Counterregulatory Hormone Levels Research Articles

Real-life hypoglycaemia partially blunts the inflammatory response to experimental hypoglycaemia in people with type 1 diabetes.

To determine whether recent repeated exposure to real-life hypoglycaemia affects the pro-inflammatory response during a hypoglycemia episode. This was a post hoc analysis of a hyperinsulinaemic normoglycaemic-hypoglycaemic clamp study, involving 40 participants with type 1 diabetes. Glucose levels 1 week before the clamp were monitored using a Freestyle Libre 1. Blood was drawn during normoglycaemia and hypoglycaemia, and 24 hours after resolution of hypoglycaemia for measurements of inflammatory responses and counterregulatory hormone levels. We determined the relationship between the frequency and duration of spontaneous hypoglycaemia, and time below range (TBR) and the inflammatory response to experimental hypoglycaemia. On average, participants experienced 0.79 (0.43, 1.14) hypoglycaemia episodes per day, with a duration of 78 (47, 110) minutes and TBR of 5.5% (2.8%, 8.5%). TBR and hypoglycaemia frequency were inversely associated with the increase in circulating granulocyte and lymphocyte counts during experimental hypoglycaemia (P < .05 for all). A protein network consisting of DNER, IF-R, uPA, Flt3L, FGF-5 and TWEAK was negatively associated with hypoglycaemia frequency (P < .05), but not with the adrenaline response. Neither other counterregulatory hormones, nor hypoglycaemia awareness status, was associated with any of the inflammatory parameters markers. Repeated exposure to spontaneous hypoglycaemia is associated with blunted effects of subsequent experimental hypoglycaemia on circulating immune cells and the number of inflammatory proteins.

Diabetic ketoacidosis in type 1 diabetes mellitus in children and adolescents

Background: Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in children with type 1 diabetes mellitus (T1DM). Although T1DM can occur in children and adults, DKA caused by T1DM is more severe in children and adolescents and metabolic changes occur more rapidly. This review discusses clinical factors associated with DKA assessed during diagnosis in children and adolescents with T1DM.Current Concepts: DKA is a severe complication that can occur in children with T1DM because of insulin deficiency, leading to high levels of catabolism with increased gluconeogenesis, glycogenolysis, lipolysis, muscle proteolysis, hyperglycemia, and osmotic diuresis. High levels of counterregulatory hormones that enhance ketogenesis have also been noted. High blood sugar levels, dehydration, and the release of ketone bodies into the circulation cause high occurrence of acidosis. DKA can lead to life-threatening complications, such as cerebral edema, which is more common in children than in adults. Other potential complications include kidney failure, respiratory distress, and cardiovascular collapse. Children with T1DM are at a higher risk of developing DKA, particularly during times of illness or stress, or when insulin doses are missed or insufficient. In addition, undiagnosed T1DM in children can lead to DKA when the body enters a state of severe insulin deficiency.Discussion and Conclusion: The risks should be detected earlier and the pathogenesis of T1DM should be understood and assessed by physicians in children and adolescents during check-ups. Furthermore, efforts to increase public awareness are required to reduce the cognitive delays associated with DKA.

Addressing recurrent hypoglycaemia through thoracic surgical intervention: understanding Doege-Potter syndrome, a rarity in syndromes

Doege-Potter syndrome (DPS), a rare paraneoplastic phenomenon characterised by non-islet cell tumour hypoglycaemia (NICTH), presents clinicians with intricate diagnostic and therapeutic challenges. This comprehensive review consolidates current understanding, clinical presentations, diagnostic modalities, therapeutic interventions, and emerging trends in managing DPS. The pathophysiology of DPS revolves around dysregulated insulin-like growth factors (IGF), particularly IGF-2, produced by mesenchymal tumours, notably solitary fibrous tumours (SFT). Clinical manifestations encompass recurrent hypoglycaemic episodes, often distinct from typical hypoglycaemia, with implications for insulin and counterregulatory hormone levels. Diagnosis necessitates a multidisciplinary approach integrating biochemical assays, imaging studies, and histopathological confirmation of the underlying neoplasm. Surgical resection remains the cornerstone of treatment, complemented by adjunctive therapies to manage persistent hypoglycaemia. Prognosis is influenced by successful tumour resection and long-term surveillance for recurrence. A patient-centred approach, incorporating supportive services and multidisciplinary care, is essential for optimal outcomes in individuals affected by DPS.

