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Reversal of diabetes by syngeneic transplantation of a radiation-induced rat insulinoma.

The growth and metabolic effects of a radiation-induced rat insulinoma were examined after subcutaneous subscapular transplantation into normal and streptozotocin diabetic NEDH rats. Streptozotocin diabetic rats exhibited hyperglycaemia, hypoinsulinaemia, impaired glucose tolerance without an insulin response, polyuria, polydipsia, hyperphagia and weight loss. Transplantation of tumour fragments gradually improved the physical and metabolic state over the following 3 weeks. Coincident with a progressive rise in plasma insulin between 10 and 17 days, the diabetic rats gained weight and reduced their food intake. The rats remained hyperglycaemic during this time, but developed hypoglycaemia with marked hyperinsulinaemia by 24 days. Furthermore, plasma glucose and insulin concentrations were not increased by an intraperitoneal glucose challenge, indicating greatly accelerated glucose clearance. Both the streptozotocin-treated and normal insulinoma-bearing rats incurred a fatal hypoglycaemic coma by 28-33 days after transplantation. Final body weights, tumour weights and concentrations of glucose and insulin were similar in the two groups. This study demonstrates reversal of streptozotocin diabetes by insulinoma transplantation. The hyperglycaemia and the accompanying diabetic environment did not modify tumour growth and development.

Adenoma, Islet Cell↗

Incidence and severity of ketoacidosis in childhood-onset diabetes in Kuwait. Kuwait Diabetes Study Group.

In 1992, the diabetes registry was started in Kuwait, as part of DiaMond, a WHO multinational collaborative project on the incidence of childhood-onset diabetes. Children (243) aged below 15 years, were identified between 1 January 1992 and 31 December 1995. Children (203) were Kuwaiti and 40 were non-Kuwaiti children but resident of Kuwait. For the years 1992, 1993, the annual incidence of childhood onset diabetes for Kuwaiti children was 15.4 per 100,000 (95% confidence interval 12.9-19), and the degree of ascertainment was 92%. Polyuria, polydypsia, weight loss and nocturia were the most frequently reported symptoms; four children were in coma and one in shock at presentation. Nearly half of the children (49%) presented ketoacidosis (venous pH < 7.3 and/or plasma bicarbonate level < 18 mmol/l). and in 53 children (23.5%) it was severe (venous pH < 7.1 and/or plasma bicarbonate level < 10 mmol/l). In 62 children (25.5%) it was mild to moderate (venous pH 7.1-7.3 and/or plasma bicarbonate level 10.1-18 mmol/l). The incidence of severe ketoacidosis was similar in all age groups and sexes. All children recovered completely without major complications and no deaths were recorded. We conclude that diabetic ketoacidosis is a common presentation at the onset of diabetes in childhood in Kuwait and attests to the lack of awareness of general practitioners and parents to the symptoms and signs of diabetes in childhood.

Adolescent↗

Clinical and laboratory characteristics of type I (insulin dependent) diabetes mellitus at presentation among Bulgarian children.

Clinical and laboratory data of 1248 newly diagnosed diabetic children at the time of diagnosis were analysed. All children were admitted to the University Children's Hospital in Sofia, 45.9% before first their insulin injection. Symptoms preceding the diagnosis and laboratory data (plasma glucose and ketonuria) were analysed, respectively for 1100 and 1022 children. Blood pH (mainly arterialized) was available in 558 ketonuria positive children and in other 82 acidotic breathing was reported. Mother's education was noted in the 1226 hospital records. Among the children with known urinanalysis 13.5% were without ketonuria (148 patients), 12 of them with fasting blood glucose < or = 6.4 mmol/1 (115 mg/dl). Eighteen-point-two percent of all children were hospitalized in a state of severe ketoacidosis (blood pH < or = 7.2 or reported acidotic breathing). The average duration of thirst and polyuria was 28 +/- 33 days. Ketonuria negative children with plasma glucose < or = 6.4 mmol/l showed a significantly shorter period of symptoms, compared to those with plasma glucose > 6.4 mmol/1 (17 +/- 25 vs. 25 +/- 31 days; P = 0.0991). The cases with severe ketoacidosis, compared to those with mild ketoacidosis (blood pH 7.21 - 7.34) showed shorter period of symptoms too (P = 0.0658). Moderate positive relation existed between the age at diagnosis and duration of symptoms (chi 2 = 43.28, D.F. = 8, P = 0.0000). The percentage of severe ketoacidosis is higher in the younger age groups. Febrile illness, preceding the start of the symptoms was more common in the groups with shorter duration of symptoms (up to 1 month), but did not change the proportion of severe ketoacidosis. No significant difference was found between the level of mother's education and duration of the symptoms before diagnosis (P = 0.9782). We conclude that the level of metabolic disturbances at the diagnosis of IDDM among children was not influenced by the duration of the preceding symptoms. The severity of clinical picture was possibly dependent on the degree of insulinopenia, i.e. the rate of beta-cell destruction. Clinical heterogeneity was possibly dependent on genetical heterogeneity related to HLA class II genes.

