Hypoglycemia‐associated autonomic failure, counterregulatory responses, and therapeutic options in type 1 diabetes

Abstract

Hypoglycemia remains a major barrier to the achievement of target levels of glycemic control for most individuals with insulin-dependent type 1 diabetes (T1D). Both the loss of β cells and an accompanying defect in the α cell response to hypoglycemia predispose patients with T1D to the development of low blood glucose. Increased glucose variability, exposure to hypoglycemia, and impaired awareness of hypoglycemia all contribute to increased risk of experiencing severe hypoglycemia, which is explained by progressive impairment in epinephrine secretion and autonomic symptom generation in response to hypoglycemia leading to defective glucose counterregulation and hypoglycemia unawareness that characterize hypoglycemia-associated autonomic failure (HAAF). Interruption of HAAF requires interfering with the mechanisms of brain adaptation to low blood glucose that affect central glucose sensing and the autonomic response to hypoglycemia, or avoidance of hypoglycemia that may allow for eventual recovery of counterregulatory and autonomic symptom responses. Strategies for hypoglycemia avoidance that include continuous glucose monitoring may reduce, but do not eliminate, clinically significant hypoglycemia, with ongoing counterregulatory defects and impaired awareness of hypoglycemia. Complete avoidance of hypoglycemia can be achieved following pancreatic islet transplantation and allows for the restoration of counterregulatory and autonomic symptom responses that evidences the potential for reversing HAAF in T1D.

Phase 3 trial of human islet-after-kidney transplantation in type 1 diabetes

“…PHPI transplant in kidney transplant recipients proved highly effective at improving and maintaining metabolic control. Median HbA 1c 28 was reduced from baseline levels of 8.1% to 6.0% at 1 year and to 6.3% at both 2 and 3 years following the initial transplant. CIT07 reached HbA 1c levels of 5.6% and 5.8% at 1 and 2 years.…”

Glycogenic hepatopathy following attempted suicide by long‐acting insulin overdose in patient with type 1 diabetes

“…Our patient was alert with stable vital signs and did not present these subjective symptoms during the follow‐up period, although eventually his blood glucose levels dropped lower than 50 mg/dL. Frequent hypoglycemia attenuates the regular sympathoadrenal reaction and adjusts to low plasma glucose level concentration; hypoglycemia‐associated autonomic failure in diabetes causes a lack of impaired awareness resulting from this lowering of the hypoglycemic level threshold 9,10 . Physicians might be able to adjust to a lower dose of glucose while monitoring the patient's symptoms.…”

Role of carnitine in regulation of blood pressure (MAP/SBP) and gene expression of cardiac hypertrophy markers (α/β‐MHC) during insulin‐induced hypoglycaemia: Role of oxidative stress

“…In 20 U InG treated group, BG level (50 mg/dL) was higher in comparison with 15 U InG treated group (42 mg/dL), but the difference wasn't significant ( P = .984). The reason of having higher BG levels in 20 U InG treated group might be referred to the over activation of the counter‐regulatory mechanisms such as regulation of endogenous insulin production, increase of glucagon synthesis, decrease of peripheral glucose metabolism and induction of hepatic gluconeogenesis to resist InG‐induced hypoglycaemia 46 . A significant elevation in systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) was shown at doses (20, 25 U/kg) with regular heart rate (HR) compared with the control group (Figure 2).…”