Hypoglycemia in type 2 diabetes

Iatrogenic hypoglycemia is the limiting factor in the glycemic management of diabetes and a barrier to true glycemic control and becomes a progressively frequent clinical problem in advanced type 2 diabetes mellitus. As patients approach the insulin-deficient end of the spectrum of type 2, hypoglycemia results from the interplay of therapeutic insulin excess and compromised physiologic and behavioral defenses against falling plasma glucose concentrations.By practicing hypoglycemia risk reduction, applying the principles of aggressive glycemic therapy, and considering conventional risk factors and those indicative of compromised glucose counterregulation,it is possible to minimize the risk of hypoglycemia and improve glycemic control. Nonetheless, people with diabetes need better treatment regimens.     

Impaired hormonal responses to hypoglycemia in spontaneously diabetic and recurrently hypoglycemic rats. Reversibility and stimulus specificity of the deficits.

To evaluate the roles of iatrogenic hypoglycemia and diabetes per se in the pathogenesis of defective hormonal counterregulation against hypoglycemia in insulin-dependent diabetes mellitus (IDDM), nondiabetic, and spontaneously diabetic BB/Wor rats were studied using a euglycemic/hypoglycemic clamp. In nondiabetic rats, recurrent (4 wk) insulin-induced hypoglycemia (mean daily glucose, MDG, 59 mg/dl) dramatically reduced glucagon and epinephrine responses by 84 and 94%, respectively, to a standardized glucose fall from 110 to 50 mg/dl. These deficits persisted for > 4 d after restoring normoglycemia, and were specific for hypoglycemia, with normal glucagon and epinephrine responses to arginine and hypovolemia, respectively. After 4 wk of normoglycemia, hormonal counterregulation increased, with the epinephrine, but not the glucagon response reaching control values. In diabetic BB rats (MDG 245 mg/dl with intermittent hypoglycemia), glucagon and epinephrine counterregulation were reduced by 86 and 90%, respectively. Chronic iatrogenic hypoglycemia (MDG 52 mg/dl) further suppressed counterregulation. Prospective elimination of hypoglycemia (MDG 432 mg/dl) improved, but did not normalize hormonal counterregulation. In diabetic rats, the glucagon defect appeared to be specific for hypoglycemia, whereas deficient epinephrine secretion also occurred during hypovolemia. We concluded that both recurrent hypoglycemia and the diabetic state independently lead to defective hormonal counterregulation. These data suggest that in IDDM iatrogenic hypoglycemia magnifies preexisting counterregulatory defects, thereby increasing the risk of severe hypoglycemia.     

Thalamic Activation During Slightly Subphysiological Glycemia in Humans

OBJECTIVE

The central nervous system mechanisms of defenses against falling plasma glucose concentrations, and how they go awry and result in iatrogenic hypoglycemia in diabetes, are not known. Hypoglycemic plasma glucose concentrations of 55 mg/dL (3.0 mmol/L) cause symptoms, activate glucose counterregulatory systems, and increase synaptic activity in a network of brain regions including the dorsal midline thalamus in humans. We tested the hypothesis that slightly subphysiological plasma glucose concentrations of 65 mg/dL (3.6 mmol/L), which do not cause symptoms but do activate glucose counterregulatory systems, also activate brain synaptic activities.

RESEARCH DESIGN AND METHODS

We measured relative regional cerebral blood flow (rCBF), an index of synaptic activity, in predefined brain regions with [¹⁵O]water positron emission tomography, symptoms, and plasma epinephrine and glucagon concentrations during a 2-h euglycemic (90 mg/dL) to hypoglycemic (55 mg/dL) clamp (n = 20) or a 2-h euglycemic to slight subphysiological (65 mg/dL) clamp (n = 9) in healthy humans.

RESULTS

Clamped plasma glucose concentrations of 65 mg/dL did not cause hypoglycemic symptoms, but raised plasma epinephrine and glucagon concentrations and increased rCBF (P = 0.007) only in the dorsal midline thalamus.

