Insulin-induced Hypoglycemia In Patients Research Articles

Impact of a Hyperkalemia Protocol Tailored to Glucose Concentration and Renal Function on Insulin-Induced Hypoglycemia in Patients with Low Pretreatment Glucose

BackgroundHyperkalemia is a common electrolyte abnormality that requires urgent treatment. Insulin is an effective treatment for hyperkalemia, but risk factors for developing insulin-induced hypoglycemia exist (e.g., low pretreatment glucose or renal impairment). ObjectiveThis study evaluated the impact of a hyperkalemia protocol tailored to glucose concentration and renal function on insulin-induced hypoglycemia. MethodsThis was a retrospective cohort study of emergency department patients with glucose ≤ 100 mg/dL treated with insulin for hyperkalemia. The primary outcome was incidence of hypoglycemia in patients treated prior to (July 1, 2018–June 30, 2019) vs. after (January 1, 2020–December 31, 2020) the protocol update, which individualized insulin and dextrose doses by glucose concentration and renal function. Secondary outcomes included change in potassium and protocol safety. We assessed factors associated with hypoglycemia using multiple logistic regression. ResultsWe included 202 total patients (preimplementation: 114, postimplementation: 88). Initial insulin dose was lower in the postimplementation group (p < 0.001). We found a nonsignificant reduction in hypoglycemia in the postimplementation group (42.1% vs. 30.7%, p = 0.10). Degree of potassium reduction was similar in patients who received insulin 5 units vs. 10 units (p = 0.72). Higher pretreatment glucose (log odds ratio [OR] −0.05, 95% confidence interval [CI] −0.08 to −0.02) and additional insulin administration (log OR −1.55, 95% CI −3.01 to −0.25) were associated with reduced risk of developing hypoglycemia. ConclusionA hyperkalemia protocol update was not associated with a significant reduction in hypoglycemia, and the incidence of hypoglycemia remained higher than anticipated. Future studies attempting to optimize treatment in this high-risk population are warranted.

Dasiglucagon for the Treatment of Insulin-induced Hypoglycemia in Patients with Type 1 Diabetes Mellitus: A Meta-analysis

The use of conventional glucagon for managing insulin-induced hypoglycemia is obscured by its chemical instability and the need for reconstitution of the lyophilized powder, leading to delayed rescue. Dasiglucagon, a glucagon analog, may potentially overcome these shortcomings. To evaluate the efficacy and safety of dasiglucagon in insulin-induced hypoglycemia in patients with type 1 diabetes mellitus (T1DM). Meta-analysis. PubMed/MEDLINE, Scopus, Embase, and Cochrane databases along with clinical trial registries were searched to include data from five randomized controlled trials conducted using dasiglucagon for the treatment of insulin-induced hypoglycemia in T1DM patients published until May 2023. We performed a risk of bias assessment to determine the quality of the included studies and a random-effects model analysis for determining the effect size. Subgroup analysis and meta-regression were done as applicable. The time to recovery (in minutes) with dasiglucagon was earlier than placebo [mean difference (MD): -24.73; 95% confidence interval (CI): -30.94 to -18.52; p < 0.00001) or oral glucose (MD: -15.00; 95% CI: -20.33 to -9.67; p < 0.00001); however, the difference between dasiglucagon and glucagon was not statistically significant (MD: -0.76; 95% CI: -2.19 to 0.66; p = 0.29). Dasiglucagon is safer and more effective than placebo or oral glucose for insulin-induced hypoglycemia in T1DM patients; however, it is not superior to conventional glucagon.

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

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. 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. 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. 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.

