Differential Expression of Inflammatory Markers in Hypoglycemia Unawareness Associated with Type 1 Diabetes: A Case Report.
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SUBMITTER: Al Zoubi Y
PROVIDER: S-EPMC7823509 | biostudies-literature | 2020 Dec
REPOSITORIES: biostudies-literature
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Differential Expression of Inflammatory Markers in Hypoglycemia Unawareness Associated with Type 1 Diabetes: A Case Report.
Al Zoubi Yousef Y Mussa Bashair M BM Srivastava Ankita A Mohammed Abdul Khader AK Abdelgadir Elamin E Bashier Alaaeldin A Awadi Fatheya Al FA Abusnana Salah S
Brain sciences 20201225 1
The recurrence of hypoglycemic episodes leads to attenuation of the normal counter-regulatory mechanisms that are controlled by the hypothalamus, which results in hypoglycemia unawareness (HU). In this case report, we described for the first time the differential expression of TNF-α, IL-1β, IL-6, and IFN-γ in a blood sample that was taken from a 27-year-old patient with type 1 diabetes mellitus (T1DM) who was diagnosed with HU. The anti-diabetic regimen is currently based on insulin injection, b ...[more]
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Project description:Among nondiabetic individuals, mild glucose decrements alter brain activity in regions linked to reward, motivation, and executive control. Whether these effects differ in type 1 diabetes mellitus (T1DM) patients with and without hypoglycemia awareness remains unclear.Forty-two individuals (13 healthy control [HC] subjects, 16 T1DM individuals with hypoglycemia awareness [T1DM-Aware], and 13 T1DM individuals with hypoglycemia unawareness [T1DM-Unaware]) underwent blood oxygen level-dependent functional MRI brain imaging during a 2-step hyperinsulinemic euglycemic (90 mg/dl)-hypoglycemic (60 mg/dl) clamp for assessment of neural responses to mild hypoglycemia.Mild hypoglycemia in HC subjects altered activity in the caudate, insula, prefrontal cortex, and angular gyrus, whereas T1DM-Aware subjects showed no caudate and insula changes, but showed altered activation patterns in the prefrontal cortex and angular gyrus. Most strikingly, in direct contrast to HC and T1DM-Aware subjects, T1DM-Unaware subjects failed to show any hypoglycemia-induced changes in brain activity. These findings were also associated with blunted hormonal counterregulatory responses and hypoglycemia symptom scores during mild hypoglycemia.In T1DM, and in particular T1DM-Unaware patients, there is a progressive blunting of brain responses in cortico-striatal and fronto-parietal neurocircuits in response to mild-moderate hypoglycemia. These findings have implications for understanding why individuals with impaired hypoglycemia awareness fail to respond appropriately to falling blood glucose levels.This study was supported in part by NIH grants R01DK020495, P30 DK045735, K23DK109284, K08AA023545. The Yale Center for Clinical Investigation is supported by an NIH Clinical Translational Science Award (UL1 RR024139).
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Project description:Supercompensated brain glycogen may contribute to the development of hypoglycemia unawareness in patients with type 1 diabetes by providing energy for the brain during periods of hypoglycemia. Our goal was to determine if brain glycogen content is elevated in patients with type 1 diabetes and hypoglycemia unawareness. We used in vivo (13)C nuclear magnetic resonance spectroscopy in conjunction with [1-(13)C]glucose administration in five patients with type 1 diabetes and hypoglycemia unawareness and five age-, gender-, and body mass index-matched healthy volunteers to measure brain glycogen content and metabolism. Glucose and insulin were administered intravenously over ?51?hours at a rate titrated to maintain a blood glucose concentration of 7?mmol/L. (13)C-glycogen levels in the occipital lobe were measured at ?5, 8, 13, 23, 32, 37, and 50?hours, during label wash-in and wash-out. Newly synthesized glycogen levels were higher in controls than in patients (P<0.0001) for matched average blood glucose and insulin levels, which may be due to higher brain glycogen content or faster turnover in controls. Metabolic modeling indicated lower brain glycogen content in patients than in controls (P=0.07), implying that glycogen supercompensation does not contribute to the development of hypoglycemia unawareness in humans with type 1 diabetes.
