These were able to reduce SH and improve glycemic control , with greater benefit from the latter two techniques in improving IAH .
Technological interventions ( insulin pump therapy , continuous glucose monitoring , and sensor-augmented pump ) reduced SH , improved glycemic control , and restored awareness when used in combination with structured education and frequent contact .
This review provides evidence for the effectiveness of a stepped-care approach in the management of patients with IAH  , initially with structured diabetes education in flexible insulin therapy , which may incorporate psychotherapeutic and behavioral therapies , progressing to diabetes technology , incorporating sensors and insulin pumps , in those with persisting need
OBJECTIVE Impaired awareness of hypoglycemia ( IAH ) increases the risk of severe hypoglycemia ( SH ) sixfold and affects 30 % of adults with type 1 diabetes ( T1D ) .
This systematic review and meta- analysis looks at the educational , technological , and pharmacological interventions aim ed at restoring hypoglycemia awareness ( HA ) in adults with T1D .
Avoidance of Hypoglycemia Restores Hypoglycemia Awareness by Increasing -Adrenergic Sensitivity in Type 1 Diabetes
Hypoglycemia unawareness is a major limiting factor in the management of type 1 diabetes ( 1 ) . This common problem , reported to occur in about 25 % of patients with type 1 diabetes ( 2 ) , is characterized by loss of autonomic warning symptoms before development of neuroglycopenia ( 2 ) . Hypoglycemia unawareness is associated with a sevenfold increase in the frequency of severe hypoglycemia ( 3 ) , which may be accompanied by seizure and coma . In the past decade , several risk factors for hypoglycemia unawareness have been identified , including long duration of diabetes , tight glycemic control ( low hemoglobin A1c values ) , and repeated episodes of hypoglycemia ( 1 , 2 , 4 - 7 ) . It has been thought that reduced counterregulatory hormone responses to hypoglycemia ( 4 , 5 ) are primarily responsible for hypoglycemia unawareness . However , recent studies suggest that impaired -adrenergic sensitivity ( 8 - 10 ) may also be involved . Patients with type 1 diabetes experience progressive reduction in the plasma catecholamine response to hypoglycemia ( 11 ) . This phenomenon may be an intrinsic element of type 1 diabetes or a consequence of cortisol release during hypoglycemia , which has been shown to blunt catecholamine response during subsequent hypoglycemic episodes ( 12 ) . Hypoglycemia-aware patients with type 1 diabetes who have reduced catecholamine responses during hypoglycemia have increased -adrenergic sensitivity ( 10 ) , perhaps because increases in plasma cortisol during hypoglycemia upregulate -receptors ( 13 , 14 ) . With continued episodes of hypoglycemia , the maximally enhanced -adrenergic sensitivity decreases and hypoglycemia unawareness ensues , probably because of exhausted -receptor upregulation ( 9 ) . Indeed , a single episode of hypoglycemia reduces -adrenergic sensitivity in patients with type 1 diabetes who are already compensating for reduced catecholamine response to hypoglycemia with maximally enhanced -adrenergic sensitivity ( 10 ) . Studies of patients with insulinoma ( 15 ) , those who have had pancreas transplantation ( 16 ) , and those with type 1 diabetes ( 17 - 21 ) indicate that hypoglycemia unawareness can be reversed by avoidance of hypoglycemia . In patients with type 1 diabetes ( 17 - 21 ) , hypoglycemia unawareness has been shown to occur in the absence of improved plasma catecholamine responses ( 20 , 22 ) , suggesting that increased sensitivity to catecholamines may be the primary mechanism . We sought to examine the effect of strict avoidance of hypoglycemia for 4 months in 10 patients with diabetes of long duration , hypoglycemia unawareness , and a history of severe hypoglycemia . Methods Participants The protocol was approved by the Ethical Committee of the University of Tbingen School of Medicine . Ten men with type 1 diabetes who had self-reported reduced awareness of hypoglycemia and a history of severe hypoglycemia as defined by the Diabetes Control and Complications