Simon J. Fisher

In order to achieve optimal glycemic control, intensive insulin regimes are needed for individuals with Type 1 Diabetes (T1D) and insulin-dependent Type 2 Diabetes (T2D). Unfortunately, intensive glycemic control often results in insulin-induced hypoglycemia. Moreover, recurrent episodes of hypoglycemia result in both the loss of the characteristic warning symptoms associated with hypoglycemia and an attenuated counterregulatory hormone responses. The blunting of warning symptoms is known as impaired awareness of hypoglycemia (IAH). Together, IAH and the loss of the hormonal response is termed hypoglycemia associated autonomic failure (HAAF). IAH is prevalent in up to 25% in people with T1D and up to 10% in people with T2D. IAH and HAAF increase the risk of severe hypoglycemia 6-fold and 25-fold, respectively. To reduce this risk for severe hypoglycemia, multiple different therapeutic approaches are being explored that could improve awareness of hypoglycemia. Current therapies to improve awareness of hypoglycemia include patient education and psychoeducation, the use of novel glycemic control technology, pancreas/islet transplantation, and drug therapy. This review examines both existing therapies and potential therapies that are in pre-clinical testing. Novel treatments that improve awareness of hypoglycemia, via improving the counterregulatory hormone responses or improving hypoglycemic symptom recognition, would also shed light on the possible neurological mechanisms that lead to the development of IAH. To reduce the risk of severe hypoglycemia in people with diabetes, elucidating the mechanism behind IAH, as well as developing targeted therapies is currently an unmet need for those that suffer from IAH.

The brain has been traditionally thought to be insensitive to insulin, primarily because insulin does not stimulate glucose uptake/metabolism in the brain (as it does in classic insulin-sensitive tissues such as muscle, liver, and fat). However, over the past 20 years, research in this field has identified unique actions of insulin in the brain. There is accumulating evidence that insulin crosses into the brain and regulates central nervous system functions such as feeding, depression, and cognitive behavior. In addition, insulin acts in the brain to regulate systemic functions such as hepatic glucose production, lipolysis, lipogenesis, reproductive competence, and the sympathoadrenal response to hypoglycemia. Decrements in brain insulin action (or brain insulin resistance) can be observed in obesity, type 2 diabetes (T2DM), aging, and Alzheimer’s disease (AD), indicating a possible link between metabolic and cognitive health. Here, we describe recent findings on the pleiotropic actions of insulin in the brain and highlight the precise sites, specific neuronal population, and roles for supportive astrocytic cells through which insulin acts in the brain. In addition, we also discuss how boosting brain insulin action could be a therapeutic option for people at an increased risk of developing metabolic and cognitive diseases such as AD and T2DM. Overall, this perspective article serves to highlight some of these key scientific findings, identify unresolved issues, and indicate future directions of research in this field that would serve to improve the lives of people with metabolic and cognitive dysfunctions.

Context Little evidence exists regarding the positive and negative impacts of continuous glucose monitor system (CGM) alarm settings for diabetes control in patients with type 1 diabetes (T1D). Objective Evaluate the associations between CGM alarm settings and glucose outcomes. Design and Setting A cross-sectional observational study in a single academic institution. Patients and Main Outcome Measures CGM alarm settings and 2-week CGM glucose information were collected from 95 T1D patients with > 3 months of CGM use and ≥ 86% active usage time. The associations between CGM alarm settings and glucose outcomes were analyzed. Results Higher glucose thresholds for hypoglycemia alarms (ie, ≥ 73 mg/dL vs < 73 mg/dL) were related to 51% and 65% less time with glucose < 70 and < 54 mg/dL, respectively (P = 0.005; P = 0.016), higher average glucose levels (P = 0.002) and less time-in-range (P = 0.005), but not more hypoglycemia alarms. The optimal alarm threshold for < 1% of time in hypoglycemia was 75 mg/dL. Lower glucose thresholds for hyperglycemia alarms (ie, ≤ 205 mg/dL vs > 205 mg/dL) were related to lower average glucose levels and 42% and 61% less time with glucose > 250 and > 320 mg/dL (P = 0.020, P = 0.016, P = 0.007, respectively), without more hypoglycemia. Lower alarm thresholds were also associated with more alarms (P < 0.0001). The optimal alarm threshold for < 5% of time in hyperglycemia and hemoglobin A1c ≤ 7% was 170 mg/dL. Conclusions Different CGM glucose thresholds for hypo/hyperglycemia alarms are associated with various hypo/hyperglycemic outcomes. Configurations to the hypo/hyperglycemia alarm thresholds could be considered as an intervention to achieve therapeutic goals.

The contribution of the sympathetic nervous system (SNS) versus the parasympathetic nervous system (PSNS) in mediating fatal cardiac arrhythmias during insulin-induced severe hypoglycemia is not well understood. Therefore, experimental protocols were performed in nondiabetic Sprague-Dawley rats to test the SNS with 1) adrenal demedullation and 2) chemical sympathectomy, and to test the PSNS with 3) surgical vagotomy, 4) nicotinic receptor (mecamylamine) and muscarinic receptor (AQ-RA 741) blockade, and 5) ex vivo heart perfusions with normal or low glucose, acetylcholine (ACh), and/or mecamylamine. In protocols 1–4, 3-h hyperinsulinemic (0.2 units/kg/min) and hypoglycemic (10–15 mg/dL) clamps were performed. Adrenal demedullation and chemical sympathectomy had no effect on mortality or arrhythmias during severe hypoglycemia compared with controls. Vagotomy led to a 6.9-fold decrease in mortality; reduced first- and second-degree heart block 4.6- and 4-fold, respectively; and prevented third-degree heart block compared with controls. Pharmacological blockade of nicotinic receptors, but not muscarinic receptors, prevented heart block and mortality versus controls. Ex vivo heart perfusions demonstrated that neither low glucose nor ACh alone caused arrhythmias, but their combination induced heart block that could be abrogated by nicotinic receptor blockade. Taken together, ACh activation of nicotinic receptors via the vagus nerve is the primary mediator of severe hypoglycemia–induced fatal cardiac arrhythmias.

It is proposed that the impaired counterregulatory response (CRR) to hypoglycemia in insulin-deficient diabetes may be due to chronic brain insulin deficiency. To test this hypothesis, streptozotocin-induced diabetic Sprague-Dawley rats were infused with insulin (3 mU/day) or artificial cerebrospinal fluid (aCSF) bilaterally into the ventromedial hypothalamus (VMH) for 2 wk and compared with nondiabetic rats. Rats underwent hyperinsulinemic (50 mU·kg⁻¹·min⁻¹)-hypoglycemic (~45 mg/dl) clamps. Diabetic rats demonstrated an impaired CRR to hypoglycemia, noted by a high glucose infusion rate and blunted epinephrine and glucagon responses. The defective sympathoadrenal response was restored by chronic infusion of insulin into the VMH. Diabetic rats had decreased VMH Akt phosphorylation and decreased VMH glucose transporter 4 (GLUT4) content, which was also restored by chronic infusion of insulin into the VMH. Separate experiments in nondiabetic rats in which GLUT4 translocation into the VMH was inhibited with an infusion of indinavir were notable for an impaired CRR to hypoglycemia, indicated by increased glucose infusion rate and diminished epinephrine and glucagon responses. Results suggest that, in this model of diabetes, VMH insulin deficiency impairs the sympathoadrenal response to hypoglycemia and that chronic infusion of insulin into the VMH is sufficient to normalize the sympathoadrenal response to hypoglycemia via restoration of GLUT4 expression in the VMH.