Haptoglobin phenotype and diabetic nephropathy.

AIMS/HYPOTHESIS: To determine if the haptoglobin 2 allele is associated with an increased risk for the development of diabetic nephropathy. METHODS: This study included 110 consecutive normotensive subjects with Type I (insulin-dependent) diabetes mellitus and Type II (non-insulin-dependent) diabetes mellitus seen in two outpatient clinics in Israel. Diabetes duration was greater than 10 years for Type I diabetes and more than 5 years for Type II diabetic subjects. Microalbuminuria was defined as urinary protein excretion of 30 to 300 mg/24 h, and macroalbuminuria was defined as urinary protein excretion of greater than 300 mg/24 h. Serum was taken from subjects for haptoglobin typing by gel electrophoresis. RESULTS: Of the participating subjects 54 had Type I and 56 had Type II diabetes. None (0/18) of the subjects homozygous for the haptoglobin 1 allele (1-1) showed any sign of diabetic nephropathy, as compared with 34 % (19/55) of subjects homozygous for the haptoglobin 2 allele (2-2) and 27 % (10/37) of heterozygous subjects (2-1) (p < 0.04). Of the subjects 29 showed macroalbuminuria. The risk of developing macroalbuminuria was found to be greater in subjects with two haptoglobin 2 alleles (22 %) (12/55) as compared with one haptoglobin 2 allele (8 %) (3/37) or no haptoglobin 2 alleles (0%) (0/18) (p < 0.03). CONCLUSION/INTERPRETATION: By showing a graded risk relation to the number of haptoglobin 2 alleles in Type I and Type II diabetic subjects, these studies further support our hypothesis that the haptoglobin phenotype is a major susceptibility gene for the development of diabetic nephropathy.

Dietary supplementation of a natural isomer mixture of beta-carotene inhibits oxidation of LDL derived from patients with diabetes mellitus.

BACKGROUND: Accelerated atherosclerosis is common in patients with diabetes mellitus which may be linked to increased lipid peroxidation. Therefore, we compared the oxidation of LDL derived from patients with diabetes to normoglycemic controls and followed-up the effect of dietary beta-carotene supplementation on LDL oxidation. METHODS: Twenty patients with long-standing non-insulin-dependent diabetes mellitus were studied in comparison with age- and sex-matched control subjects. Dunaliella bardawil-derived beta-carotene was supplemented to the patients for 3 weeks, 60 mg daily dose. LDL oxidation was analyzed by measuring malondialdehyde (MDA), lipid peroxides (PD), and conjugated dienes (CD) generation in response to CuSO(4)-induced oxidation. LDL lipid composition and the LDL associated vitamins A, E and carotenoids were also measured. RESULTS: LDL susceptibility to oxidation by CuSO(4) was increased in the patients by 40% with a 35% shorter lag time required for the initiation of LDL oxidation, i.e. 56 +/- 6 min in patients vs. 85 +/- 9 min in controls (p <0.01). Patients showed increased cholesterol/phospholipid and polyunsaturated/saturated ratios, as well as reduced content of LDL associated vitamins. Upon beta-carotene supplementation, there was a significant elevation in plasma and in LDL all-trans beta-carotene [from 0.296 +/- 0.020 to 0. 968 +/- 0.133 microg/mg LDL protein (p < 0.01)] paralleled by a significant reduction in LDL susceptibility to oxidation, as exhibited by increased lag time up to 115 +/- 10 min (p < 0.01) and reduction in MDA and PD generation (by 25 and 40%), respectively (p < 0.01). CONCLUSIONS: Increased susceptibility to oxidation of LDL derived from patients with diabetes mellitus is associated with abnormal LDL lipid composition and antioxidant content. Natural beta-carotene dietary supplementation normalizes the enhanced LDL oxidation and consequently may be of importance in delaying accelerated development of atherosclerosis in these patients.

Increased plasma oxidizability and decreased erythrocyte and plasma antioxidative capacity in patients with NIDDM.

