Patients suffering from the severe complications associated with both insulin- (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM): nephropathy, retinopathy, neuropathy, and atherosclerosis are still largely left without a prospect of an efficient treatment, This is the case even if it has been assumed for decades and now finally proved by the results from the Diabetes Control and Complications Trial (DCCT) that hyperglycemia is the single main cause of these complications. Improved glycemic control as a result of intensive insulin treatment has the potential to reduce the incidence and progression of complications, but implementation and monitoring of improved glycemic control in all groups of IDDM and NIDDM patients in different communities will be difficult and expensive. Results from the recently terminated DCCT have shown that even with intensive insulin treatment, there will still be a significant burden of complications on the diabetic population. It will, therefore, still be of immense importance for the long-term quality of life for the diabetic patient that additional possibilities are developed for prevention and intervention against diabetic complications. Almost two decades of research, animal model testing, and clinical trials have been conducted on various efficient aldose reductase inhibitors. Now the concept of inhibition of formation of advanced glycosylation endproducts on proteins and lipids resulting from extra- and intracellular hyperglycemia is entering the scene as an alternative or perhaps supplementary approach to reduce the occurrence of diabetic complications. An overview of the results from these two fields of research and associated drug-development programs will be presented along with thoughts on possible future developments.
Severe hypoglycemia is a very common complication in youths with insulin-dependent diabetes mellitus (IDDM). Seventy four children and adolescents were surveyed for a 1-year period to evaluate the frequency and associated factors of severe hypoglycemia. Patients or their parents completed a standardized questionnaire which inquired about severe and mild episodes, treatment, and prevention of hypoglycemia. Forty-four percent of the patients experienced at least one severe hypoglycemic episode [need for assistance (grade III), loss of consciousness with or without convulsions (grade IV)] during the survey period. The event rate was 0.77 episodes (grade III and IV) per patient-year. The group with severe hypoglycemic episodes was significantly older (mean age, 16.3 years; SD, 3.6 years versus mean age 13.7 years; SD, 4.9 years; p = 0.01) and had significantly longer duration of diabetes (mean, 8.2 years; SD, 4.3 years versus mean, 6.1 years; SD, 4.0 years; p = 0.04) than the group without severe hypoglycemic episodes. There were no significant differences in mean glycosylated hemoglobin (HbA1c), daily doses of insulin, type of insulin regimen, gender, and age at diagnosis between patients who reported severe episodes and those who did not. Mild hypoglycemia was reported by 72 patients. Fifty percent of the patients recognized potential precipitating factors. Older age and longer duration of diabetes seem to predispose the patient to severe hypoglycemia. This may be the result of a diminution of the counterregulation system including lower neuroadrenergic reaction, or the still unphysiologic treatment of diabetes. Continued vigilance and education is important in older adolescents with longer duration of diabetes.
Type-I (insulin-dependent) diabetes mellitus is an immunologically mediated disease that results in destruction of the insulin secreting β cells of the pancreas. T cells have been implicated in the pathogenesis of this disease. One novel form of anti-T-cell therapy is the immunoconjugate CD5-Plus®. This agent is composed of the murine IgG1 monoclonal antibody H65, which is directed toward the CD5+ antigen; and ricin A chain, a ribosomal inhibitor protein. We performed a pilot study to evaluate the safety of the immunoconjugate in subjects with type-I diabetes mellitus. We conducted a dose-escalation study using CD5-Plus given as an intravenous infusion for 5 consecutive days. Fifteen subjects (12 men and 3 women) with a mean age of 26 years, a mean duration of diabetes of 4.8 months, and a minimum stimulated C peptide of 0.3 pmol/mL were entered. Six subjects each were treated at the 0.1 and 0.2 mg/kg/day dosage levels, and three subjects were treated at the 0.33 mg/kg/day dose. Glycemic control was determined monthly by recording the glycohemoglobin, total daily insulin requirements, and fasting blood glucoses. β-cell function was measured by determining the C-peptide response to a mixed formula meal (Sustacal®) at baseline and at 1,3,6,9, and 12 months after treatment. The area under the curve (AUC) of the C-peptide response was calculated and, to reduce variability, related to that of the same subject at baseline. An analysis of subjects who retained at least 80% of their baseline β-cell function as measured by the AUC was performed. In addition, logarithms of the normalized areas under the C-peptide curve (AUC/AUC0) were determined, and the regression line was calculated. This line was compared to that generated by a similar analysis in historical controls who had participated in a previous study using placebo and cyclosporine. T cells were rapidly depleted during the infusion course and recovered to normal values within 30 days. No long-term adverse events were reported. The analysis of subjects retaining 80% of their initial AUC suggested a dose-dependent effect that was significant (p < 0.05) by the Cochran-Armitage test for trend in dose response at month 12. The slope of the linear regression line for all subjects was different from zero (p < 0.03), but this was accounted for entirely by the low-dose group. The slope of the regression line in subjects treated at the two higher doses of CD5-Plus did not significantly differ from zero and was similar to the cyclosporine-treated group of a previous study. This study demonstrates that CD5-Plus was tolerated by a group of recent onset type-I diabetic patients and resulted in reversible T-cell depletion. Preliminary efficacy analysis suggests a dose-dependent preservation of β-cell function. A full-scale, randomized, controlled trial to investigate the potential of CD5-Plus to preserve C-peptide function in new onset type-I diabetes is warranted.
