Correlation between insulin receptor binding in isolated fat cells and insulin sensitivity in obese human subjects.

This study examined the relationship between receptor binding of insulin in a metabolically significant target tissue in vitro and sensitivity to insulin in vivo in obese human subjects. Specific insulin binding was measured at 24 degrees C in isolated enlarged fat cells obtained from 16 patients, by observing the effect of increasing concentrations of unlabeled insulin on the binding of [125I]insulin. Scratchard plots of the binding data were curvilinear with an upward concavity, similarity shaped, and essentially parallel. Kinetic studies on the dissociation of [125I]insulin from fat cells indicated that these curvilinear Scratchard plots could be explained by the presence of site:site interactions of the negative cooperative type. Differences in binding between individual patients were predominantly due to differences in the numbers of receptor sites whether expressed in relation to cell number, cell volume, or cell surface area. These findings were not accounted for by differences in [125I]insulin degradation. Acute exposure of adipose tissue to insulin in vitro had no significant effect on [125I]insulin binding to isolated cells. The number of receptor sites was directly correlated with insulin sensitivity in vivo, measured as the rate constant (Kitt) for the fall in blood glucose after intravenous insulin, and was inversely correlated with the level of fasting plasma insulin. These findings corroborate those from other studies using human mononuclear leukocytes and various tissues from the obese mouse, which indicate that decreased insulin binding is a characteristic feature of insulin resistance in obesity.

Increase in remission rate in newly diagnosed type I diabetic subjects treated with azathioprine.

Azathioprine (2 mg/kg) was given, in addition to routine insulin treatment, to alternate patients presenting with recent-onset type I diabetes. Treated (N = 13) and untreated (N = 11) patients did not differ significantly at diagnosis with respect to age, duration of symptoms, body weight, blood glucose, hemoglobin A1c, or presence of ketosis. Eight patients were treated for 12 mo, three elected to stop treatment at 6 mo, and treatment was stopped in two because of side effects. Seven treated patients had a remission compared with one untreated patient. At 12 mo these seven patients were distinguished by significantly higher basal and glucagon-stimulated levels of C-peptide (1.98 +/- 0.52 and 3.88 +/- 0.34 micrograms/L, respectively) compared with the other six treated patients (0.93 +/- 0.52 and 1.32 +/- 0.85 microgram/L, respectively), and by the persistence of islet cell cytoplasmic antibodies. Remissions were not sustained in the 1-2 yr after treatment, although relapsed patients required less insulin for control. These results corroborate those from nonrandomized trials using cyclosporine and suggest that protracted treatment with nonspecific immunosuppressive drugs may be necessary to avert insulin dependence.

Clinical and histological correlations of decline in renal function in diabetic patients with proteinuria.

In 47 patients with diabetic nephropathy (29 type I, 18 type II) renal function and blood pressure (BP) (treated with or without an angiotensin-converting enzyme [ACE] inhibitor, enalapril [10 mg], in 38 hypertensive patients) were followed over 4 years. A percutaneous renal biopsy was performed in all patients initially and repeated in a representative 19 patients with treated hypertension after 4 years. Mean glomerular volume (MGV), interstitial fibrosis (IF), capillary volume, and sclerosed glomeruli (GS) were measured histomorphometrically. Mean fall in creatinine clearance (CCr) was 11.8% after 4 years with no difference between treatment groups or type of diabetes. BP both initially and during treatment correlated with initial and final serum creatinine and CCr (P < 0.01). There were no histomorphometric differences between type I and type II patients or hypertension treatment groups. Initial IF correlated with initial and final serum creatinine and CCr (P < 0.05) in all patients and type I patients alone, MGV correlated inversely with CCr in type I patients (P < 0.05). After 4 years, IF (24.8 vs. 30.0%, P < 0.01) and GS (26 vs. 37%, P < 0.05) increased significantly, and increase in IF correlated with fall in CCr (P < 0.01). Proteinuria and HbA1 did not correlate with indexes of function or structure. In this longitudinal study of patients with diabetic nephropathy, there was a close relation between BP and renal function but no difference between treatment with enalapril and other hypertensive agents. The correlations between renal function and histology at entry and after 4 years suggest that IF is a co-determinant of renal function in diabetic nephropathy.

Decreased binding of insulin by receptors on placental membranes from diabetic mothers.

