patients with > 3 months of CGM use and ≥ 86% active usage time. The associations between CGM alarm settings and glucose outcomes were analyzed.

Results: Higher glucose thresholds for glycemia alarms (ie, ≥ 73 mg/dL vs < 73 mg/dL) were related to 51% and 65% less time with glucose < 70 and < 54 mg/dL, respectively ( = 0.005; = 0.016), higher average glucose levels ( = 0.002) and less time-in-range ( = 0.005), but not more hypoglycemia alarms. The optimal alarm threshold for < 1% of time in hypoglycemia was 75 mg/dL.Lower glucose thresholds for glycemia alarms (ie, ≤ 205 mg/dL vs > 205 mg/dL) were related to lower average glucose levels and 42% and 61% less time with glucose > 250 and > 320 mg/dL ( = 0.020, = 0.016, = 0.007, respectively), without more hypoglycemia. Lower alarm thresholds were also associated with more alarms ( < 0.0001). The optimal alarm threshold for < 5% of time in hyperglycemia and hemoglobin A1c ≤ 7% was 170 mg/dL.

Conclusions: Different CGM glucose thresholds for hypo/hyperglycemia alarms are associated with various hypo/hyperglycemic outcomes. Configurations to the hypo/hyperglycemia alarm thresholds could be considered as an intervention to achieve therapeutic goals.
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http://dx.doi.org/10.1210/jendso/bvz005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977942PMC
January 2020

MicroRNA-7a overexpression in VMH restores the sympathoadrenal response to hypoglycemia.

JCI Insight 2019 10 17;4(20). Epub 2019 Oct 17.

Division of Endocrinology, Metabolism, and Diabetes, Department of Internal Medicine, and.

It is proposed that the impaired sympathoadrenal response to hypoglycemia induced by recurrent insulin-induced hypoglycemia (RH) is an adaptive phenomenon induced by specific changes in microRNA expression in the ventromedial hypothalamus (VMH). To test this hypothesis, genome-wide microRNAomic profiling of the VMH by RNA-sequencing was performed in control rats and rats treated for RH. Differential expression analysis identified microRNA-7a-5p and microRNA-665 as potential mediators of this phenomenon. To further test this hypothesis, experiments were conducted consisting of targeted lentiviral-mediated overexpression of microRNA-7a-5p and downregulation of microRNA-665 in the VMH. Hyperinsulinemic hypoglycemic clamp experiments demonstrated that targeted overexpression of microRNA-7a-5p (but not downregulation of microRNA-665) in the VMH of RH rats restored the epinephrine response to hypoglycemia. This restored response to hypoglycemia was associated with a restoration of GABAA receptor gene expression. Finally, a direct interaction of microRNA-7a-5p with the 3'-UTR of GABAA receptor α1-subunit (Gabra1) gene was demonstrated in a luciferase assay. These findings indicate that (a) the impaired sympathoadrenal response RH induces is associated with changes in VMH microRNA expression and (b) microRNA-7a-5p, possibly via direct downregulation of GABA receptor gene expression, may serve as a mediator of the altered sympathoadrenal response to hypoglycemia.
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http://dx.doi.org/10.1172/jci.insight.130521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824313PMC
October 2019

RE: RE: Impaired Awareness of Hypoglycemia Continues to be a Risk Factor for Severe Hypoglycemia Despite the use of Continuous Glucose Monitoring System in Type 1 Diabetes.

Endocr Pract 2019 10;25(10):1080-1081

Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, 615 Arapeen Drive, Suite 100, Salt Lake City, Utah 84108, E-mail: yu. utah. edu.

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http://dx.doi.org/10.4158/1934-2403-25.10.1080DOI Listing
October 2019

Severe Hypoglycemia-Induced Fatal Cardiac Arrhythmias Are Mediated by the Parasympathetic Nervous System in Rats.

Diabetes 2019 11 22;68(11):2107-2119. Epub 2019 Aug 22.