SAT059 Metastatic Insulinoma Diagnosed Postpartum

Abstract Disclosure: A. Faber: None. H. Lam: None. R. Simon: None. Introduction: Insulinomas are rare neuroendocrine tumors derived from the beta cells of the pancreas. These tumors generally occur at a rate of four cases per million per year, and they are seen across all demographics. Affected patients present with symptoms of hypoglycemia, including confusion, diaphoresis, and palpitations. Insulinomas occur as single or multiple tumors, and can be benign or malignant. Insulinomas with metastases are defined as malignant. The primary treatment is surgical resection. However, in the case of metastatic insulinomas prognosis can be quite poor with limited treatment options. Case Presentation: A 24-year-old female employed as a nurse with otherwise negative medical history originally presented around 3 months postpartum with epigastric pain which was attributed to gas. Symptoms progressed to include lightheadedness, palpitations, and sweating. She checked her blood glucose during these events and noted it to be consistently in the 30s-40s. She would treat these episodes with food and had short-term improvement in symptoms. She presented to an outside hospital where imaging revealed: hepatomegaly with innumerable hypodense liver lesions, hypo-enhancing pancreatic head lesion, sclerotic focus in T4 vertebral body, as well as multiple enlarged upper abdominal lymph nodes including peripancreatic, porta hepatis, and gastrohepatic. Liver biopsy revealed well-differentiated neuroendocrine tumor, WHO grade 3 likely from a pancreatic primary and chemotherapy was initiated with carboplatin and paclitaxel with some response. However, hypoglycemia became refractory to management with 5% dextrose drip, so she was transferred to our facility for escalation of care. TPN was initiated and dextrose drip was escalated eventually to 40% dextrose. She was also given octreotide, hydrocortisone, and eventually diazoxide. Given degree of tumor burden as well as abdominal ascites and clinical condition, surgery was deemed high risk and not recommended. Tumor board meeting was held and her chemotherapy regimen was changed to Carboplatin/Etoposide/Atezolizumab. She subsequently underwent hepatic artery embolization twice with improvement of hypoglycemia. Despite decreasing dextrose drip requirements by over 50%, patient was unable to be liberated from dextrose infusion and had multiple discussions about management options and prognosis. The patient eventually elected to go home with home hospice. Discussion: Insulinoma diagnosed in pregnancy or shortly after pregnancy is extremely rare. There are only three case reports of malignant insulinoma diagnosed in or after pregnancy. Given the degree of extensive metastases at time of presentation, we expect our patient’s insulinoma was present prior to delivery. Hypoglycemia may have only manifested in the postpartum period when there was decreased levels of placenta-derived counterregulatory hormones. Presentation: Saturday, June 17, 2023

Diabetic Ketoacidosis Complications and Management in Pediatrics: A Narrative Review