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Project description:Asprosin is a counter-regulatory hormone to insulin which plays a role in fasting. It may therefore also play a role in hypoglycaemia unawareness, which has been subsequently examined in this pilot study. Intravenous glucose tolerance test was used to induce controlled hyperglycemia whereas a hyperinsulinemic clamp test was used to induce a controlled hypoglycaemia in 15 patients with diabetes type 1, with and without hypoglycaemia unawareness. Changes in asprosin plasma levels did not differ between patients with and without hypoglycaemia unawareness. However, nine patients with insulin resistance as well as higher liver stiffness values and low-density lipoprotein but lower high-density lipoprotein levels did not show the expected increase in asprosin plasma levels during hypoglycemia. Therefore, insulin resistance and alterations in liver structure, most likely early stages of non-alcoholic fatty liver disease, seem to be relevant in type 1 diabetes and do not only lead to elevated plasma levels of asprosin, but also to a blunted asprosin response in hypoglycemia.
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Project description:Nocturnal hypoglycemia is life threatening for individuals with type 1 diabetes (T1D) due to loss of hypoglycemia symptom recognition (hypoglycemia unawareness) and impaired glucose counter regulation. These individuals also show disturbed sleep, which may result from glycemic dysregulation. Whether use of a hybrid closed loop (HCL) insulin delivery system with integrated continuous glucose monitoring (CGM) designed for improving glycemic control, relates to better sleep across time in this population remains unknown. The purpose of this study was to describe long-term changes in glycemic control and objective sleep after initiating hybrid closed loop (HCL) insulin delivery in adults with type 1 diabetes and hypoglycemia unawareness. To accomplish this, six adults (median age = 58 y) participated in an 18-month ongoing trial assessing HCL effectiveness. Glycemic control and sleep were measured using continuous glucose monitoring and wrist accelerometers every 3 months. Paired sample t-tests and Cohen's d effect sizes modeled glycemic and sleep changes and the magnitude of these changes from baseline to 9 months. Reduced hypoglycemia (d = 0.47-0.79), reduced basal insulin requirements (d = 0.48), and a smaller glucose coefficient of variation (d = 0.47) occurred with medium-large effect sizes from baseline to 9 months. Hypoglycemia awareness improved from baseline to 6 months with medium-large effect sizes (Clarke score (d = 0.60), lability index (d = 0.50), HYPO score (d = 1.06)). Shorter sleep onset latency (d = 1.53; p < 0.01), shorter sleep duration (d = 0.79), fewer total activity counts (d = 1.32), shorter average awakening length (d = 0.46), and delays in sleep onset (d = 1.06) and sleep midpoint (d = 0.72) occurred with medium-large effect sizes from baseline to 9 months. HCL led to clinically significant reductions in hypoglycemia and improved hypoglycemia awareness. Sleep showed a delayed onset, reduced awakening length and onset latency, and maintenance of high sleep efficiency after initiating HCL. Our findings add to the limited evidence on the relationships between diabetes therapeutic technologies and sleep health. This trial is registered with ClinicalTrials.gov (NCT03215914).
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Project description:ObjectiveHypoglycemia in type 2 diabetes (T2D) increases morbidity and mortality but the underlying physiological response is still not fully understood, though physiological changes are still apparent 24 hours after the event. Small noncoding microRNA (miRNA) have multiple downstream biological effects that may respond rapidly to stress. We hypothesized that hypoglycemia would induce rapid miRNA changes; therefore, this pilot exploratory study was undertaken.MethodsA pilot prospective, parallel study in T2D (n=23) and controls (n=23). Insulin-induced hypoglycemia (2mmol/l: 36mg/dl) was induced and blood sampling performed at baseline and hypoglycemia. Initial profiling of miRNA was undertaken on pooled samples identified 96 miRNA that were differentially regulated, followed by validation on a custom designed 112 miRNA panel.ResultsNine miRNAs differed from baseline to hypoglycemia in control subjects; eight were upregulated: miR-1303, miR-let-7e-5p, miR-1267, miR-30a-5p, miR-571, miR-661, miR-770-5p, miR-892b and one was downregulated: miR-652-3p. None of the miRNAs differed from baseline in T2D subjects.ConclusionA rapid miRNA response reflecting protective pathways was seen in control subjects that appeared to be lost in T2D, suggesting that mitigating responses to hypoglycemia with blunting of the counter-regulatory response in T2D occurs even in patients with short duration of disease.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT03102801?term=NCT03102801&draw=2&rank=1, identifier NCT03102801.
