Closed-loop delivery of insulin

The importance of exactly matching blood glucose levels in patients with diabetes mellitus with the dose and timing of insulin cannot be overemphasized. This is true for both type 1 and type 2 diabetes. The prevention of the serious consequences of diabetes should be a therapeutic goal because of the personal and national economic costs of treating the disease and its sequelae. Avoidance of sequelae cannot be achieved without so-called intensive treatment of the disease; however, this is a difficult and sometimes hazardous process. An automated and ’safe’ method of achieving intensive treatment (closed-loop insulin delivery) has been an important focus of research for many years since it was realized that the simple replacement of insulin saved the lives of patients with diabetes, but did not guarantee good health. Following the general successes of organ transplant, the obvious line of enquiry in the last three decades was to replace the pancreas with donor tissue; however, even when superseded by the simpler process of islet transplant, the benefits of this have not been widespread. This is because of the shortcomings and incompatibilities of immunosuppression with the functioning of the graft, among other problems. The two types of rejection that may occur in the presence of the autoimmune type of diabetes further endanger graft function; however, recently there have been advances that have partially solved this problem. Nevertheless, the lifetime risks of immunosuppression and the shortage of donor material still make transplant less attractive than first thought. Consequently, other approaches to closed-loop insulin delivery have been important. These include implantable pumps coupled with sensors and a range of devices incorporating glucose-sensitive materials that could be engineered into delivery systems to work by closed loop. Each of these has relative advantages and drawbacks, but some have the capacity to reach the market for clinical use. Of these, the MiniMed pump would appear to be in the lead, and is at present undergoing clinical trials that have given promising results but that have not yet entirely solved the closed-loop problem. Other designs may yet become important contenders in this interesting contest.     

Interaction of physiological mechanisms in control of muscle glucose uptake

1. Control of glucose uptake is distributed between three steps. These are the rate that glucose is delivered to cells, the rate of transport into cells, and the rate that glucose is phosphorylated within these same cells. The functional limitations to each one of these individual steps has been difficult to assess because they are so closely coupled to each other. Studies have been performed in recent years using complex isotopic techniques or transgenic mouse models to shed new light on the role that each step plays in overall control of muscle glucose uptake. 2. Membrane glucose transport is a major barrier and glucose delivery and glucose phosphorylation are minor barriers to muscle glucose uptake in the fasted, sedentary state. GLUT-4 is translocated to the muscle membrane during exercise and insulin-stimulation. The result of this is that it can become so permeable to glucose that it is only a minor barrier to glucose uptake. 3. In addition to increasing glucose transport, exercise and insulin-stimulation also increase muscle blood flow and capillary recruitment. This effectively increases muscle glucose delivery and by doing so, works to enhance muscle glucose uptake. 4. There is a growing body of data that suggests that insulin resistance to muscle glucose uptake can be because of impairments in any one or more of the three steps that comprise the process.     

Rapid acting insulinotropic agents: restoration of early insulin secretion as a physiologic approach to improve glucose control

The loss of early insulin secretion appears to be a critical event in the deterioration in glucose tolerance during the development of type 2 diabetes. There is therefore a strong rationale for developing new antidiabetic agents aimed at restoring or replacing early prandial insulin secretion and thereby curbing mealtime glucose excursions in patients with type 2 diabetes. Four such new agents are either now available (repaglinide and nateglinide) or in clinical development (KAD-1229 and BTS 67 582). Preclinical studies suggest that each of these new insulinotropic agents share a common receptor/effector mechanism with the sulfonylureas (SUs) but that each may have distinct characteristics that differentiate them from the SUs and from each other. Nateglinide and KAD-1229 clearly stimulate biphasic insulin secretion in vitro and in vivo and their effects are rapidly reversible, whereas the effects of repaglinide and BTS 67 582 are prolonged well beyond their removal from perfusion media in vitro or their clearance in vivo. Available data from human studies indicate that the pharmacokinetics of repaglinide and nateglinide are similar, i.e., they are both rapidly absorbed and eliminated, but consistent with findings from animal studies, the insulinotropic and glucose-lowering effects of repaglinide are slower in onset and more prolonged than those of nateglinide. Repaglinide and nateglinide have been shown to be safe and well-tolerated in patients with type 2 diabetes and to produce clinically-meaningful reductions of HbA1c, both alone and in combination with agents with complementary modes of action (e.g., metformin and thiazolidinediones). Because these new agents can potentially bring patients to near normoglycemia without an undue risk of hypoglycemia, they are important additions to the therapeutic armamentarium.     

