Effects of Intranasal Naloxone on Hypoglycemia-Associated Autonomic Failure (HAAF) in Susceptible Individuals.

CONTEXT: Hypoglycemia-associated autonomic failure (HAAF), defined as blunting of counter-regulatory hormone and symptom responses to recurrent hypoglycemia, remains a therapeutic challenge in diabetes treatment. The opioid system may play a role in HAAF pathogenesis since activation of opioid receptors induces HAAF. Blockade of opioid receptors with intravenous naloxone ameliorates HAAF experimentally, yet is not feasible therapeutically. OBJECTIVE: To investigate the effects of opioid receptor blockade with intranasal naloxone on experimentally-induced HAAF. DESIGN: Randomized, double-blinded, placebo-controlled crossover study. SETTING: Academic research center. PARTICIPANTS: Healthy non-diabetic volunteers. INTERVENTIONS: Paired two-day studies, 5-10 weeks apart, each consisting of three consecutive hypoglycemic episodes (hyperinsulinemic hypoglycemic clamps, glucose nadir: 54 mg/dL): two on day 1 with administration of intranasal naloxone vs. placebo, followed by the third episode on day 2. MAIN OUTCOME MEASURES: Differences in counter-regulatory hormones responses and hypoglycemia symptoms between first and third hypoglycemic episodes in naloxone vs. placebo studies. RESULTS: Out of 17 participants, 9 developed HAAF, confirming variable inter-individual susceptibility. Among participants susceptible to HAAF, naloxone maintained some hormonal and symptomatic responses to hypoglycemia and prevented the associated requirement for increased glucose infusion. Unexpectedly, naloxone reduced plasma epinephrine and growth hormone responses to the first hypoglycemic episode but prevented further reduction with subsequent hypoglycemia. CONCLUSIONS: This is the first study to report that intranasal naloxone, a widely used opioid receptor antagonist, may ameliorate some features of HAAF. Further investigation is warranted into mechanisms of variable inter-individual susceptibility to HAAF and the effects of intranasal naloxone in people with diabetes at risk for HAAF.

Hypoglycemia Unawareness and Recurrent Severe Hypoglycemia in an Individual With Type 1 Diabetes Mellitus on Insulin.

Background/Objective: Hypoglycemia unawareness is a complication of recurrent hypoglycemia that can complicate diabetes management and impact quality of life. We present the case of an individual with type 1 diabetes with hypoglycemia unawareness and recurrent severe hypoglycemia requiring emergency intervention. Case Report: A 55-year-old man with type 1 diabetes was referred for hypoglycemia unawareness and recurrent hypoglycemia with seizures. Over the prior 4 years he had >400 paramedic responses with 56 hospitalizations. Blood glucose levels ranged between 0.7 and 2.4 mmol/L during these episodes and presenting Hemoglobin A1c (HbA1c) was 4.6% (28 mmol/mol). He was taking insulin glargine daily and aspart with meals via insulin pens with no alternative etiology for his hypoglycemia was identified. The patient expressed difficulty with self-management, social instability, and limited appointment attendance. He was provided a continuous glucose monitor, educational support, and glycemic targets were broadened. After 6 months, HbA1c was 4.6% (28 mmol/mol) and he had 65 paramedic responses. A multidisciplinary team was organized for biweekly follow-up, community outreach, remote technological support, and psychological counseling. After 2 years, the patient had 2 emergency responses and HbA1c was 7.2% (55.2 mmol/mol). Discussion: Permissive hyperglycemia, educational interventions, and continuous glucose monitoring are validated strategies for prevention of hypoglycemia. Limiting hypoglycemia is crucial to restore hypoglycemia awareness, and in severe cases may require high intensity follow-up, community outreach, and psychosocial support. Conclusion: Hypoglycemia unawareness can complicate hypoglycemia prevention. Severe refractory cases are often multifaceted and may warrant a multidisciplinary approach to identify and target patient-specific needs.

Hypoglycemia Unawareness-A Review on Pathophysiology and Clinical Implications.