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Project description:ObjectiveTo evaluate whether nocturnal asymptomatic hypoglycemia (NAH) can be predicted by fasting glucose levels or post-breakfast glucose fluctuations in patients with type 1 diabetes (T1D) receiving insulin degludec.MethodsPatients with T1D receiving insulin degludec underwent at-home CGM assessments. Indices for glycemic variability before and after breakfast included fasting glucose levels and the range of post-breakfast glucose elevation. For comparison, the patients were classified into those with NAH and those without. The optimal cut-off values for the relevant parameters were determined to predict NAH using ROC analysis.ResultsThe study included a total of 31 patients (mean HbA1c values, 7.8 ± 0.7%), and 16 patients (52%) had NAH. Those with NAH had significantly lower fasting glucose levels than did those without (82 ± 48 mg/dL vs. 144 ± 69 mg/dL; P = 0.009). The change from pre- to post-breakfast glucose levels was significantly greater among those with NAH (postprandial 1-h, P = 0.028; postprandial 2-h, P = 0.028). The cut-off values for prediction of NAH were as follows: fasting glucose level <84 mg/dL (sensitivity 0.80/specificity 0.75/AUC 0.80; P = 0.004), 1-h postprandial elevation >69 mg/dL (0.75/0.67/0.73; P = 0.033), and 2-h postprandial elevation >99 mg/dL (0.69/0.67/0.71; P = 0.044).ConclusionsThe results suggest that fasting glucose level of < 84 mg/dL had approximately 80% probability of predicting the occurrence of NAH in T1D receiving insulin degludec. It was also shown that the occurrence of hypoglycemia led to greater post-breakfast glucose fluctuations and steeper post-breakfast glucose gradients.
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Project description:Hypoglycemia unawareness (HU) is defined at the onset of neuroglycopenia before the appearance of autonomic warning symptoms. It is a major limitation to achieving tight diabetes and reduced quality of life. HU occurs in approximately 40% of people with type 1 diabetes mellitus (T1DM) and with less frequency in T2DM. Though the aetiology of HU is multifactorial, possible mechanisms include chronic exposure to low blood glucose, antecedent hypoglycaemia, recurrent severe hypoglycaemia and the failure of counter-regulatory hormones. Clinically it manifests as the inability to recognise impeding hypoglycaemia by symptoms, but the mechanisms and mediators remain largely unknown. Prevention and management of HU is complex, and can only be achieved by a multifactorial intervention of clinical care and structured patient education by the diabetes team. Less know regarding the impact of medications on the development or recognition of this condition in patients with diabetes. Several medications are thought to worsen or promote HU, whereas others may have an attenuating effect on the problem. This article reviews recent advances in how the brain senses and responds to hypoglycaemia, novel mechanisms by which people with insulin-treated diabetes develop HU and impaired counter-regulatory responses. The consequences that HU has on the person with diabetes and their family are also described. Finally, it examines the evidence for prevention and treatment of HU, and summarizes the effects of medications that may influence it.
