Effect of lactate administration on cerebral blood flow during hypoglycemia in people with type 1 diabetes

Introduction Impaired awareness of hypoglycemia, clinically reflected by the inability to timely detect hypoglycemia, affects approximately 25% of the people with type 1 diabetes. Both altered brain lactate handling and increased cerebral blood flow (CBF) during hypoglycemia appear to be involved in the pathogenesis of impaired awareness of hypoglycemia. Here we examine the effect of lactate on CBF during hypoglycemia. Research design and methods Nine people with type 1 diabetes and normal awareness of hypoglycemia underwent two hyperinsulinemic euglycemic-hypoglycemic (3.0 mmol/L) glucose clamps in a 3T MR system, once with sodium lactate infusion and once with sodium chloride infusion. Global and regional changes in CBF were determined using pseudocontinuous arterial spin labeling. Results Lactate (3.3±0.6 vs 0.9±0.2 mmol/L during lactate infusion vs placebo infusion, respectively) suppressed the counter-regulatory hormone responses to hypoglycemia. Global CBF increased considerably in response to intravenous lactate infusion but did not further increase during hypoglycemia. Lactate also blunted the hypoglycemia-induced regional redistribution of CBF towards the thalamus. Conclusions Elevated lactate levels enhance global CBF and blunt the thalamic CBF response during hypoglycemia in patients with type 1 diabetes, mimicking observations of impaired awareness of hypoglycemia. These findings suggest that alteration of CBF associated with lactate may play a role in some aspects of the development of impaired awareness of hypoglycemia. Trial registration number NCT03730909

High prevalence of impaired awareness of hypoglycemia and severe hypoglycemia among people with insulin-treated type 2 diabetes: The Dutch Diabetes Pearl Cohort

Objective People with type 2 diabetes on insulin are at risk for hypoglycemia. Recurrent hypoglycemia can cause impaired awareness of hypoglycemia (IAH), and increase the risk for severe hypoglycemia. The aim of this study was to assess the prevalence and determinants of self-reported IAH and severe hypoglycemia in a Dutch nationwide cohort of people with insulin-treated type 2 diabetes. Research design and methods Observational study of The Dutch Diabetes Pearl, a cohort of people with type 2 diabetes treated in primary, secondary and tertiary diabetes care centers. The presence of IAH and the occurrence of severe hypoglycemia in the past year, defined as an event requiring external help to re

Effect of short-term use of dapagliflozin on impaired awareness of hypoglycaemia in people with type 1 diabetes

Item does not contain fulltextAIM: Impaired awareness of hypoglycaemia (IAH) affects about 25% of patients with type 1 diabetes (T1DM). IAH can be reversed by strict avoidance of hypoglycaemia for at least 3 weeks. Adjunctive treatment with sodium glucose cotransporter 2 inhibitors may reduce the risk of hypoglycaemia through reduction of glucose variability. We tested the hypothesis that short-term use of dapagliflozin may improve awareness of hypoglycaemia in people with T1DM and IAH. MATERIALS AND METHODS: Fifteen patients with T1DM and IAH were included in this randomized double-blind, placebo-controlled cross-over trial (age 49.7 ± 14.6 years, 40% men, disease duration 24.1 ± 14.2 years, glycated haemoglobin 7.5 ± 0.8% (58.6 ± 8.4 mmol/mol). They were treated with dapagliflozin 10 mg once daily or matching placebo, with a washout period of 2 weeks. At the end of each treatment period, participants underwent a modified hyperinsulinaemic normoglycaemic-hypoglycaemic glucose clamp (glucose nadir 2.5 mmol/L). Blinded continuous glucose monitors were used in the final treatment weeks. RESULTS: Treatment with dapagliflozin significantly improved glycated haemoglobin [-0.32 ± 0.10 vs. 0.22 ± 0.13% (-4.1 ± 0.9 vs. 2.3 ± 1.4 mmol/mol), dapagliflozin vs. placebo, p = .007] and glucose variability (standard deviation, 2.6 ± 0.2 vs. 3.1 ± 0.3 mmol/L, p = .029), but did not affect the frequency of hypoglycaemia. During the hypoglycaemic clamp, dapagliflozin did not affect symptom responses (8.0 ± 3.4 vs. 5.2 ± 1.6, p = .31), but significantly reduced the need for exogenous glucose to maintain hypoglycaemia (3.2 ± 0.3 vs. 4.1 ± 0.4 mg/kg/min, p = .022). CONCLUSIONS: Eight weeks of treatment with dapagliflozin did not restore hypoglycaemic awareness in people with T1DM and impaired awareness of hypoglycaemia, but ameliorated some clinical aspects

Effect of short-term use of dapagliflozin on impaired awareness of hypoglycaemia in people with type 1 diabetes

