Hypoglycemia in Type 1 Diabetes Mellitus

Spontaneous hypoglycemia is uncommon in the general (nondiabetic) population, but iatrogenic hypoglycemia is rife in patients with type 1 diabetes mellitus, among whom hypoglycemia constitutes a barrier to optimal glycemic control. The obligate dependence on exogenous insulin, together with the current imperfection in insulin therapies, generates degrees of blood glucose fluctuations that often exceed physiological boundaries in these patients. Downward swings in blood glucose levels, if sustained, result in hypoglycemia and significant morbidity and mortality. Hypoglycemia in type 1 diabetes indicates an imbalance between caloric supply and glucose use in response to insulin or exercise. Counterregulatory mechanisms that auto-correct iatrogenic hypoglycemia often become progressively impaired in these patients. This defective counterregulation, together with the imperfections in insulin delivery, set the stage for significant morbidity from iatrogenic hypoglycemia. Recurrent episodes of iatrogenic hypoglycemia induce a state of hypoglycemia unawareness and defective counterregulation, which defines the syndrome of hypoglycemia-associated autonomic failure (HAAF). The reduced awareness of, and counterregulatory responses to, hypoglycemia in patients with HAAF lead to worsening episodes of severe hypoglycemia. Approaches to the prevention of hypoglycemia include glucose monitoring, patient education, meal planning, and medication adjustment. In patients with HAAF, scrupulous avoidance of iatrogenic hypoglycemia may restore the symptomatic and counterregulatory responses to hypoglycemia. Behavioral training focusing on recognition of the more subtle symptoms and signs of evolving hypoglycemia may be beneficial to some patients with HAAF. A methodical search for the pattern and etiology of iatrogenic hypoglycemia is a prerequisite for the identification of the best preventive approach. With proper education, patients with type 1 diabetes and their physicians can learn to prevent or minimize the risk of hypoglycemia while pursuing excellence in glycemic control.     

Glucose counterregulation in Type 2 diabetes mellitus.

Glucose counterregulatory failure and hypoglycaemia unawareness frequently complicate treatment of Type 1 diabetes mellitus, especially when aiming for intensive metabolic control. Since tight metabolic control reduces microvascular long-term complications in Type 2 diabetes mellitus, the integrity of glucose counterregulation in Type 2 diabetic patients is important. Using a Medline search, we identified 12 studies in which counterregulatory responses to insulin-induced hypoglycaemia were compared between Type 2 diabetic patients and appropriate controls. A review of these studies showed that some patients with Type 2 diabetes mellitus develop mild counterregulatory dysfunction and reduced awareness of insulin-induced hypoglycaemia. Some studies suggested an association between counterregulatory impairment and intensity of metabolic control. We speculate that the relatively low frequency of (severe) hypoglycaemic events in Type 2 diabetes may explain why glucose counterregulation remains unaffected in most patients. We hypothesize that residual beta-cell reserve and insulin resistance provide protection against severe hypoglycaemia and limit impaired counterregulation. Diabet. Med. 18, 519-527 (2001)     

Effect of pancreas transplantation on glucose counterregulation in insulin-dependent diabetic patients prone to severe hypoglycaemia.

Pancreatic transplantation was performed in three patients with insulin-dependent diabetes mellitus in whom recurrent and severe episodes of hypoglycaemia had been found to be due to defective glucose counterregulation. Thus in these patients the spontaneous blood glucose recovery after insulin-induced hypoglycaemia (0.1 U kg-1 h-1 i.v. insulin until blood glucose levels fell below 2.8 mmol l-1) was delayed, and the responses of glucagon, epinephrine and growth hormone (GH) were absent or diminished. After pancreas transplantation the patients exhibited essentially normal blood glucose control. When the insulin infusion test was repeated 3 months after the transplantation, the blood glucose level recovered rapidly after insulin withdrawal. The glucagon response was restored, and the responses of epinephrine and GH were improved. Plasma C-peptide was suppressed by approximately 50%, which is less than is observed in normal subjects. It is concluded that glucose counterregulation improves after pancreas transplantation. This appears to be mainly due to an improvement in the hypoglycaemia-induced glucagon response, but an amelioration of sympatho-adrenal and hypothalamic-pituitary regulatory mechanisms may also be involved. The apparent failure to suppress completely the insulin release from the denervated pancreas transplant indicates that inhibition of beta-cell secretion during insulin-induced hypoglycaemia may be partly under neural control.     