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Project description:BackgroundTigecycline, the first glycylcycline-class drug, is a broad-spectrum antibiotic with activity against multi-drug resistant (MDR) organisms. We describe a case of sustained and severe hypoglycemia in a patient treated with tigecycline for pneumonia due to MDR Klebsiella pneumoniae.Case presentationA 74-year-old man was admitted for treatment of pneumonia. At admission he had prediabetes. In the hospital he developed renal failure. On day 3, the patient experienced severe shortness of breath. He was intubated and transferred to the intensive care unit (ICU) for ventilator support. In the ICU the antibiotic regimen was cefoperazone and sulbactam (1?g every 12?h). Continuous Renal Replacement Therapy was started on that day. Test for anti-neutrophil cytoplasmic antibodies (ANCA) was positive, and so the nephrologist and rheumatologist agreed on a diagnosis of ANCA-associated vasculitis, with renal and pulmonary involvement and acute renal failure. Plasmapheresis, and high-dose methylprednisolone treatment were started on day 6, and there was obvious improvement in the patient's condition. The steroid regimen was gradually tapered to oral prednisone (35?mg every day) on day 19. Afterwards, the patient's pneumonia worsened. Sputum culture showed Klebsiella pneumoniae sensitive to only tigecycline. Tigecycline treatment (100?mg every 12?h) was administered on day 20. Hypoglycemia started about 37?h after the first dose of tigecycline. Infusion of 50% glucose through the femoral vein was required for over 20?h to maintain normal blood glucose concentrations. Tigecycline was stopped, but the hypoglycemia resolved only after a further 34?h. The insulin and C-peptide levels were found to be markedly elevated during the hypoglycemia. The Naranjo scale score of 7 indicated that the likelihood of tigecycline causing severe hypoglycemia was "probable."ConclusionThis is the first report of sustained severe hypoglycemia due to tigecycline. Oversecretion of insulin appears to have been the cause of the hypoglycemia in our patient. The mechanism needs to be investigated.
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Project description:BackgroundCitrin deficiency (CD) is a recessive metabolic disease caused by biallelic pathogenic variants in SLC25A13. Although previous studies have reported ketosis in CD, it was observed at the time of euglycemia or mild hypoglycemia. Blood ketone levels concomitant with symptomatic or severe hypoglycemia in CD have not been a topic of focus despite its importance in identifying the etiology of hypoglycemia and assessing the ability of fatty acid utilization. Herein, we describe a patient with CD who had repeated episodes of hypoglycemia with insufficient ketosis.Case presentationA 1-year-old boy with repetitive hypoglycemia was referred to us to investigate its etiology. The fasting load for 13 h led to hypoketotic hypoglycemia, indicating the possibility of partial β-oxidation dysfunction. A genetic test led to the diagnosis of CD. The hypoglycemic episodes disappeared after switching to a medium-chain triglyceride-containing formula.ConclusionsThis case report suggests that symptomatic or severe hypoglycemia in patients with CD could be associated with relatively low levels of ketone bodies, implying that β-oxidation in these patients might possibly be partially disrupted. When encountering a patient with hypoglycemia, clinicians should check blood ketone levels and bear in mind the possibility of CD because excessive intravenous administration of glucose can cause decompensated symptoms in patients with CD as opposed to other disorders presenting with hypoketotic hypoglycemia, such as fatty acid oxidation disorders. Further studies in a large-scale cohort are warranted to confirm our speculation.
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Project description:Background Takotsubo syndrome (TTS) is a disorder frequently characterized by transient dysfunction of the apical portion of the left ventricle with hyperkinesis in other parts of the heart walls. TTS is also called stress cardiomyopathy because it is known to be triggered by emotional or physical stress. We report a case of TTS associated with severe hypoglycemia. Case summary An 85-year-old female patient with a history of non-insulin-dependent diabetes mellitus and hypertension presented to the emergency department with hypoglycemia-induced unconsciousness. The patient regained consciousness after an intravenous glucose injection. The patient complained of chest discomfort after the correction of hypoglycemia. Electrocardiography (ECG) revealed ST-segment elevation in leads V2-V5, therefore, ST-segment elevation myocardial infarction was highly suspected. Echocardiography showed impaired left ventricular systolic function with an ejection fraction of 40% accompanied by hypokinesis of the apex. Percutaneous coronary angiography showed 30% stenosis of the left anterior descending coronary artery. Left ventricular angiography revealed apical dyskinesia, which is typical of the classic apical ballooning shape of takotsubo. The patient was diagnosed with TTS and managed with pharmacological therapy, including antiplatelet (i.e., aspirin), lipid-lowering, anti-heart failure, and hypoglycemic drugs. The patient was successfully discharged in a stable condition. Conclusion This is a representative case of TTS caused by hypoglycemia. Due to the self-limiting nature of TTS, diagnoses can be missed among hypoglycemic patients. Thus, echocardiography is required for patients with hypoglycemia to ensure an accurate TTS diagnosis in the emergency department.
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