Division of Endocrinology, Metabolism, and Diabetes, Department of Internal Medicine, University of Utah, Salt Lake City, UT

The contribution of the sympathetic nervous system (SNS) versus the parasympathetic nervous system (PSNS) in mediating fatal cardiac arrhythmias during insulin-induced severe hypoglycemia is not well understood. Therefore, experimental protocols were performed in nondiabetic Sprague-Dawley rats to test the SNS with ) adrenal demedullation and ) chemical sympathectomy, and to test the PSNS with ) surgical vagotomy, ) nicotinic receptor (mecamylamine) and muscarinic receptor (AQ-RA 741) blockade, and ) ex vivo heart perfusions with normal or low glucose, acetylcholine (ACh), and/or mecamylamine. In protocols 1-4, 3-h hyperinsulinemic (0.2 units/kg/min) and hypoglycemic (10-15 mg/dL) clamps were performed. Adrenal demedullation and chemical sympathectomy had no effect on mortality or arrhythmias during severe hypoglycemia compared with controls. Vagotomy led to a 6.9-fold decrease in mortality; reduced first- and second-degree heart block 4.6- and 4-fold, respectively; and prevented third-degree heart block compared with controls. Pharmacological blockade of nicotinic receptors, but not muscarinic receptors, prevented heart block and mortality versus controls. Ex vivo heart perfusions demonstrated that neither low glucose nor ACh alone caused arrhythmias, but their combination induced heart block that could be abrogated by nicotinic receptor blockade. Taken together, ACh activation of nicotinic receptors via the vagus nerve is the primary mediator of severe hypoglycemia-induced fatal cardiac arrhythmias.
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http://dx.doi.org/10.2337/db19-0306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118248PMC
November 2019

Depletion of PD-1-positive cells ameliorates autoimmune disease.

Nat Biomed Eng 2019 04 4;3(4):292-305. Epub 2019 Mar 4.

Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah, Salt Lake City, UT, USA.

Targeted suppression of autoimmune diseases without collateral suppression of normal immunity remains an elusive yet clinically important goal. Targeted blockade of programmed-cell-death-protein-1 (PD-1)-an immune checkpoint factor expressed by activated T cells and B cells-is an efficacious therapy for potentiating immune activation against tumours. Here we show that an immunotoxin consisting of an anti-PD-1 single-chain variable fragment, an albumin-binding domain and Pseudomonas exotoxin targeting PD-1-expressing cells, selectively recognizes and induces the killing of the cells. Administration of the immunotoxin to mouse models of autoimmune diabetes delays disease onset, and its administration in mice paralysed by experimental autoimmune encephalomyelitis ameliorates symptoms. In all mouse models, the immunotoxin reduced the numbers of PD-1-expressing cells, of total T cells and of cells of an autoreactive T-cell clone found in inflamed organs, while maintaining active adaptive immunity, as evidenced by full-strength immune responses to vaccinations. The targeted depletion of PD-1-expressing cells contingent to the preservation of adaptive immunity might be effective in the treatment of a wide range of autoimmune diseases.
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http://dx.doi.org/10.1038/s41551-019-0360-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452906PMC
April 2019

IMPAIRED AWARENESS OF HYPOGLYCEMIA CONTINUES TO BE A RISK FACTOR FOR SEVERE HYPOGLYCEMIA DESPITE THE USE OF CONTINUOUS GLUCOSE MONITORING SYSTEM IN TYPE 1 DIABETES.

Endocr Pract 2019 Jun 13;25(6):517-525. Epub 2019 Mar 13.

Impaired awareness of hypoglycemia (IAH) is a risk factor for severe hypoglycemia in patients with type 1 diabetes (T1D) not using a continuous glucose monitoring (CGM) system. The current study investigated the prevalence of IAH and its relationship with severe hypoglycemia in T1D patients using CGM systems. This cross-sectional observational study enrolled 135 patients with T1D and ongoing real-time CGM use. A survey was conducted to assess hypoglycemia awareness with the Gold, Clarke, and Pedersen-Bjergaard questionnaires and the 6-month history of severe hypoglycemia. Other diabetes histories and the CGM glucose data were collected. The Gold, Clarke, and Pedersen-Bjergaard questionnaires demonstrated the overall prevalence of IAH/abnormal awareness to be 33.3%, 43.7%, and 77.0%, respectively. Participant age and duration of T1D were consistently related to IAH or hypoglycemia unawareness with all three questionnaires (<.05). Amongst the patients using CGM for >6 months, 24.5% were found to have at least one episode of severe hypoglycemia in the preceding 6 months. IAH identified by the Gold and Clarke questionnaires and hypoglycemia unawareness identified by the Pedersen-Bjergaard questionnaire were related to 6-, 4.63-, and 5.83-fold increased risk of severe hypoglycemia ( = .001, .004, and .013), respectively. IAH identified by the Gold/Clarke questionnaires was associated with a longer duration of CGM glucose <54 mg/dL and higher glucose coefficients of variation (<.05). IAH is highly prevalent and related to a higher risk for severe hypoglycemia in T1D patients using CGM. = continuous glucose monitoring; = confidence interval; = hypoglycemia-associated autonomic failure; = hemoglobin A1C; = impaired awareness of hypoglycemia; = type 1 diabetes.
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http://dx.doi.org/10.4158/EP-2018-0527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771275PMC
June 2019

Carvedilol prevents counterregulatory failure and impaired hypoglycaemia awareness in non-diabetic recurrently hypoglycaemic rats.