Diabetic ketoacidosis (DKA) is an endocrine emergency that affects both newly diagnosed and long-term type I diabetic patients as a result of decreasing insulin levels in the blood, insulin resistance, and elevated levels of counter-regulatory hormones. A common and deadly acute consequence in kids with diabetes mellitus is diabetic ketoacidosis. When type I diabetes is newly diagnosed, it can be accompanied by diabetic ketoacidosis. It can also happen when type I diabetes is already present, such as when the demands of an acute illness are more than usual or when insulin administration is decreased as a result of missed doses or insulin pump failure. Furthermore, there are more reports of diabetic ketoacidosis events in kids with type II diabetes mellitus. Although the diagnosis is typically simple in a patient with established diabetes and the anticipated symptoms, a sizable portion of patients with new-onset diabetes initially present with diabetic ketoacidosis. Children with diabetic ketoacidosis are typically treated in an emergency room for the first time. The differential diagnosis of pediatric metabolic acidosis must take diabetic ketoacidosis into account as a significant factor. The pathogenesis, therapy, and probable consequences of this illness will be explained to emergency medicine doctors in this review) Heddy, 2021). The management of pediatric patients draws attention to the uncommon but fatal occurrence of cerebral edema and the excessive use of fluid boluses that may or may not be related to it. Guidelines for managing DKA in adults should not be applied to children and adolescents. The diagnosis of DKA is based on clinical suspicion and subsequent laboratory confirmation: Hyperglycemia (sugar level greater than 11 mmol/L): diabetes warning sign. pH 7.3 and 15 mmol/L of bicarbonate indicate metabolic acidosis. Ketosis, which may include ketonuria or ketonaemia. The severity of DKA depends on the acidity level: Mild: pH 7.3 and/or 15 mmol/L of bicarbonate; Moderate: pH 7.2 and/or 10 mmol/L of bicarbonate. Ketoacidosis associated with diabetes (DKA) Extremely severe: pH 7.1 and/or 5 mmol/L of bicarbonate. DKA can have various deadly consequences. Acute hypoglycemia (during treatment or as a result of utilizing an excessive amount of insulin pump) Cerebral edema, Acute hypokalemia, Acute hypoglycemia, Spontaneous pneumonia. A, B, and C for initial CPR If at all possible, weigh the patient and then use that weight in all calculations. Use an estimated weight from a centile chart or a weight from a recent medical visit as an alternative. Make sure the airway is open. Insert an airway if a child is unconscious (Glasgow Coma Scale Score of 8). In the event that the patient is vomiting or has a reduced level of awareness, insert NGT, aspirate, and place on free drainage. B. An oxygen-only face mask. Draw blood when an IV cannula is in place. Only if the patient is shocked (poor peripheral pulses, poor capillary filling with tachycardia, and/or hypotension) should you provide a bolus of 10 ml/kg 0.9% sodium chloride. Repeat the fluid bolus only after contacting a doctor or pediatric endocrinologist if shock symptoms continue.

Diabetic ketoacidosis awareness and prevention for new onset Type 1 diabetes

Diabetic ketoacidosis (DKA) is an avoidable life-threatening condition and form of metabolic acidosis that develops with a relative or absolute deficiency of circulating insulin (Cashen & Peterson, 2019). The imbalance of insulin and counterregulatory hormone levels can lead to hyperglycemia, hyperosmolality, ketosis, and acidosis which results in cerebral edema and death if not addressed quickly. The incidence of DKA hospitalizations continues to increase, and the most common cause of DKA is new-onset Type 1 diabetes (T1D).

An Approach to Diabetic Ketoacidosis in an Emergency Setting.

Diabetic Ketoacidosis (DKA) is one of the most commonly encountered diabetic complication emergencies. It typically affects people with type 1 diabetes at the onset of the disease. It can also affect people with type 2 diabetes, although this is uncommon. Research and online content related to diabetes online activity is reviewed. DKA is caused by a relative or absolute deficiency of insulin and elevated levels of counter-regulatory hormones. Goals of therapy are to correct dehydration, acidosis, and to reverse ketosis, gradually restoring blood glucose concentration to near normal. It is essential to monitor potential complications of DKA and, if necessary, to treat them and any precipitating events.

Management of Diabetic Ketoacidosis in Children and Adolescents with Type 1 Diabetes Mellitus.

Diabetic ketoacidosis (DKA) is the end result of insulin deficiency in type 1 diabetes mellitus (T1D). Loss of insulin production leads to profound catabolism with increased gluconeogenesis, glycogenolysis, lipolysis, and muscle proteolysis causing hyperglycemia and osmotic diuresis. High levels of counter-regulatory hormones lead to enhanced ketogenesis and the release of 'ketone bodies' into the circulation, which dissociate to release hydrogen ions and cause an overwhelming acidosis. Dehydration, hyperglycemia, and ketoacidosis are the hallmarks of this condition. Treatment is effective repletion of insulin, fluids and electrolytes. Newer approaches to early diagnosis, treatment, and prevention may diminish the risk of DKA and its childhood complications including cerebral edema. However, the potential for some technical and pharmacologic advances in the management of T1D to increase DKA events must be recognized.