A new physiological approach to control essential hypertension

This study was conducted on 20 male patients of Essential Hypertension (EH) in order to explore the possible role of baroreflex mechanism in the etiology of EH and also to find out whether by restoration of baroreflex sensitivity to normal level either by postural tilt stimulus on a tilt table or by the equivalent yogic postural exercise (Yogic asanas), the EH could be cured or controlled. Patients on therapeutic regime were gradually withdrawn from drug therapy, and later divided into two groups of 10 each. Group-I (age 34 +/- 1.7 years) was subjected to a 3 week course of 70 degrees head-up tilt for 30 min daily, while in group-II (age 50 +/- 3.3 years), specific yogic exercises equivalent to head-up or head-down tilt were administered for the same duration. The progressive autonomic readjustments were assessed by a battery of tests including cardiovascular responses to head up tilt, cold pressor response at 4 degrees C water (CPR), alpha index of EEG (AI), level of blood catecholamines (CA) and plasma renin activity (PRA). At the end of 3 weeks, there was a significant reduction (P < 0.001) in blood pressure in both the groups. Progressive changes in BP and HR response to tilt during 3 weeks course of tilt and yogic exercise clearly indicated gradual improvement in baroreflex sensitivity. Likewise, changes in other indices like CPR, AI, CA and PRA indicated progressive attenuation of sypatho-adrenal and renin-angiotensin activity. All these changes together with the reduction in BP strongly suggest a close link between the etiology of EH and baroreflexes on the one hand and controlling influence of the latter on sympatho-adrenal and renin-angiotensin systems on the other. It also throws light on the physiological mechanism underlying the effects of selected yogic exercises in the treatment of EH.     

Validation of an insulin infusion nomogram for intensive glucose control in critically ill patients

STUDY OBJECTIVE: To evaluate the effectiveness, safety, and associated patient outcomes of a simplified, nurse-directed insulin nomogram designed to achieve intensive blood glucose level control (target range 90-144 mg/dl). DESIGN: Prospective study with a retrospective control group. SETTING: A medical-surgical intensive care unit (ICU) in a quaternary care, university-affiliated hospital in an urban center. PATIENTS: Eighty-six critically ill adult patients (aged>or=18 yrs) requiring blood glucose control, with 42 in the retrospective control group and 44 in the prospective nomogram group. INTERVENTION: Control patients received insulin subcutaneously or intravenously based on ad hoc insulin sliding scales; nomogram patients received intravenous insulin at a rate specified by the nomogram, based on capillary blood glucose levels measured at the bedside. MEASUREMENTS AND MAIN RESULTS: Insulin infusion in the prospective patient group was titrated by the bedside nurse based on a predefined nomogram to attain the target blood glucose level. The retrospective control group was used as a comparison to assess the safety and effectiveness of the nomogram. Fewer patients in the nomogram (32%) than control (67%) group had a diagnosis of diabetes mellitus on admission. Overall, blood glucose levels in the nomogram group were within the target range 52% of the time versus 20% in the control group (p<0.001). Morning blood glucose levels were significantly lower compared with the control group (mean+/-SD 128+/-32 vs 176+/-50 mg/dl, p<0.001). Nomogram patients achieved target blood glucose levels faster than control patients (median 15 vs 66 hrs, p<0.0001). This improved blood glucose control remained statistically significant after adjusting for baseline differences in diabetes status. Hyperglycemia occurred less often in the nomogram than the control group (14% vs 53%, p<0.0001), and hypoglycemia occurred more often (3.8% vs 2.2%, p=0.004). The frequency of severe hypoglycemia was similar in both groups (0.2% vs 0.4%, p=NS). Such control required slightly more blood glucose checks/day in the nomogram group (7.1+/-1.5 vs 5.8+/-1.1, p<0.001). No significant reduction was observed in duration of vasopressor or antibiotic therapy or in length of stay in the ICU. CONCLUSION: This study demonstrated that intensive blood glucose control is achievable using a nurse-directed nomogram. This improved control was achieved, regardless of diabetes status of the patient, without substantially compromising safety or increasing resource use.     

