Immunoreactive glucagon responses to intravenous tolbutamide in chronic pancreatitis.

The effects of tolbutamide infusion (1 gm. over forty minutes) on plasma pancreatic glucagon-like immunoreactivity (PGLI), serum insulin, and blood glucose were studied in six patients with chronic pancreatitis and six matched controls.asal PGLI levels were significantly higher in the patients, despite higher fasting glucose concentrations. Tolbutamide infusion had no significant effect on mean PGLI levels in controls but was associated with significant elevation in pancreatitis patients, despite higher circulating glucose levels in the latter. The data suggest that chronic calcific pancreatitis patients hypersecrete immunoreactive glucagon, possibly from a nonpancreatic source and that this immunocreactive material may be stimulated by sulfonylureas.

The inexhaustible beta cell.

Repeated intensive pancreatic beta-cell stimulation was carried out in 42 subjects, comprising 22 normal controls, 10 mild to "severe" maturity-onset diabetics, and 10 chronic pancreatitis patients. Each subject received 75 gm. oral glucose twice and 1 mg. glucagon plus 0.5 gm. tolbutamide intravenously three times at short intervals. Each of the three combined stimuli caused almost equivalent marked spikes of insulin release in all experimental groups. The total calculated output of insulin was equivalent to the total daily insulin output in normal subjects. Pancreatitics and those with severe diabetes (fasting blood sugar greater than 120 mg./100 ml.) had qualitatively similar but a quantitatively smaller response. Those with mild diabetes were similar to the normal subjects but had an exaggerated response to the second oral glucose dose, suggesting overactivity of the enteroinsular axis. Despite the inordinate insulin levels, hypoglycemia did not occur.

Parathyroid hypertension. A reversible disorder.

A retrospective study of 75 patients who were surgically cured of primary hyperparathyroidism from 1976 to 1984 was performed to evaluate the blood pressure and metabolic responses to parathyroid surgery. Published data on the population prevalence of hypertension (HT) in South Africa were used for comparison. The overall prevalence of HT before surgery was 47%, compared with 23% in the general population. Hypertension was most frequent in patients older than 60 years (62% vs 39% expected). Renal insufficiency was found in 13 of 35 hypertensive patients and in two of 40 normotensive patients. However, the prevalence of HT in patients with normal creatinine levels (37%) exceeded that expected. The frequency of urolithiasis and mean levels of serum and urine calcium and phosphate were similar in normotensive and hypertensive patients. Parathyroidectomy resulted in a substantial fall in both mean systolic and mean diastolic blood pressures in 54% of the hypertensive subjects, unrelated to improvement in renal function.

Galactorrhea and hyperprolactinemia associated with chest wall injury.

A 48 year old premenopausal woman presented with galactorrhea and amenorrhea associated with chest wall burns. Basal serum prolactin levels were raised, and were further elevated by the administration of L-dopa, chlorpromazine and TRH. Intercostal nerve block and bromocryptine treatment reduced prolactin levels to normal, but did not noticably reduce milk secretion.

Serum prolactin after chest wall surgery: elevated levels after mastectomy.

Galactorrhea is a recognized sequel of chest injury, but serum PRL levels in these patients have not been systematically documented. Therefore, we examined the PRL responses over 5 days in patients undergoing either mastectomy (10 patients) or thoracotomy (10) and in seven patients undergoing elective laparotomy (controls). Basal serum PRL levels were normal in every subject. There were no consistent or significant alterations in PRL levels after laparotomy or thoracotomy. After mastectomy, PRL levels rose from a mean preoperative level of 7.1 +/- 1.3 to 16.0 +/- 3.3 ng/ml (P < 0.01) on the first postoperative day. Mean levels continued to rise to 35.6 +/- 6.6 ng/ml (P < 0.005) on day 5; levels were supranormal in eight subjects. Hyperprolactinemia persisted in the four subjects evaluated 4 weeks postoperatively and in one of five patients evaluated at 6 months. In a retrospective study, serum PRL levels were measured months to years after thoracotomy (31 patients) and mastectomy (53 patients) and compared to levels in 41 normal female controls. Mean serum PRL levels were 8.4 +/- 1.3 ng/ml in the control group, 13.1 +/- 0.9 ng/ml in the thoracotomy group (P < 0.005), and 20.6 +/- 3.1 ng/ml in the mastectomy group (P < 0.001). One thoracotomy patient and 18 mastectomy patients (34%) had supranormal PRL levels. It is concluded that mastectomy acutely stimulates PRL secretion in most subjects, and levels may remain elevated for months, perhaps for years, in a proportion of patients. Both the acute and chronic hyperprolactinemic states are probably the result of neurogenic PRL release mediated via the suckling reflex.