Hypoglycemia is a particular problem in people with diabetes while it can also occur in other clinical circumstances. Hypoglycemia unawareness describes a condition in which autonomic and neuroglycopenic symptoms of hypoglycemia decrease and hence are hardly perceivable. A failure to recognize hypoglycemia in time can lead to unconsciousness, seizure, and even death. The risk factors include intensive glycemic control, prior episodes of severe hypoglycemia, long duration of diabetes, alcohol consumption, exercise, renal failure, and sepsis. The pathophysiological mechanisms are manifold, but mainly concern altered brain glucose sensing, cerebral adaptations, and an impaired hormonal counterregulation with an attenuated release of glucagon, epinephrine, growth hormone, and other hormones, as well as impaired autonomous and neuroglycopenic symptoms. Physiologically, this counterregulatory response causes blood glucose levels to rise. The impaired hormonal counterregulatory response to recurrent hypoglycemia can lead to a vicious cycle of frequent and poorly recognized hypoglycemic episodes. There is a shift in glycemic threshold to trigger hormonal counterregulation, resulting in hypoglycemia-associated autonomic failure and leading to the clinical syndrome of hypoglycemia unawareness. This clinical syndrome represents a particularly great challenge in diabetes treatment and, thus, prevention of hypoglycemia is crucial in diabetes management. This mini-review provides an overview of hypoglycemia and the associated severe complication of impaired hypoglycemia awareness and its symptoms, pathophysiology, risk factors, consequences, as well as therapeutic strategies.

Validation of the hypoglycemia awareness questionnaire to assess hypoglycemia awareness in patients with type 2 diabetes treated with insulin.

AIMS: Given the implications of impaired hypoglycemia awareness in patients with type 2 diabetes (T2D), it is necessary to identify reliable and valid instruments for its measurement. The Hypoglycemia Awareness Questionnaire (HypoA-Q) measures impaired awareness, symptom severity, and symptom frequency. The present study evaluated the HypoA-Q validity for assessing awareness of hypoglycemia in patients with T2D treated with insulin. METHODS: The questionnaire was administered to 406 patients diagnosed with T2D on insulin treatment at four centers in Bogotá, Colombia. The internal structure of the questionnaire was analyzed using exploratory and confirmatory factor analyses, internal consistency and test-retest reliability were evaluated, and criterion validity was rated by assessing its correlation with the Clarke scale. RESULTS: Factor analysis identified an empirical structure of four domains that adequately represented the construct. Cronbach's alpha and McDonald's Omega coefficients yielded values between 0.75 and 0.79 for the impaired awareness scale. Lin and intraclass correlation coefficients were 0.86 and 0.85, respectively. The correlation between the impaired awareness subscale and Clarke scale was 0.654, and differences were found between patients with good and poor awareness of hypoglycemia. CONCLUSIONS: The HypoA-Q is a valid and reliable tool for measuring the awareness of hypoglycemia in patients with T2D who are treated with insulin.

Hypoglycemia unawareness among insulin-treated diabetic patients in Madinah, Saudi Arabia: prevalence and risk factors.

Background: Hypoglycemia unawareness (HU) is associated with significant risks. Screening for impaired awareness of hypoglycemia in patients with diabetes is important to minimize those risks. There are limited data on the prevalence of HU in patients with diabetes in Saudi Arabia (KSA). In the current study, we investigated the frequency of HU and its risk factors among insulin treated diabetic patients in Madinah, KSA. Methods: A cross-sectional study was conducted in a diabetes center and four primary healthcare centers at Madinha, KSA. Patients ≥14 years old with type 1 or type 2 diabetes treated with insulin for more than a year were included. HU was assessed by Clarke's and modified Pedersen-Bjergaard's scores. The risk factors for HU were determined. Results: Of the 413 included patients, 60.3% were women, and 60.8% were on insulin alone. One-third of the participants had T1DM, while 68.5% had T2DM, with median ages of 25 and 56 years, diabetes durations of 10 and 15 years, and durations of insulin use of 10 and 5 years, respectively. The prevalence of HU was 25.2% by Clarke's survey. The risk factors for HU were poor knowledge of the patient's latest HbA1c, type of insulin, and dose of insulin. Poor medical follow-up, previous stroke, and ischemic heart disease were the other risk factors for HU. When the modified Pedersen-Bjergaard method was used, the prevalence of HU was 48.9%. Conclusion: Despite the advances in diabetes management, HU continues to be prevalent among diabetic patients on insulin, and poor diabetes knowledge is a major risk factor. Diabetes education on self-management is of utmost importance to reduce hypoglycemia and HU.