Recent reports suggest that appropriate glycemic control without hypoglycemia could decrease mortality in patients with diabetes mellitus (DM) and end-stage renal disease (ESRD). However, an indication of oral anti-diabetic drugs is limited in this population. The aim of this study was to evaluate efficacy of teneligliptin, a novel DPP-4 inhibitor, by continuous glucose monitoring (CGM) in patients with type 2 DM (T2DM) on hemodialysis (HD).This 4-week, open label, single arm, intervention trial included 10 diabetic patients undergoing HD and with glycated albumin (GA) level of ≥ 18.3%. Teneligliptin treatment was administered on days with HD sessions (HD day) and on days without HD sessions (NHD day); blood glucose values were measured by CGM. The primary endpoint was improvement of glycemic control evaluated by area under the curve (AUC). As secondary endpoints, changes in GA, HbA1c and fasting plasma glucose (FPG) were evaluated.Teneligliptin improved blood glucose AUC on both HD days (p = 0.004), and NHD days (p = 0.004). This was accompanied by a significant reduction in GA, HbA1c, and FPG, without severe hypoglycemia.Teneligliptin is one of the useful options for glycemic control in T2DM patients undergoing HD.
The aldose reductase pathway has been implicated in the development of chronic complications of diabetes. In this study, we investigated the effect of an aldose reductase inhibitor, statil, on glomerular synthesis of heparan sulfate and albuminuria in male Wistar rats made diabetic with streptozotocin. Heparan sulfate is the predominant glycosaminoglycan (GAG) proteoglycan in the glomerular basement membrane (GBM). It confers a negative charge on the GBM, and its loss has been related to the presence of albumin in the urine. Diabetic rats synthesized less glomerular heparan sulfate and excreted more albumin than normal rats. Glomerular sorbitol concentration was significantly higher in diabetic than in normal rats. Chronic treatment of diabetic rats with statil did not improve either heparan sulfate synthesis or albuminuria despite normalization of glomerular sorbitol content. The present study does not support the role of excess sorbitol in the development of glomerular abnormalities in this rat model of streptozotocin diabetes.
Diabetes is an important risk factor for the development of ischemic cerebrovascular disease or stroke. Diabetic patients are more susceptible to atherothromboembolic brain infarction and its consequent mortality than nondiabetic patients. Cerebrovascular disease in the diabetic population somewhat follows the same pattern as in the nondiabetic population, however, with greater severity in outcome for the former. The etiopathogenetic mechanisms of strokes and transient ischemic attacks in diabetic patients are apparently due to cerebral hemodynamic and vascular derangements, hyperglycemia, and other related risk factors. There is a great disparity in the wider information on coronary heart disease and stroke than on diabetes and stroke. A better understanding is required for the determinants of stroke and diabetes, and the epidemiology and pathophysiology of specific risk factors in different racial groups. There is a similarity in the evaluation, assessment, and management of diabetic and nondiabetic patients.