Diabetologia 2019 04 9;62(4):676-686. Epub 2019 Jan 9.

Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah, Department 15 North 2030 East, EIHG Building 533, Room 2420B, Salt Lake City, UT, 84112, USA.

Aims/hypothesis: This study evaluates whether the non-selective β-blocker, carvedilol, can be used to prevent counterregulatory failure and the development of impaired awareness of hypoglycaemia (IAH) in recurrently hypoglycaemic rats.

Methods: Sprague Dawley rats were implanted with vascular catheters and intracranial guide cannulas targeting the ventromedial hypothalamus (VMH). These animals underwent either three bouts of insulin-induced hypoglycaemia or received three saline injections (control group) over 3 days. A subgroup of recurrently hypoglycaemic animals was treated with carvedilol. The next day, the animals underwent a hypoglycaemic clamp with microdialysis without carvedilol treatment to evaluate changes in central lactate and hormone levels. To assess whether carvedilol prevented IAH, we treated rats that had received repeated 2-deoxyglucose (2DG) injections to impair their awareness of hypoglycaemia with carvedilol and measured food intake in response to insulin-induced hypoglycaemia as a surrogate marker for hypoglycaemia awareness.

Results: Compared with the control group, recurrently hypoglycaemic rats had a ~1.7-fold increase in VMH lactate and this was associated with a 75% reduction in the sympathoadrenal response to hypoglycaemia. Treatment with carvedilol restored VMH lactate levels and improved the adrenaline (epinephrine) responses. In 2DG-treated rats compared with control animals receiving saline, food intake was reduced in response to hypoglycaemia and increased with carvedilol treatment.

Conclusions/interpretation: We conclude that carvedilol may be a useful therapy to prevent counterregulatory failure and improve IAH.
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http://dx.doi.org/10.1007/s00125-018-4802-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403018PMC
April 2019

Insulin regulates GLUT4 in the ventromedial hypothalamus to restore the sympathoadrenal response to hypoglycemia in diabetic rats.

Am J Physiol Endocrinol Metab 2018 12 18;315(6):E1286-E1295. Epub 2018 Sep 18.

Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine , Salt Lake City, Utah.

It is proposed that the impaired counterregulatory response (CRR) to hypoglycemia in insulin-deficient diabetes may be due to chronic brain insulin deficiency. To test this hypothesis, streptozotocin-induced diabetic Sprague-Dawley rats were infused with insulin (3 mU/day) or artificial cerebrospinal fluid (aCSF) bilaterally into the ventromedial hypothalamus (VMH) for 2 wk and compared with nondiabetic rats. Rats underwent hyperinsulinemic (50 mU·kg·min)-hypoglycemic (~45 mg/dl) clamps. Diabetic rats demonstrated an impaired CRR to hypoglycemia, noted by a high glucose infusion rate and blunted epinephrine and glucagon responses. The defective sympathoadrenal response was restored by chronic infusion of insulin into the VMH. Diabetic rats had decreased VMH Akt phosphorylation and decreased VMH glucose transporter 4 (GLUT4) content, which was also restored by chronic infusion of insulin into the VMH. Separate experiments in nondiabetic rats in which GLUT4 translocation into the VMH was inhibited with an infusion of indinavir were notable for an impaired CRR to hypoglycemia, indicated by increased glucose infusion rate and diminished epinephrine and glucagon responses. Results suggest that, in this model of diabetes, VMH insulin deficiency impairs the sympathoadrenal response to hypoglycemia and that chronic infusion of insulin into the VMH is sufficient to normalize the sympathoadrenal response to hypoglycemia via restoration of GLUT4 expression in the VMH.
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http://dx.doi.org/10.1152/ajpendo.00324.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336954PMC
December 2018

Glibenclamide Prevents Hypoglycemia-Induced Fatal Cardiac Arrhythmias in Rats.

Endocrinology 2018 07;159(7):2614-2620

Division of Endocrinology, Metabolism, and Diabetes, Department of Internal Medicine, University of Utah, Salt Lake City, Utah.