Burden and Coping Strategies of Hypoglycemia in People with Diabetes.

Hypoglycemia is a limiting adverse effect of glucose-lowering medications and particularly insulin replacement therapy. This review provides insights into the burden of hypoglycemia in the management of diabetes and outlines strategies available to reduce the risk of hypoglycemia and improve patients' well-being. People with type 1 diabetes are primarily affected by hypoglycemic episodes which are associated with direct physical harms like injuries and cardiac events as well as indirect psychosocial consequences including constant anxiety, absenteeism, increased healthcare costs and overall poorer quality of life. These complications are more prominent amongst individuals with hypoglycemia unawareness or overnight hypoglycemia and could even extend to caregivers such as parents of children with diabetes. Patients experiencing frequent or severe hypoglycemic events might also develop a pathological fear of hypoglycemia and adopt aberrant behaviors intending to maintain higher blood glucose levels. Modern pharmaceutical options with a safer profile in terms of hypoglycemia are available including novel basal insulins with lower rates of nocturnal hypoglycemia along with ultra-rapid-acting insulin analogs with a shorter duration of action that might avert late post-meal hypoglycemia. Continuous glucose monitoring and sensor-augmented insulin pump therapy with low glucose suspend technology can also prevent hypoglycemia, although concerns about cost and patient satisfaction remain. Advancements in insulin therapy and technological modalities should be coupled with ongoing education and support for patients to become co-managers of their disease and reduce the risk of hypoglycemia.

Ghrelin does not impact the blunted counterregulatory response to recurrent hypoglycemia in mice.

Introduction: Recurrent episodes of insulin-induced hypoglycemia in patients with diabetes mellitus can result in hypoglycemia-associated autonomic failure (HAAF), which is characterized by a compromised response to hypoglycemia by counterregulatory hormones (counterregulatory response; CRR) and hypoglycemia unawareness. HAAF is a leading cause of morbidity in diabetes and often hinders optimal regulation of blood glucose levels. Yet, the molecular pathways underlying HAAF remain incompletely described. We previously reported that in mice, ghrelin is permissive for the usual CRR to insulin-induced hypoglycemia. Here, we tested the hypothesis that attenuated release of ghrelin both results from HAAF and contributes to HAAF. Methods: C57BL/6N mice, ghrelin-knockout (KO) + control mice, and GhIRKO (ghrelin cell-selective insulin receptor knockout) + control mice were randomized to one of three treatment groups: a "Euglycemia" group was injected with saline and remained euglycemic; a 1X hypoglycemia ("1X Hypo") group underwent a single episode of insulin-induced hypoglycemia; a recurrent hypoglycemia ("Recurrent Hypo") group underwent repeated episodes of insulin-induced hypoglycemia over five successive days. Results: Recurrent hypoglycemia exaggerated the reduction in blood glucose (by ~30%) and attenuated the elevations in plasma levels of the CRR hormones glucagon (by 64.5%) and epinephrine (by 52.9%) in C57BL/6N mice compared to a single hypoglycemic episode. Yet, plasma ghrelin was equivalently reduced in "1X Hypo" and "Recurrent Hypo" C57BL/6N mice. Ghrelin-KO mice exhibited neither exaggerated hypoglycemia in response to recurrent hypoglycemia, nor any additional attenuation in CRR hormone levels compared to wild-type littermates. Also, in response to recurrent hypoglycemia, GhIRKO mice exhibited nearly identical blood glucose and plasma CRR hormone levels as littermates with intact insulin receptor expression (floxed-IR mice), despite higher plasma ghrelin in GhIRKO mice. Conclusions: These data suggest that the usual reduction of plasma ghrelin due to insulin-induced hypoglycemia is unaltered by recurrent hypoglycemia and that ghrelin does not impact blood glucose or the blunted CRR hormone responses during recurrent hypoglycemia.