A Case of Multifactorial Diabetic Ketoacidosis Acquired in the Intensive Care Unit: A Case Report

Diabetic ketoacidosis (DKA) is a potentially fatal endocrine emergency resulting from uncontrolled diabetes mellitus (DM). The development of DKA has been linked to a number of precipitating factors such as infectious process, ischemia, medications, and other medical-surgical illnesses. These factors have been found to aggravate or unmask pre-existing glucose dysregulation secondary to absolute or relative insulin deficiency and increased levels of counter-regulatory hormones. We describe the case of a 61-year-old male with a history of insulin dependent DM who develops DKA postoperatively after a three-vessel coronary artery bypass surgery and mitral valve repair while in the intensive care unit (ICU). The patient’s postoperative course was complicated by presumed pneumonia and hyperactive delirium. On postoperative day (POD) five, the patient’s insulin infusion was held due to non-symptomatic hypoglycemia. Eleven hours later, the insulin infusion was resumed to treat DKA after laboratory findings revealed hyperglycemia, an elevated β-hydroxybutyrate, and anion gap metabolic acidosis. Multiple contributing factors for the development of DKA are suspected and discussed. It is paramount that clinicians are knowledgeable of the multiple factors that can contribute to the development of DKA in the ICU.

Multi-dimensional Transcriptional Remodeling by Physiological Insulin In Vivo

Regulation of gene expression is an important aspect of insulin action but invivo is intertwined with changing levels of glucose and counter-regulatory hormones. Here we demonstrate that under euglycemic clamp conditions, physiological levels of insulin regulate interrelated networks of more than 1,000 transcripts in muscle and liver. These include expected pathways related to glucose and lipid utilization, mitochondrial function, and autophagy, as well as unexpected pathways, such as chromatin remodeling, mRNA splicing, and Notch signaling. These acutely regulated pathways extend beyond those dysregulated in mice with chronic insulin deficiency or insulin resistance and involve a broad network oftranscription factors. More than 150 non-coding RNAs were regulated by insulin, many of which alsoresponded to fasting and refeeding. Pathway analysis and RNAi knockdown revealed a role for lncRNA Gm15441 in regulating fatty acid oxidation in hepatocytes. Altogether, these changes in coding and non-coding RNAs provide an integrated transcriptional network underlying the complexity of insulin action.

Substrate metabolism, hormone and cytokine levels and adipose tissue signalling in individuals with type 1 diabetes after insulin withdrawal and subsequent insulin therapy to model the initiating steps of ketoacidosis.

Lack of insulin and infection/inflammation are the two most common causes of diabetic ketoacidosis (DKA). We used insulin withdrawal followed by insulin administration as a clinical model to define effects on substrate metabolism and to test whether increased levels of counter-regulatory hormones and cytokines and altered adipose tissue signalling participate in the early phases of DKA. Nine individuals with type 1 diabetes, without complications, were randomly studied twice, in a crossover design, for 5h followed by 2.5h high-dose insulin clamp: (1) insulin-controlled euglycaemia (control) and (2) after 14h of insulin withdrawal in a university hospital setting. Insulin withdrawal increased levels of glucose (6.1 ± 0.5 vs 18.6 ± 0.5mmol/l), NEFA, 3-OHB (127 ± 18 vs 1837 ± 298μmol/l), glucagon, cortisol and growth hormone and decreased HCO3- and pH, without affecting catecholamine or cytokine levels. Whole-body energy expenditure, endogenous glucose production (1.55 ± 0.13 vs 2.70 ± 0.31mgkg-1min-1), glucose turnover, non-oxidative glucose disposal, lipid oxidation, palmitate flux (73 [range 39-104] vs 239 [151-474] μmol/min), protein oxidation and phenylalanine flux all increased, whereas glucose oxidation decreased. In adipose tissue, Ser473 phosphorylation of Akt and mRNA levels of G0S2 decreased, whereas CGI-58 (also known as ABHD5) mRNA increased. Protein levels of adipose triglyceride lipase (ATGL) and hormone-sensitive lipase phosphorylations were unaltered. Insulin therapy decreased plasma glucose concentrations dramatically after insulin withdrawal, without any detectable effect on net forearm glucose uptake. Release of counter-regulatory hormones and overall increased catabolism, including lipolysis, are prominent features of preacidotic ketosis induced by insulin withdrawal, and dampening of Akt insulin signalling and transcriptional modulation of ATGL activity are involved. The lack of any increase in net forearm glucose uptake during insulin therapy after insulin withdrawal indicates muscle insulin resistance. ClinicalTrials.gov NCT02077348 FUNDING: This study was supported by Aarhus University and the KETO Study Group/Danish Agency for Science Technology and Innovation.

