[New insulin analogues with improved pharmacokinetics].
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Humans↗
Biomedical subjects
J Bolinder
Publications and source records attributed to J Bolinder.
Indication, selection of patients and timing for pancreatic transplantation.
For more than 20 years pancreas transplantation has been advocated as a therapeutic modality in patients with insulin-dependent diabetes mellitus. When successful, this procedure is the only method for attaining long-term normoglycaemia in diabetic recipients. However, because of the potential morbidity and mortality, pancreas transplantation should be restricted to diabetic patients in whom the complications of the diabetic state are more serious than those of surgery and chronic immunosuppression. Currently three recipient categories have been identified in which pancreas transplantation would seem justifiable. The first includes diabetic patients with end-stage nephropathy who are already obligated to life-long immunosuppressive therapy because of the kidney replacement. In this recipient category the main benefit of receiving a pancreas transplant in addition to a kidney is that the quality of life is markedly improved. In addition, it seems that a functioning pancreas transplant prevents the recurrence of diabetic nephropathy in the simultaneously transplanted kidney. Since the success rate with combined pancreas-kidney transplantations is approaching that of renal transplantation alone, there is little controversy about performing the combined procedure in diabetic uraemic patients. However, if the main objective of pancreas transplantation, namely to prevent the late diabetic microvascular complications, were to be fulfilled this intervention would have to be performed earlier in the course of the disease. Therefore, single pancreatic transplantations have recently been conducted in diabetic patients with early signs of clinical nephropathy which, currently, is the most powerful predictor of susceptibility to detrimental diabetic complications. Preliminary findings indicate that, in this second recipient category, single pancreatic transplantation and subsequent euglycaemia may prevent the progression of diabetic neuropathy and nephropathy; with regard to diabetic retinopathy the results remain obscure.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes Mellitus, Type 1↗
Surgical techniques and results in pancreatic transplantation.
A major stumbling block preventing success with pancreatic transplantation has been the handling of the exocrine secretion from the pancreatic graft. As a consequence, numerous surgical techniques have been evaluated such as duct ligation, free intraperitoneal drainage, ductal filling with polymers, exocrine diversion to the urinary tract, to the bowel and to the stomach. Also, because of problems encountered with the duodenum, segmental body-and-tail pancreatic grafts have been used for many years. However, it seems today that mainly two different techniques for pancreatic transplantation remain. In both whole pancreaticoduodenal grafts are used with a vascular supply from the coeliac axis and the portal vein. The exocrine drainage is either to the urinary tract by means of a side-to-side anastomosis between donor duodenum and recipient urinary bladder, or to the bowel by a side-to-side anastomosis between donor duodenum and recipient proximal jejunum. With both these techniques the technical complications have been much reduced and as a consequence the graft survival rates are now approaching those obtained with the transplantation of the liver, heart and kidney.
Duodenum↗
Microdialysis of subcutaneous adipose tissue in vivo for continuous glucose monitoring in man.
Subcutaneous adipose tissue extracellular glucose was investigated in vivo in man with a microdialysis technique. A small dialysis probe (4 or 10 x 0.5 mm) was implanted subcutaneously, and was perfused continuously with a micro-infusion pump. Dialysate samples were collected in 15-min periods. A transient yield of ATP was recorded immediately after insertion of the probe; thereafter ATP was almost undetectable. During steady-state conditions the tissue dialysate glucose concentration remained constant for at least 2 h, which indicated that there was no drainage of glucose from the interstitial fluid to the tissue dialysate. Simultaneous dialysis of venous blood and subcutaneous fat in rats showed that the recovery of glucose from the adipose tissue interstitial fluid to the dialysate was only 20% of that from blood. However, in vivo dialysis of human adipose tissue with glucose-containing solutions produced an equilibrium with the extracellular space at a glucose concentration that was similar to the blood glucose concentration. After oral glucose ingestion and following i.v. insulin and glucose administration the relative variations in subcutaneous glucose closely resembled those in blood glucose. It is concluded that the subcutaneous implantation of the presently used small dialysis device causes only minor and transient traumatic effects. The dialysis recovery of glucose is lower in adipose tissue than in blood. However, the relative kinetics of subcutaneous tissue dialysate glucose are closely related to variations in the blood glucose concentration, and thus may be used for monitoring of glycaemic control in man.
