The external artificial pancreas: an instrument to induce remissions in severe recent juvenile diabetes. Comparison with a preprogrammed insulin infusion system.

Remission of juvenile insulin-dependent diabetes is a rare, temporary, and partial phenomenon which seems to be related to an improvement of the residual insulin secretion supported by prompt and rigorous insulin therapy. Thus, remissions allowing the replacement of insulin by oral drugs were attempted in 23 insulin dependent ketotic juvenile diabetics (age 10 +/- 2 years) of recent onset (apparent duration of diabetes 71 +/- 5 days) treated by an external artificial pancreas during 5 +/- 1 days and compared with 10 control diabetics treated by a less effective technique (preprogrammed insulin pump without feedback control) during 6 +/- 1 days. 18 (78%) remissions of long duration (1-26 months) occurred after artificial pancreas compared with 3 (30%) in the control group. Measurement of daily urinary C-peptide excretion confirmed the improvement of the residual insulin secretion in patients with insulin-induced remissions. Thus, the excellent blood glucose control given by an artificial pancreas seems necessary to lead to much more frequent remissions of diabetes than usually reported.     

The effect of three days of blood glucose normalization by means of an "artificial endocrine pancreas" on the concentrations of growth hormone, glucagon, and cortisol in juvenile diabetics.

Glucagon, growth hormone, and cortisol secretion was studied in seven male insulin-dependent diabetics under conventional subcutaneous insulin therapy and after three days of blood glucose normalization attained by the artificial endocrine pancreas (Biostator-GCIIS). The diurnal hormonal profiles under the two types of therapy were compared. Six healthy male students served as control group. A three-day period of blood glucose normalization in insulin-dependent diabetic can restore glucagon secretion to normal. Growth hormone secretion is decreased but not completely normalised. Cortisol secretion is slightly decreased. It is concluded that prolonged normoglycemia achieved by means of an artificial endocrine pancreas may completely control endocrine abnormalities in insulin-dependent diabetics.     

Effect of a long-acting somatostatin derivative SMS 201-995 (sandostatin) on glucose homeostasis in type I diabetes mellitus

The infusion of natural somatostatin (SRIF) has been able to partially correct postprandial hyperglycemic reactions in insulin-dependent diabetes mellitus (IDDM). SMS 201-995 (Sandostatin) is a long-acting derivative with a growth hormone-suppressive effect 10-60 times more potent than the native peptide. The effect of SMS 201-995 (50 micrograms s.c.) on glucose control by exogenous insulin has been documented in a series of type I diabetics after stabilization of blood sugar by an artificial pancreas. Inhibition of counterregulatory mechanisms significantly diminished the postprandial hyperglycemia, and insulin requirements, both total and 2 h after meals, were markedly decreased. Also the effect of a single s.c. injection of 100 micrograms SMS 201-995 on the dawn phenomenon in a patient with poorly adjustable diabetes was investigated. The glucose escape observed during the control night was blocked by SMS 201-995. Thus, the stabilizing action of this peptide on postprandial and nocturnal hyperglycemia in unstable diabetes warrants further studies.     

Effect of sera from male type 2 (non-insulin-dependent) diabetics on human aortic smooth muscle cells in culture

The effect of sera from male type 2 (non-insulin dependent) diabetics in variable metabolic control on the proliferation of, and on the synthesis of hyaluronic acid and collagen in human aortic smooth muscle cells (HSMCs) in culture was studied. Pooled sera from diabetics in poor metabolic control either with or without antidiabetic drugs stimulated the proliferation and hyaluronic acid synthesis of the cells more than did pooled serum from healthy controls. On the other hand, pooled serum from diabetics in good metabolic control did not have a higher stimulatory effect on the growth of HSMCs than pooled control serum. Indeed, it increased the synthesis of hyaluronic acid similarly as did the pooled serum from poorly controlled diabetics. The synthesis of collagen was not affected by pooled diabetic sera. When the effects of 14 male diabetic sera were individually measured using the same functions of HSMCs, metabolic control of diabetes did not correlate with various activities of diabetic sera on HSMCs. The results show that sera of type 2 diabetics contain factors affecting the functions of HSMCs. The activity of the factors on cell proliferation is related to some extent to the degree of glycemic control, as shown in experiments with serum pools, but experiments with individual sera show that other serum properties unrelated to the metabolic control of diabetes are also of importance.     