Insulin inhibits autophagy signaling independent of counterregulatory hormone levels but does not affect the effects of exercise.

Acute exercise increases autophagic signaling through Unc-51 like kinase-1 (ULK1) in human skeletal muscle during both anabolic and catabolic conditions. The aim of the present study was to investigate if changes in ULK1 Ser555 phosphorylation during exercise are reflected by changes in phosphorylation of a newly identified ULK1 substrate (ATG14 Ser29) and to elucidate the involvement of circulatory hormones in the regulation of autophagy in human skeletal muscle. We show that 1 h of cycling exercise increases ATG14 Ser29 phosphorylation during both hyperinsulinemic euglycemic and euinsulinemic euglycemic conditions. This could suggest that counterregulatory hormones stimulate autophagy in skeletal muscle, as circulating concentrations of these hormones are highly elevated during exercise. Furthermore, ATG14 Ser29 correlated positively with ULK1 phosphorylation, suggesting that ULK1 Ser555 (activating site) phosphorylation reflects ULK1 kinase activity. In a separate series of experiments, we show that insulin stimulates ULK1 phosphorylation at Ser757 (inhibitory site) in both hypoglycemic and euglycemic conditions, suggesting that counterregulatory hormones (such as epinephrine, norepinephrine, growth hormone, and glucagon) have limited effects on autophagy signaling in human skeletal muscle. In conclusion, 1 h of cycling exercise increases phosphorylation of ATG14 at Ser29 in a pattern that mirrors ULK1 phosphorylation at Ser555. Moreover, insulin effects on autophagy signaling in human skeletal muscle are independent of hypoglycemic and euglycemic conditions.NEW & NOTEWORTHY Autophagy signaling is regulated in a hierarchical order by exercise, insulin, and counterregulatory hormones. Exercise-induced autophagy signaling is stimulated by local factors in skeletal muscle rather than circulatory hormones. Unc-51 like kinase-1 (ULK1) phosphorylation at Ser555 reflects ULK1 kinase activity.

Substrate Metabolism and Insulin Sensitivity During Fasting in Obese Human Subjects: Impact of GH Blockade.

Insulin resistance and metabolic inflexibility are features of obesity and are amplified by fasting. Growth hormone (GH) secretion increases during fasting and GH causes insulin resistance. To study the metabolic effects of GH blockade during fasting in obese subjects. Nine obese males were studied thrice in a randomized design: (1) after an overnight fast (control), (2) after 72 hour fasting (fasting), and (3) after 72 hour fasting with GH blockade (pegvisomant) [fasting plus GH antagonist (GHA)]. Each study day consisted of a 4-hour basal period followed by a 2-hour hyperinsulinemic, euglycemic clamp combined with indirect calorimetry, assessment of glucose and palmitate turnover, and muscle and fat biopsies. GH levels increased with fasting (P < 0.01), and the fasting-induced reduction of serum insulin-like growth factor I was enhanced by GHA (P < 0.05). Fasting increased lipolysis and lipid oxidation independent of GHA, but fasting plus GHA caused a more pronounced suppression of lipid intermediates in response to hyperinsulinemic, euglycemic clamp. Fasting-induced insulin resistance was abrogated by GHA (P < 0.01) primarily due to reduced endogenous glucose production (P = 0.003). Fasting plus GHA also caused elevated glycerol levels and reduced levels of counterregulatory hormones. Fasting significantly reduced the expression of antilipolytic signals in adipose tissue independent of GHA. Suppression of GH activity during fasting in obese subjects reverses insulin resistance and amplifies insulin-stimulated suppression of lipid intermediates, indicating that GH is an important regulator of substrate metabolism, insulin sensitivity, and metabolic flexibility also in obese subjects.