Specific binding of insulin to microsomal membranes from the placentae of insulin-dependent diabetics was significantly decreased when compared with normals. This was due to an apparent decrease in the concentration of insulin receptors.

Treatment of non-toxic multinodular goiter with radioactive iodine.

Fourteen patients with large non-toxic multinodular goiters were treated with 20 to 100 mCi (740 to 3,700 MBq) of radioactive iodine (iodine-131). In seven, the goiter had recurred after a partial thyroidectomy and four of these had had two operations. Eight had symptoms of respiratory obstruction, two had dysphagia, and the others sought treatment for cosmetic reasons. After administration of iodine-131, there was a significant decrease in goiter size in 11 of the 14 patients, and all those with obstructive symptoms showed improvement. No significant local side effects occurred, but hypothyroidism and Graves' disease each occurred once during follow-up from one to 13 years. Radioactive iodine in doses of 20 to 100 mCi is an effective, safe therapeutic alternative in patients with large non-toxic multinodular goiter, particularly when there is recurrence following surgery or when there are contraindications to surgery.

Iodine-induced hyperthyroidism due to nonionic contrast radiography in the elderly.

PURPOSE: To identify the number of cases of hyperthyroidism that followed the performance of contrast radiography in elderly patients at a geriatric hospital in a non-iodine-deficient area and to determine the clinical course of the condition. PATIENTS AND METHODS: All patients over a 20-month period with biochemical hyperthyroidism (plasma free thyroxine level greater than 25.0 pmol/L and thyroid-stimulating hormone level less than 0.10 IU/L) were identified. Clinical features of hyperthyroidism and exposure to nonionic contrast media radiographs within the previous 12 months were sought. Follow-up extended from 6 to 22 months. RESULTS: A total of 28 patients with hyperthyroidism (aged 70 to 96 years) were identified. Seven patients (25%) had documented biochemical development of hyperthyroidism (five) or subsequent hyperthyroidism (two) 3 to 8 weeks after nonionic contrast media radiography. The four patients who underwent scanning had a multinodular thyroid, and thyroid antibodies were not detected in five of five patients. Although the condition appeared self-limited and six of six patients were euthyroid after 18 months, the condition was not benign; progress and recovery were adversely affected by hyperthyroidism. Four patients had a good response to treatment with an antithyroid drug (carbimazole). CONCLUSION: Iodine-induced thyrotoxicosis following contrast radiography was found in 7 of 28 cases of hyperthyroidism seen at a geriatric hospital. Although the condition appears ultimately self-limited, pharmacologic control of severe clinical features may be required. The frequency of this condition in a non-iodine-deficient area appears related to the more common occurrence of autonomous thyroid nodules in the elderly. Because performance of contrast radiography is more common in this age group, the recognition and treatment of iodine-induced thyrotoxicosis are of increasing clinical importance.

Factors influencing the prognosis of vascular disease in insulin-deficient diabetes of long duration: a seven-year follow-up.

Fifty-one insulin-dependent nonobese diabetics with duration of disease from 15 to 40 yr were reassessed after 7 yr. Those presenting with clinical vascular disease, hypertension, or elevated fasting triglycerides initially were found to have a bad prognosis. Serum cholesterol fasting blood sugar, age, or duration of diabetes were not related to outcome, Acute insensitivity to intravenous insulin was correlated with presence of initial vascular disease and was significantly related to both death and clinical deterioration in either large or small vessels over the period of follow-up. Insulin sensitivity was reproducible and may be of value in predicting the progression of long-term vascular changes in the insulin-requiring diabetic.

Effects of perindopril on renal histomorphometry in diabetic subjects with microalbuminuria: a 3-year placebo-controlled biopsy study.