Pituitary and thyroid function before and after portacaval anastomosis in patients with normal livers.

Basal plasma thyroid hormone, testosterone and cortisol levels, TSH and PRL responses to TRH, and LH and FSH responses to LRH were assessed in six young subjects with normal liver function and anatomy before and after portacaval anastomosis. All tests were normal and unchanged by the operations. It is concluded that in patients with normal liver function, portal systemic shunting does not produce alterations in the pituitary-gonadal and pituitary-thyroid axes. The abnormalities of these endocrine functions in patients with cirrhosis are probably related to the severity of hepatocellular dysfunction rather than to the effects of portal systemic shunting.

Insulin responses to crude cholecystokinin-pancreozymin in normal subjects, in patients with chronic pancreatitis and patients with mild maturity onset diabetes.

The effects of repeated injections of 75 U crude cholecystolinin-pancreozymin (CCK-PZ) at increasing plateau glucose concentrations achieved by glucose infusion were studied in 15 controls, 8 chronic pancreatitics and 8 mild maturity onset diabetics. In control subjects CCK-PZ alone caused minor insulin release but proportinally greater secretion with increasing blood glucose concentrations. Chronic pancreatitis patients who had normal responses to intravenous glucose responded normally to the CCK-PZ but at significantly higher plateau glucose levels. Diabetics had no response to IV glucose boluses of 5 g or 10 g, but with glucose infusions of 250-500 mg/min had almost normal insulin responses to CCK-PZ. The responses to CCK-PZ plus glucose were greater than either stimulus alone, indicating an interaction between these and the beta cell. These studies suggest that the gut homone-receptor in the beta cell is intact in maturity onset diabetes and chronic pancreatitis, whether the glucose receptor is normal or defective. The peptide-responsible in the crude CCK-PZ is not secretin, glucagon or gut glucagon, but may be gastric inhibitory polypeptide (GIP) since pure CCK-PZ has no insuli releasing properties.

Fasting blunts the TSH response to synthetic thyrotropin-releasing hormone (TRH).

Thyrotropin (TSH) responses to intravenous thyrotropin-releasing hormone (TRH) were studied in 9 men after 12 and 36-h fasts separated by more than a week and performed in random order. The TSH, basally and in response to TRH, was significantly lower after the 36-h fast compared to that after 12 h. The mechanism for this effect is not clear, but may be related to the altered hormonal or fuel status associated with prolonged fasting.

Influence of dietary protein on glomerular filtration and urinary albumin excretion in insulin-dependent diabetes.

We investigated the effects of dietary constituents on glomerular filtration (GFR) and albumin excretion rates (AERs) in a cross-sectional study in 39 young subjects with insulin-dependent diabetes. Dietary protein intake correlated significantly in patients with GFRs less than 150 mL/min per 1.73 m2 (r = 0.53, n = 23, P = 0.009), but not with AER. GFR also correlated with mean blood glucose at a concentration less than 12.0 mmol/L (r = 0.61, P = 0.0035). Protein and fat intakes were similar in patients with and without microalbuminuria (AER greater than 20 mg/L) but long-term glycemic control was worse in the former [HbA1 12.4 +/- 2.9% (mean +/- SD) and 10.6 +/- 2.1%, respectively, P = 0.043]. In seven patients, short-term reduction of dietary protein from 2.0 to 1.0 to 0.5 g.kg-1.d-1 produced a progressive fall in GFR by 11.6 +/- 6.0 and 9.6 +/- 5.9 mL/min, respectively (P less than 0.05), but did not consistently affect AER. We conclude that both dietary protein and glycemic control influence GFR but neither alone appears to explain glomerular hyperfiltration. Microalbuminuria was associated with poor glycemic control but not with dietary fat or protein consumption.