Islet cell transplantation and other new technologies for treating type 1 diabetes: a paediatric view

Recent advances in diabetes care have facilitated the achievement and maintenance of excellent metabolic control. New insulin pumps and continuous glucose monitoring systems provide cause for optimism that an artificial pancreas may soon be developed. In addition, transplantation biology has advanced to the point where pancreas and islet transplants are being performed with increasing frequency. Recent reports suggest that improved techniques for isolation of islets and immune suppression may allow these procedures to become more commonplace. However, serious questions regarding long-term safety and efficacy need to be answered in older individuals before consideration is given to their more routine use in children and adolescents with diabetes.     

Effect of metabolic control on urinary excretion and plasma levels of catecholamines in diabetics.

Urinary excretion and plasma levels of catecholamines were determined in 20 normal and 39 diabetic subjects to evaluate the sympathetic activity. Diabetic patients were divided into 4 groups according to the metabolic control. Sympathetic activity showed no differences between normal and subjects with chemical diabetes (group I, n = 5). In insulin-treated diabetics in good metabolic control (group II, n = 11) only urinary excretion of free norepinephrine was significantly higher than normals (p less than .05). In insulin-treated diabetics in poor metabolic control (group III, n = 16) urinary excretion and plasma levels of norepinephrine showed a marked increase over groups I and II (p less than .001). In insulin-treated diabetics with ketosis (group IV, n = 7) urinary excretion and plasma levels of both norepinephrine and epinephrine showed the highest values (p less than .001 and less than .1). Finally, in groups III and IV, after achieving improved metabolic control, a significant decrease of urinary excretion and plasma levels of catecholamines was observed. The results confirm that there is an increased rate of catecholamine release in poorly controlled diabeties and suggest a close correlation between sympathetic activity and metabolic derangement in diabetes.     

Use of glucose-controlled insulin infusion system for improvement of subcutaneous insulin regimen.

The use of an artificial pancreas for blood glucose monitoring and feedback correction for evaluation and improvement of subcutaneous insulin therapy facilitates the process of finding an optimal therapy regime for the individual patient. The frequency of hypoglycemic episodes can be reduced while maintaining good control, and hospital stays can be considerably shortened. This procedure is particularly useful in achieving tight control in pregnant diabetics.     

Application of an artificial endocrine pancreas in the management of the diabetic surgical patient.

Application of the artificial endocrine pancreas in 12 patients undergoing total duodenopancreatectomy and 3 diabetics in whom different operations were performed proved to be safe for the patients with respect to blood glucose control and prevention of ketosis. In the postoperative period, essentially normal blood glucose values were obtained despite high caloric parenteral nutrition.     

A closed-loop artificial pancreas based on model predictive control: Human-friendly identification and automatic meal disturbance rejection

Type 1 diabetes is characterized by a lack of insulin production by the pancreas, causing high blood glucose concentrations and requiring external insulin infusion to regulate blood glucose. Continuous glucose sensors can be coupled with continuous insulin infusion pumps to create a closed-loop artificial pancreas. A novel procedure of “human-friendly” identification testing using multisine inputs is developed to estimate suitable models for use in an artificial pancreas. A constrained model predictive control (MPC) strategy is developed to reduce risks of hypo- and hyperglycemia (low and high blood glucose concentration). Meal detection and meal size estimation algorithms are developed to improve meal glucose disturbance rejection when incoming meals are not announced. Closed-loop performance is evaluated through simulation studies of a type 1 diabetic individual, illustrating the ability of the MPC-based artificial pancreas control strategy to handle announced and unannounced meal disturbances.     

Evaluation of various hemorheologic parameters in diabetes mellitus

It has been speculated that changes in intrinsic blood flow properties may contribute to the evolution of vascular complications in diabetes mellitus. To verify this hypothesis we measured hematocrit, fibrinogen, plasma and blood viscosity in 30 diabetic patients and in 25 healthy volunteers. Diabetics showed blood and plasma viscosity and fibrinogenemia higher than healthy subjects, although only plasma viscosity and fibrinogenemia were statistically significant (p less than 0.001). Moreover the diabetic patients with the highest HbAlc values had a significant increase in plasma viscosity compared with the patients with lower HbAlc values (p less than 0.001), despite a similar fibrinogenemia. This study confirms the presence of hemorheological changes in diabetes mellitus and shows a correlation between plasma viscosity and metabolic control.     