Hypoglycemia unawareness

Iatrogenic hypoglycemia is the limiting factor in the glycemic control of diabetes. It causes recurrent symptomatic and sometimes, at least temporally, disabling episodes in most people with type 1 diabetes, as well as in many with advanced type 2 diabetes. Furthermore, iatrogenic hypoglycemia precludes maintenance of euglycemia during the lifetime of a person with diabetes and thus full realization of the well established benefits of glycemic control. In this article I discuss the clinical problem of hypoglycemia in diabetes from the perspective of pathophysiology. First, the syndromes of defective glucose counterregulation and hypoglycemia without warning symptoms (known as hypoglycemia unawareness) are described, followed by the unifying concept of Hypoglycemia-Associated Autonomie Failure (HAAF). The concept of hypoglycemia-associated autonomie failure in diabetes posits that recurrent antecedent hypoglycemia causes both defective glucose counterregulation and hypoglycemia unawareness and thus leads to a vicious cycle of recurrent hypoglycemia and further impairment of glucose counterregulation. The clinical relevance of this phenomenon is now well established, but the mechanisms and mediators remain largely unknown. The short-term avoidance of hypoglycemia reverses hypoglycemia unawareness in most affected patients. The ultimate goal of lifelong maintenance of euglycemia in patients with diabetes remains elusive because of the pharmacokinetic imperfections of all current glucose-lowering therapies and the resulting barrier of hypoglycemia. Nonetheless, it is now possible both to improve the control of glycemia and to reduce the frequency of hypoglycemia in many people with diabetes. These results can be accomplished by recognizing the problem of hypoglycemia applying the principles of aggressive glycemic therapy and reducing the risk factors of hypoglycemia in people with diabetes.     

Non‐insulin treatments for Type 1 diabetes: critical appraisal of the available evidence and insight into future directions

Intensive insulin therapy is the mainstay of treatment for people with Type 1 diabetes, but hypoglycaemia and weight gain are often limiting factors in achieving glycaemic targets and decreasing the risk of diabetes‐related complications. The inclusion of pharmacological agents used traditionally in Type 2 diabetes as adjuncts to insulin therapy in Type 1 diabetes has been explored, with the goal of mitigating such drawbacks. Pramlintide and metformin result in modest HbA_1c and weight reductions, but their use is limited by poor tolerability and, in the case of pramlintide, by frequency of injections and cost. The addition of glucagon‐like peptide‐1 receptor agonists to insulin results in improved glycaemic control, reduced insulin doses and weight loss, but this is at the expense of higher rates of hypoglycaemia and hyperglycaemia with ketosis. Sodium‐glucose co‐transporter‐2 and dual sodium‐glucose co‐transporter‐2 and ‐1 inhibitors also improve glucose control, but with reductions in weight and insulin requirements potentiating the risk of acidosis‐related events and hypoglycaemia. The high proportion of people with Type 1 diabetes not achieving glycaemic targets, the negative clinical impact of intensive insulin therapy and the rise in obesity and cardiovascular disease and mortality, underline the need for individualized clinical care. The evaluation of new therapies, effective in Type 2 diabetes, as adjuncts to insulin therapy represents a promising strategy, particularly given the beneficial effects on cardiovascular and renal outcomes in people with Type 2 diabetes with or at high risk of complications that are also observed in patients with Type 1 diabetes. As the population with Type 1 diabetes ages, our mission is to evolve and provide better tools and improved therapies to excel, not only in glycaemic control but also in risk reduction and reduction of complications.     