Trial ( 7 , 23 ) ( hypoglycemia result ing in coma or seizure , requiring assistance of another person and treatment with glucagon or intravenous glucose ) were studied . All participants gave written informed consent . Clinical characteristics are shown in the Table . Table . Patient Characteristics and Responses during Hypoglycemic Clamp In all participants , autonomic neuropathy was excluded by st and ard cardiovascular testing ( variation in resting heart rate according to spectral analysis , the Valsalva maneuver , lying-to-st and ing , and deep breathing [ 24 ] ) . All patients were receiving an intensive insulin regimen with injections of long-acting insulin in the morning and at bedtime and short-acting insulin before meals ( usually three times daily ) . We compared the study patients with 10 patients who had type 1 diabetes and hypoglycemia awareness and 10 nondiabetic controls ; data on these 20 persons were published elsewhere ( 10 ) . These 20 persons had been studied by using methods identical to those in the present study . Prevention of Hypoglycemia To avoid hypoglycemia , we followed modifications of the guidelines proposed by Amiel ( 25 ) . Target prepr and ial blood glucose levels were increased from 5.6 mmol/L to 8.3 mmol/L ( 100 mg/dL to 150 mg/dL ) , and target bedtime blood glucose levels were increased from 5.6 mmol/L to 10 mmol/L ( 100 mg/dL to 180 mg/dL ) to avoid nighttime hypoglycemia . To achieve these targets , the dose of long-acting insulin  ( preferably that given at bedtime ) was reduced . The daily short-acting insulin dose was reduced and adjusted individually to the carbohydrate content of the meal to be consumed and the actual blood glucose level . Patients were instructed to measure blood glucose at least five times daily . During the study , participants were contacted at least biweekly for adjustments of insulin dosage intended to prevent blood glucose levels from decreasing to less than 3.9 mmol/L ( 70 mg/dL ) . Patient adherence to the new blood glucose targets was reinforced by discussion with patients of the importance of the problem . Protocol Participants underwent hyperinsulinemic hypoglycemic clamp before and after 4 months of prevention of hypoglycemia . Isoproterenol testing was performed to measure -adrenergic sensitivity before and after 2 and 4 months of prevention of hypoglycemia . Isoproterenol testing was performed approximately 1 week before the corresponding hypoglycemic clamp . For both the hypoglycemic clamp and the isoproterenol test , participants were admitted to the university 's clinical research unit at 8:00 pm . They had been instructed to reduce their insulin dose by 10 % for 3 days before testing to avoid blood glucose lower than 5 mmol/L ( 90 mg/dL ) . They had injected their last regular dose of insulin before dinner on the day before testing . At 11:00 pm , they injected a 10 % reduced dose of neutral protamine Hagedorn insulin to avoid blood glucose levels less than 6.7 mmol/L ( 120 mg/dL ) . During the night , blood glucose was checked every 2 hours . Oral administration of 10 g of glucose was planned if blood glucose levels decreased below 6.7 mmol/L ( 120 mg/dL ) ; this did not occur in any patient . Isoproterenol Testing At 7:00 a.m. , an indwelling catheter was inserted into an antecubital vein for infusion of insulin and injection of isoproterenol . A variable insulin infusion ( 0 to 1 mU/kg/min ) was begun to keep blood glucose levels between 6.7 and 10 mmol/L ( 120180 mg/dL ) during isoproterenol testing . Participants were connected to a computer-assisted electrocardiograph ( NeuroDiag , Munich , Germany ) for determination of cardiovascular responses . Blood pressure was recorded by using an automatic device ( DINAMAP , Critikon , Tampa , Florida ) . Appropriately diluted isoproterenol ( Isuprel , Sanofi , Brussels , Belgium ) was injected as a 5-mL bolus in a forearm vein through a three-way valve in doses of 0 ( 5 mL NaCl , 0.9 % ) , 0.25 , 0.5 , 0.75 , 1.0 , 1.5 , 2.0 , 2.5 , 3.0 , and 4.0 g. The interval between each injection was 20 minutes . An electrocardiogram was recorded online for 1 minute before and 5 minutes after each injection . The basal heart rate was defined as the mean of the rate obtained in the 20 seconds before the first injection . The maximal heart rate was usually reached approximately 30 to 60 seconds after each injection and returned to baseline before the end of the 5-minute recording interval . The maximal heart rate was determined by search ing for the shortest RR interval after injection ; extrasystoles were excluded by graphical analysis of heart rate recordings . Blood pressure was recorded at baseline and at 2 minutes and 5 minutes after injection , by which time heart rate had returned to baseline .  