[Diabetes mellitus and road traffic-a position paper of the Austrian Diabetes Association (update 2023)]. / Diabetes mellitus und Straßenverkehr ­ ein Positionspapier der Österreichischen Diabetesgesellschaft (Update 2023).

Public safety (prevention of accidents) is the primary objective in assessing fitness to drive a motor vehicle. However, general access to mobility should not be restricted if there is no particular risk to public safety. For people with diabetes mellitus, the Führerscheingesetz (Driving Licence Legislation) and the Führerscheingesetz-Gesundheitsverordnung (Driving Licence Legislation Health enactment) regulate important aspects of driving safety in connection with acute and chronic complications of the disease. Critical complications that may be relevant to road safety include severe hypoglycemia, pronounced hyperglycemia and hypoglycemia perception disorder as well as severe retinopathy and neuropathy, endstage renal disease and certain cardiovascular manifestations. If there is a suspicion of the presence of one of these complications, a detailed evaluation is required.In addition, the individual antihyperglycemic medication should be checked for existing potential for hypoglycemia. Sulfonylureas, glinides and insulin belong to this group and are therefore associated with the requirement of a 5-year limitation of the driver's license. Other antihyperglycemic drugs without potential for hypoglycemia such as Metformin, SGLT­2 inhibitors (Sodium-dependent-glucose-transporter­2 inhibitors, gliflozins), DPP-4-inhibitors (Dipeptidyl-Peptidase inhibitors, gliptins), and GLP­1 analogues (GLP­1 rezeptor agonists) are not associated with such a time limitation.The relevant laws which regulate driving safety give room for interpretation, so that specific topics on driving safety for people with diabetes mellitus are elaborated from a medical and traffic-relevant point of view. This position paper is intended to support people involved in this challenging matter.

Big insulin-like growth factor 2-producing multiple solitary fibrous tumors treated with debulking surgery: A case report.

Background: Non-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome caused by a tumor-producing high molecular weight form of insulin-like growth factor 2 (IGF2) known as big IGF2. The only curative treatment for this condition is surgical resection of the responsible tumors. However, this may not be feasible in cases with multiple metastases at diagnosis of NICTH, and no standard treatment strategy for multiple tumors has been established. The effects of pharmacological therapies including somatostatin analogs are often inefficient and remain difficult to predict. Case description: A 68-year-old man was admitted to our hospital due to impaired consciousness and severe hypoglycemia. His medical history included diagnosis of a left temporal solitary fibrous tumor (SFT) at the age of 48 years, after which local recurrent and metastatic tumors were repeatedly resected. Four years before admission, multiple intraabdominal and subcutaneous tumors were detected and, being asymptomatic, were managed conservatively. Laboratory exam on admission demonstrated hypoglycemia accompanied with low serum insulin and IGF1 levels. Computed tomography (CT) scan revealed multiple intraabdominal and subcutaneous tumors increasing in size. Serum big IGF2 was detected on immunoblot analysis, and he was diagnosed as NICTH. In addition, tumor uptake was observed on 68Ga-labelled 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-d-Phe1-Tyr3-octreotide positron emission tomography/CT (DOTATOC-PET/CT). Since larger tumor is more suspicious about responsible producibility of big IGF2, we planned to resect large ones preferentially and reduce the amounts of residual tumors. Debulking surgery was performed by removing eleven intraabdominal tumors; the hypoglycemia was then completely corrected. Histological analyses revealed the resected tumors to be metastases of SFT having somatostatin receptor 2 expression. In immunoblot analysis, the resected tumors were found to be positive for big IGF2; serum big IGF2 was undetectable after surgery. Conclusion: We present a case of NICTH with multiple metastatic SFTs. We strategically performed debulking surgery, which led to remission of hypoglycemia. This result demonstrates a pioneering practical solution for NICTH cases with multiple tumors. In addition, in cases of SFTs presenting with NICTH, positivity of DOTATOC-PET/CT as well as single-dose administration of octreotide may be predictive of the efficacy of somatostatin-based therapy.