Physiological,Symptomatic and Hormonal Responses to Acute Hypoglycaemia in Type 1 Diabetic Patients with Autonomic Neuropathy

The effects of peripheral autonomic neuropathy on the symptomatic, physiological, and hormonal responses to acute insulin-induced hypoglycaemia were studied in two groups of patients with Type 1 diabetes, matched for age, duration of diabetes, and prevailing glycaemic control. A group of eight patients who gave a history of normal awareness of hypoglycaemia and had normal cardiovascular autonomic function tests were compared to a group of six patients who had symptoms of autonomic dysfunction and gross abnormalities of cardiovascular autonomic function tests. An additional two patients with autonomic neuropathy who also had hypoglycaemia unawareness were studied. Acute hypoglycaemia was induced by intravenous infusion of insulin (2.5 ***mU kg^?1 min^?1) and the onset of the acute autonomic reaction (R) was identified objectively by the sudden rise in heart rate and onset of sweating. Cognitive function and hypoglycaemia symptom scores were estimated serially, and plasma counterregulatory hormones were measured. Acute autonomic activation was observed to occur in all subjects in response to hypoglycaemia and commenced at similar venous plasma glucose concentrations in both groups (neuropathic patients: 1.6 ± 0.2 mmol I^?1 vs non-neuropathic patients 1.6 ± 0.2 mmol I^?1, p = 0.9,). In the neuropathic patients plasma adrenaline responses were significantly lower at all time points from time R until time R + 30 min (MANOVA for repeated measures, F = 19.4, p < 0.001). The total autonomic symptom score at R was slightly lower in the neuropathic patients (12 (8–12) median (range)) but was not significantly different from the non-neuropathic patients (14 (10–26), p = 0.10), and the total neuroglycopenic symptom scores were very similar (neuropathic group: 11 (6–21) vs non-neuropathic group: 11.5 (6–22), p = 0.95). Although some of the autonomic responses were lower, but not significantly so, in the patients with autonomic neuropathy this study suggests that peripheral autonomic neuropathy is not the principal cause of hypoglycaemia unawareness in patients with Type 1 diabetes.     

Diabetic hypoglycaemia.

Hypoglycaemia is a major factor preventing insulin-treated patients from achieving normoglycaemia. This reflects the inadequacy of current insulin treatment, which causes high insulin concentrations in the post-absorptive period. Physiological defences to hypoglycaemia include autonomic activation, which limits the fall in glucose level and causes symptoms, alerting patients to an impending episode. Many patients develop defective responses and hypoglycaemia unawareness after longstanding disease or with tight glycaemic control and are then prone to severe attacks. This may be the result of repeated hypoglycaemic episodes, which by altering cerebral glucose uptake, disturb the mechanisms that activate the central response to hypoglycaemia. Preventing further hypoglycaemia can partially reverse these defects and restore symptomatic awareness. Clinical hypoglycaemia has also been implicated in the 'dead in bed' syndrome and in chronic cognitive impairment. The problem of hypoglycaemia will eventually be solved by better insulin delivery and non-invasive glucose meters, but until then, more focused education may have a more substantial impact.     

Counterregulatory hormonal responses to hypoglycaemia in Type 1 (insulin-dependent) diabetes: evidence for diminished hypothalamic-pituitary hormonal secretion