CONCLUSIONS

Slightly subphysiological plasma glucose concentrations increase synaptic activity in the dorsal midline thalamus in humans.Iatrogenic hypoglycemia is the limiting factor in the glycemic management of diabetes (1). It causes recurrent morbidity in most people with type 1 diabetes and many with advanced type 2 diabetes, and is sometimes fatal (2). Indeed, as many as 1 in 10 people with type 1 diabetes may die of treatment-induced hypoglycemia (3). In addition, hypoglycemia per se causes a vicious cycle of recurrent hypoglycemia and that barrier generally precludes maintenance of euglycemia over a lifetime of diabetes.Hypoglycemia in diabetes is generally the result of the interplay of therapeutic hyperinsulinemia and compromised physiological and behavioral defenses against falling plasma glucose concentrations (1). The compromised defenses include: 1) loss of a decrease in insulin, 2) loss of an increase in glucagon, and 3) attenuation of the central nervous system (CNS)–mediated increase in sympathoadrenal activity as plasma glucose levels fall. The attenuated adrenomedullary epinephrine response causes defective glucose counterregulation and the attenuated sympathetic neural response is largely responsible for hypoglycemia unawareness. These are the two components of hypoglycemia-associated autonomic failure in diabetes (1). The mechanisms of the normal CNS-mediated sympathoadrenal response to hypoglycemia and how it goes awry in diabetes are not known, but it is thought to involve a cerebral network that includes the thalamus (4–7). It is our premise that insight into the CNS physiology of the sympathoadrenal response in nondiabetic humans will lead to insight into its pathophysiology in people with diabetes.There is a hierarchy among the responses to falling plasma glucose concentrations in humans (4). Among the CNS-mediated responses, the glycemic threshold for epinephrine secretion is 65–70 mg/dL and for symptoms is 50–55 mg/dL. It is not known if there is a hierarchy among the brain synaptic responses.Measurements of regional cerebral blood flow (rCBF), an index of synaptic activity, with [¹⁵O]water positron emission tomography (PET) indicate that frank hypoglycemia (e.g., clamped plasma glucose concentrations of 50–55 mg/dL) causes increases in rCBF in a network of interconnected brain regions including the dorsal midline thalamus and the medial prefrontal cortex (anterior cingulate) among other sites in humans (5–7). Indeed, recent antecedent hypoglycemia results in a greater increase in synaptic activity in the dorsal midline thalamus during subsequent hypoglycemia (6). Because slightly subphysiological plasma glucose concentrations of 65 mg/dL also stimulate epinephrine secretion but do not cause symptoms (4), we tested the hypothesis that such slightly subphysiological plasma glucose concentrations also activate brain synaptic activities in humans.     

Improving epinephrine responses in hypoglycemia unawareness with real-time continuous glucose monitoring in adolescents with type 1 diabetes

OBJECTIVE

To determine whether real-time continuous glucose monitoring (CGM) with preset alarms at specific glucose levels would prove a useful tool to achieve avoidance of hypoglycemia and improve the counterregulatory response to hypoglycemia in adolescents with type 1 diabetes with hypoglycemia unawareness.

RESEARCH DESIGN AND METHODS

Adolescents with type 1 diabetes with hypoglycemia unawareness underwent hyperinsulinemic hypoglycemic clamp studies at baseline to determine their counterregulatory hormone responses to hypoglycemia. Subjects were then randomized to either standard therapy or real-time CGM for 4 weeks. The clamp study was then repeated.

RESULTS

The epinephrine response during hypoglycemia after the intervention was greater in the CGM group than in the standard therapy group.

CONCLUSIONS

A greater epinephrine response during hypoglycemia suggests that real-time CGM is a useful clinical tool to improve hypoglycemia unawareness in adolescents with type 1 diabetes.Hypoglycemia unawareness is defined as the onset of neuroglycopenia before autonomic activation (1). Patients have defective symptomatic and counterregulatory responses, in particular impaired epinephrine response to hypoglycemia. Both defective counterregulatory responses and hypoglycemia unawareness constitute the hypoglycemia-associated autonomic failure associated with recurrent iatrogenic hypoglycemia (2–4).In adults, it has been demonstrated that as little time as 2 to 3 weeks of avoidance of hypoglycemia reverses hypoglycemia unawareness and improves the attenuated epinephrine component of defective counterregulation in affected patients (5–7). Although strict avoidance of hypoglycemia can restore autonomic symptoms of hypoglycemia and improve counterregulatory responses to hypoglycemia, this is difficult to achieve in practice. Real-time continuous glucose monitoring (CGM) allows patients to view their blood glucose levels almost instantaneously and offers potential to reduce hypoglycemia frequency.This study was designed to determine whether real-time CGM with preset alarms at specific glucose levels would prove a useful tool to achieve avoidance of hypoglycemia and therefore improve the counterregulatory response to hypoglycemia in adolescents with type 1 diabetes with hypoglycemia unawareness.     

