Development of a diabetes-like syndrome in an athymic nude Balb/c mouse colony.
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Biomedical subjects
Publications and source records attributed to D Kumar.
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An analysis of 84 children with peptic ulcer disease seen at The Hospital for Sick Children, in London, revealed only 30 primary ulcers over a period of 30 years. While most of these responded to conservative measures, it is recognized that a significant proportion may ultimately require surgical treatment for recurrence of the disease in adult life. Secondary ulcers occurred with almost twice the frequency of primary disease. Hemorrhage was the first sign of the ulceration in 55 per cent of these seriously ill children and could be controlled with conservative measures in 14 of 17 patients. Only three patients required surgical treatment for uncontrolled hemorrhage. Secondary ulceration was largely a terminal event and despite intensive resuscitation carried a high mortality (77.7 per cent).
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Plasma fibronectin and serum thyroid parameters were determined in 6 hyperglycemic nonketoacidotic patients (HNK) and 12 subjects with diabetic ketoacidosis (DKA). The DKA patients showed a marked increase in both plasma fibronectin and serum T3 over 5 days of insulin treatment [175.2 +/- 18.1% (+/- SEM) and 208.7 +/- 17.6% of initial values respectively], while these parameters did not change in the HNK patients despite equivalent control of diabetes. Serum rT3 levels declined, as expected, to 65.8 +/- 10.9% of the initial values in the DKA patients, but did not change in the HNK patients. There was a significant positive correlation between changes in plasma fibronectin and serum T3 values in the DKA patients (r = 0.5; P less than 0.005). Other reports have shown a decrease in plasma fibronectin concentrations in fasted patients, a well known low T3 state; therefore, the association between changes in plasma fibronectin and serum T3 values may be a widely observed phenomenon. The parallel changes in fibronectin and T3 may reflect alterations in the metabolic state of these patients. The precise nature of the relationship between changes in fibronectin and T3 concentrations requires additional investigations.
To evaluate possible advantages of human insulin of recombinant DNA origin (HI) in the treatment of diabetic patients, we compared cellular and humoral immunoreactivities of HI and porcine insulin (PI). Anti-insulin IgE bound equal amounts of 125I-HI and 125I-PI. There was no difference between HI- and PI-stimulated lymphocyte transformation indices. The binding of 125I-HI with circulating anti-insulin IgG was lower compared with 125I-PI binding (12.1 +/- 1% versus 15.4 +/- 1.5%, P less than 0.001) in 60 insulin-treated cases. Thirteen sera were selected for high antibody titers and analyzed in detail. In the competitive inhibition assays, a 50% displacement of 125I-PI required a fourfold higher concentration of HI than PI. Although total insulin binding capacities were almost equal, 63 +/- 11 nM/L for PI and 60 +/- 12 nM/L for HI, the high-affinity antibodies had significantly reduced avidity for HI compared with PI. These differences in avidities suggest that HI may be useful in treatment of immune-type insulin resistance.
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A 17 year old male with a history of bronchial asthma was admitted to the intensive care unit in severe respiratory distress. During a two week period of intensive respiratory care he received large doses of aminophylline and corticosteroids. In addition, pancuronium was given to facilitate ventilation and to reduce airway pressure. Large doses of pancuronium, as much as 5 mg/hr, were required to stop spontaneous respiratory efforts and restlessness. The total pancuronium dose given during the two week period was 800 mg. One hour after pancuronium was discontinued the patient could open his eyes and move his lips. Peripheral nerve stimulation indicated partial paralysis which improved promptly following a test dose of edrophonium. The authors speculate the aminophylline, which is a known inhibitor of the enzyme phosphodiesterase, raised the level of c-AMP and, in turn, the level of acetylcholine at the neuromuscular junction and thus antagonized the blocking effect of pancuronium. In addition, the large doses of corticosteroids that the patient had received may have enhanced the release of acetylcholine and further facilitated neuromuscular transmission.
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Fifteen diabetics with recurrent painful local reactions to insulin were studied. Reactions occurring after intradermal insulin injection were observed in nine patients over 48 hr and biopsies were taken at intervals for microscopic study using the 1 mu Giemsa technique. Insulin-specific IgE and IgG levels were measured on all patients. Five patients had biphasic reactions in which wheal and flare (WFR) were followed by an indurated lesion 4 to 6 hr later. These reactions lasted up to 24 hr and were histopathologically identical to similar "late-phase reactions" seen with ragweed. They were transferable with Prausnitz-Küstner (P-K) testing. Three patients had reactions that developed 8 to 12 hr after injection, peaked around 24 hr, and were not preceded by WFR. These reactions were morphologically delayed hypersensitivity reactions and were not transferred by P-K testing. One patient had a reaction that developed in 4 to 6 hr after injection and peaked by 12 hr. Histologically, this reaction was "Arthus" in type and was not transferred by P-K testing. Specific insulin antibody determinations were not helpful in distinguishing patients with different types of reactivity. These data show that recurrent local reactions to insulin may be of three distinct types: "late-phase reactions" (which are IgE dependent), "Arthus" local vasculitic reactions, or tuberculin-type delayed hypersensitivity reactions. These findings may influence the approach to management of these reactions.