Adipose Tissue↗
Markers for pancreas-graft rejection in humans.
Rejection episodes were studied in 15 patients, in whom no kidney graft could serve as a marker for rejection, subjected to pancreas transplantation with pancreatoenterostomy and temporary exteriorization of the pancreatic juice (10 pancreas alone, 3 pancreas after kidney, and 2 combined pancreas and kidney in which the kidney was not functioning.) Twelve patients (80%) had a total of 18 rejection episodes. In the first 11 patients, 13 rejection episodes were diagnosed by a decline in amylase activity in the pancreatic juice, whereas in the next 4 patients, 5 rejection episodes were diagnosed by positive cytology in the pancreatic juice. Neopterin in pancreatic juice and immunoreactive anionic trypsin in serum showed promise as rejection markers, whereas serum neopterin, serum amylase, and serum immunoreactive cationic trypsin did not. Unspecific signs of rejections were an increase in white blood cell count, clinical symptoms such as fever, abdominal pain, and arthralgia. All acute rejection episodes were successfully reversed by antirejection treatment. However, late rejections diagnosed by impaired endocrine function were seen in 6 of the 15 (40%) patients, and the prognoses for these rejections were worse: 4 patients (27%) lost their grafts because of chronic rejections, and 2 patients still had impaired endocrine function.
Amylases↗
Effects of pancreas transplantation on metabolic and hormonal profiles in IDDM patients.
The diurnal patterns of relevant metabolites and hormones in five pancreas-kidney-transplanted patients (aged 36 +/- 2 yr, mean +/- SD) with insulin-dependent diabetes mellitus (IDDM) were compared with those in five kidney-transplanted nondiabetic patients (aged 28 +/- 2 yr). The groups were matched for body mass and current dose and type of immunosuppressive treatment. The serum creatinine levels did not differ between the two study groups, but the serum urea level in the nondiabetic patients was slightly but significantly higher than in the diabetic patients. In the pancreas-kidney-transplanted group the investigation was performed 8-47 mo posttransplantation; in the kidney-transplanted nondiabetic patients, 12-18 mo posttransplantation. The mean 24-h levels and rhythms of blood glucose, free fatty acid, 3-hydroxybutyrate, and alanine did not differ between the groups. The mean 24-h levels of blood lactate and glycerol were moderately but significantly higher in the pancreas-kidney-transplanted diabetic patients. At fasting, the level of serum immunoreactive insulin was more than twice as high in the pancreas-kidney-transplanted patients, whereas the plasma C-peptide levels did not differ significantly between the two groups. The meal-induced increases in serum insulin as well as in the plasma C-peptide levels were more marked in the pancreas-kidney-transplanted patients. The findings suggest that the hyperinsulinemia in these patients was due to both the systemic delivery of insulin and an increase in insulin resistance, the latter being particularly apparent in the postprandial phase.(ABSTRACT TRUNCATED AT 250 WORDS)
3-Hydroxybutyric Acid↗
Long-term metabolic control in recipients of segmental-pancreas grafts with pancreaticoenterostomy or duct obstruction.
Metabolic control in recipients of segmental-pancreas grafts with pancreaticoenterostomy (performed in Stockholm) or duct obstruction by polymer injection (performed in Oslo) were compared. The recipients were uremic diabetic patients and also received a kidney from the same donor. Because the patient population in the two Scandinavian countries is very similar and the immunosuppressive protocols used are almost identical, such a comparison seemed reasonable. The number of patients available for study at 1, 2, and 3 yr was 22, 10, and 4, respectively, with duct injection and 28, 10, and 3 with pancreaticoenterostomy. The mean age of the patients was somewhat higher in the Oslo series. There were no significant differences regarding immunosuppression or kidney-graft function as estimated by serum creatinine at 1, 2, and 3 yr. No significant differences were found in fasting blood glucose, glycosylated hemoglobin, and intravenous glucose tolerance between the two groups at 1, 2, and 3 yr.
Adult↗
Ultrasonic measurement of forearm subcutaneous adipose tissue thickness suitable for monitoring of subcutaneous glucose concentration?