Blood glucose  was measured every 15 minutes . The test was stopped prematurely if the increase in heart rate exceeded 50 beats/min or maximal blood pressure exceeded 170/90 mm Hg . -Adrenergic sensitivity was expressed as the dose of isoproterenol that increased heart rate by 25 beats/min ( IC25 ) . This value was determined by fitting a curve through the change in heart rates plotted over the isoproterenol doses and calculating the intercept , with the change in heart rate equal to 25 beats/min . Hypoglycemic Clamp At 7:00 a.m. , indwelling catheters were inserted into an antecubital vein for infusion of glucose and insulin and into a dorsal h and vein for arterial blood sampling . The h and was kept in a heated chamber during this procedure . An insulin infusion with a constant rate of 1 mU/kg per minute was begun , and blood glucose was clamped at 3 mmol/L ( 54 mg/dL ) for 180 minutes . Afterward , participants received a st and ardized meal containing 48 g of carbohydrates and were discharged as soon as blood glucose levels exceeded 6.7 mmol/L ( 120 mg/dL ) . Symptom Question naire A semiquantitative symptom question naire was administered twice before hypoglycemic clamp and at 30 , 90 , 150 , and 180 minutes during the clamp . Participants scored their symptoms from 0 ( none ) to 7 ( severe ) in response to 9 autonomic symptoms ( tremor , sweating , shivering , hunger , pounding heart , anxiety , nausea , feeling tearful ) , 10 neuroglycopenic symptoms ( difficulty speaking , double vision , headache , drowsiness , blurred vision , tingling around the mouth , inability to concentrate , confusion , tiredness , weakness ) and 10 dummy symptoms . All of these symptoms were presented to patients in r and om order ( 26 ) . Total symptom score and the neuroglycopenic and autonomic symptom scores were calculated for each time point . Blood Sampling and Analysis Plasma epinephrine and norepinephrine levels were measured at 30 and 15 minutes before and 30 , 90 , 150 , and 180 minutes during hypoglycemic clamp . Blood glucose was measured at the bedside by using a Hemocue blood glucose photometer ( Hemocue AB , Angelham , Sweden ) . Catecholamines were measured in ethylenediamine tetraacetic acidtreated plasma by using high-performance liquid chromatography with electrochemical detection ( ClinRep Analysis Kit , Recipe Pharma , Munich , Germany ) . Statistical Analysis Unless otherwise stated , data are given as the mean ( SE ) . For increments of catecholamine
These were able to reduce SH and improve glycemic control , with greater benefit from the latter two techniques in improving IAH .
Technological interventions ( insulin pump therapy , continuous glucose monitoring , and sensor-augmented pump ) reduced SH , improved glycemic control , and restored awareness when used in combination with structured education and frequent contact .
This review provides evidence for the effectiveness of a stepped-care approach in the management of patients with IAH  , initially with structured diabetes education in flexible insulin therapy , which may incorporate psychotherapeutic and behavioral therapies , progressing to diabetes technology , incorporating sensors and insulin pumps , in those with persisting need
OBJECTIVE Impaired awareness of hypoglycemia ( IAH ) increases the risk of severe hypoglycemia ( SH ) sixfold and affects 30 % of adults with type 1 diabetes ( T1D ) .
This systematic review and meta- analysis looks at the educational , technological , and pharmacological interventions aim ed at restoring hypoglycemia awareness ( HA ) in adults with T1D .