We conducted a 3-year randomized placebo-controlled double-blind study to determine the effects of the angiotensin-converting enzyme (ACE) inhibitor perindopril (PE) on the progress of renal function and histology in subjects with diabetes and microalbuminuria. Forty non-insulin-dependent (NIDDM) and insulin-dependent (IDDM) diabetic subjects, either normotensive or hypertensive, were randomly assigned to receive PE (n = 20) or placebo (n = 20). A percutaneous renal biopsy was performed initially in all patients and repeated in 29 patients after 3 years. The mean glomerular volume, glomerular basement membrane (GBM) thickness, interstitial fibrosis, sclerosed glomeruli, and volume fraction of capillary lumina were measured histomorphometrically. Before treatment, both groups had similar clinical characteristics, blood pressure, glycosylated hemoglobin (Hb), albumin excretion rate, glomerular filtration rate (GFR), serum creatinine, and renal structural damage. Blood pressure was well controlled in both groups. After 3 years' therapy, there was no significant change in renal function and albuminuria in the PE or placebo groups. The increase in GBM thickness in nine paired biopsies was significantly less in PE-treated subjects (P = .0275). Interstitial fibrosis tended to increase less in the PE group, although this did not reach statistical significance. This study indicates that long-term therapy with PE may decrease or delay the progression of structural glomerular damage in microalbuminuric diabetic subjects.

A comparison between islet transplantation and parenteral insulin in the control of diabetes and prevention of renal complications in mice.

The control of diabetes and the prevention of renal complications were studied in mice that received different treatment regimes for six months. Transplantation of syngeneic cultured fetal pancreas completely reversed streptozotocin-induced diabetes (mean FBG 5.1 +/- 0.4 mmole/liter six months after transplantation, versus 5.8 +/- 0.2 mmole/liter in normal mice). The mean fasting blood glucose (FBG) level of insulin-treated mice was lower than the mean FBG level of untreated diabetic mice (9.0 +/- 1.2 mmole/liter versus 11.5 +/- 1.3 mmole/liter, P less than 0.05) but exceeded the FBG level of transplanted mice (P less than 0.001) or normal controls (P less than 0.001). There were no significant differences between the mean level of glycosylated hemoglobin (HbA1c) of normal (4.8 +/- 0.3%), transplanted (4.5 +/- 0.3%), or insulin-treated mice (5.3 +/- 0.4%), but the HbA1c level in the untreated diabetic group was increased (7.0 +/- 0.5%; P less than 0.001). Six months after transplantation, the thickness of the glomerular capillary basement membrane (GCBM) was not different in the transplanted group and normal controls (156.4 +/- 5.7 nm versus 157.3 +/- 12.6 nm); the GCBM was thicker in the insulin-treated mice than in the transplanted mice (179.8 +/- 4.2 nm versus 156.4 +/- 5.7 nm; P less than 0.02), but thinner than in untreated diabetic mice (179.8 +/- 4.2 nm versus 202.2 +/- 4.4 nm; P less than 0.001). It is concluded that islet transplantation, in contrast to good control as judged by normalization of HbA1c levels achieved with parenteral insulin, prevents GCBM thickening in experimental diabetes.

A prospective study of the effect of nonionic contrast media on thyroid function.

To observe the effect of iodine in nonionic contrast media on thyroid function, we measured free thyroxine (FT4) and thyroid stimulating hormone (TSH) following nonionic contrast radiography in 73 patients (49 males; 24 females) aged 50 to 84 years, mean 65.7 years. FT4 was significantly (p < 0.01) raised above baseline at 8 weeks but not 4 weeks following contrast injection (mean +/- standard deviation, 17.1 +/- 5.9 and 14.3 +/- 4.0 vs 13.3 +/- 2.7 pmol/L at baseline); however, TSH was significantly (p < 0.03) depressed at both 4 and 8 weeks (1.09 +/- 0.68 and 1.21 +/- 1.56 vs 1.40 +/- 0.90 mIU/L). T3 did not change significantly. FT4 rose by more than 20% in 15/73 and TSH fell by more than 20% in 41/73 compared to a fall of FT4 in 3/73 and a rise in TSH of 8/73 (p < 0.005 and < 0.001, respectively). Two patients became hyperthyroid and in four others either FT4 was elevated or TSH suppressed, one of whom developed atrial fibrillation. Although frank hyperthyroidism following contrast radiography was uncommon, there was a significant trend towards thyroid stimulation rather than suppression after iodine exposure. This may be related to the age of the patients studied.

The 75 g oral glucose tolerance in pregnancy.