Adolescent↗

Diagnosis and treatment of juvenile endocrine disorders in puppies and kittens.

Endocrine and metabolic disorders affecting puppies and kittens from birth until 6 months of age may manifest as clinical problems related to growth, water metabolism (polydipsia or polyuria), or as episodic weakness. Endocrine and metabolic disorders that affect stature, such as pituitary or hypothyroid dwarfism, present to the veterinarian for assessment of delayed or aberrant growth. Conversely, juvenile-onset diabetes mellitus and diabetes insipidus cause excessive thirst, urination, and difficulty in house-breaking.

Animals↗

Ascites, renal abnormalities, and electrolyte and acid-base disorders associated with liver disease.

Ascites and renal dysfunction are often associated with decreased liver function and reflect the complex abnormalities of water, protein, electrolyte, and acid-base metabolism that may complicate severe liver disease. This article discusses the pathophysiology and management of ascites, polydipsia and polyuria, decreased renal function, and acid-base and electrolyte alterations that can complicate liver disease.

Acid-Base Imbalance↗

Urologic disorders of the geriatric dog.

Disorders of the urinary system are common in geriatric dogs. Common urinary disorders that are seen in older dogs include chronic renal failure, urinary incontinence, bladder tumors, and prostate problems. Therapy for chronic renal failure is aimed at both slowing the progression of the disease and ameliorating the signs of uremia. Therapeutic recommendations for the conservative medical management of chronic renal failure include reducing dietary protein, moderately reducing salt intake, maintaining normal serum phosphorus levels, providing free access to water, avoiding stress, supplementing water soluble vitamins, using anabolic steroids to treat the anemia of chronic renal failure, treating acidosis, and controlling hypocalcemia. Urinary incontinence can often be controlled or eliminated. The appropriate approach to management of this disorder is to identify and remove specific causes. Common causes of urinary incontinence are urethral incompetence, urinary tract infection, and polyuria and polydypsia. Bladder tumors are, fortunately, not a common tumor of dogs, but are more common in geriatric dogs than in the young. The most common bladder tumor is the transitional cell carcinoma. Therapy for this tumor is usually palliative because of its malignant nature and because it is usually located in the neck of the bladder. Its location in the bladder often makes it impossible to resect the tumor completely without removing the entire bladder and diverting the ureters. New chemotherapeutic modalities are being evaluated that may increase life expectancy after diagnosis and, therefore, improve prognosis. Prostate disease is also seen in older dogs. Types of prostate abnormalities seen in dogs include prostatic hyperplasia, cysts, abscesses, acute and chronic infection, and neoplasia. The institution of proper therapy requires an accurate diagnosis; neutering is often recommended as a part of therapy regardless of the type of prostatic disease present.

Aging↗

Hypercalcemia complicating an industrial near-drowning.

A 28-year-old man presented with lethargy, solmulence, and polyuria following near-drowning in a vessel of an offshore oil rig. Laboratory evaluation demonstrated severe hypercalcemia that responded to saline diuresis and nasogastric suctioning. Calcium salts are used frequently in the drilling and completion of oil wells, and it is presumed that this patient's hypercalcemia represented acute intoxication from swallowed and aspirated fluid. This case highlights the need to consider the potential constituents of the drowning fluid in victims of near-drowning, particularly if unexplained clinical phenomena are evident.

Accidents, Occupational↗

[Diabetes mellitus and pancreatic tumor].