D-Trp8-D-Cys14-somatostatin--demonstration of its differential suppressive activity in juvenile diabetics.

In 8 insulin-dependent diabetics, the effect of D-Trp8-D-Cys14-somatostatin on blood glucose, growth hormone, and glucagon levels as well as on insulin requirements from an artificial endocrine pancreas was studied during a balanced meal. The somatostatin analogue was infused at a rate of 25 microgram/h preceeded by a bolus injection of 25 microgram 30 minutes before ingestion of the meal. At this dose the analogue had no effect on glucagon levels and insulin requirements from the artificial pancreas. On the other hand, there was a significant lowering effect on fasting blood glucose levels, possibly indicating a direct inhibition of hepatic glucose production. Furthermore, there might be a slight effect on growth hormone levels, as was demonstrated by a rebound increase after termination of analogue infusion.     

Relation of high-density lipoprotein cholesterol concentration to type of diabetes and its control.

Serum cholesterol and high-density lipoprotein (HDL) cholesterol concentrations were measured in 192 diabetics (94 with juvenile-onset and 98 with maturity-onset diabetes) and 177 non-diabetic controls. Hb A1C, an index of blood sugar control, was also measured in the diabetics. Serum cholesterol concentrations were similar in all the diabetics and controls, but HDL cholesterol concentrations were lower in patients with maturity-onset diabetes than in those with juvenile-onset diabetes and controls. There was no correlation in diabetics between HDL cholesterol and Hb A1C. We conclude that HDL cholesterol concentrations are abnormally low in patients with maturity-onset diabetes but essentially normal in those with juvenile-onset diabetes. They are not related to diabetic control.     

The artificial beta cell (Biostator) in the adjustment of instable diabetics--results after 20 months.

In 55 poorly controlled insulin-dependent diabetics, we tried to discover criteria for an improvement of metabolism by means of the "artificial beta-cell" (Biostator). To this end, during the first 24 h of hospitalization, blood glucose was monitored continuously under conventional insulin therapy (monitoring period). Insulin requirement was determined during the next 24 h by the artificial beta-cell (feedback period). Corrections of diabetes regimen were made with reference to the insulin consumption during the feedback period and to the extent of the postprandial blood sugar increases and decreases during the monitoring period. The resulting new diabetes regimen led to a significant improvement of the daily blood sugar profiles.     

Reversal of insulin resistance in type I diabetes after treatment with continuous subcutaneous insulin infusion.

Insulin responsiveness was studied with the euglycaemic glucose clamp technique in seven patients with type I diabetes and in six control subjects matched for age and weight. The glucose disposal rate was significantly reduced in the diabetic subjects when they were receiving conventional insulin treatment compared with the control group, showing insulin resistance in the diabetics. The diabetic patients were again studied after eight days of intensified metabolic control achieved with continuous subcutaneous insulin infusion. During the infusion a more physiological insulin regimen was used compared with their regular treatment, less of the total insulin dose being given as continuous infusion and more as bolus doses before meals. The insulin resistance in the diabetics was largely reversed after this improved metabolic control. Dose response studies showed an increased glucose disposal rate at all plasma insulin concentrations, including the maximum insulin concentration, indicating a predominant effect of the continuous infusion regimen at the postreceptor level. The improved insulin effect seen with continuous subcutaneous insulin infusion could be due to the improved metabolic control achieved as well as the more physiological regimen.     

Use of an artificial endocrine pancreas in diabetic pregnancy.

Insulin demand of 12 pregnant diabetics has been investigated with an artificial endocrine pancreas. A rise in insulin requirement during pregnancy which can be attributed to the effort of reaching normoglycemia and to the effect of contrainsular hormones has also been observed by this objective method. Assessment of basal insulin demand during the night might be helpful in optimizing conventional therapy by using long-acting insulins for supplementing basal insulin need. According to our results, pregnancy complicated by diabetes can be foreseen as one of the main applications of a glucose-controlled insulin infusion system.     