Effect of moderate dietary protein restriction on the progression of overt diabetic nephropathy: a 6-mo prospective study.

To assess whether moderate dietary protein restriction can delay the progression of overt diabetic nephropathy, 22 subjects with insulin-dependent diabetes mellitus were randomly assigned to an unrestricted protein diet (> 1.6 g.kg body wt-1.d-1) or a moderately protein-restricted diet (0.8 g.kg body wt-1.d-1) and followed prospectively for six mo. Direct isotope methods were used to assess renal function. Protein intake was assessed by measurement of urinary urea nitrogen. The two groups were well-matched for age, sex, duration of diabetes, glycemic control, blood pressure, and degree of renal insufficiency. Patients consuming the unrestricted protein diet (n = 11) showed a progressive decline in glomerular filtration rate of 1.3 mL.min-1.mo-1 with no change in proteinuria. Patients consuming the moderately protein-restricted diet showed a marked decrease in the degree of proteinuria (2.15-1.13 g/d, P = 0.036) and a stabilization of glomerular filtration rate. This occurred independently of changes in blood pressure or glycemic control. Moderate dietary protein restriction can ameliorate progression of overt diabetic nephropathy.

Thyroid hormone and carrier protein interrelationships in children recovering from kwashiorkor.

We have studied 15 infants with severe protein energy malnutrition (PEM) as a model of nutritional nonthyroidal illness. Changes in circulating thyroid hormones, binding proteins, and their interrelationships were assessed before and during recovery. Serum concentrations of total thyroxine and triiodothyronine and of thyroxine-binding proteins were extremely reduced, and increased progressively during 3 wk of refeeding. The T4:TBG molar ratio was initially 0.180 +/- 0.020, and increased progressively, parallel to the increases in TT4, to 0.344 +/- 0.038 after 21 days (p less than 0.025). The changes in free T4 estimates varied according to the methods used--FTI and analogue FT4 increased, dialysis FT4 fraction decreased. Serum TSH levels increased transiently during recovery. It is concluded 1) there is reduced binding of T4 and T3 to TBG in untreated PEM which takes 2-3 wk to recover; 2) there are methodological differences in evaluating free T4 levels in PEM; 3) increased TSH secretion appears to be an integral part of the recovery from PEM.

Hypoglycemia in hepatocellular carcinoma: failure of short-term growth hormone administration to reduce enhanced glucose requirements.

The mechanism of tumor-associated hypoglycemia was investigated in 10 (six hypoglycemic and four normoglycemic) southern African blacks with hepatocellular carcinoma. The mean basal blood glucose concentration was significantly lower (2.4 +/- 0.1 v 3.6 +/- 0.2 mmol/L; P less than .01) and steady-state exogenous glucose requirements were increased fourfold (3.6 +/- 0.6 v 0.97 +/- 0.2 mg/kg/min; P less than .01) in the hypoglycemic compared with the normoglycemic patients. Plasma insulin and C-peptide levels were suppressed to the lower limit of sensitivity of each of the assays in both groups of patients. The concentrations of insulin-like growth factors (IGF) I and II were lower (19 +/- 1.6 v 25 +/- 4.6 insulin-like growth factors (IGF) I and II were lower (19 +/- 1.6 v 25 +/- 4.6 ng/L) and higher (230 +/- 42 v 173 +/- 40 ng/L), respectively, in the hypoglycemic patients, although the differences were not statistically significant. Of the counterregulatory hormones measured, only the growth hormone (GH) concentration was significantly lower in the hypoglycemic patients (0.9 +/- 0.2 v 18.6 +/- 5.6 micrograms/L; P less than .01). Correction of the plasma GH level into the high-normal physiological range in two hypoglycemic patients failed to reduce steady-state exogenous glucose requirements. However, the glucose requirements were reduced from 2.6 to 1.1 mg/kg/min in the same two patients when "acromegalic" plasma concentrations of GH were achieved. We conclude that steady-state glucose requirements are increased in black patients with hypoglycemia complicating hepatocellular carcinoma, and that short-term correction of the associated hyposomatotropism fails to reduce the enhanced requirements.