Role of Epinephrine-mediated β-Adrenergic Mechanisms in Hypoglycemic Glucose Counterregulation and Posthypoglycemic Hyperglycemia in Insulin-dependent Diabetes Mellitus

Initially euglycemic (overnight insulin-infused) patients with insulin-dependent diabetes mellitus (IDDM), compared with nondiabetic controls, exhibit similar, but somewhat delayed plasma glucose nadirs, delayed glucose recovery from hypoglycemia, and posthypoglycemic hyperglycemia after the rapid intravenous injection of 0.075 U/kg of regular insulin. These abnormalities are associated with and potentially attributable to markedly diminished glucagon secretory responses, partially reduced epinephrine secretory responses and delayed clearance of injected insulin in the diabetic patients. Because glucagon normally plays a primary role in hypoglycemic glucose counterregulation and enhanced epinephrine secretion largely compensates for glucagon deficiency, we hypothesized that patients with IDDM, who exhibit diminished glucagon secretory responses to hypoglycemia, would be more dependent upon epinephrine to promote glucose recovery from hypoglycemia than are nondiabetic persons. To test this hypothesis, glucose counterregulation during beta-adrenergic blockade with propranolol was compared with that during saline infusion in both nondiabetic controls and in patients with IDDM. Glucose counterregulation was unaffected by beta-adrenergic blockade in controls. In contrast, glucose recovery from hypoglycemia was significantly impaired during beta-adrenergic blockade in diabetic patients. This finding confirms the hypothesis that such patients are more dependent upon epinephrine-mediated beta-adrenergic mechanisms to promote glucose recovery from hypoglycemia and indicates that the measured deficiency of glucagon secretion is functionally important in patients with IDDM. Further, in the time frame of these studies, posthypoglycemic hyperglycemia was prevented by beta-adrenergic blockade in these patients. There was considerable heterogeneity among the diabetic patients with respect to the degree to which beta-adrenergic blockade limited the posthypoglycemic rise in plasma glucose. This rise was directly related to the degree of residual glucagon secretion and inversely related to plasma-free insulin concentrations.THUS, WE CONCLUDE: (a) that patients with IDDM are, to varying degrees, dependent upon epinephrine-mediated beta-adrenergic mechanisms to promote glucose recovery from hypoglycemia and that the degree of this dependence upon epinephrine is an inverse function of the residual capacity to secrete glucagon in response to hypoglycemia in individual patients; (b) that sympathoadrenal activation, coupled with the inability to secrete insulin, plays an important role in the pathogenesis of posthypoglycemic hyperglycemia in patients with IDDM.     

Relevance of glucose counterregulatory systems to patients with diabetes: critical roles of glucagon and epinephrine

Glucagon normally plays a primary role in promoting glucose recovery from insulin-induced hypoglycemia. Epinephrine compensates largely for deficient glucagon secretion. Glucose recovery from hypoglycemia fails to occur only in the absence of both glucagon and epinephrine. Perhaps as a relatively early feature of autonomic neuropathy, patients with insulin-dependent diabetes mellitus commonly have blunted or absent glucagon secretory responses to hypoglycemia. However, this deficient response is commonly compensated for by epinephrine and glucose recovery occurs. In some patients, progression of adrenergic neuropathy to the point of deficient epinephrine secretory responses to hypoglycemia, coupled with deficient glucagon responses, leads to frequent, severe, and prolonged hypoglycemia. Thus, these glucose counterregulatory systems are of critical importance to patients with insulin-dependent diabetes mellitus. The efficacy of glucose counterregulation in a given patient may determine the degree to which euglycemia can be achieved with aggressive insulin therapy in that patient.     