Metformin: An Old Taboo yet a New Friend for Targeted Glucose Control in Critically Ill Patients

Glucose management in critically ill adults and children has always been controversial. A few recent studies mention that the use of any drug other than insulin for glucose control in intensive care unit is not recommended anymore1. Increased levels of counter-regulatory hormones and insulin resistance at organ levels contribute immensely to the emergence of hyperglycemia in these patients. Consequently, in some patients higher doses of insulin are required for the maintenance of normoglycemia and in such scenarios incidence of hypoglycemia becomes a real concern. Moreover, insulin therapy might lead to hypokalaemia and hypomagnesaemia which in turns promote insulin resistance and higher blood glucose level (BGL). All these events make insulin administration unavoidable; thereby, beginning a vicious cycle with adverse outcomes. One of therapeutic options in this scenario is using insulin sensitizing agents as an adjunct therapy for glycemic control in critically ill patients. Different studies have shown that metformin, similar to insulin, is of anti-inflammatory and antioxidant properties, improves lipid profile, decreases nursing workload and lowers the incidence of adverse effects related to high-dose insulin therapy without being associated with the increased risk of lactic acidosis or hypoglycemia2-4. Panahi et al., in their study, showed that metformin therapy in hyperglycemic critically ill patients resulted in similar outcomes with insulin thersapy5. Also, there are some studies reporting that metformin limits ischemia reperfusion injury, modulates inflammation; it consequently contributes to the survival benefits probably through increasing adenosine receptor stimulation6-8. In sepsis, there is a biphasic inflammatory response; Systemic Inflammatory Response Syndrome (SIRS), as an initial hyperinflammatory phase, and Counterregulatory anti-inflammatory response syndrome as a later hypoactive phase. Therefore, anti-inflammatory drugs like metformin may be associated with the best results only if added prior to the initial hyperinflammatory response and might have detrimental effects if added during hypoactive phase9,10. Timing of metformin administration may be an important factor contributing to its effect in critically ill patients. Finally, in patients with refractoriness to insulin who require high doses of insulin, metformin could be used as a safe adjunct therapy to reach targeted glucose levels. Metformin plus insulin appears to lower the incidence of insulin resistance, insulin requirements while maintaining blood glucose level control, and consequently the incidence of adverse effects related to high-dose insulin therapy, particularly hypoglycaemia. Declined nursing workload is also considered a major benefit. However, two important items should be noted: first, timing of drug administration and second, characteristics of the patients like renal function, hypoperfusion status and monitoring of drug complications.

Naltrexone for treatment of impaired awareness of hypoglycemia in type 1 diabetes: A randomized clinical trial

AimsImpaired awareness of hypoglycemia (IAH) is a limiting factor in the treatment of type 1 diabetes (T1D) and is a challenging condition to reverse. The objective of this study was to test the hypothesis that naltrexone therapy in subjects with T1D and IAH will improve counterregulatory hormone response and recognition of hypoglycemia symptoms during hypoglycemia. MethodsWe performed a pilot randomized double blind trial of 4weeks of naltrexone therapy (n=10) or placebo (n=12) given orally in subjects with T1D and IAH. Outcome measures included hypoglycemia symptom scores, counterregulatory hormone levels and thalamic activation as measured by cerebral blood flow using MRI during experimental hypoglycemia in all subjects before and after 4weeks of intervention. ResultsAfter 4weeks of therapy with naltrexone or placebo, no significant differences in response to hypoglycemia were seen in any outcomes of interest within each group. ConclusionsIn this small study, short-term treatment with naltrexone did not improve recognition of hypoglycemia symptoms or counterregulatory hormone response during experimental hypoglycemia in subjects with T1D and IAH. Whether this lack of effect is related to the small sample size or due to the dose, the advanced stage of study population or the drug itself should be the subject of future investigation.

Counter-regulatory hormone responses to hypoglycaemia in people with type 1 diabetes after 4 weeks of treatment with liraglutide adjunct to insulin: a randomized, placebo-controlled, double-blind, crossover trial.