Dasiglucagon for treating severe hypoglycemia in patients with diabetes

Introduction Diabetic patients are prone to hypoglycemia when treated with insulin. Dasiglucagon is a water-soluble and ready-to-use glucagon analog developed for treating hypoglycemia in patients with diabetes. Areas covered A comprehensive literature search was conducted in PubMed. Key search terms included dasiglucagon and hypoglycemia. The pharmacological characteristics, clinical evidence, and place in therapy of dasiglucagon were reviewed. Expert opinion Dasiglucagon is a glucagon analogue that is stable in water-soluble formulation. It can increase plasma glucose in a dose-dependent manner. Clinical studies have shown that dasiglucagon rapidly and effectively increased insulin-induced hypoglycemia in patients with diabetes. Dasiglucagon was well tolerated and the common adverse events included nausea and vomiting.

C-peptide enhances glucagon secretion in response to hyperinsulinemia under euglycemic and hypoglycemic conditions.

Several studies have associated the presence of residual insulin secretion capability (also referred to as being C-peptide positive) with lower risk of insulin-induced hypoglycemia in patients with type 1 diabetes (T1D), although the reason is unclear. We tested the hypothesis that C-peptide infusion would enhance glucagon secretion in response to hyperinsulinemia during euglycemic and hypoglycemic conditions in dogs (5 male/4 female). After a 2-hour basal period, an intravenous (IV) infusion of insulin was started, and dextrose was infused to maintain euglycemia for 2 hours. At the same time, an IV infusion of either saline (SAL) or C-peptide (CPEP) was started. After this euglycemic period, the insulin and SAL/CPEP infusions were continued for another 2 hours, but the glucose was allowed to fall to approximately 50 mg/dL. In response to euglycemic-hyperinsulinemia, glucagon secretion decreased in SAL but remained unchanged from the basal period in CPEP condition. During hypoglycemia, glucagon secretion in CPEP was 2 times higher than SAL, and this increased net hepatic glucose output and reduced the amount of exogenous glucose required to maintain glycemia. These data suggest that the presence of C-peptide during IV insulin infusion can preserve glucagon secretion during euglycemia and enhance it during hypoglycemia, which could explain why T1D patients with residual insulin secretion are less susceptible to hypoglycemia.

351-OR: Six-Day Subcutaneous GIP Infusion Increases Glycemic Time-in-Range in Patients with Type 1 Diabetes

The glucagonotropic effect of glucose-dependent insulinotropic polypeptide (GIP) during insulin-induced hypoglycemia in patients with type 1 diabetes (T1D) prompted us to investigate the effect of a 6-day subcutaneous (sc) GIP infusion on glucose variability in patients with T1D. In a randomized, placebo-controlled, double-blinded, crossover study, 20 men with T1D (age [mean± SD] 26±8 years, BMI 23.8±1.8 kg/m2, HbA1c 51±10 mmol/mol), underwent 2 × 6 days of continuous sc GIP (6 pmol/kg/min) and placebo (saline) infusion, respectively, with an interposed 7-day washout period. Participants wore a continuous glucose monitoring system. GIP significantly increased daytime time in range (3.9-7.8 mmol/L) by [mean±SEM] 104±69 min/day (P=0.035) without statistically significant effects on time below range (&amp;lt;3.9 mmol/L), time above range (&amp;gt;10.1 mmol/L), mean glucose or hypoglycemic events. Compared to placebo, GIP increased hepatic fat content by 12.6±4.2 percentage points (assessed by FibroScan®) (P=0.006), decreased 24-hour systolic and diastolic blood pressure by 4.6±2.8 (P=0.001) and 2.6±1.3 mmHg (P=0.028), respectively, and increased heart rate by 4.4±2.0 beats per minute (P=0.002) (Figure). Compared to placebo, a 6-day sc GIP infusion in patients with T1D increased glycemic time in range and hepatic fat content and reduced systolic and diastolic blood pressure while increasing heart rate. Disclosure S.M. Nguyen Heimbürger: None. B. Hoe: None. C.N. Nielsen: None. N.C. Bergmann: Employee; Self; Zealand Pharma A/S. B. Hartmann: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. J. Størling: None. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp &amp; Dohme Corp., Sanofi. T.F. Dejgaard: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. M.B. Christensen: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, Merck Sharp &amp; Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Consultant; Self; Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Gubra, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Lupin Pharmaceuticals, Inc., Merck Sharp &amp; Dohme Corp., Norgine B.V., Novo Nordisk A/S. Funding The Leona M. and Harry B. Helmsley Charitable Trust (2018PG-T1D037)