How to ameliorate the problem of hypoglycemia in intensive as well as nonintensive treatment of type 1 diabetes

Maintenance of long-term near-normoglycemia by intensive therapy largely, if not fully, prevents the onset of microangiopathic complications and delays progression of complications in type 1 diabetic patients. However, intensive therapy has been reported to increase the frequency of severe hypoglycemia. In addition, a number of experimental studies have shown that a few episodes of mild, recurrent hypoglycemia blunt the symptom and hormonal responses to hypoglycemia over the next few days. At present, the critical "post-DCCT" (Diabetes Control and Complications Trial) questions are: is it possible to maintain long-term HbA1c < 7.0%, first, without increasing the frequency of severe hypoglycemia, and second, without increasing the frequency of mild, recurrent hypoglycemia? The answer is yes. The key factors are use of a physiological model of insulin replacement and the education of patients to appropriate the decision of insulin dose based on blood glucose monitoring and eating patterns. Hypoglycemia unawareness should be suspected whenever HbA1c is < 6.0 (upper normal limit 5.5%) and the patient does not report autonomic symptoms when their blood glucose level is < 3.0 mmol/l. The unaware patients should be treated with a short-term program of meticulous prevention of hypoglycemia, which reverses the abnormalities of responses of symptoms, hormonal counterregulation, and brain cognitive function. In turn, reversal of these abnormalities decreases the risk for severe hypoglycemia. Importantly, a program of meticulous prevention of hypoglycemia does not result in loss of long-term near-normoglycemia, i.e., it is compatible with the glycemic targets of intensive therapy.     

Complications of insulin-dependent diabetes mellitus: management of insulin reactions and acute illness

Occasional mild hypoglycemia is an unavoidable and usually acceptable side effect of intensive insulin therapy. Patients with insulin-dependent diabetes mellitus may have impaired glucose counterregulation, which may increase the risk of hypoglycemia and justify less ambitious glycemic goals. A conservative but flexible approach to the treatment of insulin reactions is appropriate in order to avoid hyperglycemia. Insulin requirements are often increased during acute illness, and frequent self-monitoring of blood glucose concentrations is necessary to determine the need for supplementation with regular insulin. Frequent supplementation, together with modification of diet and maintenance of fluid intake, should not only minimize the need for hospitalization but also prevent severe deterioration in glycemic control.     

Hypoglycemia in type 1 diabetes: a still unresolved problem in the era of insulin analogs and pump therapy

The Diabetes Control and Complications Trial demonstrated that in patients with type 1 diabetes, tight metabolic control achieved with intensive insulin therapy can reduce the risk of long-term microvascular complications. However, strict glycemic control carries an increased risk of severe hypoglycemia. Recurrent episodes of hypoglycemia, especially at young ages, can lead to hypoglycemia unawareness, exert adverse effects on neurocognitive function, and cause significant emotional morbidity in the child and parents. Although the introduction of the new insulin analogs in diabetes therapy and the use of continuous subcutaneous insulin infusion raised hopes for a solution to this problem, these modalities have not been associated with the expected reduction in hypoglycemic episodes. The findings suggest that the prevention of hypoglycemia in patients with type 1 diabetes lies in biologically controlled insulin secretion, as in islet transplantation, or the development of an autonomous closed-loop system that efficiently mimics the action of the pancreatic beta-cells and maintains blood glucose levels within the desired range.     

Mechanisms of sympathoadrenal failure and hypoglycemia in diabetes

A reduced sympathoadrenal response, induced by recent antecedent hypoglycemia, is the key feature of hypoglycemia-associated autonomic failure (HAAF) and, thus, the pathogenesis of iatrogenic hypoglycemia in diabetes. Understanding of the mechanism(s) of that reduced response awaits new insight into its basic molecular, cellular, organ, and whole-body physiology and pathophysiology in experimental models. In this issue of the JCI, McCrimmon and colleagues report that application of urocortin I (a corticotrophin-releasing factor receptor-2 agonist) to the ventromedial hypothalamus reduces the glucose counterregulatory response to hypoglycemia in rats (see the related article beginning on page 1723). Thus, hypothalamic urocortin I release during antecedent hypoglycemia is, among other possibilities, a potential mechanism of HAAF.     

Blunted Counterregulatory Hormone Responses to Hypoglycemia in Young Children and Adolescents With Well-Controlled Type 1 Diabetes

OBJECTIVE

Hypoglycemia in young children with type 1 diabetes is an acute complication of intensive insulin therapy and is commonly observed in the absence of signs or symptoms. The effect of intensive treatment and patient age on sympathoadrenal responses has not been established in youth with type 1 diabetes because of difficulties in testing procedures.