Clinical and biochemical responses to nadolol and clonidine in hyperthyroidism.

Some features of hyperthyroidism mimic sympathetic nervous system overactivity. We have compared the clinical (scored on the Wayne Therapeutic Index), hemodynamic (blood pressure and heart rate) and biochemical (plasma epinephrine, norepinephrine, glucose, free fatty acids, insulin, growth hormone and free thyroxine index) effects of clonidine (alpha 2-agonist, which reduces plasma catecholamine levels) with those of nadolol (non-selective beta adrenergic receptor antagonist) in ten female hyperthyroid patients. Each patient received nadolol for 1 week followed by clonidine for 1 week in a single-blind manner. All measurements were made before treatment and then repeated at the end of the nadolol and clonidine treatment periods. Thyroid function remained unaltered during the study. Both agents caused significant clinical improvement--the mean Wayne Index score was 18 pretreatment, 2 on nadolol and 6 on clonidine (P less than .003 for each). Heart rate was reduced by both drugs, but blood pressure was unchanged. Side effects occurred in eight out of ten patients while on clonidine. Nadolol increased plasma concentrations of epinephrine from 47 +/- 18 pg/mL to 87 +/- 24 pg/mL, and norepinephrine from 241 +/- 154 pg/mL to 338 +/- 224 pg/mL (P less than .001 for each). In contrast, clonidine depressed norepinephrine levels from 241 +/- 154 pg/mL to 110 +/- 49 pg/mL (P less than .001) without lowering plasma epinephrine significantly. Plasma free fatty acids tended to fall on both agents compared to pretreatment levels. The blood glucose, insulin and growth hormone concentrations were unaffected by either drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Prior long term glycaemic control and insulin therapy in insulin-dependent diabetic adolescents with microalbuminuria.

Adolescence seems to be a period of increased risk for the initiation of diabetic renal disease in insulin-dependent diabetic children. Poor glycaemic control is a risk factor for diabetic nephropathy. We have therefore evaluated prior long-term glycaemic control in 23 diabetic adolescents with microalbuminuria (albumin excretion rate (AER) 20-200 micrograms/min, median 39.0 micrograms/min) and in 23 matched diabetic controls with AER less than 20 micrograms/min (median 9.3 micrograms/min). Glycaemic control was assessed by mean HbA1 and clinic blood glucose levels over a period ranging from 12 to 84 months (median 48 months). Mean HbA1 was 13.6 +/- 2.0% in the microalbuminuric subjects, compared to 11.5 +/- 2.2% in the controls (P less than 0.002); mean blood glucose levels were 13.5 +/- 3.0 and 11.4 +/- 3.0 mmol/l, respectively (P less than 0.02). There appeared to be a 'threshold effect' (mean HbA1 greater than 12.0%), above which the development of microalbuminuria was more likely. More patients with microalbuminuria than controls had been treated with a single rather than twice-daily insulin injections (P less than 0.001), and glycaemic control was significantly worse in patients treated with one injection. We conclude that poor long term glycaemic control is a risk factor for microalbuminuria, and that improving control during childhood is likely to reduce the prevalence of later microalbuminuria. Two insulin injections, of combined intermediate and short-acting preparations, are more likely to provide better control than a single daily insulin dose.

The relationship between the development and progression of microalbuminuria and arterial blood pressure in type 1 (insulin-dependent) diabetes mellitus.