Sulfonylureas increase the incidence of severe hypoglycemia in people with type 2 diabetes and might increase the risk of sudden cardiac death. Sulfonylureas stimulate insulin secretion by closing pancreatic ATP-sensitive potassium ion (KATP) channels. To investigate the role of KATP channel modulators on cardiac arrhythmias and mortality in the setting of severe hypoglycemia, adult Sprague-Dawley rats underwent hyperinsulinemic (0.2 U/kg/min) severe hypoglycemic (10 to 15 mg/dL) clamps with continuous electrocardiography. The rats were randomized for treatment with intravenous vehicle (VEH), the sulfonylurea glibenclamide (GLIB; KATP channel blocker; 5 mg/kg/h), or diazoxide (DIAZ; KATP channel opener; 5 mg/kg/h). The results demonstrated that GLIB completely prevented first-degree heart block compared with VEH (0.18 ± 0.09/min) and DIAZ (0.2 ± 0.05/min). Second-degree heart block was significantly reduced with GLIB (0.12 ± 0.1/min) compared with VEH (0.6 ± 0.2/min) and DIAZ (6.9 ± 3/min). The incidence of third-degree heart block was completely prevented by GLIB compared with VEH (67%) and DIAZ (87.5%). Hypoglycemia-induced mortality was completely prevented by GLIB compared with VEH (60%) and DIAZ (82%). In conclusion, although GLIB increases the risk of hypoglycemia by increasing insulin secretion, these results have demonstrated a paradoxical protective role of GLIB against severe hypoglycemia-induced fatal cardiac arrhythmias.
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http://dx.doi.org/10.1210/en.2018-00419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669817PMC
July 2018

Prevention of Severe Hypoglycemia-Induced Brain Damage and Cognitive Impairment With Verapamil.

Diabetes 2018 10 3;67(10):2107-2112. Epub 2018 May 3.

Division of Endocrinology, Metabolism, and Diabetes, Department of Internal Medicine, University of Utah, Salt Lake City, UT

People with insulin-treated diabetes are uniquely at risk for severe hypoglycemia-induced brain damage. Because calcium influx may mediate brain damage, we tested the hypothesis that the calcium-channel blocker, verapamil, would significantly reduce brain damage and cognitive impairment caused by severe hypoglycemia. Sprague-Dawley rats (10 weeks old) were randomly assigned to one of three treatments: ) control hyperinsulinemic (200 mU ⋅ kg ⋅ min)-euglycemic (80-100 mg/dL) clamps ( = 14), ) hyperinsulinemic-hypoglycemic (10-15 mg/dL) clamps ( = 16), or ) hyperinsulinemic-hypoglycemic clamps, followed by a single treatment with verapamil (20 mg/kg) ( = 11). Compared with euglycemic controls, hypoglycemia markedly increased dead/dying neurons in the hippocampus by 16-fold and cortex by 14-fold. Verapamil treatment strikingly decreased hypoglycemia-induced hippocampal and cortical damage, by 87% and 94%, respectively. Morris Water Maze probe trial results demonstrated that hypoglycemia induced a retention, but not encoding, memory deficit (noted by both abolished target quadrant preference and reduced target quadrant time). Verapamil treatment significantly rescued spatial memory as noted by restoration of target quadrant preference and target quadrant time. In summary, a one-time treatment with verapamil after severe hypoglycemia prevented neural damage and memory impairment caused by severe hypoglycemia. For people with insulin-treated diabetes, verapamil may be a useful drug to prevent hypoglycemia-induced brain damage.
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http://dx.doi.org/10.2337/db18-0008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152340PMC
October 2018

Severe hypoglycemia-induced sudden death is mediated by both cardiac arrhythmias and seizures.

Am J Physiol Endocrinol Metab 2018 08 27;315(2):E240-E249. Epub 2018 Feb 27.

Division of Endocrinology, Metabolism, and Diabetes, Department of Internal Medicine, University of Utah , Salt Lake City, Utah.

We previously demonstrated that insulin-induced severe hypoglycemia-associated sudden death is largely mediated by fatal cardiac arrhythmias. In the current study, a pharmacological approach was taken to explore the potential contribution of hypoglycemic seizures and the sympathoadrenergic system in mediating severe hypoglycemia-associated sudden death. Adult Sprague-Dawley rats were randomized into one of four treatment groups: 1) saline (SAL), 2) anti-arrhythmic (β blocker atenolol), 3) antiseizure (levetiracetam), and 4) combination antiarrhythmic and antiseizure (β Blocker+Levetiracetam). All rats underwent hyperinsulinemic severe hypoglycemic clamps for 3.5 h. When administered individually during severe hypoglycemia, β blocker reduced 2nd and 3rd degree heart block by 7.7- and 1.6-fold, respectively, and levetiracetam reduced seizures 2.7-fold, but mortality in these groups did not decrease. However, it was combined treatment with both β blocker and levetiracetam that remarkably reduced seizures and completely prevented respiratory arrest, while also eliminating 2nd and 3rd degree heart block, leading to 100% survival. These novel findings demonstrate that, in mediating sudden death, hypoglycemia elicits two distinct pathways (seizure-associated respiratory arrest and arrhythmia-associated cardiac arrest), and therefore, prevention of both seizures and cardiac arrhythmias is necessary to prevent severe hypoglycemia-induced mortality.
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http://dx.doi.org/10.1152/ajpendo.00442.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6139495PMC
August 2018

Hypoglycemia in type 2 diabetes: understanding patients' and physicians' knowledge and experience.