RESEARCH DESIGN AND METHODS

We developed a standardized inpatient continuous subcutaneous insulin infusion protocol to produce a progressive fall in plasma glucose concentrations in insulin pump–treated patients. Plasma glucose and counterregulatory hormone concentrations were measured in 14 young children (3 to <8 years, A1C 7.7 ± 0.6%) vs. 14 adolescents (12 to <18 years, A1C 7.6 ± 0.8%).

RESULTS

Plasma glucose decreased to similar nadir concentrations in the two groups. Four young children and four adolescents never had an epinephrine response. In the four young children and five adolescents who had a modest epinephrine response, this only occurred when plasma glucose fell to <60 mg/dl. In evaluating symptom scores, 29% of parents of young children felt that their child looked hypoglycemic, even at the lowest plasma glucose concentrations. Adolescents were better able to detect symptoms of hypoglycemia. In comparison with our data, epinephrine response to hypoglycemia in 14 nondiabetic adolescents studied at the Children''s Hospital of Pittsburgh was higher.

CONCLUSIONS

These data suggest that even young children and adolescents with type 1 diabetes are prone to develop hypoglycemia-associated autonomic failure regardless of duration. Whether these abnormalities can be reversed using continuous glucose monitoring and closed-loop insulin delivery systems awaits further study.Severe hypoglycemia is a life-threatening complication of intensive therapy of type 1 diabetes, especially in youth. In the Diabetes Control and Complications Trial, adolescents had a higher rate of severe hypoglycemia than adults (1). Young children are at even greater risk (2) and pose a particular therapeutic dilemma, because recurrent episodes of hypoglycemia may have adverse effects on brain development, and anecdotal reports from parents indicate that hypoglycemic events are commonly observed in this age-group in the absence of any signs or symptoms. In nondiabetic children hypoglycemia triggers counterregulatory responses that include increases in plasma glucagon and epinephrine concentrations. In nondiabetic adolescents and in conventionally treated adolescents with poorly controlled type 1 diabetes, the plasma glucose threshold that stimulates an epinephrine response has been reported to be higher and the rise in epinephrine levels is greater than in nondiabetic adults (3). Because glucagon responses to hypoglycemia are lost early in the disease (4), an intact plasma epinephrine response is critical in patients with type 1 diabetes.In adults with type 1 diabetes, the episodes of mild hypoglycemia that accompany intensive treatment induce a defect in sympathoadrenal responses that has been termed hypoglycemia-associated autonomic failure (5–8). Whether intensive treatment causes similar defects in youth with type 1 diabetes has not been well studied, in part because of difficulties in performing controlled hypoglycemia clamps in children.We developed a continuous subcutaneous insulin infusion protocol to produce a progressive fall in plasma glucose in insulin pump–treated youth with well-controlled type 1 diabetes. Counterregulatory hormone concentrations were measured sequentially to compare the plasma glucose threshold for and magnitude of these hormone responses in young children versus adolescents. Although not strictly comparable, we also report the epinephrine responses to a similar degree of hypoglycemia in nondiabetic adolescents to provide a frame of reference to judge responses to hypoglycemia in the type 1 diabetic subjects.     

Recognition, prevention, and proactive management of hypoglycemia in patients with type 1 diabetes mellitus

Hypoglycemia is the key barrier that prevents patients from optimizing glycemic control with the use of pharmacotherapeutic interventions. Optimal glycemic control for patients with type 1 diabetes (T1DM) includes methods that provide glucose-regulated physiologic insulin replacement or secretion in association with glucose monitoring methods designed to predict and prevent acute extreme changes in glycemic variability. Patients with T1DM experience an average of 2 episodes of symptomatic hypoglycemia each week and at least 1 episode of severe, disabling hypoglycemia annually. Asymptomatic hypoglycemia is common, as shown in studies using continuous glucose monitoring (CGM). Episodes of hypoglycemia (symptomatic and asymptomatic) impair counterregulatory defenses against subsequent events, resulting in the inability to respond to and recover from serious hypoglycemia. This defective counterregulation is known as hypoglycemic-associated autonomic failure. When patients are prescribed a more intensive medication regimen or reinforcing lifestyle interventions, such as medical nutrition therapy and exercise therapy, providers should also assess their ability to proactively identify and manage hypoglycemia. Although self-monitoring of blood glucose regimens, such as pre- and post-meal and periodic middle-of-the-night glucose testing, can help predict the risk of developing hypoglycemia, CGM technology allows patients to receive real-time notification of impending events either through preset alarms or simply by looking at the device display. This review explores the utility of initiating CGM within the primary care setting for patients at high risk for developing hypoglycemia.     

