Effect of strict glycemic control on renal hemodynamic response to amino acids and renal enlargement in insulin-dependent diabetes mellitus

BACKGROUND. Many patients with insulin-dependent diabetes mellitus have an increase in the glomerular filtration rate and renal enlargement early in the course of their disease. Both these changes may be risk factors for the later development of diabetic nephropathy. Their cause is not known, but they could be due to augmented renal responses to the increase in plasma amino acid concentrations that occurs when dietary protein intake is high, a factor known to increase glomerular filtration and renal blood flow in normal subjects. METHODS. We measured the glomerular filtration rate and renal plasma flow after an overnight fast and during an infusion of amino acids in 12 patients with insulin-dependent diabetes mellitus and 9 normal subjects. The diabetic patients were studied when they were hyperglycemic, when they were euglycemic after an insulin infusion for 36 hours, and after intensive insulin therapy for 3 weeks. Kidney volume was measured by ultrasonography before and after the period of intensive insulin therapy. RESULTS. The glomerular filtration rate and renal plasma flow were normal after fasting when the patients were hyperglycemic (mean [+/- SE] fasting plasma glucose level, 11.5 +/- 0.7 mmol per liter). After the amino acid infusion, these values increased more in the patients (glomerular filtration rate, 2.65 +/- 0.07 ml per second per 1.73 m2 of body-surface area; renal plasma flow, 13.30 +/- 0.68 ml per second per 1.73 m2; P less than 0.05 for both) than in the normal subjects (2.25 +/- 0.08 and 11.20 +/- 0.65 ml per second per 1.73 m2, respectively). The 36-hour infusion of insulin in the diabetic patients did not alter the glomerular filtration rate or renal plasma flow either before or during the amino acid infusion. After three weeks of intensive insulin therapy (fasting plasma glucose level, 5.3 +/- 0.2 mmol per liter), the glomerular filtration rate and renal plasma flow after the amino acid infusion (2.33 +/- 0.03 and 11.30 +/- 0.43 ml per second per 1.73 m2, respectively) were similar to those in the normal subjects. The kidney volumes in the normal subjects and the patients with diabetes were 219 +/- 14 and 312 +/- 14 ml per 1.73 m2, respectively (P less than 0.01); the volume decreased to 267 +/- 22 ml per 1.73 m2 (P less than 0.001) in the diabetic patients after three weeks of intensive insulin therapy, which was not significantly different from the volume in the normal subjects (P = 0.1). CONCLUSIONS. Conventionally treated diabetic patients who have normal renal function while fasting have augmented renal hemodynamic responses to increased plasma amino acid concentrations. The concomitant decrease in these hemodynamic responses and in kidney size with strict glycemic control suggests that these phenomena are related and influenced by the metabolic state.     

Muscle adaptations and glucose control after physical training in insulin-dependent diabetes mellitus

Six men and three women with insulin-dependent diabetes (without complications) participated in physical training three times a week for 20 weeks. Physical training did not change the concentration of fasting blood-glucose, glucose excretion in urine or glucosylated haemoglobin (HbA1). However, the glucose disposal rate during euglycaemic clamp increased after training. In two patients a minor reduction of insulin dosage was necessary to alleviate slight hypoglycaemic episodes. The training resulted in significant increases in quadriceps isometric and dynamic strength and endurance. Maximal oxygen uptake increased by 8%, the activity of glycolytic enzymes in vastus lateralis muscle by 47% for hexokinase, and 30% for tri-osephosphate dehydrogenase and 25% for lactic dehydrogenase, the activity of oxidative enzymes by 42% for citrate synthase and 46% for 3-hydroxy-acyl-CoA-dehydrogenase. The glycogen concentration in the vastus lateralis muscle did not change significantly. Lipoprotein lipase activity did not change in muscle, nor in adipose tissue. The mean muscle fibre area increased by 25% and the area of FTa fibres by 30%. The new formation of capillaries around different muscle fibres was significant for FTb fibres (26%). The proliferation of capillaries, however, appeared to be insufficient to cope with the increased area of muscle fibres. As a result, the mean area of muscle fibre supplied by one capillary (a measure of diffusion distance) significantly increased after training for FTa fibres. It is concluded that with the exception of deficient proliferation of capillaries, patients with insulin-dependent diabetes mellitus show a normal central and peripheral adaptation to physical training. Physical training does not apparently improve blood glucose control in most cases, despite an increased insulin sensitivity.     