BACKGROUND: Atherosclerosis and microvascular complications in patients with non-insulin-dependent diabetes have been linked to increased oxidative stress. The glutathione redox cycle is a major determinant of the antioxidative capacity of plasma and its constituents. METHODS: We attempted to investigate plasma oxidation and plasma and erythrocyte glutathione and glutathione enzymes in 20 patients with NIDDM, compared with euglycemic matched controls. Plasma oxidation was analyzed both basally (without) and as induced by 2,2'-azobis,2-amidopropane hydrochloride measured by the generation of thiobarbituric acid reactive substances and lipid peroxides. RESULTS: There was a significant increase in oxidation both basally (without) and as induced by AAPH. Plasma glutathione was lowered by 50% (P < 0.01) and erythrocyte glutathione peroxidase, glutathione s-transferase and glutathione reductase activities were lower by 30%, 27% and 46%, respectively (P < 0.01) in the patients with NIDDM. CONCLUSIONS: Confronted by increased oxidation, patients with NIDDM show an abnormal plasma and erythrocyte antioxidative capacity, which may result in an accelerated rate of complications.

Outcome of trigger finger treatment in diabetes.

Trigger finger is an underdiagnosed hand disorder causing disability in longstanding diabetic patients. Sixty diabetic patients [39 insulin-dependent diabetes mellitus (IDDM) and 21 non-insulin-dependent diabetes mellitus (NIDDM)] and 60 nondiabetic patients were examined. All were initially treated by steroid injections: failure to alleviate symptoms was the indication for surgery. The incidence of multiple digit involvement was higher in IDDM patients as compared with the control group (p < 0.001). The diffuse type was 1.45 times more frequent in IDDM and NIDDM than in nondiabetic patients (p < 0.008). The diabetic patients had a relatively longer duration of symptoms (p < 0.003). Significantly, a higher recovery rate upon steroid injection was achieved in control patients as compared with the diabetic ones (p < 0.001). IDDM patients required more surgery compared with NIDDMs and, in 13.3% of diabetic patients, the surgical outcome was not successful. Diabetic patients should be diagnosed early for multiple and diffuse types of trigger digits. Steroid injection as the first mode of therapy is highly recommended although not always successful. Surgery is the definitive treatment but requires a long course of physiotherapy and may be associated with some complications.

Polyneuropathy in impotence.

Three hundred and forty-one consecutive impotent patients were evaluated for the presence of polyneuropathy (PNP) by neurophysiological and psychophysical tools, including nerve conduction and quantitative sensory tests (thermal and vibratory). PNP was present in 38% of diabetics, and 10% of non diabetics. Overall, PNP was found in 19% of impotent patients. PNP is relatively common among impotent patients, and might play a causative role. Patients judged 'neurogenic' and those judged 'vasculogenic', based on nocturnal tumescence test (NPT) and vasoactive drug injection tests, had very similar rates of PNP (21 and 23%, respectively). Thus it is suggested that the vasoactive drug injection test does not serve in discriminating neurogenic from non-neurogenic impotence. NPT, however, faithfully discriminates psychogenic from organic impotence, as far as PNP is involved, since a very low percentage of patients with normal NPT had PNP.

Parasympathetic autonomic neuropathy in diabetes mellitus: the heart is denervated more often than the pupil.

In one hundred subjects with diabetes mellitus assessed by the techniques of power spectral analysis of heart rate variability and heart rate variability during deep breathing, parasympathetic (vagal) cardiac denervation was shown to occur approximately twice as commonly as parasympathetic pupillary denervation measured by the maximal velocity of pupillary constriction. The pupillary dysfunction was detectable only when both tests of cardiac innervation were abnormal as well. No correlation was found between any of the autonomic measures and duration of known diabetes or degree of metabolic control.

DC photoplethysmography in the evaluation of sympathetic vasomotor responses.

The d.c. component of the photoplethsmographic signal was used to determine the response of the finger vasculature to three standard tests of vasomotor function: (1) an inspiratory gasp (IG), (2) immersion of the contralateral hand in ice water (IW), and (3) the Valsalva manoeuvre. The vasoconstrictor response to the first two of these stimuli could be measured in all of 25 normal subjects. The response to the Valsalva manoeuvre could not be detected consistently. Seven patients with known sympathetic autonomic dysfunction showed no response to either IG or IW. In 30 patients with diabetes mellitus of over 10 years duration, 46.7% had no response to IG, and 20% had no response to IW. Absent responses correlated with abnormal autonomic cardiovascular reflexes, with absent sympathetic skin responses and with the severity of peripheral somatic neuropathy. The d.c. photoplethysmographic determination of the vasoconstrictor response in the finger after a deep inspiratory gasp and after ice water immersion offers an additional measure of the function of small (2 mu-6 mu) peripheral nerve fibres. Because of variability in the amplitude of the responses in normals, only an absent response should be accepted as abnormal.