A 68 year old Ecuadorian man was investigated for polyuria, polydipsia and weight loss of 3 kg during the previous two months. Insulin dependent diabetes mellitus was diagnosed 10 year before admission and treated with appropriate diet and insulin (35 U/d). 18 months before was diagnosed in El Ecuador of "multiple liver nodes non-suggestive of malignancy". Physical examination showed a large multinodular petrous hepatomegaly. There was no evidence of skin lesions. Results of laboratory studies included a basal plasma glucose level that ranged between 275-367 mg/dl (N=60-100), glycosylated haemoglobin of 8.9% (N<5) and a serum albumin of 2.8 gr./dl (N=3.4-4.8). At admission non-other laboratory alterations were detected. Computed tomography showed a mass on the head of the pancreas with loco-regional lymph nodes and liver metastases. Tumor markers were normal. Fine-needle aspiration cytology of the liver masses revealed the presence of liver metastases of a non-differentiated malignant tumor. A 111In-DTPAOC scintigraphy revealed the presence of somatostatin receptors in the liver metastases, also detecting the presence of multiple bone metastases in the axial and appendicular skeleton. Plasma glucagon level was 678 pg/ml (N<250). A diagnosis of metastatic glucagonoma was established and therapy with streptozocin, 5-FU, insulin and synthetic somatostatin analogs was initiated. Three months after the therapy initiation the patient was symptom free. Some weeks after the patient suffered from left hip pain, and a control 111In-DTPA scintigraphy showed progression of his bone metastases. In conclusion, glucagonoma must be suspected in all diabetic patients with metastatic liver, even in absence of necrotic migratory erythema. In these circumstances, plasmatic glucagon level and somatostatin receptors scintigraphy will be a useful tool for establishing the final diagnosis.

Aged↗

Thymic reticulum of autoimmune mice. I. Ultrastructural studies of the diabetic (db/db) mouse thymus.

The thymus of the db/db mouse, an autoimmune strain with insulin-dependent diabetes mellitus and manifesting hyperglycemia, polyuria, glycosuria and obesity, was observed by electron microscopy. Its comparison with normal thymuses and thymuses from non-diabetic obese mice has revealed two major differences: first, the presence of crystal-like structures in some of the numerous clear vacuoles in cells, and second, a modification of the cells forming the border of cystic cavities. These cells contain two types of granules which are quite plentiful. One variety is clear and big, and a second type is small and dense, with an aspect similar to that of secretion granules. It is hypothesized that the crystalloid formations found in epithelial cells, and the presence of small, dense granulations in cells bordering the cystic cavities, are a consequence of the abnormal storage of the thymic hormone, thymulin, which results from a secretory function defect. These observations suggest a possible role for the thymic reticulum in thymic function deficiencies.

Animals↗

[Neoplastic hypercalcemia: prognostic factors of survival of patients; from 51 cases seen in internal medicine].

In our Internal Medicine department, we conducted a retrospective study of prognostic factors in patients with malignant hypercalcaemia. The records of 51 patients who had both hypercalcaemia and a histologically proven cancer were analyzed; 42 had a solid tumour and 9 had a myeloma. In 61% of the patients cancer had been revealed by hypercalcaemia. The main warning signs were alteration of the general condition (68.6%), pain in the bones (54.9%) and polyuria with dehydration (58.8%). Osteolysis was observed in 75% of the cases. The overall median survival was 86 days. Patients with myeloma had a significantly longer survival than patients with other tumours (312 versus 60 days; p < 0.05). Patients who had received a causal treatment had a longer survival (176 versus 36 days, p < 0.001). In patients with solid tumours we found a negative correlation between survival and initial calcaemia, and a positive correlation between phosphoraemia, albuminaemia and survival. Multivariate analysis showed that the initial calcaemia level and the possibility of causal treatment were the two cardinal prognostic factors. Although the overall survival rate is mediocre, we believe that hospitalization of patients with malignant hypercalcaemia is justified for their better survival comfort and for the possibility of discovering a neoplasia that could benefit from an effective causal treatment, which is the principal factor of improved prognosis.

Adult↗

[International study of the effect of dexfenfluramine in obesity (ISIS): 6 months' results].