An elevated serum ferritin concentration recently has been shown to be associated with coronary artery disease and its risk factors, including blood glucose concentration. The purpose of this study is to establish the prevalence of elevated levels of serum ferritin in patients with non-insulin-dependent diabetes mellitus (NIDDM) without hemochromatosis and to determine whether or not deferoxamine is of therapeutic value in treating such patients. The level of serum ferritin was measured in consecutive eligible patients with NIDDM seen at routine outpatient visits. Five patients with an elevated serum ferritin were treated with deferoxamine, 1 g intramuscularly, twice a week for 12 weeks. The level of serum ferritin was measured every 4 weeks, and the level of glycosylated hemoglobin was measured at baseline, at the end of the treatment, and 12 weeks after treatment was completed. The level of serum ferritin was elevated in 34 of 102 (33%) patients with NIDDM. The level of serum ferritin remained elevated in 30 of 32 (94%) of these patients on repeat testing. In three of the five patients treated with deferoxamine, the level of serum ferritin was normalized, but no patient had an appreciable change in dosage of medication for diabetes or glycemic control. Non-insulin-dependent diabetes is a condition frequently associated with elevated levels of serum ferritin. Treatment with deferoxamine intramuscularly was not effective in improving control of glucose in our patient group.
Capillary basement membrane thickening has been compared in retina, renal glomerulus, and leg muscle of dogs alloxan-diabetic 5 years and dogs experimentally galactosemic 5 years, and the effects of inhibition of aldose reductase have been examined. Basement membrane in each site became thickened as a result of either galactosemia or diabetes, but showed appreciable variation among the sites. The thickening of basement membrane in retina and muscle of galactosemic animals was similar in quantity and appearance to that seen in the diabetics, notwithstanding large differences between the two animal models with respect to tissue polyol concentrations and nonenzymatic glycation of hemoglobin and plasma protein. Aldose reductase inhibition was without influence on capillary basement membrane thickening in each tissue from dogs diabetic or galactosemic 5 years, despite substantial polyol path inhibition.
The association between urinary albumin concentration (UAC) in a morning urine sample and medical risk factors was evaluated in a cross-sectional study of 451 type II (noninsulin-dependent) diabetic patients. The following four groups of patients were created according to their urinary albumin levels: A) normal (less than 12.5 mg/L); B) high normal (12.5-30 mg/L); C) microalbuminuria, ie, incipient nephropathy (31-299 mg/L); and D) clinical nephropathy (greater than or equal to 300 mg/L). The patients with high normal levels had higher HbA1c and systolic blood pressure levels than patients with values within normal limits. The prevalence of incipient and clinical diabetic nephropathy was 20 and 7%, respectively. Incipient nephropathy was associated with higher blood pressures and body weights. Patients with clinical nephropathy had even further increases in these parameters, were older, and had longer duration of diabetes. In both groups of nephropathy, men were preponderant. Thirty six percent of all patients and 73% of patients with clinical nephropathy were treated for hypertension; 55% were treated with insulin. The insulin-treated patients had poorer metabolic control, but there were no differences in blood pressure or serum creatinine levels as compared with those of patients not receiving insulin treatment. The proportion of patients with severe retinopathy increased with the degree of albuminuria, although 22% of the patients with clinical nephropathy continued to be nonretinopathic.
Renal metabolism of amino acids (AAs) was evaluated in 5 patients with early IDDM, and in 7 controls (C) in the basal state for 80 minutes after the ingestion of an AA mixture simulating an animal protein meal. Insulin was withdrawn 20 hours before the study. Renal metabolism of AAs was evaluated by the arterial-venous difference technique. In the basal state in IDDM, as in C, the kidney takes up large amounts of a few nonessential AAs (NEAAs): it releases many NEAAs and a few essential AAs (EAAs). After AA ingestion in C, renal extraction of most EAAs, mainly BCAAs, Lys, and Thr, occurs; Pro extraction also increases and a significant uptake of Gly, Glu, Asp, Orn, and Tyr takes place. EAA extraction accounts for 30–40% of total AA uptake. In IDDM, after AA ingestion, a) renal uptake of total AAs is significantly lower, owing mainly to a markedly lower uptake of BCAAs, Lys, and also of Pro, Orn, and Ala; b) renal EAA uptake accounts for less than 20% of total AA extraction. These results indicate that in IDDM postprandial renal N repletion is impaired and unbalanced.
To study the role of laminin in the rat mesangial cell attachment, cell adhesion to laminin-coated dishes was assayed by adding various amounts of a pentapeptide (YIGSR). YIGSR (20–100 μg/mL) inhibited the cell attachment to laminin-coated dishes. Mesangial laminin B2 messenger RNA (mRNA) levels were attenuated during exposure to 30 mM glucose or high osmolarity achieved by the addition of 25 mM choline chloride to 5 mM glucose (310 mOsm/kg H2O) for 3 hours. These results suggest that laminin, which may have a physiologic role in mesangial cell attachment, is produced in mesangial cells, and that the decrease of laminin B2 mRNA during hyperglycemia or exposure to high osmolarity may have some pathophysiologic significance in the development of diabetic nephropathy.