Endocrine 2018 06 19;60(3):435-444. Epub 2018 Feb 19.

Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA.

Purpose: The aim of the current study is to assess the patient and physician experience and knowledge of hypoglycemia in the management of type 2 diabetes (T2DM).

Methods: T2DM patients (N = 1002) completed questionnaires on hypoglycemia experience, familiarity, and fear. Their responses were compared across various antihyperglycemic treatment regimens; specifically, (1) insulin only or insulin combined with sulfonylurea [SU] and/or metformin, (2) SU only with/without metformin, and (3) neither insulin nor SU. Physicians (N = 1003) completed questionnaires on hypoglycemia knowledge and decision-making, and their responses were compared by specialty [75% primary care providers (PCPs) and 25% endocrinologists].

Results: T2DM patients treated with, (1) insulin only, or (2) insulin plus SU or metformin, reported the most experience and familiarity with-but also fear of-hypoglycemic events. Insulin-treated patients (insulin alone or insulin plus SU/metformin) also reported experiencing more hypoglycemia (all p-values <0.012). For physicians, endocrinology specialty was significantly associated with higher hypoglycemia knowledge scores (all p-values <.001). Irrespective of specialty, physician hypoglycemia knowledge, in turn, was associated with correct treatment decision-making (all p-values <0.001).

Conclusions: Insulin-based antihyperglycemic regimens were associated with high prevalence, severity, familiarity, and fear of hypoglycemia. An effective strategy to mitigate the burden of hypoglycemia may be to optimize pharmacological therapy to prevent these events. Since physician hypoglycemia knowledge was highly correlated to correct therapeutic decision-making, continued physician education regarding this acute complication of diabetes treatment should be prioritized for those managing patients with T2DM.
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http://dx.doi.org/10.1007/s12020-018-1545-0DOI Listing
June 2018

Severe Hypoglycemia-Induced Fatal Cardiac Arrhythmias Are Augmented by Diabetes and Attenuated by Recurrent Hypoglycemia.

Diabetes 2017 12 8;66(12):3091-3097. Epub 2017 Sep 8.

Division of Endocrinology, Metabolism, and Diabetes, Department of Internal Medicine, University of Utah, Salt Lake City, UT

We previously demonstrated that insulin-mediated severe hypoglycemia induces lethal cardiac arrhythmias. However, whether chronic diabetes and insulin deficiency exacerbates, and whether recurrent antecedent hypoglycemia ameliorates, susceptibility to arrhythmias remains unknown. Thus, adult Sprague-Dawley rats were randomized into four groups: ) nondiabetic (NONDIAB), ) streptozotocin-induced insulin deficiency (STZ), ) STZ with antecedent recurrent (3 days) hypoglycemia (∼40-45 mg/dL, 90 min) (STZ+RH), and ) insulin-treated STZ (STZ+Ins). Following treatment protocols, all rats underwent hyperinsulinemic (0.2 units ⋅ kg ⋅ min), severe hypoglycemic (10-15 mg/dL) clamps for 3 h with continuous electrocardiographic recordings. During matched nadirs of severe hypoglycemia, rats in the STZ+RH group required a 1.7-fold higher glucose infusion rate than those in the STZ group, consistent with the blunted epinephrine response. Second-degree heart block was increased 12- and 6.8-fold in the STZ and STZ+Ins groups, respectively, compared with the NONDIAB group, yet this decreased 5.4-fold in the STZ+RH group compared with the STZ group. Incidence of third-degree heart block in the STZ+RH group was 5.6%, 7.8-fold less than the incidence in the STZ group (44%). Mortality due to severe hypoglycemia was 5% in the STZ+RH group, 6.2-fold less than that in the STZ group (31%). In summary, severe hypoglycemia-induced cardiac arrhythmias were increased by insulin deficiency and diabetes and reduced by antecedent recurrent hypoglycemia. In this model, recurrent moderate hypoglycemia reduced fatal severe hypoglycemia-induced cardiac arrhythmias.
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http://dx.doi.org/10.2337/db17-0306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697941PMC
December 2017

Brain GLUT4 Knockout Mice Have Impaired Glucose Tolerance, Decreased Insulin Sensitivity, and Impaired Hypoglycemic Counterregulation.