To investigate the effect of glucagon-like peptide 1 receptor agonist liraglutide on the counter-regulatory hormone response to hypoglycaemia in type 1 diabetes. We conducted a randomized, double-blind, placebo-controlled, single-centre trial, in which a total of 45 adults with type 1 diabetes [mean ± standard deviation age 34.5 ± 11.2 years, BMI 23.9 ± 2.4 kg/m(2) , glycated haemoglobin (HbA1c) 7.6 ± 0.8%, diabetes duration 16.6 ± 9.4 years] underwent a hypoglycaemic clamp after 4 weeks' crossover treatment with once-daily liraglutide/placebo added to insulin in one of three liraglutide dose groups: 0.6 mg (n = 15); 1.2 mg (n = 14); and 1.8 mg (n = 16). The main outcome measure was glucagon concentration at nadir plasma glucose (2.5 mmol/l). Clinical outcomes were also evaluated. Five participants were withdrawn from the trial; three because of adverse events. All participants were included in the analysis. Glucagon concentration at nadir plasma glucose was modest, trending towards lower concentrations at increasing liraglutide dose versus placebo: 34.7 versus 38.1 pg/ml, p = 0.555 (0.6 mg); 28.8 versus 37.2 pg/ml, p = 0.126 (1.2 mg); and 28.4 versus 37.5 pg/ml, p = 0.092 (1.8 mg). There was no difference, however, between liraglutide and placebo in incremental change in glucagon during hypoglycaemia. Other counter-regulatory hormone levels increased during hypoglycaemia with no systematic differences between groups. Glucose infusion rates were significantly lower with liraglutide versus placebo during the clamp. After 4 weeks' treatment, HbA1c remained unchanged in the liraglutide and placebo groups. Greater reductions in insulin dose and body weight were seen with liraglutide versus placebo. Liraglutide did not compromise hypoglycaemic responses in type 1 diabetes after 4 weeks' treatment.

A case of hypothalamic hypopituitarism accompanied by recurrent severe hypoglycemia.

IntroductionHypothalamic hypopituitarism is relatively rare cause of secondary adrenal deficiency which is often accompanied by severe hypoglycemia. Hydrocortisone replacement therapy is essential for this condition, but gastrointestinal symptom such as nausea and vomiting is not well-recognized adverse effect of hydrocortisone.Case descriptionA 64-year-old-woman was referred to our hospital because of frequent severe hypoglycemia. She was diagnosed as type 2 diabetes when she was 58 years old but had not been treated since she was 60. We ruled out the possibility of exogenous administration of insulin or other anti-diabetic drugs, insulinoma and insulin autoimmune syndrome. After glucose injection, she once became conscious, but severe hypoglycemia was often observed even after that. In addition, counter-regulatory hormone levels were not increased even at the time of hypoglycemia. We conducted several hormone load tests. In corticotropin-releasing hormone (CRH) load test, excess and delayed reaction of ACTH was observed. In thyrotropin-releasing hormone (TRH) load test, TSH and prolactin were normally secreted in response to TRH. In luteinizing hormone-releasing hormone (LHRH) load test, delayed reaction of LH and FSH was observed. Based on such hormone loading tests, we diagnosed this patient as idiopathic hypothalamic hypopituitarism and consequent adrenal deficiency. We immediately intravenously injected hydrocortisone and started oral hydrocortisone therapy. However, just after taking hydrocortisone, vomiting was often observed which disturbed sufficient steroid hormone replacement, leading to recurrent hypoglycemia. Therefore, we stopped hydrocortisone and instead started an alternative treatment with prednisolone. After that, vomiting and hypoglycemia were not observed at all.Discussion and EvaluationWe diagnosed this subject as hypothalamic hypopituitarism mainly by the following two findings: (1) excess and delayed reaction of ACTH in CRH load test, (2) delayed reaction of LH and FSH in LHRH load test.ConclusionsWe should be aware of the possibility of hypothalamic hypopituitarism as a cause of recurrent severe hypoglycemia. Also, we should be aware that hydrocortisone could induce gastrointestinal symptom and that in such a case we should stop hydrocortisone and start prednisolone to sufficiently replace steroid hormone and avoid recurrent hypoglycemia.