The insulin receptor--a critical link in glucose homeostasis and insulin action

We have achieved significant progress in understanding the central role of the insulin receptor in an increasingly complicated web of intracellular signal transduction leading to the ultimate biological actions of insulin on glucose, lipid, and other metabolic pathways. The excitement for the future lies not only in clarifying these pathways but also returning to whole-body physiology to readdress basic mechanisms of insulin action in known and novel insulin-sensitive tissues. Hopefully, these new techniques and new perspectives will bring us closer to understanding the pathophysiology of type 2 diabetes mellitus.     

Effect of glucose electrolyte ingestion on physiological changes due to severe heat stress

Severe heat stress experienced by aircrew during summer months can cause deterioration in performance. Acute heat stress can also lead to dehydration and loss of electrolytes. Previous studies emphasised the need of K+ replacement. This study was carried out to determine the effect of glucose electrolyte ingestion (ELECTRAL) on thermal strain parameters. Ten healthy male subjects in the age group of 19-43 years were exposed to an acute thermal environment of 50 degrees C Tdb with relative humidity of 30% for 40 min. twice each day on two different days with an interval of one hour in between the exposures. At the beginning of rest period electrolyte solution was ingested during electrolyte trials and water under control trials. Physiological parameters of Tsk, T or, HR and electrolyte concentration of Na+ and K+ in sweat did not show any significant difference in both the trials. Sweat loss was significantly higher during electrolyte trials.     

Type 1 diabetes: benefits of intensive insulin therapy. Patients should control blood glucose strictly

The DCCT randomised trial compared insulin therapy with strict glycaemic control versus less strict insulin therapy in patients with type 1 diabetes. The trial itself lasted more than 6 years, and most of the patients were subsequently followed up for another 4 years. The initial benefit of strict glycaemic control on the onset or worsening of diabetic retinopathy and nephropathy does appear to persist in the long term     

化学修饰胰岛素降血糖作用及抗胰蛋白酶降解能力的研究

目的评价化学修饰胰岛素的降血糖作用及抗胰蛋白酶降解的能力。方法将修饰胰岛素和胰岛素经小鼠皮下注射 ,用血糖仪测定它们的降血糖作用 ,比较它们抗胰蛋白酶降解的能力。结果修饰胰岛素和胰岛素有相似的降血糖作用 ,但修饰胰岛素抗胰蛋白酶降解的能力比胰岛素有明显的改善 ,降解的时间延长了 4h。结论修饰胰岛素具有较好的降血糖作用 ,并具有一定的抗胰蛋白酶降解能力     

Beta-blockers and glucose control

Literature on the effects of beta-blockers on blood glucose is reviewed. Data are presented regarding the adrenergic influences on glucose regulation and the effects of beta-blockade during hypo- and hyperglycemia in normal and diabetic individuals. beta-adrenergic stimulation enhances insulin and glucagon secretion, as well as glycogenolysis, gluconeogenesis, and lipolysis. alpha-adrenergic stimulation inhibits insulin secretion and may inhibit glucagon secretion and enhance liver glycogenolysis. In nondiabetics, beta-blockers represent minimal risk of affecting glucose control. In insulin-dependent diabetics, beta-blockers can prolong, enhance, or alter the symptoms of hypoglycemia, while hyperglycemia appears to be the major risk in noninsulin-dependent diabetics. beta-blockers can potentially increase blood glucose concentrations and antagonize the action of oral hypoglycemic drugs.     