A 75 g oral glucose tolerance test was performed between 26 and 32 weeks gestation in 1371 women attending an ante-natal clinic in Melbourne. Gestational diabetes according to various criteria was present in 4.2% (2 h plasma glucose > or = 8.0 mmol/l), 5.2% (2 h plasma glucose > or = 7.8 mmol/l) and 5.5% by the proposed Australian criteria (fasting plasma glucose > or = 5.5 mmol/l and/or 2 h plasma glucose > or = 8.0 mmol/l). The long-term implications of gestational diabetes in the development of diabetes and metabolic abnormalities for both the mother and her child in addition to related infant morbidity emphasise the urgent need for an agreed definition of this condition.

A high prevalence of diabetes in a rural village in Papua New Guinea.

The prevalence of glucose intolerance was determined in a sample of 192 adults (34% of the adult population) from Wanigela in rural Central Province, Papua New Guinea. This centre was chosen to compare the high prevalence rates previously found in residents from this village who had become urbanized in Port Moresby. The age- and sex-standardised rates for abnormal glucose tolerance in Wanigela were significantly lower than those recorded in the urban community. However, the crude rates of 8.9% for diabetes and 5.7% for impaired glucose tolerance are among the highest reported for rural populations in the Pacific. These results strongly suggest that a genetic predisposition to glucose intolerance is present in this ethnic group, and argue for the early adoption of primary prevention programmes as the process of development encroaches rapidly upon the traditional lifestyles of previously isolated communities in Papua New Guinea.

The nature and use of purified insulins.

The limited availability of highly purified insulin preparations for the treatment of diabetes mellitus in australia since 1975, has prompted a review of their history, clinical use and potential in the treatment of diabetics receiving insulin.

Diabetes in an elderly population. A controlled study of morbidity and outcomes.

OBJECTIVE: To determine in an elderly diabetic population the frequency of vascular and related disorders, the mortality, and outcomes compared with a matched control group. SETTING: The Queen Elizabeth Geriatric Centre, Ballarat, Victoria. METHOD: The medical records of all diabetics admitted between 1982 and 1987 inclusive, and a control group matched for age, sex and ward of admission were studied retrospectively. The presence of associated conditions and outcome parameters were entered in to a database and analysed statistically. RESULTS: Increased prevalence in individuals with diabetes of ischaemic heart disease (2.0:1.0), cerebrovascualr accident (1.9:1.0) and hypertension (1.5:1.0). Similar death rate, cumulative bed days, discharge destination and use of discharge services. CONCLUSION: Despite the more frequent presence of clinical vascular disease, an elderly population with diabetes had the same outcomes as matched controls and did not require more bed occupancy or use of community based services.

The clinical characteristics of diabetes mellitus in Papua New Guinea.

The typical patient with diabetes mellitus seen at major hospitals in Papua New Guinea between 1974 and 1977 had florid symptoms, a very high blood glucose, was non-obese and non-ketotic and, frequently had neuropathy and proteinuria. In 25% hypertension was present which was significantly more common in the presence of proteinuria. Diagnosis was often delayed by failure to test urine for glucose and treatment was usually ineffective so that coma, usually non-ketotic, severe infections and gangrene occurred frequently. Although not as common as in other South Pacific countries, diabetes is increasing in Papua New Guinea. The provision of simple adequate facilities to test urine for glucose in all hospitals and the establishment of diabetic out-patient clinics in major centres to instruct both patients and other health workers are essential to improve treatment and reduce mortality and morbidity.

Experience in the treatment of diabetes at Port Moresby General Hospital.

Dietary restriction of refined carbohydrate with regular meals and exercise, preventative foot care, and often daily inulin injections will reduce the mortality and morbidity from diabetes in Papua New Guinea. It is necessary to explain to both the diabetic and their family practical means of treatment including urine tests for glucose. Regular follow up is essential and the establishment of diabetic clinics in major centres would provide the best means of achieving this.

Diabetic surveys in Papua New Guinea - results and implications.

Glucose intolerance was found in 22% of the residents of Koki in Port Moresby, 5% of residents in the coastal village of Kalo and in 3% of 120 young civil servants. The respective prevalences of frank diabetes mellitus were 15.6%, 1% and 0%. Cholesterol and triglyceride levels were similar and low in all groups, despite both obesity and glucose intolerance in the urban-Koki residents who also had a significantly higher blood pressure. There is a need to identify those areas of Papua New Guinea where, in a similar fashion to other countries in the South Pacific, diabetes mellitus is increasing. Simple measures of dietary restriction and increased exercise may be effective in preventing diabetes from becoming a major health problem particularly in identified high prevalence areas.