Defective inducer T-cell function before the onset of insulin-dependent diabetes mellitus.

To investigate the possible role of CD4+ T lymphocyte immunoregulatory abnormalities in the pathogenesis of human insulin-dependent diabetes mellitus (IDD), we studied the in vitro function of CD4+ helper/inducer and suppressor/inducer T-cell subpopulations in 25 high risk non-diabetic individuals who tested positive for islet-cell antibodies (ICA). Helper-inducer T-cell function, as measured in the pokeweed mitogen T-B co-culture system, was decreased in the ICA+ subjects in comparison to controls. This abnormality in helper/inducer T-cell function was present for both IgG (P = 0.0001) and IgM (P = 0.004) secretion by B cells. Diminished helper/inducer function correlated with ICA titer (Pearson correlation coefficient -0.44) with subjects having an ICA titer greater than or equal to 40 JDF units demonstrating the most significant disturbances in function (P = 0.01). The helper/inducer T-cell subset percentage was also decreased in ICA+ subjects when compared to matched controls (30 +/- 3% vs 39 +/- 2%; P = 0.02). The abnormality in helper/inducer function was intrinsic to the CD4+ CD45RA+ subset and was not simply due to diminished numbers of helper/inducer T-cells added in the co-culture experiments, since the defect persisted when CD4+ CD45RA+ helper/inducer T-cells were purified and added to B cells as the only source of T-cell help. Our results indicate that ICA+ subjects have functional defects in the helper/inducer subpopulation of CD4+ T-cells. This abnormality may contribute to the pathogenesis of IDD and may provide a novel marker for identifying persons at risk for developing IDD.     

Immunotherapy of insulin-dependent diabetes mellitus

Type 1 diabetes mellitus is caused by the T cell mediated autoimmune destruction of insulin-producing beta cells of the islets of Langerhans within the pancreas. Current immunotherapy strategies are aimed at directly inactivating the autoreactive T cells and/or inducing T cells with regulatory capabilities. At the preclinical level, several strategies that employ TCR antagonists -- including monoclonal antibodies, autoantigen-specific peptides and soluble TCR ligands -- are showing promise and being developed for clinical application. Several of these approaches employing monoclonal antibodies against the TCR-CD3 complex or soluble peptide antigens are producing favorable results in the clinic.     

Immunotherapy of insulin-dependent diabetes mellitus.

Immunotherapy of diabetes is now focusing on induction of tolerance to beta cell antigens using either soluble antigens or monoclonal anti-T-cell antibodies. These approaches have reached the clinical arena. At the experimental level, strategies are being developed that use or target cytokines (with gene therapy) or stimulate regulatory T cells.     

Progression of diabetic retinopathy after pancreas transplantation for insulin-dependent diabetes mellitus

We studied the effect of successful pancreas transplantation and consequent normoglycemia (mean total hemoglobin A1, 7.0 percent; range, 5.8 to 8.3) on visual function and diabetic retinopathy in 22 patients with Type I diabetes mellitus (study group). Sixteen similar patients in whom pancreas transplantation had been unsuccessful (mean total hemoglobin A1, 12.0 percent; range, 8.0 to 18.0) served as a control group. The majority of patients in both groups had advanced proliferative retinopathy. At a mean follow-up of 24 months we found no significant difference between the groups in the rate of progression of retinopathy, expressed as a score. Success of the transplantation did not prevent progression of retinopathy across the range of retinopathy studied. Progressive retinopathy was observed more commonly in patients with low retinopathy scores (nonproliferative or mild proliferative retinopathy) at base line in both the study group (13 of 17 eyes, or 76 percent) and the control group (7 of 12 eyes, or 58 percent). Further analysis suggested the possibility that after three years of euglycemia, the study group had less deterioration than the control group, particularly in eyes with advanced retinopathy. We observed no difference in the rate of loss of vision between the two groups. This study provides evidence that pancreas transplantation and subsequent normoglycemia neither reverse nor prevent the progression of diabetic retinopathy.     