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Adipose Tissue↗
Antilipolytic effect of insulin in non-insulin-dependent diabetes mellitus after conventional treatment with diet and sulfonylurea.
Insulin-induced antilipolysis was investigated in fat cells obtained after an overnight fast and 60 min after glucose ingestion in seven non-obese patients with non-insulin-dependent diabetes mellitus (NIDDM). The study was performed before and after long-term therapy with diet and glibenclamide. After treatment, the antilipolytic potency of insulin in fat cells was threefold enhanced (p less than 0.05) in the fasting state and remained unaltered after glucose ingestion. In untreated NIDDM oral glucose induced a significant (p less than 0.01) increase in insulin sensitivity. In consequence, in the glucose-fed state insulin sensitivity was similar before and after therapy. Adipocyte insulin receptor binding was comparable before and after therapy, both in the fasting state and following glucose intake. In untreated NIDDM, despite relative hypoinsulinemia, plasma glycerol was markedly reduced after oral glucose. After therapy, plasma glycerol was significantly reduced both in the fasting state and following glucose ingestion. At the same time, fasting and glucose-stimulated circulating insulin were significantly (p less than 0.01) increased. It is concluded that conventional antidiabetes therapy in NIDDM mediates a suppression of adipose tissue lipolysis. This seems to be due to an improvement in insulin secretion in combination with a potentiation of the antilipolytic effectiveness of insulin in fat cells in the fasting state, the latter being secondary to post-binding alterations in insulin action.
Adipose Tissue↗
Microdialysis of adipose tissue and blood for in vivo lipolysis studies.
Glycerol levels (lipolysis index) were continuously monitored in intact rats using simultaneous microdialysis of venous blood and subcutaneous adipose tissue. Dialysis probes (0.5 X 4 mm) were implanted and perfused using a microinjection pump. The basal glycerol levels in perfusates of blood and adipose tissue were stable. Intravenous isoproterenol (isoprenaline) increased the glycerol levels in a similar fashion in blood perfusate as compared with plasma and the dialysate of two different adipose tissue probes implanted in the same animal. Isoproterenol included in the adipose tissue dialysis solvent increased the glycerol level in adipose tissue perfusate but not in the blood perfusate; this indicates a local lipolytic effect of catecholamines. Increases in intravenous doses of isoproterenol caused a transient and marked dose-dependent elevation of glycerol in the adipose tissue perfusate and a gradual but less marked rise of glycerol in blood perfusate. This indicates that glycerol kinetics in blood and adipose tissue differ after catecholamine stimulation. In conclusion, microdialysis of blood and subcutaneous adipose tissue offers new and unique possibilities for in vivo lipolysis studies in intact animals.
Adipose Tissue↗
Pancreatic transplantation in diabetics with preuremic nephropathy.
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Adult↗
Metabolic effects of living related pancreatic graft donation.
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Aged↗
Acute adaptation in adrenergic control of lipolysis during physical exercise in humans.
During prolonged exercise, the free fatty acids derived from adipocyte lipolysis are the principal fuel utilized by muscles. In humans, the lipid mobilization from adipose tissue is mainly regulated by insulin and catecholamines: the latter hormones have both beta-adrenergic stimulatory and alpha 2-adrenergic inhibitory effects on lipolysis. The aim of this study was to determine whether rapid alterations in the peripheral action of the regulatory hormones occur during physical work and whether they are of importance for the enhanced lipid mobilization. The acute effects of exercise on the regulation of lipolysis were investigated in isolated adipocytes removed from the gluteal region of 14 healthy volunteers before and immediately after the exercise period. Exercise induced a 20-35% significant increase in the lipolytic response to noradrenaline alone and in combination with the selective alpha 2-antagonist yohimbine and to the pure beta-agonist isoproterenol in isolated adipocytes. The antilipolytic effects of both the alpha 2-agonist clonidine and insulin were unaffected by exercise. Exercise did not influence the specific adipocyte receptor binding of 125I-cyanopindolol (beta-adrenergic receptor), [3H]yohimbine (alpha-adrenergic receptor), and mono-125I-[Tyr A14]insulin (insulin receptor). In conclusion, a single period of submaximal exercise increases adipocyte lipolytic responsiveness to catecholamines through an increased beta-adrenoceptor-mediated effect at steps distal to the receptor binding. Thus the increased peripheral action of catecholamines may be of importance for the observed enhanced lipid mobilization during physical work.