Diabetes 2017 03 17;66(3):587-597. Epub 2016 Oct 17.

Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University in St. Louis, St. Louis, MO

GLUT4 in muscle and adipose tissue is important in maintaining glucose homeostasis. However, the role of insulin-responsive GLUT4 in the central nervous system has not been well characterized. To assess its importance, a selective knockout of brain GLUT4 (BG4KO) was generated by crossing Nestin-Cre mice with GLUT4-floxed mice. BG4KO mice had a 99% reduction in GLUT4 protein expression throughout the brain. Despite normal feeding and fasting glycemia, BG4KO mice were glucose intolerant, demonstrated hepatic insulin resistance, and had reduced glucose uptake in the brain. In response to hypoglycemia, BG4KO mice had impaired glucose sensing, noted by impaired epinephrine and glucagon responses and impaired activation in the hypothalamic paraventricular nucleus. Moreover, in vitro glucose sensing of glucose-inhibitory neurons from the ventromedial hypothalamus was impaired in BG4KO mice. In summary, BG4KO mice are glucose intolerant, insulin resistant, and have impaired glucose sensing, indicating a critical role for brain GLUT4 in sensing and responding to changes in blood glucose.
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http://dx.doi.org/10.2337/db16-0917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319720PMC
March 2017

Even silent hypoglycemia induces cardiac arrhythmias.

Diabetes 2014 May;63(5):1457-9

Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University, St. Louis, MO.

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http://dx.doi.org/10.2337/db14-0108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994962PMC
May 2014

Severe hypoglycemia-induced lethal cardiac arrhythmias are mediated by sympathoadrenal activation.

Diabetes 2013 Oct 8;62(10):3570-81. Epub 2013 Jul 8.

Division of Endocrinology, Metabolism, & Lipid Research, Department of Medicine, Washington University, St. Louis, Missouri.

For people with insulin-treated diabetes, severe hypoglycemia can be lethal, though potential mechanisms involved are poorly understood. To investigate how severe hypoglycemia can be fatal, hyperinsulinemic, severe hypoglycemic (10-15 mg/dL) clamps were performed in Sprague-Dawley rats with simultaneous electrocardiogram monitoring. With goals of reducing hypoglycemia-induced mortality, the hypotheses tested were that: 1) antecedent glycemic control impacts mortality associated with severe hypoglycemia; 2) with limitation of hypokalemia, potassium supplementation could limit hypoglycemia-associated deaths; 3) with prevention of central neuroglycopenia, brain glucose infusion could prevent hypoglycemia-associated arrhythmias and deaths; and 4) with limitation of sympathoadrenal activation, adrenergic blockers could prevent hypoglycemia-induced arrhythmic deaths. Severe hypoglycemia-induced mortality was noted to be worsened by diabetes, but recurrent antecedent hypoglycemia markedly improved the ability to survive an episode of severe hypoglycemia. Potassium supplementation tended to reduce mortality. Severe hypoglycemia caused numerous cardiac arrhythmias including premature ventricular contractions, tachycardia, and high-degree heart block. Intracerebroventricular glucose infusion reduced severe hypoglycemia-induced arrhythmias and overall mortality. β-Adrenergic blockade markedly reduced cardiac arrhythmias and completely abrogated deaths due to severe hypoglycemia. Under conditions studied, sudden deaths caused by insulin-induced severe hypoglycemia were mediated by lethal cardiac arrhythmias triggered by brain neuroglycopenia and the marked sympathoadrenal response.
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http://dx.doi.org/10.2337/db13-0216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3781452PMC
October 2013

Antecedent glycemic control reduces severe hypoglycemia-induced neuronal damage in diabetic rats.

Am J Physiol Endocrinol Metab 2013 Jun 16;304(12):E1331-7. Epub 2013 Apr 16.

Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine;

Brain damage due to severe hypoglycemia occurs in insulin-treated people with diabetes. This study tests the hypothesis that chronic insulin therapy that normalizes elevated blood glucose in diabetic rats would be neuroprotective against brain damage induced by an acute episode of severe hypoglycemia. Male Sprague-Dawley rats were split into three groups: 1) control, non-diabetic; 2) STZ-diabetic; and 3) insulin-treated STZ-diabetic. After 3 wk of chronic treatment, unrestrained awake rats underwent acute hyperinsulinemic severe hypoglycemic (10-15 mg/dl) clamps for 1 h. Rats were subsequently analyzed for brain damage and cognitive function. Severe hypoglycemia induced 15-fold more neuronal damage in STZ-diabetic rats compared with nondiabetic rats. Chronic insulin treatment of diabetic rats, which nearly normalized glucose levels, markedly reduced neuronal damage induced by severe hypoglycemia. Fortunately, no cognitive defects associated with the hypoglycemia-induced brain damage were observed in any group. In conclusion, antecedent blood glucose control represents a major modifiable therapeutic intervention that can afford diabetic subjects neuroprotection against severe hypoglycemia-induced brain damage.
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http://dx.doi.org/10.1152/ajpendo.00084.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3680694PMC
June 2013

Recurrent hypoglycemia: boosting the brain's metabolic flexibility.

J Clin Invest 2013 May 1;123(5):1922-4. Epub 2013 Apr 1.

Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University, St. Louis, Missouri 63110, USA.

For people with diabetes, recurrent episodes of hypoglycemia limit the brain's ability to sense dangerously low blood sugar levels. In this issue of the JCI, the mechanisms behind this clinical problem of hypoglycemia unawareness are addressed by Herzog et al. The authors provide compelling evidence that recurrent hypoglycemia enhances transport of lactate into the brain and, although not itself a major alternative fuel source, lactate may preserve neuronal function during hypoglycemia by maintaining neuronal glucose metabolism. These findings redefine our understanding of the brain's metabolic adaptations that result from recurrent hypoglycemia.
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http://dx.doi.org/10.1172/JCI69796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3635749PMC
May 2013

Defective counterregulation and hypoglycemia unawareness in diabetes: mechanisms and emerging treatments.

Endocrinol Metab Clin North Am 2013 Mar 12;42(1):15-38. Epub 2012 Dec 12.

Division of Endocrinology, Metabolism & Lipid Research, Department of Medicine, Washington University, St Louis, MO 63110, USA.

For people with diabetes, hypoglycemia remains the limiting factor in achieving glycemic control. This article reviews recent advances in how the brain senses and responds to hypoglycemia. Novel mechanisms by which individuals with insulin-treated diabetes develop hypoglycemia unawareness and impaired counterregulatory responses are outlined. Prevention strategies for reducing the incidence of hypoglycemia are discussed.
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http://dx.doi.org/10.1016/j.ecl.2012.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3568263PMC
March 2013

Repairing a "broken heart" with hormone replacement therapy: case report of cardiogenic shock due to undiagnosed pituitary insufficiency.

Endocr Pract 2012 Mar-Apr;18(2):e26-31

Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University, St. Louis, Missouri 63110, USA.

Objectives: To indicate cardiogenic shock as a very rare but serious clinical consequence of untreated panhypopituitarism attributable to Sheehan syndrome; to emphasize the importance of eliciting a detailed endocrine and obstetric history in women presenting with idiopathic heart failure; to highlight the diagnostic shortcomings of screening for thyroid dysfunction solely with thyroid-stimulating hormone determinations; and to report the reversibility of severe heart failure induced by long-term pituitary insufficiency.

Methods: Described is a case report of a 35-year-old woman who presented with severe congestive heart failure, hypotension, and confusion. Her 2-dimensional echocardiogram revealed appreciable systolic and diastolic dysfunction. In screening for possible endocrine causes of heart failure, a normal thyroid-stimulating hormone level of 0.72 mIU/L (reference range, 0.35 to 5.5) was unremarkable; however, a profoundly low free thyroxine level of 0.12 ng/dL (reference range, 0.9 to 1.8) led clinicians to pursue a work-up of central hypothyroidism.

Results: Endocrine testing confirmed the presence of panhypopituitarism and adrenal insufficiency. Magnetic resonance imaging of the brain revealed empty sella syndrome. Further questioning of the patient revealed a history of extensive postpartum bleeding 15 years earlier, failure to lactate, and secondary amenorrhea--all consistent with undiagnosed Sheehan syndrome. In the hospital, the patient was treated with intravenously administered corticosteroids and levothyroxine. Her mental status and symptomatic heart failure improved dramatically. After 9 months of oral levothyroxine and glucocorticoid therapy, the patient remained asymptomatic, and repeated echocardiography indicated completely normalized cardiac function.

Conclusion: Severe heart failure and cardiogenic shock can be a very rare (but fortunately reversible) complication of long-standing panhypopituitarism resulting from undiagnosed Sheehan syndrome.
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http://dx.doi.org/10.4158/EP11284.CRDOI Listing
August 2012

Improved insulin sensitivity by GLUT12 overexpression in mice.