Effect of 2 weeks of theophylline on glucose counterregulation in patients with type 1 diabetes and unawareness of hypoglycemia

BACKGROUND AND OBJECTIVE: A single dose of theophylline improves hypoglycemia unawareness in type 1 diabetic patients. Prolonged theophylline use is, however, associated with emergence of tolerance. This study investigated whether prolonged use of theophylline retains efficacy for counterregulatory defects in patients with type 1 diabetes and hypoglycemia unawareness. METHODS: Experiments were performed with 12 subjects with type 1 diabetes and hypoglycemia unawareness. All subjects participated in a crossover study of 2 randomly scheduled 15-day study periods during which 250 mg theophylline twice daily or matching placebo was used. On the final day of each period, hyperinsulinemic (360 pmol x m(-2) x min(-1)) hypoglycemic (5.0, 3.5, 2.5 mmol x L(-1)) glucose clamps were used to assess counterregulatory and cardiovascular responses. RESULTS: Under normoglycemic conditions, there were no differences between theophylline and placebo. Under hypoglycemic conditions, theophylline enhanced responses of growth hormone, symptoms, heart rate, and pulse pressure (all P <.05), induced sweating at higher plasma glucose levels (P =.039), and reduced exogenous glucose requirements (P =.018). Hypoglycemia-induced responses of epinephrine, norepinephrine, and cortisol were not enhanced by theophylline. CONCLUSIONS: Prolonged use of theophylline has a sustained effect on cardiovascular, metabolic, and symptom responses to hypoglycemia in patients with type 1 diabetes and hypoglycemia unawareness. Whether these results translate into clinical benefit remains to be determined.     

Philip E. Cryer,MD: Seminal Contributions to the Understanding of Hypoglycemia and Glucose Counterregulation and the Discovery of HAAF (Cryer Syndrome)

Optimized glycemic control prevents and slows the progression of long-term complications in patients with type 1 and type 2 diabetes. In healthy individuals, a decrease in plasma glucose below the physiological range triggers defensive counterregulatory responses that restore euglycemia. Many individuals with diabetes harbor defects in their defenses against hypoglycemia, making iatrogenic hypoglycemia the Achilles heel of glycemic control. This Profile in Progress focuses on the seminal contributions of Philip E. Cryer, MD, to our understanding of hypoglycemia and glucose counterregulation, particularly his discovery of the syndrome of hypoglycemia-associated autonomic failure (HAAF).Open in a separate windowPhilip E. Cryer, as a mature professor and as a U.S. Naval officer.     

Catecholamine response during human and pork insulin-induced hypoglycemia in IDDM patients.

OBJECTIVE--To evaluate the catecholamine response during human and pork insulin-induced hypoglycemia. RESEARCH DESIGN AND METHODS--Ten insulin-dependent diabetes mellitus (IDDM) patients without any signs of autonomic neuropathy received either human or pork insulin in a randomized crossover fashion on 2 nonconsecutive days. The glucose clamp technique was applied to achieve stable glycemic plateaus of 5.6, 3.3, 2.2, and 1.7 mM. RESULTS--The effect of both types of insulin on glucose metabolism and circulating catecholamines was almost identical. There was a sharp rise of both epinephrine (P less than 0.05) and norepinephrine (P less than 0.02) during hypoglycemia, which did not depend on the type of insulin applicated. Symptom awareness increased significantly during the decrease of blood glucose concentration. Only during developing hypoglycemia (3.3-mM plateau), was this effect more pronounced (cumulative symptom score 2 vs. 26, P less than 0.05) with pork insulin. CONCLUSIONS--AN attenuated catecholamine secretion seems not to be the putative mechanism of a reduced awareness of human insulin-induced hypoglycemia.     

CGMS监测无知觉性低血糖的效果观察

目的 探讨CGMS监测无知觉性低血糖的效果和意义.方法 将接受胰岛素泵治疗的120例Ⅱ型糖尿病患者按照自愿的原则分为实验组和对照组,实验组使用CGMS,对照组使用强生血糖仪监测血糖,比较2组对患者发生无知觉性低血糖的检测效果和住院期间控制血糖需支付的医疗费用.结果 实验组对Ⅱ型糖尿病治疗中无知觉性低血糖检测率明显高于对照组(P＜0.01);实验组患者住院期间控制血糖的平均费用与对照组无明显差异(P＞0.05).结论 CGMS能准确有效地监测无知觉性低血糖,及时调整胰岛素用量,减少低血糖发生率,从而降低住院期间控制血糖需支付的总费用.     