Adaptation, Biological↗
Studies of acute effects of insulin-like growth factors I and II in human fat cells.
The acute metabolic effects and receptor binding of insulin-like growth factors (IGFs) I and II were studied in human adipose tissue. The IGFs inhibited fat cell glycerol release and stimulated adipocyte 3-O-methylglucose transport and adipose tissue glucose oxidation as effectively as did insulin, but the biological potencies of the IGFs, on a molar basis, were 600-1000 times less than that of insulin. The insulin dose-response curve for antilipolysis gradually shifted to the left in the presence of submaximally and maximally effective IGF-I concentrations, whereas no additive response was found when fat cells were incubated with maximally effective concentrations of insulin and the IGFs. Adipocyte [125I]IGF-I and -II binding was low and was not inhibited by excess unlabeled IGF. In contrast, IGF-I inhibited [125I]insulin binding with a molar potency 1600 times lower than that of native insulin. In adipose tissue segments obtained from patients with untreated noninsulin-dependent diabetes mellitus, IGF-I and insulin inhibited glycerol release in a normal way. Conversely, neither insulin nor IGF-I increased the rate of glucose oxidation significantly above the nonhormone-stimulated level. We conclude that human fat cells lack specific cell surface IGF-binding sites. However, the IGFs definitely produce acute insulin-like effects in the human adipocyte, which seems to be mediated via the insulin receptor.
Adipose Tissue↗
Insulin receptor binding and metabolic effects of insulin in human subcutaneous adipose tissue in untreated non-insulin dependent diabetes mellitus.
Insulin action at the target tissue level in non-insulin dependent diabetes mellitus was investigated using human adipose tissue. Specific adipocyte receptor binding of insulin and the effects of the hormone on glucose oxidation and lipolysis were determined in subcutaneous adipose tissue. The study included 25 patients with untreated non-insulin dependent diabetes mellitus and 38 healthy control subjects matched for age, sex and body weight. Insulin stimulated adipose tissue glucose oxidation in a dose-dependent way in the control subjects. On the other hand, a marked inhibition of this insulin effect was observed in the diabetics. A weak stimulation was observed only at high unphysiological hormone concentrations [greater than or equal to 0.7 nmol/l] and the maximal insulin response was 6 times lower than that in the control subjects. However, neither specific insulin receptor binding nor the antilipolytic effect of insulin were inhibited in diabetes. Similar results with insulin binding and the metabolic effects of insulin were obtained in non-obese normoinsulinemic diabetics as compared to moderately obese hyperinsulinemic diabetics. It is concluded that adipose tissue insulin resistance in non-insulin dependent diabetes mellitus only involves glucose metabolism and not antilipolysis. Furthermore, it may solely be due to postreceptor defects in insulin action and seems not to be influenced by obesity or oversecretion of insulin.
Adipose Tissue↗
Diagnosis of rejection in recipients of pancreatic grafts with enteric exocrine diversion by monitoring pancreatic juice cytology and amylase excretion.
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Amylases↗
Pancreatic transplantation with enteric exocrine diversion--the Stockholm experience.
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Diabetes Mellitus, Type 1↗
Transfer from porcine insulin to human insulin in insulin-dependent diabetes mellitus: effects on insulin binding to IgG and glycemic control.
Thirty type I diabetic patients who were treated for at least 2 years with a combination of regular and lente monocomponent porcine insulins were allocated in a double-blind study to either continued porcine insulin treatment or a transfer to the corresponding semi-synthetic human insulins. Insulin binding to IgG measured by an immunoelectrophoretic method, was followed at 3-month intervals for 1 year, and did not change after the transfer. The glycemic control, as assessed by hemoglobin A1 levels, tended to deteriorate in the human insulin group during the first 3 months of the trial and then return to the baseline level. It is concluded that a transfer from highly purified porcine insulin to human insulin apparently does not change the insulin binding to IgG in already sensitized patients.
Adult↗