Barriers to glucose control in the intensive care unit

Despite published evidence supporting glycemic control in critically ill patients, achieving euglycemia remains a problem in the intensive care units (ICUs) of many institutions. Clinicians seeking to implement the findings of published evidence in their practice face many potential barriers that make euglycemia difficult to achieve in patients in the ICU. Developing a comprehensive understanding of the many barriers to ICU glucose control can aide clinicians in attempting to change practice and improve patient outcomes. Barriers to ICU glucose control include the role of different health professionals in glucose management, communication among health care professionals, guidelines, protocols, ICU culture, fear of hypoglycemia, glucose monitoring, education, systems analysis, health care resources, nutritional needs, and drug utilization. By ensuring compliance, changing ICU culture, developing guidelines and protocols, and incorporating a multidisciplinary approach, clinicians can achieve glycemic control in the critically ill population and improve patient outcomes.     

Effect of biphasic insulin aspart on glucose and lipid control in patients with Type 2 diabetes mellitus

Objective: this study examined the efficacy and safety of biphasic insulin aspart 30 (BIAsp 30) monotherapy in insulin-naive patients with Type 2 diabetes mellitus. Research design and methods: in this 12-week, open-labelled, uncontrolled, clinical-experience study involving 71 patients with secondary oral antidiabetic agent failure, patients received BIAsp 30 after discontinuing oral antidiabetic drugs (OADs). Glucose and lipid concentrations, hypoglycaemic episodes and adverse events were assessed before and after treatment. Patient data were categorised according to previous OADs into the biguanides (BI) plus sulfonylureas/meglitinides (SU/MEG) and SU-only groups. Results: after treatment, glucose and lipid control was significantly improved in both groups, with a greater improvement in the SU-only group. Mean glycated haemoglobin, fasting blood glucose and postprandial blood glucose excursion improved by 2.15 ± 1.24%, 3.70 ± 3.18 mmol/l and 1.26 ± 2.65 mmol/l in the BI plus SU/MEG group, and by 3.09 ± 1.62%, 6.11 ± 5.02 mmol/l and 2.06 ± 2.33 mmol/l in the SU-only group, respectively. Mean high-density lipoprotein cholesterol and triglycerides improved by 0.09 ± 0.18 mmol/l and 0.94 ± 1.17 mmol/l in the BI plus SU/MEG group and by 0.09 ± 0.18 mmol/l and 1.04 ± 2.72 mmol/l in the SU-only group, respectively. No major hypoglycaemic episodes or serious treatment-related adverse events were reported. Conclusions: our study showed that BIAsp 30 treatment safely improved glucose and lipid control in insulin-naive patients with Type 2 diabetes poorly controlled on BI plus SU/MEG and SU-only. Key limitations were the lack of a comparator group and the short study duration.     