Summary Acute insulin-induced hypoglycaemia in humans provokes autonomic neural activation and counterregulatory hormonal secretion mediated in part via hypothalamic stimulation. Many patients with Type 1 (insulin-dependent) diabetes have acquired deficiencies of counterregulatory hormonal release following hypoglycaemia. To study the integrity of the hypothalamic-pituitary and the sympatho-adrenal systems, the responses of pituitary hormones, beta-endorphin, glucagon and adrenaline to acute insulin-induced hypoglycaemia (0.2 units/kg) were examined in 16 patients with Type 1 diabetes who did not have autonomic neuropathy. To examine the effect of duration of diabetes these patients were subdivided into two groups (Group 1: 8 patients < 5 years duration; Group 2 8 patients>15 years duration) and were compared with 8 normal volunteers (Group 3). The severity and time of onset of hypoglycaemia were similar in all 3 groups, but mean blood glucose recovery was slower in the diabetic groups (p<0.01). The mean responses of glucagon, adrenaline, adrenocorticotrophic hormone, prolactin and beta-endorphin were similar in all 3 groups, but the mean responses of growth hormone were lower in both diabetic groups than in the normal group (p<0.05). The mean increments of glucagon and adrenaline in the diabetic groups were lower than the normal group, but these differences did not achieve significance; glucagon secretion was preserved in several diabetic patients irrespective of duration of disease. Various hormonal responses to hypoglycaemia were absent or diminished in individual diabetic patients, and multiple hormonal deficiencies could be implicated in delaying blood glucose recovery. The demonstration of subnormal secretion of adrenaline and pituitary hormones following hypoglycaemia in individual patients supports the concept that central (hypothalamic) activation of counterregulation may be diminished in Type 1 diabetes.     

Pathophysiology and management of recurrent hypoglycaemia and hypoglycaemia unawareness in diabetes

Iatrogenic hypoglycaemia is a well-known complication of insulin therapy in patients with diabetes mellitus and a limiting factor for glycaemic control. In a setting of endogenous insulin deficiency (type 1 and advanced type 2 diabetes), one episode of hypoglycaemia reduces both counterregulatory hormone responses to and subjective awareness of subsequent hypoglycaemia, thus impairing physiological defences against hypoglycaemia. This phenomenon may lead to a vicious cycle of recurrent hypoglycaemia and glucose counterregulatory failure, of which hypoglycaemia unawareness (i.e. the inability to perceive symptoms of hypoglycaemia) is the clinical representative. The underlying mechanism of hypoglycaemia-induced counterregulatory failure has not yet been disclosed. Patients with clinical hypoglycaemia unawareness are at high risk of severe hypoglycaemia that requires third-party assistance. Management options include avoidance of hypoglycaemic events and optimisation of insulin therapy to limit deterioration of glycaemic control associated with hypoglycaemia avoidance. Several counterregulatory-stimulating agents have been found to improve hypoglycaemic awareness in small clinical trials, but none have been tested in sufficiently large randomised studies to justify their use in daily practice. More research is required to elucidate the pathogenesis of counterregulatory failure and to develop adequate treatment strategies.     

Role of incretin‐based therapies and sodium‐glucose co‐transporter‐2 inhibitors as adjuncts to insulin therapy in Type 2 diabetes,with special reference to IDegLira

The progressive nature of Type 2 diabetes necessitates treatment intensification over time in order to maintain glycaemic control, with many patients ultimately requiring insulin therapy. While insulin has unlimited potential efficacy, its initiation is often delayed and improvements in glycaemic control are typically accompanied by weight gain and an increased risk of hypoglycaemia, particularly as HbA_1c approaches and falls below target levels. This may account for the sub‐optimal control often achieved after insulin initiation. Combining insulin with antihyperglycaemic therapies that have a low risk of hypoglycaemia and are weight‐neutral or result in weight loss is a therapeutic strategy with the potential to improve Type 2 diabetes management. Although the effects differ with each individual class of therapy, clinical trials have shown that adding a glucagon‐like peptide‐1 receptor agonist, dipeptidyl peptidase‐4 inhibitor or sodium‐glucose co‐transporter‐2 inhibitor to insulin regimens can offer a significant reduction in HbA_1c without substantially increasing hypoglycaemia risk, or weight. The evidence and merit of each approach are reviewed in this paper. Once‐daily co‐formulations of a basal insulin and a glucagon‐like peptide‐1 receptor agonist have been developed (insulin degludec/liraglutide) or are under development (lixisenatide/insulin glargine). Insulin degludec/liraglutide phase III trials and a lixisenatide/insulin glargine phase II trial have shown robust HbA_1c reductions, with weight loss and a low risk of hypoglycaemia. With insulin degludec/liraglutide now approved in Europe, an important consideration will be the types of patients who may benefit most from a fixed‐ratio combination; this is discussed in the present review, and we also take a look toward future developments in the field.     