Diabetes 2011 May 25;60(5):1478-82. Epub 2011 Mar 25.

Department of Obstetrics and Gynecology, Washington University in St. Louis, St. Louis, Missouri, USA.

Objective: Evidence suggests that insulin-sensitive glucose transporters (GLUTs) other than GLUT4 may exist. To investigate whether GLUT12 may represent another insulin-sensitive GLUT, transgenic (TG) mice that overexpress GLUT12 were characterized.

Research Design And Methods: TG mice that overexpressed GLUT12 under a β-actin promoter were generated. Glucose metabolism in TG and wild-type control mice was compared using glucose and insulin tolerance tests and hyperinsulinemic-euglycemic clamps. In addition, basal and insulin-stimulated glucose clearance rates into insulin-sensitive peripheral tissues were measured using [(3)H]-2-deoxy-D-glucose.

Results: GLUT12 was overexpressed by 40-75% in TG compared with wild-type mice in insulin-sensitive tissues with no change in GLUT4 content. Body weight and fasting blood glucose did not differ between wild-type and TG mice; however, insulin concentrations were reduced in TG mice. Enhanced oral glucose tolerance was noted in TG mice by a reduced blood glucose excursion compared with wild-type mice (P < 0.05). Enhanced insulin sensitivity was noted by a greater decrease in blood glucose in TG mice during insulin tolerance testing. Hyperinsulinemic-euglycemic clamps confirmed enhanced insulin sensitivity in GLUT12-overexpressing mice (P < 0.01). Tissues of TG mice exhibited normal basal glucose clearance rates; however, under insulin-stimulated conditions, glucose clearance was significantly increased (P < 0.01) in tissues of TG mice.

Conclusions: Increased expression of GLUT12 results in improved whole-body insulin sensitivity mediated by an increased glucose clearance rate in insulin-responsive tissues under insulin-stimulated, but not basal, conditions. These findings provide evidence that GLUT12 represents a novel, second insulin-sensitive GLUT.
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http://dx.doi.org/10.2337/db11-0033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292321PMC
May 2011

Regulation of glucose homeostasis through a XBP-1-FoxO1 interaction.

Nat Med 2011 Mar 13;17(3):356-65. Epub 2011 Feb 13.

Division of Endocrinology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.

To date, the only known role of the spliced form of X-box-binding protein-1 (XBP-1s) in metabolic processes has been its ability to act as a transcription factor that regulates the expression of genes that increase the endoplasmic reticulum (ER) folding capacity, thereby improving insulin sensitivity. Here we show that XBP-1s interacts with the Forkhead box O1 (FoxO1) transcription factor and directs it toward proteasome-mediated degradation. Given this new insight, we tested modest hepatic overexpression of XBP-1s in vivo in mouse models of insulin deficiency or insulin resistance and found it improved serum glucose concentrations, even without improving insulin signaling or ER folding capacity. The notion that XBP-1s can act independently of its role in the ER stress response is further supported by our finding that in the severely insulin resistant ob/ob mouse strain a DNA-binding-defective mutant of XBP-1s, which does not have the ability to increase ER folding capacity, is still capable of reducing serum glucose concentrations and increasing glucose tolerance. Our results thus provide the first evidence to our knowledge that XBP-1s, through its interaction with FoxO1, can bypass hepatic insulin resistance independent of its effects on ER folding capacity, suggesting a new therapeutic approach for the treatment of type 2 diabetes.
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http://dx.doi.org/10.1038/nm.2293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3897616PMC
March 2011

Brain insulin controls adipose tissue lipolysis and lipogenesis.

Cell Metab 2011 Feb;13(2):183-94

Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1055, New York, NY 10029-6574, USA.

White adipose tissue (WAT) dysfunction plays a key role in the pathogenesis of type 2 diabetes (DM2). Unrestrained WAT lipolysis results in increased fatty acid release, leading to insulin resistance and lipotoxicity, while impaired de novo lipogenesis in WAT decreases the synthesis of insulin-sensitizing fatty acid species like palmitoleate. Here, we show that insulin infused into the mediobasal hypothalamus (MBH) of Sprague-Dawley rats increases WAT lipogenic protein expression, inactivates hormone-sensitive lipase (Hsl), and suppresses lipolysis. Conversely, mice that lack the neuronal insulin receptor exhibit unrestrained lipolysis and decreased de novo lipogenesis in WAT. Thus, brain and, in particular, hypothalamic insulin action play a pivotal role in WAT functionality.
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http://dx.doi.org/10.1016/j.cmet.2011.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3061443PMC
February 2011
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