22-OR: Nasal Glucagon: A Viable Alternative to Treat Insulin-Induced Hypoglycemia in Japanese Patients with Type 1 and Type 2 Diabetes

Background/Objective: Currently available glucagon products for rescue treatment of severe hypoglycemia require cumbersome multistep reconstitution and injection procedures in an emergency situation. Nasal glucagon (NG) is a nasally administered, single-use, drug-device combination containing 3 mg glucagon dry powder. We aimed to evaluate noninferiority of NG to intramuscular glucagon (IMG) for treatment of insulin-induced hypoglycemia in patients with type 1 and type 2 diabetes (T1D/T2D) (NCT03421379). Methods: This was a randomized, two-period, crossover trial with NG and IMG. Hypoglycemia was induced by an intravenous insulin infusion; insulin was stopped once plasma glucose (PG) reached &amp;lt;60 mg/dL. Approximately 5 minutes (min) after stopping insulin either 3 mg NG or 1 mg IMG was administered followed by PG measurements up to 4 hours. Treatment success was defined as an increase in PG to ≥70 mg/dL or an increase of ≥20 mg/dL from the PG nadir within 30 min after receiving glucagon. Spontaneously reported adverse events (AEs) and a Nasal and Non-Nasal Symptom Questionnaire (NNSQ) assessed local tolerability of NG. Results: Of the 68 evaluable patients (T1D 32, T2D 36) who received both NG and IMG, all patients achieved treatment success with a mean time of 12.0 min (NG) and 11.0 min (IMG). Noninferiority of NG to IMG was demonstrated. PG responses were similar between T1D and T2D. During the treatment period 26 treatment-emergent AEs (TEAEs) occurred with NG and 13 with IMG. Most TEAEs were mild in severity and none was severe. TEAEs with an incidence ≥5% were rhinalgia (NG 8.5%, IMG 0%), nausea (NG 5.6%, IMG 11.4%), and blood pressure increase (NG 5.6%, IMG 0%). With NG, very common (≥10%) symptoms from NNSQ were watery eyes and nasal congestion. Conclusion: NG was noninferior compared to IMG for the treatment of insulin-induced hypoglycemia in Japanese patients with T1D/T2D supporting the use of NG as a rescue treatment for severe hypoglycemia. Disclosure M. Matsuhisa: Advisory Panel; Self; Eli Lilly and Company. Board Member; Self; Daiichi Sankyo Company, Limited. Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Astellas Pharma Inc., Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. Y. Takita: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. R. Nasu: None. K. Ohwaki: Employee; Self; Eli Lilly and Company. H. Nagashima: None.

Pharmacokinetic and Pharmacodynamic Characteristics of Dasiglucagon, a Novel Soluble and Stable Glucagon Analog.

Treatment of severe hypoglycemia outside of the hospital setting is limited to glucagon formulations requiring reconstitution before use, which may lead to erroneous or delayed glucagon administration. We compared the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics and safety and tolerability of different doses of dasiglucagon, a novel soluble glucagon analog, with approved pediatric and full doses of GlucaGen in insulin-induced hypoglycemia in patients with type 1 diabetes. In this single-center, randomized, double-blind trial, 58 patients with type 1 diabetes received single subcutaneous injections of 0.1, 0.3, 0.6, or 1.0 mg dasiglucagon or 0.5 or 1.0 mg GlucaGen in a state of hypoglycemia (blood glucose target 55 mg/dL) induced by an intravenous insulin infusion. Dasiglucagon demonstrated a dose-dependent and rapid increase in plasma concentrations, reaching a maximum at ∼35 min with a half-life of ∼0.5 h. Dasiglucagon rapidly increased plasma glucose (PG) by ≥20 mg/dL (9-14 min) to PG ≥70 mg/dL (within 6-10 min), similar to GlucaGen, but with a longer-lasting and greater effect on PG. All patients on both treatments reached these end points within 30 min (predefined success criteria). Both treatments were well tolerated. Nausea was the most frequent adverse event, occurring at a similar rate (44-56%). Dasiglucagon was well tolerated and showed an early PD response similar to that of GlucaGen at corresponding doses, suggesting comparable clinical effects of the two glucagon formulations. Dasiglucagon has the potential to become an effective and reliable rescue treatment for severe hypoglycemia in a ready-to-use pen.