Different awareness of hypoglycaemia induced by human or purified pork insulin in type I diabetic patients.

Recently, there have been reports on a diminished awareness of hypoglycaemia after a switch from purified pork insulin (PPI) to human insulin (HI) in insulin-dependent diabetes mellitus (IDDM). To clarify this phenomenon we investigated nine IDDM patients without signs of autonomic neuropathy. After an overnight euglycaemic clamp, blood glucose was lowered to hypoglycaemic levels by means of an artificial pancreas (Biostator) on 2 days. Insulin was used in a double-blind, randomized, cross-over fashion, either PPI or HI. The symptomatology and the hormonal counterregulation of developing hypoglycaemia was recorded. Venous concentrations of free insulin, cortisol, glucagon, growth hormone and the prevailing blood glucose were similar under both insulins. Eight out of nine IDDM patients felt more symptoms and at a higher blood glucose concentration under PPI than under HI. The first symptom of developing hypoglycaemia appeared at a mean blood glucose concentration of 61.1 +/- 5.4 mg.dl-1 under PPI and 44.4 +/- 5.3 mg.dl-1 under HI respectively (P less than 0.05). We conclude that HI may cause symptoms of hypoglycaemia to appear later and with a lesser number in comparison to PPI.     

A Comparative Study of Responses to Acute Hypoglycaemia Induced by Human and Porcine Insulins in Patients with Type 1 Diabetes

The effects of human and porcine insulins on the symptomatic, physiological, and counterregulatory hormonal responses to acute hypoglycaemia were compared in 40 patients with Type 1 diabetes, 20 of whom were newly diagnosed while 20 had been treated for between 5 and 20 years. In a double-blind, cross-over trial all patients were treated with human or porcine insulin, in random order, for two consecutive 3-month periods. At the end of each treatment period they were subjected to an acute episode of experimental hypoglycaemia induced by a continuous intravenous infusion (2.0 mU kg⁻¹ min⁻¹) of the same insulin species. Haemodynamic, sweating, and tremor responses were measured during both studies, symptom scores were recorded and the arterialized plasma glucose thresholds for autonomic activation and the onset of subjective symptoms were identified. In all patients the glycaemic thresholds for the initiation of the autonomic physiological responses to hypoglycaemia and the onset of the symptomatic response were concurrent and did not differ with insulin species (plasma glucose 1.94 vs 1.96 mmol l⁻¹, human vs porcine studies). The onset, temporal pattern, nature, and magnitude of the physiological responses (sweating, heart rate, blood pressure, and tremor) during acute experimental hypoglycaemia were also identical with each insulin species. The magnitude and temporal pattern of the response of counterregulatory hormones (adrenaline, noradrenaline, glucagon, ACTH, and GH) to hypoglycaemia as induced by human and porcine insulins were indistinguishable, as were the total and individual scores of autonomic and neuroglycopenic symptoms. In conclusion, in patients who had newly diagnosed and intermediate duration (5–20 years) of diabetes, the symptomatic, physiological, and counterregulatory hormonal responses to acute insulin-induced hypoglycaemia did not differ between human and porcine insulins, and the plasma glucose thresholds at which the symptomatic and autonomic responses were initiated were identical with both insulin species. This study does not support the hypothesis that treatment with human insulin modifies the symptomatic, physiological, and counterregulatory hormonal responses to acute hypoglycaemia.     