Oral health and salivary composition in diabetic patients.

The salivary composition and flow rate were examined in 20 patients with insulin-dependent diabetes mellitus (IDDM) and in 19 patients with non-insulin-dependent diabetes mellitus (NIDDM) and compared with 20 healthy controls. Resting and stimulated whole and submandibular saliva was analyzed. Significantly lower resting salivary flow rates were found in the IDDM patients as compared to the NIDDM group. In the IDDM patients potassium concentration in resting saliva was significantly higher compared with healthy controls and in stimulated whole saliva compared with NIDDM patients. No difference in salivary total protein, amylase, lactoferrin, or lysozyme was found among the three groups examined. The IgA concentration of the IDDM patients was significantly higher in whole resting saliva compared with controls and in the submandibular saliva compared with both NIDDM patients and controls. No difference was found between controls and the diabetic patients examined in prevalence of complaint of dry mouth. The salivary flow rates, however, were significantly lower in the three subgroups with dry mouth compared with the subgroups without this complaint. Caries were detected in 100% of the diabetic patients and controls. No correlation was observed between the incidence of caries and any of the salivary parameters examined. A higher prevalence and severity of periodontal disease was detected in the diabetic patients as compared to the controls. A significant positive correlation was found between the gingival index and the concentrations of total protein, albumin, lysozyme, and lactoferrin in whole resting saliva in the three groups examined.

Intravenous glucose tolerance test in gestational diabetes and pregnancy: 'manual' versus computerized assessment.

In order to assess the reliability of 'manual' versus computerized interpretation of the intravenous glucose tolerance test (IVGTT), fifty-five women, aged 19 to 41, underwent an IVGTT. Fifteen subjects had overt diabetes mellitus, sixteen were evaluated for gestational diabetes and twenty-four were healthy controls, fourteen of whom were pregnant. Each IVGTT was analysed by two trained physicians independently and by a simple computerized program, and the k' values obtained were compared, using the Student t-test for paired data. Significant difference (p less than 0.005) was found comparing either the 'manual' assessments or the 'manual' versus computer calculations. It is concluded that the IVGTT test must be interpreted using a simple computerized program, especially in borderline cases of pregnancy where the traditional 'manual' analysis might result in misclassification or misdiagnosis of the patient.

Salivary composition in diabetic patients.

Salivary composition and flow rate were examined in 35 patients with insulin-dependent diabetes mellitus (IDDM) and compared to 31 healthy controls. Significantly lower whole-saliva flow rate was observed in the IDDM patients, but was not correlated with the subjective complaint of xerostomy. Glucose concentration was significantly higher in the parotid saliva of the IDDM patients. Potassium concentration was significantly higher in whole and parotid, resting and stimulated saliva, as was total protein concentration in resting whole and in stimulated parotid saliva of the diabetics. No significant difference between diabetics and healthy controls was found in sodium and IgA concentration or in amylase activity. The significantly higher glucose, lower flow rate, and higher potassium and protein concentrations indicate that salivary glands are affected in IDDM. The subjective complaint of dry mouth, often present in diabetics, while not correlated with salivary flow rate, might reflect qualitative changes in salivary composition and/or altered mucosal perception. Salivary glucose concentration, although significantly higher in the diabetics, was not significantly correlated with serum glucose, preventing the use of saliva for monitoring blood sugar.

Glucose, insulin and glucagon response to intravenous glucose load in patients on chronic hemodialysis.

We examined the theory that patients with chronic renal failure exhibit glucose intolerance that is not completely corrected by dialysis. I.v. glucose tolerance tests (IVGTT) were performed in 11 uremic patients who were on chronic intermittent hemodialysis therapy for a mean of 33 months, before and 24 h after dialysis. The glucose disappearance constants (K-glucose) were normal in all subjects and were not affected by dialysis. Insulin response was within normal limits, with minimal changes by dialysis. Serum glucagon was higher than normal. The early, middle and late insulin levels were the same as in the normal population. These results indicate that chronic hemodialysis therapy, together with continuous effective control of biochemical impairment, can achieve normal glucose tolerance in uremic patients.