Pancreas Transplantation: Current Challenges, Considerations, and Controversies.

Pancreas transplantation (PTx) reestablishes an autoregulating source of endogenous insulin responsive to normal feedback controls. In addition to achieving complete ß-cell replacement that frees the patient with diabetes from the need to monitor serum glucose and administer exogenous insulin, successful PTx provides counterregulatory hormone secretion and exocrine function. A functioning PTx mitigates glycemic variability, eliminates the daily stigma and burden of diabetes, restores normal glucose homeostasis in patients with complicated diabetes, and improves quality of life and life expectancy. The tradeoff is that it entails a major surgical procedure and requisite long-term immunosuppression. Despite the high likelihood of rendering patients euglycemic independent of exogenous insulin, PTx is considered a treatment rather than a cure. In spite of steadily improving outcomes in each successive era coupled with expansion of recipient selection criteria to include patients with a type 2 diabetes phenotype, a decline in PTx activity has occurred in the new millennium related to a number of factors including: (1) lack of a primary referral source and general acceptance by the diabetes care community; (2) absence of consensus criteria; and (3) access, education, and resource issues within the transplant community. In the author's experience, patients who present as potential candidates for PTx have felt as though they needed to circumvent the conventional diabetes care model to gain access to transplant options. PTx should be featured more prominently in the management algorithms for patients with insulin requiring diabetes who are failing exogenous insulin therapy or experiencing progressive diabetic complications regardless of diabetes type. Furthermore, all patients with diabetes and chronic kidney disease should undergo consideration for simultaneous pancreas-kidney transplantation independent of geography or location.

Hypoglycemia unawareness identified by continuous glucose monitoring system is frequent in outpatients with type 2 diabetes without receiving intensive therapeutic interventions.

BACKGROUND: Patients with diabetes are prone to asymptomatic hypoglycemia (AH) due to diminished ability to perceive the onset of hypoglycemia. However, the actual prevalence and influencing factors of AH in outpatients with type 2 diabetes (T2DM) have not been well investigated. METHODS: A total of 351 outpatients with T2DM underwent glucose monitoring by continuous glucose monitoring system (CGMS) for consecutive 72 h without changing their lifestyle and treatment regimens. Hypoglycemia is defined as a blood glucose level less than 3.9 mmol/L, which was further divided into Level 1 hypoglycemia (blood glucose 3.0-3.9 mmol/L) and Level 2 hypoglycemia (blood glucose < 3.0 mmol/L). Univariate and multivariate logistic regression analyses were used to determine the possible risk factors of AH. RESULTS: In all 351 subjects studied, 137 outpatients (39.0%) were captured AH events, in which Level 1 AH and Level 2 AH accounted for 61.3% and 38.7%, respectively. 85 (62.0%) of the AH patients experienced nocturnal asymptomatic hypoglycemia (NAH) and 25 (18.2%) exclusively NAH. Multivariate logistic regression analysis demonstrated that patients with younger age, lower hemoglobin A1c (HbA1c), and higher systolic blood pressure (SBP) levels were associated with increased risk of AH. While after further grading of AH, male sex and Dipeptidylpeptidase-4 inhibitors (DPP4i) regime were shown to be associated with lower risk of Level 2 AH. CONCLUSIONS: Hypoglycemia unawareness could be frequently observed at either daytime or nighttime, although NAH was more common, in outpatients with T2DM. Relative relax HbA1c targets should be considered for patients who are prone to AH.

Scientific advisory on nocturnal hypoglycemia in insulin-treated patients with diabetes: Recommendations from Indian experts.