Comparing hormonal and symptomatic responses to experimental hypoglycaemia in insulin‐ and sulphonylurea‐treated Type 2 diabetes

Aims Patients with diabetes rely on symptoms to identify hypoglycaemia. Previous data suggest patients with Type 2 diabetes develop greater symptomatic and hormonal responses to hypoglycaemia at higher glucose concentrations than non‐diabetic controls and these responses are lowered by insulin treatment. It is unclear if this is as a result of insulin therapy itself or improved glucose control. We compared physiological responses to hypoglycaemia in patients with Type 2 diabetes patients treated with sulphonylureas (SUs) or insulin (INS) with non‐diabetic controls (CON). Methods Stepped hyperinsulinaemic hypoglycaemic clamps were performed on 20 subjects with Type 2 diabetes, 10 SU‐treated and 10 treated with twice‐daily premixed insulin, and 10 age‐ and weight‐matched non‐diabetic controls. Diabetic subjects were matched for diabetes duration, glycated haemoglobin (HbA_1c) and hypoglycaemia experience. We measured symptoms, counterregulatory hormones and cognitive function at glucose plateaux of 5, 4, 3.5, 3 and 2.5 mmol/l. Results Symptomatic responses to hypoglycaemia occurred at higher blood glucose concentrations in SU‐treated than INS‐treated patients [3.5 (0.4) vs. 2.6 (0.5) mmol/l SU vs. INS; P = 0.001] or controls [SU vs. CON 3.5 (0.4) vs. 3.0 (0.6) mmol/l; P = 0.05]. They also had a greater increase in symptom scores at hypoglycaemia [13.6 (11.3) vs. 3.6 (6.1) vs. 5.1 (4.3) SU vs. INS vs. CON; P = 0.017]. There were no significant differences in counterregulatory hormone responses or impairment of cognitive function among groups. Conclusions Sulphonylurea‐treated subjects are more symptomatic of hypoglycaemia at a higher glucose level than insulin‐treated subjects. This may protect them from severe hypoglycaemia but hinder attainment of glycaemic goals.     

Mathematical Models of the Metabolic System in Health and in Diabetes: A Model of Self-Treatment Behavior, Glucose Variability, and Hypoglycemia-Associated Autonomic Failure in Type 1 Diabetes

Background

Type 1 diabetes patients face a lifelong behaviorally controlled optimization problem: maintaining strict glycemic control without increasing the risk of hypoglycemia. Because internal insulin secretion in type 1 diabetes (T1DM) is practically absent, this optimization is entirely dependent on the interplay among (i) self-treatment behavior, (ii) interaction between exogenous insulin and carbohydrates utilization, and (iii) internal defenses against hypoglycemia. This article presents a mathematical model and a computer simulation of the relationship among self-treatment in T1DM, blood glucose (BG) variability, and hypoglycemia-associated autonomic failure (HAAF).

Method

A stochastic behavioral self-control process was coupled with a dynamical system simulation of the dampening effect of counterregulation on BG oscillations. The resulting biobehavioral control system was compared to data from a field clinical trial (85 T1DM patients, 21–62 years old, T1DM of at least 2 years duration, and at least two documented severe hypoglycemia episodes during the previous year).

Results

The mathematical simulation was able to reproduce characteristics of hypoglycemic events observed during a field clinical trial, such as temporal clustering of hypoglycemic episodes associated with HAAF and occurrence of severe hypoglycemia as a result of periods of HAAF augmented by increased BG variability.

Conclusion

This investigation offers a mathematical model of HAAF—the primary barrier to intensive insulin treatment. This combined modeling/computer simulation/data analysis approach explains the temporal relationship among behaviorally induced hypoglycemia, glucose variability, and autonomic failure in T1DM. This explanation is valuable not only because it indicates that signs of HAAF can be detected in patients'' natural environment via self-monitoring or continuous glucose monitoring, but also because it allows for tracking of the risk of severe hypoglycemia over time.     

Plasma glucagon decreases during night-time sleep in Type 1 diabetic patients and healthy control subjects.