Platelet aggregation and physiological anticoagulants in acute insulin-induced hypoglycemia in patients with type 1 diabetes (DM1)

Platelet aggregation and physiological anticoagulants in acute insulin-induced hypoglycemia in patients with type 1 diabetes (DM1)

Glucose-dependent insulinotropic polypeptide augments glucagon responses to hypoglycemia in type 1 diabetes.

Glucose-dependent insulinotropic polypeptide (GIP) is glucagonotropic, and glucagon-like peptide-1 (GLP-1) is glucagonostatic. We studied the effects of GIP and GLP-1 on glucagon responses to insulin-induced hypoglycemia in patients with type 1 diabetes mellitus (T1DM). Ten male subjects with T1DM (C-peptide negative, age [mean ± SEM] 26 ± 1 years, BMI 24 ± 0.5 kg/m(2), HbA1c 7.3 ± 0.2%) were studied in a randomized, double-blinded, crossover study, with 2-h intravenous administration of saline, GIP, or GLP-1. The first hour, plasma glucose was lowered by insulin infusion, and the second hour constituted a "recovery phase." During the recovery phase, GIP infusions elicited larger glucagon responses (164 ± 50 [GIP] vs. 23 ± 25 [GLP-1] vs. 17 ± 46 [saline] min ⋅ pmol/L, P < 0.03) and endogenous glucose production was higher with GIP and lower with GLP-1 compared with saline (P < 0.02). On the GIP days, significantly less exogenous glucose was needed to keep plasma glucose above 2 mmol/L (155 ± 36 [GIP] vs. 232 ± 40 [GLP-1] vs. 212 ± 56 [saline] mg ⋅ kg(-1), P < 0.05). Levels of insulin, cortisol, growth hormone, and noradrenaline, as well as hypoglycemic symptoms and cognitive function, were similar on all days. Our results suggest that during hypoglycemia in patients with T1DM, exogenous GIP increases glucagon responses during the recovery phase after hypoglycemia and reduces the need for glucose administration.

Concentrations of the Stress Hormone Copeptin Increase upon Hypoglycaemia in Patients with Type 1 Diabetes Dependent of Hypoglycaemia Awareness

ObjectiveCopeptin, a marker for stress mirroring vasopressin concentrations, has been shown to increase upon insulin-induced hypoglycaemia in patients after transsphenoidal surgery of pituitary adenomas. Patients with type 1 diabetes mellitus are prone to hypoglycaemia, but no data about copeptin levels upon hypoglycaemia are available. Furthermore, the perception of hypoglycaemia can vary from total unawareness to disabling episodes. The aim of this study was to investigate whether copeptin increases upon hypoglycaemia in patients with type 1 diabetes mellitus and is associated with the degree of hypoglycaemia awareness.Materials and MethodsIn this prospective observational study, 17 patients with type 1 diabetes underwent a standardized insulin infusion test. Blood sampling for glucose and copeptin was performed at baseline and after 60 minutes (min). To assess hypoglycaemia associated symptoms the Mood and Symptom Questionnaire (MSQ) was conducted at baseline and after 60 min.ResultsDuring insulin infusion, blood glucose decreased from 5.1 (SD±0.2) to 3.0 (±0.5) mmol/L at 60 min (p<0.001). Copeptin concentrations increased from 3.2 (±1.7) to 3.8 (±1.9) pmol/L (p = 0.03). Mood and Symptoms Questionnaire scores increased from 14 (±3.0) to 18 (±5.8), (p = 0.006). Patients with good hypoglycaemia awareness had an increase in copeptin from 3.0 (±1.8) to 4.2 (±2.4) pmol/L (p = 0.03) in contrast to patients more unaware of hypoglycaemia who only showed an increase in copeptin from 3.3 (±1.6) to 3.6 (±1.4) pmol/L (p = 0.4). There was a trend to a larger copeptin increase in patients aware of hypoglycemia compared to patients unaware of hypoglycemia (p = 0.074).ConclusionCopeptin increases in patients with type 1 diabetes upon insulin induced hypoglycaemia. Interestingly, the copeptin increase seems associated with the degree of hypoglycaemia awareness. This hypothesis warrants further verification.Trial RegistrationClinicalTrials.gov NCT00515801