Aim Impaired awareness of hypoglycaemia (IAH) affects about 25% of patients with type 1 diabetes (T1DM). IAH can be reversed by strict avoidance of hypoglycaemia for at least 3 weeks. Adjunctive treatment with sodium glucose cotransporter 2 inhibitors may reduce the risk of hypoglycaemia through reduction of glucose variability. We tested the hypothesis that short-term use of dapagliflozin may improve awareness of hypoglycaemia in people with T1DM and IAH. Materials and Methods Fifteen patients with T1DM and IAH were included in this randomized double-blind, placebo-controlled cross-over trial (age 49.7 +/- 14.6 years, 40% men, disease duration 24.1 +/- 14.2 years, glycated haemoglobin 7.5 +/- 0.8% (58.6 +/- 8.4 mmol/mol). They were treated with dapagliflozin 10 mg once daily or matching placebo, with a washout period of 2 weeks. At the end of each treatment period, participants underwent a modified hyperinsulinaemic normoglycaemic-hypoglycaemic glucose clamp (glucose nadir 2.5 mmol/L). Blinded continuous glucose monitors were used in the final treatment weeks. Results Treatment with dapagliflozin significantly improved glycated haemoglobin [-0.32 +/- 0.10 vs. 0.22 +/- 0.13% (-4.1 +/- 0.9 vs. 2.3 +/- 1.4 mmol/mol), dapagliflozin vs. placebo, p = .007] and glucose variability (standard deviation, 2.6 +/- 0.2 vs. 3.1 +/- 0.3 mmol/L, p = .029), but did not affect the frequency of hypoglycaemia. During the hypoglycaemic clamp, dapagliflozin did not affect symptom responses (8.0 +/- 3.4 vs. 5.2 +/- 1.6, p = .31), but significantly reduced the need for exogenous glucose to maintain hypoglycaemia (3.2 +/- 0.3 vs. 4.1 +/- 0.4 mg/kg/min, p = .022). Conclusions Eight weeks of treatment with dapagliflozin did not restore hypoglycaemic awareness in people with T1DM and impaired awareness of hypoglycaemia, but ameliorated some clinical aspects

Effect of Hypoglycemia on Heart Rate Variability in People with Type 1 Diabetes and Impaired Awareness of Hypoglycemia

BACKGROUND: People with impaired awareness of hypoglycemia (IAH) are at elevated risk of severe, potentially hazardous, hypoglycemia and would benefit from a device alerting to hypoglycemia. Heart rate variability (HRV) changes with hypoglycemia due to sympathetic activity. Since IAH is associated with suppressed sympathetic activity, we investigated whether hypoglycemia elicits a measurable change in HRV in patients with T1D and IAH. METHOD: Eligible participants underwent a modified hyperinsulinemic euglycemic hypoglycemic clamp (glucose nadir, 43.1 ± 0.90 mg/dl), while HRV was measured by a VitalConnect HealthPatch. Measurements of HRV included Root Mean Square of the Successive Differences (RMSSD) and low to high frequency (LF:HF) ratio. Wilcoxon rank-sum test was used for testing within-subject HRV changes. RESULTS: We included 12 participants (8 female, mean age 57 ± 12 years, mean HbA1c 57 ± 5 mmol/mol (7.4 ± 0.4%)). Symptoms increased from 4.0 (1.5-7.0) at euglycemia to 7.5 (5.0-11.0) during hypoglycemia (P = .003). In response to hypoglycemia, the LF:HF ratio and RMSSD increased when normalized for data obtained during euglycemia (both P < .01). The LF:HF ratio increased in 6 participants (50%) and declined in one other participant (8%). The RMSSD decreased in 3 (25%) and increased in 4 (33%) participants. In 2 patients, no change in HRV could be detected in response to hypoglycemia. CONCLUSIONS: This study reveals that hypoglycemia-induced changes in HRV are retained in the majority of people with T1D and IAH, and that these changes can be detected by a wearable device. Real-time HRV seems usable for detection of hypoglycemia in patients with IAH

High prevalence of impaired awareness of hypoglycemia and severe hypoglycemia among people with insulin-treated type 2 diabetes:The Dutch Diabetes Pearl Cohort

Objective People with type 2 diabetes on insulin are at risk for hypoglycemia. Recurrent hypoglycemia can cause impaired awareness of hypoglycemia (IAH), and increase the risk for severe hypoglycemia. The aim of this study was to assess the prevalence and determinants of self-reported IAH and severe hypoglycemia in a Dutch nationwide cohort of people with insulin-treated type 2 diabetes. Research design and methods Observational study of The Dutch Diabetes Pearl, a cohort of people with type 2 diabetes treated in primary, secondary and tertiary diabetes care centers. The presence of IAH and the occurrence of severe hypoglycemia in the past year, defined as an event requiring external help to recover, were assessed using the validated Dutch version of the Clarke questionnaire. In addition, clinical variables were collected including age, diabetes duration, hemoglobin A1c, ethnicity and education. Results 2350 people with type 2 diabetes on insulin were included: 59.1% men, mean age 61.1±10.4 years, mean diabetes duration 14.8±9.2 years and 79.5% on basal-bolus therapy. A total of 229 patients (9.7%) were classified as having IAH and 742 patients (31.6%) reported severe hypoglycemia. Increased odds for IAH were found with complex insulin regimens and lower odds with having a partner and body mass index ≥30 kg/m 2. Severe hypoglycemia was associated with complex insulin regimens, non-Caucasian ethnicity and use of psychoactive drugs, and inversely with metformin use. Conclusions In this nationwide cohort, almost one out of ten people with type 2 diabetes on insulin had IAH and >30% had a history of severe hypoglycemia in the past year