AIMS: In Type 1 diabetes mellitus (T1DM), the glucagon response to hypoglycaemia is known to disappear within a few months after the onset of the disease, whereas the response to other stimuli remains intact. The dynamics of spontaneous glucagon release have rarely been assessed. We monitored spontaneous glucagon release in T1DM patients and healthy subjects during a 7-h period of night-time sleep. METHODS: Measurements were made in 14 T1DM patients and 14 control subjects matched for age, gender and body mass index after one night's adaptation in our laboratory. Circulating glucose, insulin and glucagon concentrations were measured at 30-min intervals. In diabetic patients, hypoglycaemia (< 3.9 mmol/l) was avoided by infusion of glucose whenever necessary. RESULTS: During the entire night, plasma glucose and serum insulin levels were higher in T1DM patients than in healthy subjects (P < 0.03 and P < 0.001, respectively). Plasma glucagon concentrations decreased throughout the night in both groups (P < 0.001). Glucagon levels were similar in T1DM patients and healthy subjects (P > 0.87). The duration of diabetes (less and more than 5 years) did not affect glucagon secretion (P > 0.87). CONCLUSIONS: Plasma glucagon levels decrease significantly during night-time sleep in healthy control subjects. This nocturnal decrease is preserved in T1DM patients regardless of the duration of diabetes. These observations point to distinct nocturnal regulation of spontaneous glucagon release that does not depend on circulating glucose and insulin levels and is unaltered in T1DM patients.     

Symptomatic and hormonal hypoglycaemic responses to human and porcine insulin in patients with type I diabetes mellitus.

In recent years there has been great concern that human insulin (HI) may induce fewer hypoglycaemic warning symptoms than porcine insulin (PI). We addressed this issue in eight patients aged 25.6 +/- 3.3 (SEM) years with Type I (insulin-dependent) diabetes mellitus of 15.1 +/- 3.7 years duration who complained that hypoglycaemia unawareness had appeared after transferring from PI to HI. Acute induction of hypoglycaemia was induced on two occasions with semisynthetic HI and purified PI under double-blind conditions. Blood glucose was first clamped for 2 h at 4.4-6.7 mmol l-1 with an intravenous infusion of HI or PI at 50 mU kg-1 h-1 and 20% glucose at a variable rate. Thereafter, insulin infusion alone was maintained for 100 minutes. Heart rate, arterial pressure, reflex times, autonomic and neuroglycopenic signs and symptoms were assessed every 10 min. Arterialized venous blood samples were taken to measure blood glucose every 10 min and catecholamines, insulin, glucagon, growth hormone, and cortisol every 20 min. Autonomic symptoms first appeared at a plasma glucose level of 2.92 +/- 0.21 mmol l-1 with HI vs 2.92 +/- 0.48 mmol l-1 with PI (NS). There were no significant differences between the two studies concerning any of the above mentioned clinical parameters or the counterregulatory hormone responses. A differential effect of insulin species on the ability to perceive hypoglycaemia in patients who ascribed diminished perception of hypoglycaemia to the use of HI was thus not observed.     

Reducing hypoglycaemia with insulin analogues

Numerous studies have demonstrated that tight glycaemic control reduces long-term complications in both Type 1 and Type 2 diabetes. However, current intensive insulin regimens increase the risk of hypoglycaemia, dissuading many attempting this approach. Normal physiological insulin profiles consist of a stable, basal component and meal-related surges in secretion. Conventional insulin regimens cannot mimic this profile accurately due to pharmacokinetic limitations. Human insulin has a slow onset of action, thus patients are advised to inject about 30 min before a meal, ensuring peak insulin concentrations coincide with postprandial glucose excursions. This is clearly impractical for many and can lead to pre-meal hypoglycaemia if the meal is delayed. Furthermore, it only partially overcomes the unphysiological insulin profile and patients experience postprandial hyperglycaemia and are vulnerable to postabsorptive hypoglycaemia. Insulin aspart and insulin lispro are rapid-acting analogues that allow a more physiological replacement of mealtime insulin secretion. They reduce postprandial glucose and usefully reduce the incidence of hypoglycaemia when used in a basal-bolus regimen in tightly controlled patients. Pre-mixed insulins, containing a combination of rapid-acting and intermediate-acting insulin, are widely used, particularly in Type 2 diabetes. They have limitations achieving tight glucose targets but early data suggest that the combination of 30% insulin aspart and 70% protaminated insulin aspart may also reduce severe hypoglycaemia. On-going clinical trials will establish whether they can be used to achieve better glycaemic control with less hypoglycaemia.     