慢性膵炎における低血糖刺激時の各種ホルモン分泌動態 特にグルカゴン, コーチゾール, 成長ホルモン分泌能を中心にして

慢性膵炎における低血糖刺激時の各種ホルモン分泌動態 特にグルカゴン, コーチゾール, 成長ホルモン分泌能を中心にして

The Effect of Glycemic Variability on Counterregulatory Hormone Responses to Hypoglycemia in Young Children and Adolescents with Type 1 Diabetes

Glycemic variability (GV) is associated with hypoglycemia and possibly diabetes-related outcomes. We hypothesized that GV and glucose excursion risk may predict counterregulatory (CR) hormone responses to hypoglycemia. This is a secondary analysis of a Diabetes Research in Children Network study containing continuous interstitial glucose monitoring records for 28 patients with type 1 diabetes between 3 to <8 or 12 to <18 years of age. GV and excursion measures, including continuous overall net glycemic action (CONGA), High Blood Glucose Index (HBGI), Low Blood Glucose Index (LBGI), and coefficient of variation (CV), were calculated 72 h prior to insulin-induced hypoglycemia. CR hormones were measured during the progressive fall in plasma glucose. CV was inversely correlated with change in glucagon concentration (r=-0.41, P=0.046), but CONGA (log-transformed for better fit of the models) was not statistically significant in univariate analysis (r=-0.34, P=0.10). Other CR hormones were not significantly associated with measures of variability. In multivariate analysis, higher CONGA, but not CV, was associated with a smaller rise in glucagon following induced hypoglycemia (estimate=-9.73, P=0.048), independent of hemoglobin A1c, duration of diabetes, and insulin dose. HBGI, LBGI, and antecedent time spent in hypoglycemia were not significantly correlated with CR response to subsequent hypoglycemia. CV and CONGA may be predictors of impaired glucagon responses to insulin-induced hypoglycemia in patients with type 1 diabetes. Further study is indicated to characterize the role of GV and glycemic excursions on the defensive response to hypoglycemia.

Concordant and discordant adrenocorticotropin (ACTH) responses induced by growth hormone-releasing peptide-2 (GHRP-2), corticotropin-releasing hormone (CRH) and insulin-induced hypoglycemia in patients with hypothalamopituitary disorders: evidence for direct ACTH releasing activity of GHRP-2

The insulin-induced hypoglycemia test (insulin tolerance test: ITT) and corticotropin-releasing hormone (CRH) test are used to examine the activities of the hypothalamo-pituitary-adrenal (HPA) axis. Growth hormone-releasing peptide-2 (GHRP-2), a potent GH secretagogue, also stimulates adrenocorticotropin (ACTH) secretion. To evaluate the role of GHRP-2 in assessing the HPA axis, we examined 6 patients with various hypothalamo-pituitary disorders, and measured ACTH and cortisol responses during provocative tests (ITT, CRH, and GHRP-2 test). None of the 6 patients showed any significant ACTH or cortisol responses to ITT, but significant ACTH release was observed during CRH and GHRP-2 tests. These findings suggest GHRP-2 may directly stimulate ACTH secretion in patients with hypothalamo-pituitary disorders.