International study of the effect of dexfenfluramine in obesity (ISIS): 6 months results. ISIS is a multicentre therapeutic trial of the "intention to treat" type organized to test the effectiveness and side-effects of dexfenfluramine combined with diet in the treatment of obesity. This was a randomized, double-blind drug versus placebo study programmed for a one-year period. Eight hundred and twenty-two obese patients were included. Dexfenfluramine was administered in doses of 15 mg b.d. The intermediate results after 6 months of treatment are presented. Significant differences were observed between the dexfenfluramine group (n = 404) and the placebo group (n = 418). In the treated group: 1) the drug withdrawal rate was lower, mainly due to a greater number of patients in the placebo group dissatisfied with their weight loss; 2) about twice as many patients achieved an important loss of weight in terms of percentage of the initial weight or overweight; 3) the cumulative loss of weight was greater; 4) there was a higher incidence of transient side-effects, such as fatigue, diarrhoea, dry mouth, polyuria and drowsiness. These results suggest that dexfenfluramine will be suitable for a more prolonged treatment of obese patients, in addition to diet.

Adult↗

Renal tubular acidosis and vasculitis associated with IgE deposits in the kidney and small vessels.

We report a woman with a history of allergies, polyuria, polydipsia, proteinuria, renal loss of electrolytes, renal tubular acidosis, nephrocalcinosis, and palpable purpura. A proximal defect was excluded by a normal bicarbonate reabsorption curve, and a distal tubular defect was shown because urine pH did not decrease to less than 6.4 despite ammonium chloride-induced systemic acidosis. Moreover, furosemide failed to improve urinary acidification. Urine-to-blood PCO(2) gradient was less than 14 mm Hg, although the urine bicarbonate level reached values as high as 89 mEq/L. Combining bicarbonate and neutral phosphate infusions increased the urine-to-blood PCO(2) gradient to only 20 mm Hg. These subnormal PCO(2) gradient values point to proton-pump dysfunction in the collecting tubule. Histological evidence of tubulointerstitial disease accompanied the tubular defects. The striking histological feature was the presence of immunoglobulin E (IgE) deposits in glomeruli, tubuli, and vessels. Concurrent with these findings, she had high serum IgE titers and CD23 levels. IgE antibodies from her serum were reactive against human renal tubuli, with binding to two regions that matched two different proteins present in cortex and medulla. One of these proteins corresponded to carbonic anhydrase II (31 kd); the second, to an unidentified protein that seems attached to cell membranes. We suggest that these IgE antibodies could have had a pathogenic role in this patient's glomerular, tubular, and small-vessel disease.

Acidosis, Renal Tubular↗

Cisplatin nephrotoxicity.

Cis-dichlorodiammine platinum (II), or cisplatin, has emerged as a principal chemotherapeutic agent in the treatment of otherwise resistant solid tumors and is currently among the most widely used agents in the chemotherapy of cancer. The chief limit to its greater efficacy is its nephrotoxicity, which has made it necessary both to lower its dosage and actively hydrate patients to reduce it. The vulnerability of the kidney to cisplatin is almost certainly related to its primary role in the excretion of cisplatin. Cisplatin enters renal cells by a process that depends on normal oxygen utilization and is specifically inhibited by organic bases. Greater localization of platinum to the S3 segment of the proximal tubules suggests that the vulnerability of this segment may depend on its specific uptake of the drug. The majority of intracellular platinum is bound to macromolecules, including protein and DNA, yet a significant portion of cell platinum is biotransformed to a nonmutagenic and possibly nontoxic compound. Polyuria and hypomagnesemia, which are commonly associated with cisplatin nephrotoxicity, may be due to defects in deep nephron or collecting duct fluid and solute transport. Low single nephron glomerular filtration rates (SNGFR) during early cisplatinum-induced acute renal failure is accompanied by reduced renal blood flow and transglomerular hydrostatic pressure without elevated intratubular hydrostatic pressure, suggesting preglomerular vasoconstriction as an important determinant of renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Angiotensin-converting enzyme inhibition ameliorates the defect in glomerular size selectivity in hyponatremic hypertensive syndrome.