Decreased hypoglycemic effect of insulin at night in insulin-dependent diabetes mellitus and healthy subjects.

Diurnal variations in insulin-induced hypoglycemia and in plasma counterregulatory hormone concentrations were explored in eight insulin-dependent diabetic and six healthy subjects during a 100-min iv insulin infusion performed at 0300 h and 1500 h. In healthy subjects, plasma glucose concentrations (mean +/- SD) fell by 35 +/- 2% during the daytime test and by 26.5 +/- 2% during the nocturnal test (P less than 0.01). Plasma cortisol, GH, and epinephrine concentrations increased more during the daytime than during the nocturnal test. In contrast, plasma glucagon concentrations rose more during the nocturnal tests. In insulin-dependent diabetes mellitus patients, insulin infusion had to be interrupted in three subjects because plasma glucose fell below 1.9 mmol/L 80 min after the beginning of the test. In the other five patients plasma glucose fell by 34 +/- 5% during the daytime test while no significant decrease in plasma glucose was observed in any of the eight patients during the nighttime test. Counterregulatory hormone concentrations were consistent with the results of plasma glucose, with no change during the nocturnal test and significant increases in cortisol, GH, and epinephrine during the daytime test. These results show that insulin sensitivity is decreased at night in comparison to midafternoon in healthy subjects and that in insulin-dependent diabetes mellitus patients this phenomenon is exaggerated, even in patients with defective counterregulation to hypoglycemia.     

Is an artificial pancreas (closed‐loop system) for Type 1 diabetes effective?

The artificial pancreas is now a viable treatment option for people with Type 1 diabetes and has demonstrated improved glycaemic outcomes while also reducing the onus of self‐management of Type 1 diabetes. Closed‐loop glucose‐responsive insulin delivery guided by real‐time sensor glucose readings can accommodate highly variable day‐to‐day insulin requirements and reduce the hypoglycaemia risk observed with tight glycaemic control in Type 1 diabetes. In 2011, the James Lind Alliance research priorities for Type 1 diabetes were produced and priority 3 was to establish whether an artificial pancreas (closed‐loop system) for Type 1 diabetes is effective. This review focuses on the progress that has been made in the evolution of closed‐loop systems as an effective treatment option for Type 1 diabetes. Development of closed‐loop systems has advanced from feasibility evaluations in highly supervised settings over short periods, to clinical studies in free‐living, unsupervised conditions lasting several months. The approval in the USA of the first hybrid closed‐loop system (MiniMed^® 670G pump, Medtronic, Northridge, CA, USA) in 2016 for use in Type 1 diabetes reflects these advancements. We discuss the evidence from clinical studies that closed‐loop systems are effective with improved glycaemic outcomes, reduced hypoglycaemia and had positive end‐user acceptance in children, adolescents, adults and pregnant women with Type 1 diabetes. We also present the outlook for future closed‐loop systems in the treatment of Type 1 diabetes and identify the challenges facing the wide‐spread clinical adoption of this technology.     

Hypoglycaemia in Type 2 diabetes

Rates of hypoglycaemia in those with Type 2 diabetes newly started on insulin are less than in Type 1 diabetes but rise with time. As insulin secretion declines, the ability to release glucagon is diminished. Adrenaline release partially compensates for deficient glucagon secretion but is vulnerable to repeated hypoglycaemia leading to diminished sympathoadrenal activation. Thus the inevitable decline in endogenous insulin, eventually produces a similar failure of physiological protection to hypoglycaemia as in Type 1 diabetes.