INTRODUCTION: Insulin is one of the commonly prescribed glucose lowering agents in diabetes. Hypoglycemia is the most common complication, and severe hypoglycemia is the most serious complication of insulin therapy. Almost half of all severe hypoglycemia episodes (HEs) occur at night. However, patients are often unaware of their nocturnal hypoglycaemia (NH) risk. Additionally, both healthcare professionals and patients find it difficult to manage NH. The purpose of this expert group meeting is to improve NH awareness and provide guidance for the physicians to recognize and manage NH. METHOD: The panel of experts in an e-board deliberated extensively upon the available literature and guidelines on hypoglycemia and NH discussed the consensus on definition, detection, reporting, monitoring, treatment, and optimization of therapy in NH. RESULT: & Conclusion: Though there are many guidelines on the management of HEs in patients with diabetes, very few touch the topic of NH. This scientific advisory on management of NH in insulin treated patients with diabetes is formulated to address this gap in understanding regarding management of NH. The experts provide recommendations for the nocturnal window, defining NH based on blood glucose values, recognition, prevention and management of NH.

Relationship Between Hypoglycemia Awareness Status on Clarke/Gold Methods and Counterregulatory Response to Hypoglycemia.

Context: Impaired awareness of hypoglycemia (IAH) is characterized by the diminished ability to perceive symptoms of hypoglycemia. Gold and Clark questionnaires are commonly used to identify patients with IAH. The relationship between IAH status on questionnaires and a person's symptom and epinephrine responses to hypoglycemia are not well understood. Objective: We aimed to examine the relationship between hypoglycemia awareness status on Clarke and Gold questionnaires with both hormonal and symptomatic responses to experimental hypoglycemia. Methods: In this university medical center study, we examined data from 78 subjects with type 1 diabetes (T1D) who completed both questionnaires and underwent a hyperinsulinemic hypoglycemic clamp (target glucose 50 mg/dL). Results: Clarke and Gold scores were highly correlated with one another (r = 0.82) and each had a moderate negative relationship with epinephrine (Clarke: r = -0.51, Gold: r = -0.50) and total symptom response (Clarke: r = -0.59, Gold: r = -0.57). However, 32% of the subjects were classified inconsistently by Clark vs Gold. A clustering analysis was done to examine how disagreement between the 2 questionnaires on IAH classification relates to epinephrine and symptoms responses during hypoglycemia. Subjects who had partial loss of symptoms or of epinephrine response were more likely to be classified inconsistently. Conclusion: Our results show that IAH classification may be discordant between Clark and Gold questionnaires and that hypoglycemia awareness status on Clarke and Gold questionnaires poorly predicts hormonal and symptomatic responses to hypoglycemia in subjects with T1D and moderate blunting of symptoms or epinephrine.

Hypoglycemia unawareness in type 1 diabetes patients using intermittent continuous glucose monitoring: Identification of risk factors and glycemic patterns.

BACKGROUND: Hypoglycemia unawareness designates failure to detect eminent hypoglycemia. Clarke's questionnaire is one of the most used systems to evaluate this problem. AIMS: To relate Clarke's questionnaire (QQ) results with continuous glucose monitoring data. METHODS: Application of the questionnaire in a sample of type 1 diabetes mellitus (T1DM) patients using intermittent continuous glucose monitoring (iCGM). RESULTS: 111 T1DM patients were evaluated, 56.8% female, mean age 35.0 ± 12.4 years and mean disease duration 18.8 ± 10.5 years. According to CQ, 13.5% had unawareness, 76.6% awareness and 9.9% indeterminate awareness to hypoglycemia. Those with unawareness had longer disease duration (25.1 ± 10.4 vs 18.2 ± 10.3 for awareness and 14.9 ± 9.9 for indeterminate awareness, p = 0.047), more time below range (10.3 ± 4.9% vs 6.3 ± 5.1 and 6.3 ± 4.8; p = 0.009) and higher mean duration of hypoglycemia (131.7 ± 38.6 vs 116.6 ± 49.6 and 131.7 ± 38.6; p = 0.008). In multivariate analysis, mean duration of hypoglycemia was an independent predictor of CQ results. In a receiver operating curve (AUC 0.746; p = 0.004) a mean duration of hypoglycemia ≥106.5 min showed 84.6% sensitivity/64.4% specificity for unawareness. CONCLUSIONS: Our sample had a significative prevalence of hypoglycemia unawareness which increased with longer diabetes duration. iCGM data can be indicative of this problem, with a mean hypoglycemia duration ≥106.5 min being suggestive, albeit unspecific.