Reduced epinephrine reserve in response to insulin-induced hypoglycemia in patients with pituitary adenoma

Hypoglycemia induces rapid secretion of counterregulatory hormones such as catecholamine, glucagon, cortisol, and GH. Insulin-induced hypoglycemia is used for evaluating GH-IGF-I and ACTH-adrenal axes in patients with pituitary disorders. The aim of this study was to determine whether the response of catecholamine secretion to hypoglycemia is disrupted in patients with pituitary adenoma. The study population comprised 23 patients with pituitary adenoma (non-functioning adenoma or prolactinoma). An insulin tolerance test was performed and serum catecholamines as well as plasma GH and serum cortisol were measured. The study patients showed diminished response of plasma epinephrine to insulin-induced hypoglycemia. With the cutoff level of peak epinephrine for defining severe impairment set at 400 pg/ml, more patients with secondary adrenal insufficiency showed severe impairment of the epinephrine response than did those without it. Peak epinephrine levels to insulin-induced hypoglycemia were significantly correlated with peak cortisol levels. In patients with secondary hypothyroidism, secondary hypogonadism, GH deficiency, or diabetes insipidus, the prevalence of severe impairment of the epinephrine response was similar to that in patients without these deficiencies. Impaired epinephrine secretion in response to insulin-induced hypoglycemia was frequently observed in patients with pituitary adenoma. This disorder was especially severe in patients with secondary adrenal insufficiency.

Hypothalamic-pituitary-adrenal axis activity in patients with active rheumatoid arthritis: a controlled study using insulin hypoglycemia stress test

Aim: To study the response of cortisol to insulin-induced hypoglycemia in patients with active rheumatoid arthritis (RA). Methods: We measured the response of cortisol to insulin-induced hypoglycemia (0.15 µ/kg) in 10 patients (6 female, 4 male) with active RA and 10 (6 female, 4 male) healthy controls. All patients had never received glucocorticoids before the study. The cortisol concentration was assessed by radioimmunoassay. Results: The mean age was 47.3 years (± 14.2 years) in patients and 43.5 years (± 10.6 years) in control subjects. The mean disease duration was 66.3 months (range 12–120). The basal serum levels of cortisol in patients with RA were not significantly different from those of controls. Although the mean serum cortisol levels after insulin-induced hypoglycemia were lower in patients with RA than controls in all samples, the significant difference was seen only in the samples 60 min after insulin injection (18.59 vs. 24.28 µg/dL, P = 0.041). Conclusion: Our findings suggest that active RA is associated with dysfunction of the hypothalamic–pituitary-adrenal axis.

Somatotropic, lactotropic and adrenocortical responses to insulin-induced hypoglycemia in patients with rheumatoid arthritis.

Neuroendocrine mechanisms have been suggested to play an important role in the onset and progression of rheumatoid arthritis (RA). The aim of this study was to evaluate hypothalamic-pituitary functions in RA patients by measurement of hormone responses to insulin-induced hypoglycemia. Insulin-hypoglycemia (Actrapid HM 0.1 IU/kg, i.v. as a bolus) was induced in 17 male patients and in 11 age-, gender-, and weight-matched healthy subjects. Concentrations of growth hormone (GH), prolactin (PRL) and cortisol were analyzed in plasma. PRL release after thyreoliberin stimulation (TRH, 200 g, i.v.) was determined in 21 patients with active forms of RA and in 12 control subjects to evaluate pituitary lactotropic response. In RA patients, basal concentrations of glucose, GH, PRL, and cortisol were in the normal range and they were comparable to those in the control group. Stress of hypoglycemia induced significant elevation of GH, PRL, and cortisol concentrations in all groups. Cortisol responses to hypoglycemia were comparable in patients and in control subjects. GH release during hypoglycemia was increased (p < 0.05) and PRL response was attenuated (p < 0.05) in RA patients versus control subjects. After TRH administration, PRL response was the same in patients as in healthy subjects. In conclusion, the present study revealed an altered hypothalamic-pituitary function in patients with RA, namely, an enhanced somatotropic and reduced lactotropic activation in response to insulin-induced hypoglycemia. Basal hormone levels and cortisol release during hypoglycemia were similar to those in healthy subjects.