强化胰岛素治疗不同血糖控制水平对内科脓毒症患者的影响

目的：探讨应用强化胰岛素模式治疗不同血糖控制水平对内科脓毒症患者的影响。方法：按随机原则,符合条件的病例分成强化胰岛素治疗A组和强化胰岛素治疗B组,A组32例,B组33例。 A组血糖控制在4.4～6.1mmol/L,B组血糖控制在6.1～8.3mmol/L。对两组患者的ICU住院天数、ICU住院医疗费用、总住院天数、病死率、MODS发生率、低血糖发生率,治疗前及治疗后第五天血清CRP水平变化进行比较。结果：两组患者入重症医学科时在平均年龄、性别比例和APACH II评分上相似（P>0.05）,具有可比性。两组在ICU住院时间、ICU住院费用和总住院时间差异均无统计学意义（P>0.05）。A组MODS发病率、低血糖发生率和病死率明显低于B组,差别有统计学意义（P<0.05）。两组患者治疗后的CRP水平比治疗前均有显著下降,差异有统计学意义（P<0．05）。两组患者之间比较,治疗前CRP水平无明显差异（P>0.05）,治疗后A组患者CRP水平比B组患者低,有显著差异（P<0．05）。结论：对于脓毒症进行强化胰岛素治疗可以减轻炎症反应,且将血糖严格控制在4.4～6.1mmol/L水平比将血糖控制在较高水平6.1～8.3mmol/L,MODS的发病率明显降低,但同时要注意严密监测血糖,以避免低血糖给患者带来危害。     

Long-term effects of glipizide on insulin secretion and blood glucose control in patients with non-insulin-dependent diabetes mellitus

Summary Of 23 patients with non-insulin-dependent diabetes mellitus (NIDDM), whose fasting blood glucose had not reached 6.0 mmol·l^–1 after 10 weeks of dietary regulation, 15, who had had a weight reduction of –2.8 kg by dietary control, did achieve a fasting blood glucose 6.0 mmol·l^–1 after addition of 20 mg glipizide daily. They had a sustained (2 years) increase in meal-induced insulin secretion (32% increase in postprandial C-peptide AUC), and a sustained reduction in postprandial hyperglycaemia (34% reduction in AUC). Ten of the patients took a mean daily dose <5mg (4.8 mg) and had a sustained increase in insulin secretion rate (increased C-peptide slope). The 15 patients had no elevation of basal insulin secretion and no impairment of weight reduction. The remaining 8 subjects, who showed little or no weight reduction on dietary control, had little or no reduction in fasting blood glucose despite long-term treatment with 20 mg glipizide daily, a less sustained increase in meal-induced insulin secretion, a smaller reduction of postprandial hyperglycaemia, and an increase in body weight. On diagnosis the 8 subjects did not differ from the other 15 subjects in age, body weight, blood glucose, HbA₁c, C-peptide or insulin, nor in their glucose and insulin responses to a test dose of glipizide; the main reason for the apparent drug failure appeared to be deficient compliance with dietary regulation rather than a primary inability to respond to sulphonylurea treatment. The findings indicate that glipizide is able to promote and maintain increased meal-induced insulin secretion and near-normal fasting and non-fasting blood glucose levels without continuous B cell stimulation. However, these improvements prevail mainly in subjects who persist with hypocaloric dietary regulation.     

Increase in insulin response to glucose in the rat chronically treated with clonidine

Summary Effect of chronic clonidine treatment on the response to glucose of rat pancreatic B-cells was investigated. Clonidine treatment was carried out for 10 days by dissolving the drug into drinking water at a concentration of 10 g/ml. Control rats were given drug-free tap water. Serum insulin responses to glucose (750 mg/kg, i. v.) of clonidinetreated rats were much smaller than those of control rats. However, after 1 day's withdrawal of clonidine, the rise in the serum insulin level induced by glucose was approximately 2-fold larger in clonidine-treated rats as compared to that in control rats. Since clonidine treatment decreased body weight of the rat by 10%–20% in 10 days, the same experiments were carried out with rats whose body weight loss was made comparable to that of clonidine-treated rats by restricting food for 10 days. Then, some animals of the group thus treated had food-restriction discontinued for 1 day. In both of the above two groups, no increment in glucoseinduced rise in serum insulin level was observed. Islets of Langerhans isolated from clonidine-treated rats showed pronounced insulin releasing capacity in response to glucose. Insulin content per islet of the clonidine-treated rat was slightly larger than that of control rat. These results indicate that the enhancement of serum insulin response to glucose following clonidine treatment is mainly attributable to the hyper-responsiveness developed in the pancreatic B-cells.     