Randomized controlled clinical trial of glargine versus ultralente insulin in the treatment of type 1 diabetes

OBJECTIVE: Multiple daily insulin injection programs are commonly accompanied by considerable glycemic variation and hypoglycemia. We conducted a randomized crossover design clinical trial to compare glargine with ultralente insulin as a basal insulin in type 1 diabetes. RESEARCH DESIGN AND METHODS: To determine whether the use of glargine insulin as a basal insulin would result in a comparable HbA1c and less glycemic variation and hypoglycemia than ultralente insulin, 22 individuals (aged 44 +/- 14 years [+/-SD], 55% men) with type 1 diabetes who were experienced with multiple daily insulin injections and had an HbA1c of <7.8% were randomized in a crossover design to receive either glargine or ultralente as the basal insulin for 4 months. Aspart insulin was used as the prandial insulin. Physicians providing insulin dose adjustment advice were masked to the type of basal insulin. RESULTS: Treatment with glargine resulted in lower mean HbA1c (6.82 +/- 0.13 vs. 7.02 +/- 0.13, difference: 0.2 +/- 0.08, P = 0.026), less nocturnal variability (plasma glucose 49.06 +/- 4.74 vs. 62.36 +/- 5.21 mg/dl, P = 0.04), and less hypoglycemia (24.5 +/- 2.99 vs. 31.3 +/- 4.04 events, P = 0.05), primarily due to less daytime hypoglycemia (P = 0.002). On the other hand, serious hypoglycemia and average glucose concentration measured with continuous subcutaneous glucose monitoring did not differ. CONCLUSIONS: We conclude that while use of either ultralente or glargine as a basal insulin can result in excellent glycemic control, treatment with glargine is associated with slightly but significantly lower HbA1c and less nocturnal glycemic variability and hypoglycemia.     

Glucagon, catecholamine and pancreatic polypeptide secretion in type I diabetic recipients of pancreas allografts.

Successful pancreas transplantation in type I diabetic patients restores normal fasting glucose levels and biphasic insulin responses to glucose. However, virtually no data from pancreas recipients are available relative to other islet hormonal responses or hormonal counterregulation of hypoglycemia. Consequently, glucose, glucagon, catecholamine, and pancreatic polypeptide responses to insulin-induced hypoglycemia and to stimulation with arginine and secretin were examined in 38 diabetic pancreas recipients, 54 type I diabetic nonrecipients, and 26 nondiabetic normal control subjects. Glucose recovery after insulin-induced hypoglycemia in pancreas recipients was significantly improved. Basal glucagon levels were significantly higher in recipients compared with nonrecipients and normal subjects. Glucagon responses to insulin-induced hypoglycemia were significantly greater in the pancreas recipients compared with nonrecipients and similar to that observed in control subjects. Glucagon responses to intravenous arginine were significantly greater in pancreas recipients than that observed in both the nonrecipients and normal subjects. No differences were observed in epinephrine responses during insulin-induced hypoglycemia. No differences in pancreatic polypeptide responses to hypoglycemia were observed when comparing the recipient and nonrecipient groups, both of which were less than that observed in the control subjects. Our data demonstrate significant improvement in glucose recovery after hypoglycemia which was associated with improved glucagon secretion in type I diabetic recipients of pancreas transplantation.     

Management of type 1 diabetes

Although less prevalent than type 2 diabetes, autoimmune type 1 diabetes presents numerous challenges, including many that must be addressed daily. Patients must have appropriate tools to confront and manage their physiologic insulin deficiency syndrome. The vast majority of patients who have type 1 diabetes require a basal insulin to suppress hepatic glucose production in the fasting state, as well as prandial (mealtime) insulin to cover glycemic excursions that occur as carbohydrate absorption occurs in response to meals. Patients need algorithms to self-adjust both their prandial and basal insulin doses. The ultimate goal of all patients who have diabetes is to attain and maintain an A1C as close to normal as possible, while maintaining safety, avoiding hypoglycemia, and minimizing glycemic variability, as close to normal as possible, while maintaining safety and avoiding severe hypoglycemia.