Reversal of insulin resistance in diabetic rat adipocytes by insulin therapy. Restoration of pool of glucose transporters and enhancement of glucose-transport activity.

To determine the role of insulin in reversing the insulin resistance associated with depletion of the intracellular pool of glucose transporters, streptozocin-induced diabetic rats were treated with 5 U/day s.c. of insulin for 0, 8, or 14 days. At each time point, adipose cells were isolated, and 3-O-methylglucose transport was measured in the absence and presence of 1000 microU/ml insulin. With the cytochalasin B-binding assay, concentrations of glucose transporters in the plasma and the low-density microsomal membrane fractions were determined. Eight-day insulin therapy enhanced glucose transport rate (mean +/- SE) from 0.2 +/- 0.0 to 1.1 +/- 0.1 fmol X cell-1 X min-1 in the basal state and from 0.8 +/- 0.1 to 5.5 +/- 0.4 fmol X cell-1 X min-1 in the insulin-stimulated state in untreated and treated diabetic rats, respectively; this is a 3-fold increment of glucose transport rate in both states compared with control rats. After 14-day insulin therapy, glucose-transport activity declined toward normal but still remained approximately 1.5- and 4-fold higher than control and diabetic rats, respectively. Despite the persistent enhancement of glucose transport rate, concentration of glucose transporters in the intracellular pool was restored only to its prediabetic state. Likewise, the increased concentration of glucose transporters in the plasma membranes after insulin stimulation was similar to that of control rats. Thus, we suggest that 8-14 days of insulin therapy reversed the insulin resistance in diabetic rat adipocytes by at least two mechanisms: restoration of the intracellular pool of glucose transporters and enhancement of glucose-transport activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Amylase/creatinine clearance ratio response to hyperglucagonemia in diabetes and obesity.

Hyperglucagonemia accompanies several disorders such as acute pancreatitis and diabetic ketoacidosis characterized by increased amylase/creatinine clearance ratio (ACCR). We tested the hypothesis that glucagon may be responsible for the augmental ACCR among diabetic and/or obese subjects. A constant glucagon infusion (15 ng/kg/min) was given to eight noninsulin-dependent diabetics and to eight obese subjects to attain glucagon levels comparable with those obtained during acute pancreatitis. The ACCR significantly increased from 0.9 +/- 0.1 to 1.5 +/- 0.1% (p less than 0.005) in both noninsulin-dependent diabetics and obese subjects, whereas among normal control subjects the ACCR increased from 0.84 +/- 0.8 to 1.3 +/- 0.14% (p less than 0.001). Because the increased values observed in either noninsulin-dependent diabetics or obese subjects are less than the ACCR values observed in acute pancreatitis or in diabetic ketoacidosis, the elevated ACCR in those conditions is only partially explained by the hyperglucagonemia.

Auditory brainstem evoked potentials in insulin-dependent diabetics with and without peripheral neuropathy.

Auditory Brainstem Evoked Potentials (ABEP) were recorded from 33 insulin-dependent diabetes mellitus (IDDM) patients (17 with diabetic peripheral neuropathy and 16 without) as well as from 20 normals. Pure-tone audiometry, speech reception threshold and discrimination were also evaluated. Sub-clinical pure-tone threshold elevation was observed for IDDM patients with neuropathy. Pure-tone thresholds of IDDM patients without neuropathy were not significantly different from those of normals. ABEP abnormality (at 10/sec click rate) was observed in 31% of IDDM patients with neuropathy, rising to 44% when 55/sec click rate measures were included. Abnormalities included bilateral and symmetrical peak-latency prolongations for all waves, greater for the later waves, and prolongation of V-I and V-III interpeak latency differences, all at 10/sec, and only prolonged peak latency for I at increased rate. Abnormalities coincided with microangiopathy and peripheral neuropathy. The incidence of ABEP abnormality for IDDM patients without neuropathy was only 12%, unilateral and sporadic in nature. As a group, IDDM patients with neuropathy had significantly prolonged IV and V peak-latencies, compared with the normals, or with the IDDM patients without peripheral neuropathy. In contrast, IDDM patients without neuropathy resembled the normals in all respects. ABEP have proven useful in understanding the variety of pathologies underlying the clinical manifestation of diabetes.