Oral glibenclamide suppresses glucagon secretion during insulin-induced hypoglycemia in patients with type 2 diabetes.

Intensifying pharmacological therapy in patients with type 2 diabetes increases the risk of hypoglycemia and often requires the simultaneous use of more than one agent. Combining insulin and sulfonylurea is an effective and frequently used therapy in such patients. However, sulfonylurea derivatives have been shown to affect the release of glucagon, indicating a possible effect of such therapy on hormonal counterregulation to hypoglycemia. Thirteen patients receiving combined therapy were studied on two occasions: 1) after a wash-out period of glibenclamide (-GLIB), and 2) after resuming combined treatment for 6 months (+GLIB). We performed nonstep-wise, hyperinsulinemic hypoglycemic clamps using a constant i.v. insulin infusion and clamping blood glucose at 2.7 mmol/L (48 mg/dL) for 60 min. C Peptide levels were significantly higher during + GLIB, but no significant differences were seen in peripheral plasma insulin levels (+GLIB mean +/- SD, 70 +/- 17 mU/L vs. -GLIB, 75 +/- 14; P = 0.26). Epinephrine responses were similar in the two tests, but when glibenclamide was present the glucagon response was smaller, both the peak value (P = 0.016) and the incremental area under the curve (P = 0.011) as well as the total area under the curve (P = 0.016). These results suggest that intraislet insulin secretion is of importance for the alpha-cell responsiveness to hypoglycemia in these patients.

Oral Glibenclamide Suppresses Glucagon Secretion during Insulin-Induced Hypoglycemia in Patients with Type 2 Diabetes

Oral Glibenclamide Suppresses Glucagon Secretion during Insulin-Induced Hypoglycemia in Patients with Type 2 Diabetes

Normal Short Synacthen Test in Patients with Secondary Adrenal Failure

The short synacthen test (SST), first introduced by Wood et al. 1 in 1965, is widely used to confirm the diagnosis of primary adrenal insufficiency. The optimum method for the diagnosis of secondary adrenal insufficiency remains controversial. The insulin tolerance test (ITT) is accepted by most endocrinologists as the gold standard 2 for the assessment of the hypothalamic-pituitary-adrenal (HPA) axis, but is hazardous at times, with some morbidity and occasional mortality. The short synacthen test is gaining popularity, and by 1994, up to 50% of UK endocrinologists were using it to assess the HPA axis. 3 We describe two cases presenting with hyponatremia in whom hypoadrenalism was suspected, but with normal SST. The secondary adrenal insufficiency was later confirmed in these cases on clinical features, associated hormonal deficiencies, ancillary investigations and most important of all, the therapeutic response to replacement steroids. Case 1 A 63-year-old male presented with a history of six to seven episodes of fainting/loss of consciousness over the previous year-and-a-half. These episodes were never preceded by any palpitations or associated with seizure activity and/or incontinence of urine or feces. He also experienced occasional nausea with vomiting. He was labelled to have ischemic heart disease on the basis of ECG changes, but did not have angina and was taking diltiazem, moduretic (amiloride and hydrochlorothiazide), ranitidine and amitriptyline regularly. He appeared unwell upon admission, and was pale-looking, with a pulse of 90/min. His blood pressure was in the range of 120-140 mm Hg systolic and 70 mm Hg diastolic, but with a significant postural drop of 20 mm Hg. The rest of the examination was unremarkable. Routine investigations revealed serum sodium of 112 mmol/L, potassium of 3.3 mmol/L, and creatinine of 1.0 mg/dL. It was thought that electrolyte imbalance was due to diuretics and associated vomiting. He was rehydrated with normal saline and the