18 F-fluorodeoxyglucose uptake in brown adipose tissue during insulin-induced hypoglycemia and mild cold exposure in non-diabetic adults

ObjectiveHypoglycemia is associated with increased heat production and, despite of this, hypothermia. Heat production is likely to be mediated by sympathetic innervation. Brown adipose tissue is activated by cold exposure and stimulated by the sympathetic nervous system. We therefore examined the effect of hypoglycemia on uptake of the labeled glucose analogue 18F-fluorodeoxyglucose in brown adipose tissue using positron emission tomography and computer tomography. MethodsIn nine healthy adults 18F-fluorodeoxyglucose uptake as measure of brown adipose tissue activity was assessed in a cold environment (17°C) during euglycemia (blood glucose 4.5mmol/L) and hypoglycemia (2.5mmol/L) using a hyperinsulinemic glucose clamp. ResultsBrown adipose tissue activity was observed in all participants. No difference was observed in the median (range) maximal standardized uptake values of 18F-fluorodeoxyglucose in brown adipose tissue between euglycemia and hypoglycemia: 4.2 (1.0–7.7) versus 3.1 (2.2–12.5) g/mL (p=0.7). Similarly there were no differences in mean standardized 18F-fluorodeoxyglucose uptake values or total brown adipose tissue volume between euglycemia and hypoglycemia. Body temperature dropped by 0.6°C from baseline during the hypoglycemic condition and remained unchanged during the euglycemic condition. There was no correlation between the maximal standardized uptake values of 18F-fluorodeoxyglucose in brown adipose tissue and levels of counterregulatory hormones. ConclusionsThis study shows that there is a similar amount of 18F-fluorodeoxyglucose uptake in brown adipose tissue during hypoglycemia when compared to euglycemia, which makes a role for systemic catecholamines in brown adipose tissue activation and a role for brown adipose tissue thermogenesis in hypoglycemia associated hypothermia unlikely. Future studies in humans should determine whether hypoglycemia indeed increases energy expenditure, and if so which alternative source can explain this increase.

Reducing the impact of insulin sensitivity variability on glycaemic outcomes using separate stochastic models within the STAR glycaemic protocol.

BackgroundThe metabolism of critically ill patients evolves dynamically over time. Post critical insult, levels of counter-regulatory hormones are significantly elevated, but decrease rapidly over the first 12–48 hours in the intensive care unit (ICU). These hormones have a direct physiological impact on insulin sensitivity (SI). Understanding the variability of SI is important for safely managing glycaemic levels and understanding the evolution of patient condition. The objective of this study is to assess the evolution of SI over the first two days of ICU stay, and using this data, propose a separate stochastic model to reduce the impact of SI variability during glycaemic control using the STAR glycaemic control protocol.MethodsThe value of SI was identified hourly for each patient using a validated physiological model. Variability of SI was then calculated as the hour-to-hour percentage change in SI. SI was examined using 6 hour blocks of SI to display trends while mitigating the effects of noise. To reduce the impact of SI variability on achieving glycaemic control a new stochastic model for the most variable period, 0–18 hours, was generated. Virtual simulations were conducted using an existing glycaemic control protocol (STAR) to investigate the clinical impact of using this separate stochastic model during this period of increased metabolic variability.ResultsFor the first 18 hours, over 80% of all SI values were less than 0.5 × 10-3 L/mU.min, compared to 65% for >18 hours. Using the new stochastic model for the first 18 hours of ICU stay reduced the number of hypoglycaemic measurements during virtual trials. For time spent below 4.4, 4.0, and 3.0 mmol/L absolute reductions of 1.1%, 0.8% and 0.1% were achieved, respectively. No severe hypoglycaemic events (BG < 2.2 mmol/L) occurred for either case.ConclusionsSI levels increase significantly, while variability decreases during the first 18 hours of a patients stay in ICU. Virtual trials, using a separate stochastic model for this period, demonstrated a reduction in variability and hypoglycaemia during the first 18 hours without adversely affecting the overall level of control. Thus, use of multiple models can reduce the impact of SI variability during model-based glycaemic control.

A Focused Review of the Role of Ketone Bodies in Health and Disease

Ketone bodies are produced in the liver and are utilized in other tissues in the body as an energy source when hypoglycemia occurs in the body. There are three ketone bodies: acetoacetate, beta hydroxy butyrate, and acetone. Ketone bodies are usually present in the blood, and their level increases during fasting and starvation. They are also found in the blood of neonates and pregnant women. In diabetic ketoacidosis, high levels of ketone bodies are produced in response to low insulin levels and high levels of counter-regulatory hormones.