Platelet spreading in diabetes mellitus

In 162 test persons divided into healthy control persons and diabetics of type I and type II the thrombocyte spreading was investigated according to the method of Breddin. Age, sex, degree of seriousness of retinopathy, duration of diseases, present level of blood sugar and HbA1 concentration were taken into account. Spread thrombocyte forms were increasingly found in old age, in diabetics of both types and a close relation to the extent of retinopathy was evident. As diabetic retinopathy became evident and with growing degree of seriousness, spread forms of thrombocytes were increasingly found, so that the increased spreading capacity may be interpreted as a disturbed metabolic and blood vessel situation in diabetes mellitus.     

Can technological solutions for diabetes replace islet cell function?

The central objective of diabetes research and management is to restore the deficient secretion of insulin, thereby restoring a state of euglycemia and minimizing short- and long-term risks associated with poor glucose control. The development of the artificial pancreas seeks to imitate the action of the pancreatic beta cell by employing closed-loop control to respond to glycemic excursions by appropriately infusing appropriate amounts of insulin. This article examines progress towards implementing an artificial pancreas in the context of the pancreatic islet as the ideal model for controlling blood glucose. Physiologic insulin secretion will form our foundation for considering the technical design elements relevant to electromechanically imitating the beta cell. The most recent clinical trials using closed-loop control are reviewed and this modality is compared to other curative approaches including islet cell transplantation and preservation. Finally, the potential of the artificial pancreas as a method to adequately reestablish euglycemia is considered.     

Lack of relation between glycosylated haemoglobin concentrations and number of daily insulin injections: cross sectional study in care of ambulatory diabetes.

Diabetic treatment aims at achieving a normal blood glucose concentration as reflected by the glycosylated haemoglobin concentration. Intensive treatment by insulin pump or multiple insulin injections is thought to achieve this. In an unselected group of outpatient diabetics metabolic control was the same after one, two, three, or more injections, which suggests that the mode of treatment was optimal for each group.     

Using mouse models to understand normal and abnormal urogenital tract development

The central objective of diabetes research and management is to restore the deficient secretion of insulin, thereby restoring a state of euglycemia and minimizing short- and long-term risks associated with poor glucose control. The development of the artificial pancreas seeks to imitate the action of the pancreatic beta cell by employing closed-loop control to respond to glycemic excursions by appropriately infusing appropriate amounts of insulin. This article examines progress towards implementing an artificial pancreas in the context of the pancreatic islet as the ideal model for controlling blood glucose. Physiologic insulin secretion will form our foundation for considering the technical design elements relevant to electromechanically imitating the beta cell. The most recent clinical trials using closed-loop control are reviewed and this modality is compared to other curative approaches including islet cell transplantation and preservation. Finally, the potential of the artificial pancreas as a method to adequately reestablish euglycemia is considered.     

Variation induced by a three-days application of the artificial beta-cell on glucagon, growth hormone and catecholamine secretion, glycosylated hemoglobin, and erythrocyte 2,3-diphosphoglycerate concentration.

Five insulin-dependent diabetics with poor metabolic control were examined at the beginning and after a three-day application of artificial endocrine pancreas (AEP). Pancreatic alpha cell function evaluated by arginine infusion (0.5 g/Kg b.w. over 30 minutes) showed no significant differences between the beginning and during artificial beta cell aplication, but the increment in plasma glucagon level over basal values observed in both tests appeared significantly higher at 30 and 60 min in comparison with a control group. Growth hormone response to arginine infusion was clearly reduced in the second test. C-peptide concentration appeared very low in basal conditions and during arginine infusion; no improvement was observed after three days of AEP application. Urinary excretion of norepinephrine markedly increased at the beginning of the study, reversed almost to normal during AEP treatment, while minor changes were observed in urinary excretion of epinephrine. The Concentration of glycosylated hemoglobin, markedly higher than normally before the connection with AEP, showed a slight but significant decrease during glucose-controlled insulin infusion. Finally, 2,3-diphosphoglycerate was normal and no modifications were observed in the course of the study.