The differences in deranged renal hemodynamics in non-insulin-dependent diabetes mellitus (NIDDM) and insulin-dependent diabetes mellitus (IDDM) have never been fully investigated. Whether or not autoregulatory mechanism of renal hemodynamics in NIDDM and IDDM is preserved remains to be clarified. In the present study we directly compared renal hemodynamics and its autoregulatory function in the early stage of NIDDM and IDDM before and after short-term glycemic control. Before glycemic control, mildly exaggerated glomerular filtration rate (GFR), subnormal renal plasma flow (RPF), and elevated filtration fraction (FF) were found in NIDDM as well as in IDDM; but there were no differences in these parameters of renal hemodynamics between the two types of diabetics. Glycemic control decreased GFR, whereas it did not alter RPF, resulting in normalization of FF in NIDDM and in IDDM. Before glycemic control, mean blood pressure was significantly correlated with GFR, but was not correlated after glycemic control in either type of diabetes. In conclusion, hyperglycemia induced glomerular hyperfiltration evenly and disturbed autoregulation of renal hemodynamics in NIDDM and in IDDM.
Urinary enzyme activities (N-acetyl-beta-D-glucosaminidase [NAG], alkaline phosphatase [ALP], leucine aminopeptidase [LAP], gamma-glutamyl transpeptidase [gamma-GTP]) were investigated to determine their clinical significance in diabetic nephropathy. There were correlations among ALP, LAP, and gamma-GTP, though no correlation existed between NAG and the other three enzymes. Activities of NAG isozymes (both A and B) were higher than in normal controls. It has been reported that NAG isozyme A might be associated with glomerular diseases, and isozyme B might be associated with proximal tubular damage. The results of our study suggest that NAG reflects lysosomal dysfunction of both glomerular and proximal tubular epithelial cells, which may be caused by poor glycemic control, and that ALP, LAP, and gamma-GTP reflect brush border damage of proximal tubules, which may be caused by diabetic nephropathy.
We measured serum and urinary concentrations of type IV collagen by radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA) in diabetics. Serum and urinary concentrations of type IV collagen measured by RIA and ELISA were increased compared to those of control subjects. In diabetics with macroproteinuria or with renal insufficiency, serum and urinary concentrations of type IV collagen were higher than in diabetics without nephropathy or with early renal damage as determined by the presence of microproteinuria. These results suggest that serum and urinary concentrations of type IV collagen are increased in patients with advanced diabetic nephropathy. These increases may indicate that alteration of basement membrane metabolism has occurred in diabetics.
We evaluated the progression of microangiopathic lesions in 22 type I diabetic patients with residual C-peptide excretion and in 22 type I diabetic patients matched for age at onset and disease duration without residual C-peptide excretion. We also wished to elucidate whether certain HLA-DR phenotypes were associated with preserved insulin secretory activity and/or microvascular lesions. The two groups of patients were investigated in 1984 and 1985. In the previous report, we observed less frequent signs of early microangiopathic lesions in association with a lower HbA1c in the group with a detectable urinary C-peptide excretion. The HbA1c level has been measured regularly (7–12 times) since the initial investigation; the mean value was lower in the patient group with residual C-peptide excretion than in the non-C-peptide group (p = 0.01). Nine of the patients in the group without urinary C-peptide excretion had increased severity of retinopathy, but only two in the group with urinary C-peptide excretion (p = 0.04) had progression of retinopathy. Incipient and/or manifest albuminuria was observed in six of the nonexcretor group and one of the C-peptide excretors. Four of the patients were receiving antihypertensive treatment and three others had a diastolic blood pressure ≥ 90 mmHg in the non-C-peptide excretor group as compared with one with a pressure ≥ 90 mmHg in the C-peptide excretor group. All 16 patients with moderate to advanced nonproliferative background retinopathy and/or incipient albuminuria had HLA-DR 34, 3x, or 4x antigens, as compared with 20 of 28 patients with few if any signs of microangiopathy. We conclude that urinary C-peptide excretion together with regular measurements of HbA1c may be used for prognostic evaluation of the increase in severity of retinopathy in groups of patients with type I diabetes.