Evaluation of Clinical Metrics for Identifying Defective Physiologic Responses to Hypoglycemia in Long-Standing Type 1 Diabetes.

Repeated hypoglycemia exposure leads to impaired awareness of hypoglycemia (IAH) and the development of defective counterregulatory responses. To date, only pancreas or islet transplantation has demonstrated normalization of hypoglycemia awareness and the endogenous glucose production (EGP) response to defend against insulin-induced hypoglycemia in long-standing type 1 diabetes (T1D). This study aims to validate clinical metrics of IAH (Clarke score), hypoglycemia severity (HYPO score), glycemic lability (lability index), and continuous glucose monitoring (CGM) as predictors of absent autonomic symptom (AS) recognition and defective glucose counterregulation during insulin-induced hypoglycemia, thus enabling early identification of individuals with compromised physiologic defense against clinically significant hypoglycemia. Forty-three subjects with mean ± standard deviation age 43 ± 13 years and T1D duration 28 ± 13 years, including 32 with IAH and 11 with hypoglycemia awareness (Aware), and 12 nondiabetic control subjects, underwent single-blinded randomized-paired hyperinsulinemic-euglycemic and hypoglycemic clamp experiments. Receiver operating characteristic (ROC) curves and sensitivity analyses were performed to assess metric prediction of absent AS recognition and defective EGP responses to hypoglycemia. Clarke score and CGM measures of hypoglycemia exposure demonstrated good ability to predict absent AS recognition (area under the curve ≥0.80). A composite threshold of IAH-Clarke ≥4 with ROC curve-derived thresholds for CGM measures of hypoglycemia exposure showed high specificity and predictive value in identifying an absent AS response during the hypoglycemic clamp. Metrics demonstrated poor ability to predict defective glucose counterregulation by the EGP response, which was impaired even in the Aware group. Screening for IAH alongside assessment of CGM data can increase the specificity for identifying individuals with absent hypoglycemia symptom recognition who may benefit from further intervention.

High prevalence of depressive symptoms among people with pediatric-onset and adolescent-onset type 1 diabetes: A cross-sectional analysis of the Diabetes Study from the Center of Tokyo Women's Medical University.

AIMS/INTRODUCTION: To investigate the prevalence of depressive symptoms by the age of onset of type 1 diabetes, and its association with the condition of individuals with pediatric- and adolescent-onset type 1 diabetes. MATERIALS AND METHODS: This single-center cross-sectional study enrolled Japanese participants with type 1 diabetes. All participants completed a questionnaire about their diabetes-related condition and the Patient Health Questionnaire-9, which was used to evaluate depression. Individuals with a Patient Health Questionnaire-9 score of ≥10 points were defined as having moderate depressive symptoms. RESULTS: A total of 1,267 participants (mean age 40 years; mean duration of type 1 diabetes 21 years; 68% female; mean glycated hemoglobin 7.8%) were included and classified according to the age of onset of type 1 diabetes to identify the proportion of moderate depressive symptoms in each group: 21% (0-12 years), 18% (13-19 years) and 13% (20-40 years). The prevalence of moderate depressive symptoms was significantly higher among participants with pediatric-onset type 1 diabetes (P < 0.05). Moderate depressive symptoms were associated with increased glycated hemoglobin, neuropathy and hypoglycemia unawareness. CONCLUSIONS: Regular screening for depressive symptoms and hypoglycemia awareness is important. Healthcare professionals should provide appropriate psychosocial care for people with pediatric-onset and adolescent-onset type 1 diabetes from childhood through to adulthood.

Finding Eden - alternative transplantation sites for pancreatic islets.