OBJECTIVE: to investigate the association between urinary albumin excretion and arterial blood pressure in type 1 (insulin-dependent) diabetes. RESEARCH DESIGN AND METHODS: urinary albumin excretion and blood pressures were followed prospectively for a mean period of 26 months (range 18-29 months) in 46 young type 1 (insulin-dependent) diabetic subjects without overt nephropathy. Supine blood pressures (BP) were measured by a single observer using a random zero sphygmomanometer. Albumin excretion was assessed at baseline by a timed clinic excretion rate (AER; microalbuminuria = AER greater than 33 micrograms/min), and at follow-up in at least two urine specimens by the albumin/creatinine (A/Cr) ratio (micro-albuminuria = A/Cr greater than 3.7 mg/mmol). RESULTS: 39 subjects initially had normal AERs. Seven had developed microalbuminuria at follow-up: their mean BP rose from 114 +/- 13/62 +/- 13 to 119 +/- 7/77 +/- 5 mmHg (for diastolic BP, P less than 0.05), while there was no change in the mean BP in the remaining 32 patients. A rise in diastolic BP of greater than 10 mmHg occurred in five of the seven subjects who developed microalbuminuria, and in only seven of 32 who did not (P = 0.02). In the seven patients in whom microalbuminuria persisted (n = 3) or progressed to overt proteinuria (n = 4), BP increased from 123 +/- 12/70 +/- 14 to 139 +/- 12/88 +/- 10 mmHg (P less than 0.02 for both). CONCLUSIONS: this study has shown that BP is normal before the onset of microalbuminuria, and that a rise in diastolic BP accompanies the development or progression of microalbuminuria. The rate of rise in BP may be more important than the absolute level in defining 'hypertension' in young diabetic patients with microalbuminuria.

The prevalence of micro-albuminuria and glomerular hyperfiltration in young patients with IDDM.

We have assessed the prevalence of two risk factors for diabetic nephropathy, i.e., micro-albuminuria and a raised glomerular filtration rate (GFR), in 127 insulin-dependent diabetic patients aged 13-36 years. Micro-albuminuria (albumin excretion rate (AER) 20-200 micrograms/min) was found in 46 subjects (36%) and GFR was elevated (greater than 135 ml/min/1.73 m2) in 43 (34%). The prevalence of supranormal GFR declined and that of micro-albuminuria rose progressively with the increasing duration of diabetes. While age and sex distribution were similar in subjects with and without raised AER, duration of diabetes was significantly longer, blood pressure (BP) was significantly greater and age of onset was lower in the micro-albuminuria group. Blood pressure was significantly elevated only in the patients with AER of 70-200 micrograms/min; there was a linear trend for BP to rise as AER increased. Stepwise logistic regression analysis indicated that duration of diabetes (P less than 0.0001), age of onset of diabetes (P less than 0.005) and current glycaemic control (HbA1) (P less than 0.01) were risk factors for micro-albuminuria. The association with a rising blood pressure appears to be secondary to the renal involvement. In this cross-sectional study an association of micro-albuminuria with a raised GFR could not be demonstrated.

The management of diabetes at primary level in South Africa: the results of a facility-based assessment.

Diabetes is a widespread condition in South Africa and is often managed at primary level health facilities. This study aimed to assess the quality of diabetes management using a rapid assessment approach, focusing on three indicators as proxy measurements of quality: the regularity of blood glucose level (BGL) measurement; the percentage of patients whose BGLs were within 'acceptable' limits (under 10.0 mmol/l) on at least 75% of visits; the rate at which action was taken in response to high BGLs. Five sites were included in the study, including public and private, doctor- and nurse-based facilities. A total of 128 records were examined. Only 33% of all records were found to be well-managed according to the study criteria. None of the individual facilities were found to have more than 40% of patients achieving BGLs within the study limits. Some obstacles to good glycaemic control were costs to patients, transport problems, a lack of health education and shortcomings in clinical expertise. Policy implications and recommendations are suggested.