The glomerular size-selective properties in a patient with "hyponatremic hypertensive syndrome" were investigated before and after administration of the angiotensin-converting enzyme inhibitor enalapril. Hyponatremic hypertensive syndrome is a rare condition of renovascular hypertension characterized by electrolyte abnormalities (hyponatremia, hypokalemia), polyuria, and high renin activity. In this patient a marked increase in urinary protein excretion was observed. Treatment with enalapril normalized BP, corrected electrolyte abnormalities, and reduced proteinuria. Glomerular filtration rate (GFR), renal plasma flow (RPF), and the clearance of neutral dextrans of graded sizes were measured before and after 6 months of enalapril (20 mg/d) administration. Theoretical analysis of dextran and inulin clearance data with a model of glomerular size selectivity were adopted to separate effects of hemodynamic changes on macromolecule filtration from changes of intrinsic membrane selective properties. After enalapril urinary protein excretion decreased, GFR was unchanged and RPF almost doubled. Fractional clearance values of dextran molecules were markedly elevated in comparison with the corresponding values measured in a group of normal controls and were normalized by enalapril. Theoretical calculation of membrane pore characteristics showed that enalapril treatment reduced the radius of all membrane pores by approximately 1 nm. Altogether these results indicate that enalapril normalized glomerular filtration of neutral macromolecules and circulating proteins in a human condition of angiotensin II-induced proteinuria. Enalapril effectively restored glomerular size-selective function, reducing dimensions of membrane pores, independently of its effect on renal hemodynamics.

Aged↗

Nephrogenic diabetes insipidus and renal tubular acidosis secondary to foscarnet therapy.

Foscarnet is used as therapy of cytomegalovirus (CMV) infection in immunosuppressed subjects. We present a patient with human immunodeficiency virus infection under treatment with foscarnet for CMV retinitis who complained of thirst and polyuria. Laboratory data showed hypernatremia with increased plasma osmolality and metabolic hyperchloremic acidosis. A water deprivation test demonstrated a nephrogenic diabetes insipidus. Other laboratory studies, including urine pH, anion gap, titratable acidity, and bicarbonate, showed a distal tubular acidification defect. All abnormalities were transient, with recovery a few days after foscarnet withdrawal. No cases of renal acidosis, and only one case of nephrogenic diabetes insipidus, has been previously reported as a complication of foscarnet treatment. Our patient developed both nephrogenic diabetes insipidus and renal tubular acidosis with a temporal pattern that demonstrated a link between foscarnet therapy and these abnormalities.

AIDS-Related Opportunistic Infections↗

Central diabetes insipidus and Cushing's syndrome due to ectopic ACTH production by disseminated small cell lung cancer: a case report.

The present case report describes the rare clinical presentation of diabetes insipidus in a patient with an ectopic ACTH syndrome (morning plasma cortisol 1.10 mumol/l, morning plasma ACTH 322 ng/l) due to disseminated small cell lung cancer including a metastasis in the posterior pituitary. The patient was treated by combination chemotherapy and at the same time received octreotide to control hypercortisolism and desmopressin (DDAVP) to control polyuria. Partial tumour remission was achieved resulting in decreased cortisol production and disappearance of the diabetes insipidus. Medical treatment could be discontinued. Several months later tumour regrowth occurred, with recurrence of hypercortisolism (mean morning plasma cortisol 0.74 mumol/l, mean morning plasma ACTH 112 ng/l) but without diabetes insipidus. Early treatment of hypercortisolism in patients with an ectopic ACTH syndrome and disseminated small cell lung cancer may prolong survival and improve the quality of life.

ACTH Syndrome, Ectopic↗

Central diabetes insipidus preceding acute myeloid leukemia with t(3;12)(q26;p12).

A 52-year-old woman presented with polyuria and polydipsia. A diagnosis of central diabetes insipidus (DI) was made, which turned out to be the first sign of acute myeloid leukemia (AML). Cytogenetic analysis revealed a balanced translocation between chromosome 3 and 12 t(3;12)(q26;p12). The patient was treated with standard induction chemotherapy and vasopressin. Before consolidation chemotherapy could be administered, deep venous thrombosis was diagnosed and leukemia relapsed. Rescue chemotherapy was started. This is the first report of an association between AML with t(3;12) and DI. Its possible pathogenesis is discussed with a review of the literature.

Acute Disease↗

Posterior pituitary function in health and disease.

This chapter has reviewed briefly the neuroanatomy relevant to the synthesis and release of AVP and OXT. Osmoregulation and baroregulation of AVP secretion has been discussed in detail, emphasizing the importance of osmotic control under normal physiological conditions. The remainder of the text has covered the two major pathophysiological disturbances of AVP secretion. In considering diabetes insipidus a pragmatic approach has been taken in the differentiation of the causes of polyuria and its treatment. A similar approach has been applied to the syndrome of inappropriate antidiuresis. Brief mention was made of the function of OXT.

Adult↗