Pancreatic islets transplantation is an established treatment method for type 1 diabetic patients with the hypoglycemia unawareness syndrome in whom a therapy with modern technologies fails. Islet transplantation is most commonly done using an interventional radiology method: a tissue suspension of pancreatic islets is applied into a branch of the portal vein through a percutaneously installed catheter. Although being minimally invasive unlike pancreas organ transplant, this method is associated with many technical difficulties. Possible complications of the procedure include hemorrhage and portal vein thrombosis. Unlike their natural dispersed localization in exocrine pancreas, isolated pancreatic islets are exposed to hypoxia, toxins and immunosuppressive drugs in the liver parenchyma. Direct contact with the recipients blood causes an instant blood mediated inflammatory reaction (IBMIR) resulting in the death of more than half of the pancreatic islets shortly after their application. Therefore the size of the islet graft is often insufficient and a number of transplanted patients require administration of exogenous insulin. All of these are reasons for seeking an alternative transplantation site with more hospitable conditions for long-term islet survival. Various transplantation sites have been tested in experimental and clinical research. The advantages and disadvantages of some of them are summarized in this paper. Currently, transplantation into the greater omentum seems most promising, which has already been used in clinical practice at several institutions.

Persistent Postgastrectomy Hypoglycemia Unawareness in Patients With Gastric Cancer Unveiled by a Prospective Study.

Objective: Late dumping syndrome is a common postgastrectomy complication characterized by reactive hypoglycemia. This study aimed to explore the glycemic trend in patients who underwent gastrectomy for gastric cancer and clarify its changes over time in association with postgastrectomy symptoms. Summary Background Data: Changes over time in glycemic trend in association with postgastrectomy symptoms have not been evaluated. Methods: We conducted a prospective study of 71 patients who underwent curative gastrectomy for gastric cancer between November 2017 and April 2020. The patients underwent continuous glucose monitoring twice-at 1- and 12-month postgastrectomy-and were assessed using the Post-Gastrectomy Syndrome Assessment Scale 37-item questionnaire (PGSAS-37) at 1-, 6-, and 12-month postgastrectomy. Results: Our results revealed that hypoglycemia (<70 mg/dL), especially nocturnal hypoglycemia (00:00-06:00), frequently occurred even at 12-month postgastrectomy. Hypoglycemia improved in total gastrectomy patients but remained unchanged in distal gastrectomy patients, which was still high in both groups at 12-month postgastrectomy. Glycemic variability (SD of the glycemic trend) was exacerbated in both gastrectomy groups. However, the PGSAS-37 symptom scores remained unchanged, and the living status and quality of life tended to improve. Hypoglycemia unawareness, including postprandial hypoglycemia without symptoms and nocturnal hypoglycemia, was evident even 12-month postgastrectomy. Conclusions: Persistent postgastrectomy hypoglycemia unawareness, including late dumping syndrome without symptoms and nocturnal hypoglycemia, should be recognized as an important issue in postgastrectomy syndrome. Therefore, meticulous long-term evaluation for glycemic trends and care of patients is required.

Transplant Options for Patients With Diabetes and Advanced Kidney Disease: A Review.

Optimal glycemic control in kidney transplant recipients with diabetes is associated with improved morbidity and better patient and allograft survival. Transplant options for patients with diabetes requiring insulin therapy and chronic kidney disease who are suitable candidates for kidney transplantation should include consideration of ß-cell replacement therapy: pancreas or islet transplantation. International variation related to national regulatory policies exists in offering one or both options to suitable candidates and is further affected by pancreas/islet allocation policies and transplant waiting list dynamics. The selection of appropriate candidates depends on patient age, coexistent morbidities, the timing of referral to the transplant center (predialysis versus on dialysis) and availability of living kidney donors. Therefore, early referral (estimated glomerular filtration rate < 30 mL/min/1.73 m2) is of the utmost importance to ensure adequate time for informed decision making and thorough pretransplant evaluation. Obesity, cardiovascular disease, peripheral vascular disease, smoking, and frailty are some of the conditions that need to be addressed before acceptance on the transplant list, and ideally before dialysis becoming imminent. This review offers insights into selection of pancreas/islet transplant candidates by transplant centers and an update on posttransplant outcomes, which may have practice implications for referring nephrologists.