The effect of asymptomatic nocturnal hypoglycemia on glycemic control in diabetes mellitus

To assess the effect of asymptomatic nocturnal hypoglycemia on glycemic control in insulin-dependent diabetes mellitus, we studied, on three nights, 10 patients receiving their usual regimens of continuous subcutaneous insulin infusion. During a control night, the patients' mean (+/- SE) plasma glucose level reached a nadir of 4.5 +/- 0.2 mmol per liter at 3 a.m.; the fasting glucose level was 5.9 +/- 0.3 mmol per liter at 7:30 a.m., and a peak glucose level of 8.6 +/- 0.3 mmol per liter was reached at 10 a.m., after breakfast. During nights two and three, supplemental insulin was infused intravenously from 10 p.m. to 2 a.m. to simulate a clinical overdose of insulin. On these nights, either hypoglycemia (2.4 +/- 0.2 mmol per liter) was permitted to occur or a nearly normal glucose level (5.5 mmol per liter) was maintained by infusion of glucose. The subjects were asymptomatic on all three nights. Despite comparable plasma free insulin levels from 4 to 11 a.m., both fasting (7.3 +/- 0.2 mmol per liter) and postbreakfast (12.5 +/- 0.4 mmol per liter) plasma glucose levels were significantly higher after hypoglycemia than when hypoglycemia was prevented (6.2 +/- 0.2 mmol per liter and 8.7 +/- 0.4 mmol per liter, respectively; P less than 0.001 in both cases). Fasting levels of plasma glucose correlated directly with overnight plasma levels of epinephrine (r = 0.78, P less than 0.001), growth hormone (r = 0.57, P less than 0.009), and cortisol (r = 0.52, P less than 0.02) but correlated inversely with the overnight nadir of plasma glucose (r = -0.62, P less than 0.005). We conclude that asymptomatic nocturnal hypoglycemia can cause clinically important deterioration in glycemic control (the Somogyi phenomenon) in patients receiving intensive insulin therapy, and should therefore be considered in the differential diagnosis of unexplained morning hyperglycemia.     

Immunogenetics of insulin-dependent diabetes mellitus in humans

Diabetes mellitus is the second most prevalent chronic disease in children in the U.S. It is associated with severe manifestations which include blindness and circulation deficiencies as well as markedly increased risk of death. The etiology of diabetes mellitus remains a mystery although both genetic and environmental factors have been implicated. The geneticist is confronted with a number of obstacles in his attempts to unravel this problem, including differences in the definition of affected individuals. This matter was certainly clarified by the separation of noninsulin-dependent diabetes (NIDDM) and insulin-dependent diabetes mellitus (IDDM) into two separate disease entities. Twin studies, however, show that IDDM cannot be entirely due to genetic causes as concordance is no more than about 50%. Although the disease is then clearly not inherited per se, the "susceptibility" to diabetes seems almost surely inherited and, provided this susceptibility, the disease can be brought on by environmental factors. Until the underlying mechanism causing IDDM is completely ascertained, we have to rely on genetic markers to approach the study of the inheritance thereof. Since, in the early 1970s, research by Nerup's and Cudworth's groups revealed associations between the HLA-B locus and IDDM, the HLA markers are considered the classical genetic markers for IDDM susceptibility. In this paper, we review the nature of the genetic susceptibility to IDDM and the possible environmental factors which can bring on the disease.     