Serum glucose,insulin and C-peptide response to oral glucose after intravenous administration of hydrocortisone and methylprednisolone in man

Glucocorticoid-induced glucose intolerance and insulin resistance are dependent on the type of steroid, its dose and route of administration. Although the intravenous (i.v.) route is used mainly, the effects of different steroids have so far been compared using the oral route. The present study was therefore planned to compare the effects on glucose metabolism of hydrocortisone (HC) and methylprednisolone (MP) administered i.v. at equivalent antiinflammatory doses in healthy subjects.Eighteen healthy volunteers with normal glucose tolerance, divided into three groups (A,B,C) matched for age, sex and body mass index were subjected to oral glucose tolerance tests (oGTT) 12 h after HC or MP i.v. injection. The two tests were performed at a 1-month interval and in random sequence. Group A received low doses (HC 100 mg, MP 20 mg), group B intermediate doses (HC 200 mg, MP 40 mg) and group C high doses (HC 400 mg, MP 80 mg). Serum glucose, insulin and C-peptide were measured during both fasting and oGTT.Serum glucose values were not significantly different after HC or MP, during both fasting and oGTT. However, there was a positive correlation between fasting serum glucose or the area under the glucose curve and the dose·kg^–1 body weight of HC (r=0.748; r=0.462) and MP (r=0.708; r=0.736). Serum insulin values were significantly higher after MP than after HC when fasting (A: 115 vs 223; B: 95 vs 215, C: 158 vs 268 pmol·l^–1) and as area under the oGTT curve (A: 57.8 vs 87; B: 48.5 vs 92.1; C: 57.8 vs 94.5 pmol·l^–1·2 h). In contrast, serum C-peptide values were not significantly different after HC or MP, neither fasting nor as area under the insulin curve. Fasting C-peptide/insulin molar ratio was significantly lower after MP than HC at the three doses administered.In conclusion the dose-related decreases in glucose tolerance are more marked after a single i.v. injection of MP than HC at the same anti-inflammatory dose, MP 20 or 40 mg as well as HC 100 or 200 mg do not impair glucose tolerance, but the former is associated with higher serum insulin levels, suggesting insulin resistance. MP-induced hyperinsulinaemia seems to be mainly due to reduced hepatic insulin extraction.     

The physiological effects of vasopressin when used to control intra-abdominal bleeding

Vasopressin was used in ten critically ill patients with massive intra-abdominal bleeding unresponsive to conventional therapy. Vasopressin controlled bleeding in four patients, three of whom had continued to bleed following laparotomy for haemostasis; in two other patients, bleeding was reduced. All the patients were intensively monitored throughout the period of the vasopressin treatment; this enabled other physiological effects of vasopressin to be documented and reported. Mean arterial pressure and central venous pressure increased following the administration of vasopressin and there was a decrease in heart rate. Core body temperature rose significantly. Although all the patients had impaired renal function before receiving vasopressin, five had a prompt diuresis following its administration. Eight patients died but only three of intra-adbominal bleeding; two patients survived to leave hospital. Four patients had post-mortem evidence of ischaemia in the heart, liver and gastrointestinal tract; vasopressin may have contributed to the development of this. Vasopressin may have a place in the management of patients with life-threatening intra-abdominal haemorrhage but its use should be confined to those patients in whom conventional therapy has failed.     

Massive insulin overdose: detailed studies of free insulin levels and glucose requirements

The course of a diabetic patient who self-administered 2500 U of NPH insulin subcutaneously was examined in detail. Despite resumption of oral intake on day 3, she required iv glucose for 6 days, during which time serum free insulin levels remained elevated. Glucose requirements closely matched those calculated from published euglycemic clamp data on maximal glucose disposal rates during insulin infusion. We postulate that her prolonged course was due to delayed absorption of the subcutaneous insulin. This is the first case of massive insulin overdose studied in such detail, and the results may facilitate management of future cases.