The effects of diabetes mellitus on serum thyroid hormone parameters were studied in 54 patients divided into 4 groups. Treated asymptomatic patients (group I) had normal thyroid values which did not correlate with serum or urinary glucose. Untreated nonketoacidotic patients (group II) showed a mild persistent depression in T3 and an elevation in rT3. Patients with ketoacidosis with a brief history of symptoms (group III) had a moderate T3 decrease and a mild rT3 elevation which quickly resolved with treatment. Ketoacidotic patients with a long history of symptoms (group IV) had marked depression of T3 and elevation of rT3 which was only partially rectified by treatment. Serum T4 was generally normal, except for a minimal decrease on the day after admission, probably resulting from rehydration and a subsequent increase associated with an increase in TSH. We concluded that thyroid hormone parameters were not influenced by variations in serum glucose, but seemed to reflect the effects of a preexisting catabolic state, ketoacidosis, or both.
To determine the association of histocompatability antigens (HLA) with insulin-dependent diabetes (IDD) in Mexican-Americans, we determined HLA-A, -B, and -C specificities in 112 unrelated patients and 332 controls, and HLA-DR specificities in 85 patients and 209 controls. We also studied immunoglobulin G (IgG) insulin antibody formation in 56 Mexican-Americans with IDD, and the relationship between antibody formation and HLA-DR antigens. IDD patients have a significant increase in HLA-DR4 compared to the control population (chi 2 = 14.75; corrected P less than 0.0001). HLA-DR2 was not detected in any patient with IDD. A significant association between HLA-Aw30 and HLA-B18 was found in IDD patients (chi 2 = 9.39; P less than 0.05) as compared to controls. IgG insulin antibody formation was significantly increased in HLA-DR3- and -DR4-negative patients compared to that in patients positive for both antigens (P less than 0.05). These findings support previous observations in caucasians and black Americans indicating that HLA-DR specificities are associated with IDD and may play a role in determining its mode of inheritance, and perhaps its pathogenesis, independent of ethnic differences. HLA-DR immune-associated antigens are also of importance in determining IgG insulin antibody formation.
Basal plasma glucose, glucose tolerance, and insulin secretion were investigated in young and mature athymic nude BALB/c mice and in age-matched controls. Basal plasma glucose levels in male athymic nude mice were similar to those of controls at 1, 3, and 4 wk of age. At 6, 8, and 12 wk of age, male athymic nudes had significantly higher basal plasma glucose levels when compared with controls (P less than 0.01). Plasma immunoreactive insulin concentrations were similar in athymic nudes and controls at 1 wk of age, but at 3 wk of age and subsequently at 6, 8, and 12 wk athymic nude mice had significantly decreased insulin levels when compared with their age-matched controls (P less than 0.05). We found impaired glucose tolerance in male athymic nude mice at all age groups when compared with both female athymic nudes and control BALB/c mice. The discovery of a spontaneous diabetic syndrome (hyperglycemia, impaired glucose tolerance, and decreased insulin secretion) in a colony of athymic nude mice may provide an excellent model for studying the genetics and interactions between the immune and endocrine systems.
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Monocyte insulin receptor binding was studied in six nonpregnant control patients and in 40 pregnant patients with varying degrees of carbohydrate tolerance. Competitive binding assays were performed to determine insulin binding to monocytes. Fasting insulin levels were determined. We obtained the following results: (1) When compared to values not associated with pregnancy, the number of insulin receptor sites per cell increases twofold (31,000 versus 16,300); (2) Class A diabetic patients have higher numbers of receptor sites than normal pregnant patients (80,800 versus 31,000; (3) untreated Class B diabetic patients have markedly reduced receptor sites (4,575) and bind less insulin at physiologic concentrations (p less than 0.01); (4) insulin therapy of previously untreated Class B diabetic patients restored the number of receptor sites to normal pregnant levels (29,700); and (5) Classes C and D diabetic patients had similar numbers of receptor sites (30,140) and showed a greater receptor affinity for insulin than pregnant control subjects (p less than 0.01).
Autoradiographic studies using 3H-uridine in the salivary gland of adult Lygaeus sp. were carried out. The gland cell nuclei, particularly the multiple nucleoli, are the sites of incorporation of the label exhibiting RNA synthesis. The labelled molecules (RNA) are transported to the cell cytoplasm and then into the gland lumen in which no turnover of the radioactivity is observed.
A new approach to a more constant steroid delivery system was made in which 7,9 mg of norethisterone acetate was shaped into a cylindrical pellet (diameter 1.47 mm, length 4 mm) and placed inside a silastic capsule (i.d. 1.57 mm, o.d. 3.18 mm) of 5 mm effective length. The extra space available around the pellet was filled with physiological saline. For the sake of comparison, the same amount of crystalline norethisterone acetate was packed up to 5 mm length inside a silastic capsule of the same dimensions. The incorporation of fluid (saline) in the system not only caused a marked decrease in the initial high release but also a more constant release. Varying the pellet diameter showed that release of the steroid increases with the increase in surface area of the pellet.