Randomized trial of technology-assisted self-monitoring of blood glucose by low-income seniors: improved glycemic control in type 2 diabetes mellitus

Self-monitoring of blood glucose (SMBG) has been recommended for people with type 2 diabetes mellitus. This trial tested an automated self-management monitor (ASMM) that reminds patients to perform SMBG, provides feedback on results of SMBG, and action tips for improved self-management. This delayed-start trial randomized participants to using the ASMM immediately (IG), or following a delay of 6 months (DG). Glycated hemoglobin (HgbA1c) level and survey data was collected at home visits every 3 months. 44 diabetic men and women, mean age 70, completed the 12-month trial. Baseline HgbA1c was 8.1 % ± 1.0, dropping to 7.3 ± 1.0 by 9 months, with a 3-month lag in the DG (F = 3.56, p = 0.004). Decrease in HgbA1c was significantly correlated to increased frequency of SMBG, R = 0.588, p < 0.01. Providing older diabetics with objective immediate contingent feedback resulted in more frequent SMBG that correlated with better glycemic control. This type of technology may provide real-time feedback not only to patient users, but to the health care system, allowing better integration of provider recommendations with patient-centered action.     

Glycaemic control and suppressor cell activity in patients with insulin-dependent diabetes mellitus

Suppressor cell activity (SCA) in patients with insulin-dependent diabetes mellitus (IDDM), has been found depressed at diagnosis and normal in the remission period. To investigate whether poor metabolic control as seen at diagnosis influences SCA, two groups of patients in poor glycaemic control were examined. Group 1 consisted of nine patients with IDDM of 27±4 months, with a mean glucosuria of 84±19 (s.e.m.) g/24 hr. Group 2 comprised eight patients with newly diagnosed IDDM, examined for the first time 4±1 days after diagnosis, when having a mean glucosuria of 43±14 g/24 hr. After 1 week of hospitalization with strict glycaemic control resulting in a massive reduction of the glucosuria (group 1 now showing 0±0 g/24 hr, group 2, 16±5 g/24 hr), the patients were re-examined. SCA was investigated for the third time after approximately 4 weeks (group 1) and after 5 months (group 2), when the patients were outpatients (glucosuria: group 1, 61±20 g/24 hr; group 2, 17±6 g/24 hr). The suppressive effect of lymphocytes was investigated after incubation with concanavalin A followed by inactivation. Suppression was measured as the ability of the lymphocytes to inhibit ³H-thymidine incorporation in concanavalin A-stimulated normal donor lymphocytes. There were no significant differences in SCA between the first (group 1,25±7; group 2, 22±11) and the second (group 1, 22±8; group 2, 15±5) examination. At the third examination, group 1 patients displayed 35±5, and group 2 patients, now being in the remission period, 44±4. Only the third value of group 2 patients was significantly higher than the second value (P<0·01). SCA of healthy controls were 35±3. It is concluded that short-term effects on SCA of improvement of the glycaemic control are unlikely, at least in patients without severe ketoacidosis. On the other hand, late effects on SCA of good metabolic control, after weeks or months, could not be excluded.     

Defective monocyte chemotactic responses in diabetes mellitus

A variety of polymorphonuclear leukocyte (PMN) defects has been described in diabetics, but to date no investigations of monocyte (MN) function have been reported in diabetics. In the present studies, we have employed an underagarose chemotactic assay to examine directed and random motility of MNs from diabetic individuals. Among 45 diabetics and 25 controls there was no significant difference in the maximal distance migrated by the leading front of cells to zymosan-activated serum (chemotaxis) or medium alone (random migration). In contrast, many fewer diabetic MNs [293±28 (SE)] moved toward the attractant than did control MNs (446±21;P<0.001). Random motility of the diabetic MNs (121±14 SE) was also decreased compared to that of the controls (225±24;P<0.0004).In vitro incubation of the diabetic monocytes with insulin (25, 75, and 100 µU/ml) failed to improve chemotactic function. Treatment of diabetic MNs with 2,3-dihydroxybenzoic acid, a scavenger of H₂O₂ and O ₂ ^? , increased both random motility and directed movement, however. In addition,in vivo therapy of 7 diabetic patients with α-tocopherol (vitamin E) resulted in a marked increase in the number of MNs moving toward the chemoattractant (pretherapy, 118±12; posttherapy, 246±31;P<0.05). These results indicate that diabetic individuals have defective monocyte chemotactic function which can be corrected, in part, byin vitro orin vivo treatment with antioxidants. Thus, defective function may be, at least partly, the result of autooxidative membrane damage.