Assessment of sympathetic innervation of the heart in diabetes mellitus using 123I-MIBG.

Radio-labeled metaiodobenzylguanidine (MIBG) is considered an established sympathetic neuron imaging agent capable of scintigraphically visualizing the organs richly innervated by the sympathetic nervous system. Its clinical applications now include cardiac and pulmonary adrenergic imaging. The quantitative determination of global and/or regional abnormalities of MIBG heart uptake has been demonstrated to be very useful in several clinical settings representing one of the major determinants of adverse prognosis. The presence and the severity of autonomic neuropathy are known as important prognostic factors in patients with diabetes. MIBG scintigraphy is able to non-invasively assess and characterize the adrenergic abnormalities of the cardiac innervation also in these patients. In order to evaluate whether 123I-MIBG is able to reveal abnormalities of myocardial adrenergic function in different groups of diabetic patients, we performed 123I-MIBG scintigraphy in control subjects and in normotensive Type 1 diabetic patients with and without autonomic neuropathy (N+ and N- patients), selected according to results of cardiovascular reflex tests. Regional abnormalities of adrenergic innervation were revealed in 10% of control subjects, in 70% of N- patients and in 100% of N+ patients. The finding of a higher than expected prevalence of MIBG regional abnormalities in patients without signs or symptoms of autonomic neuropathy allows to hypothesize that cardiac autonomic nervous damage occurs earlier than previously known in diabetic patients whose cardiovascular tests are still completely normal.

Myocardial SPECT in the study of ischemic heart disease detection of hibernating myocardium and evaluation of cost/benefit ratio.

From over ten years, the assessment of myocardial viability in akinetic zones (stunned or hibernating myocardium) is considered fundamental to the correct management of postinfarction patients. The assessment can be performed with myocardial scintigraphy (201Thallium rest-redistribution, dobutamine stress echocardiography, MRI, 18F-fluorodeoxyglucose PET). A number of experiences have shown that scintigraphy is very sensitive but poorly specific in the assessment of myocardial akinetic zones with contractile functional recovery after revascularization. However, most recent reports have highlighted that the recovery of contractile function is not the single purpose of myocardial revascularization; in fact, it is able to prevent or attenuate remodeling, the contractile reserve is maintained or enhanced, the diastolic function is improved, arrhythmias are prevented, symptoms and functional capacity are improved. Therefore, the role of very sensitive procedures as myocardial scintigraphy or MRI of the heart is still of major diagnostic and prognostic significance. The present socioeconomic situation and the most recent advances in cardiology tend to shift the clinician's interest from the diagnosis to the prognosis of patients with ischemic heart disease and consequently, from maximum diagnostic accuracy to the highest prognostic value and maximum cost/effective benefit. Therefore, the nuclear cardiologist must become familiar with this novel terminology and new diagnostic and prognostic end-points.

[Benign insulinoma. Efficacy of preoperative treatment for persistent hyperinsulinemia using a synthetic somatostatin analog]. / Insulinoma benigno. Efficacia del trattamento preoperatorio sulla persistente iperinsulinemia con l'analogo sintetico della somatostatina.

We investigated the 24-hour mean blood glucose and serum insulin (IRI), C peptide (C pep) and glucagon concentrations before (pre) and after (post) continued treatment with octreotide (100 mcg three time daily by s.c. injection) in a woman, 68 years old, affected by a nine years long benign insulinoma. The blood pool to dose 24-hour mean glucose and all hormone concentrations was obtained by equal quantities of blood samples taken every 2-hour over 24-hour. The IRI, C pep, glucagon, glucose circadian pattern and IRI/glucose ratio were determined on remaining blood portions. After continued treatment with octreotide was significantly reduced the exaggerated and inappropriate insulin (pre = 77.08 +/- 23.6 microUI/ml; post = 15.19 +/- 2.3 microUI/ml; p < 0.001) and C pep secretion (pre = 4.17 +/- 0.4 ng/ml; post--1.64 +/- 0.04; p < 0.001), while the blood glucose levels were significantly elevated (pre = 40.46 +/- 3.1 mg/dl; post = 132.46 +/- 6.9 mg/dl; p < 0.001). Also glucagon levels were significantly inhibited (pre = 73.53 +/- 12.19 pg/ml; post = 46.80 +/- 9.1 pg/ml; p < 0.05). The long-acting somatostatin analogue has improved a lot IRI/glucose ratio (pre = 1.9 +/- 0.4; post = 0.12 +/- 0.04; p < 0.001). A significant positive correlation was found between IRI and C pep before (r = 0.93; p < 0.001) as well after octreotide treatment (r = 0.85; p < 0.001). A significant positive correlation (r = 0.69; p < 0.008) between IRI and glucose was observed only after octreotide treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential roles of splanchnic and peripheral tissues in determining diurnal fluctuation of glucose tolerance.

To identify the mechanisms and the sites of the diurnal fluctuation in glucose tolerance in humans, we selectively quantitated the components of net splanchnic glucose balance, i.e., splanchnic glucose uptake and hepatic glucose output, as well as peripheral glucose uptake, by combining tritiated glucose infusion with hepatic and femoral venous catheterization. The studies were carried out in 11 healthy volunteers at 8:00 A.M. and at 6:00 P.M. on different days after 12 h of fasting. After intravenous glucose infusion (6.5 mg.kg-1.min-1 for 120 min) blood glucose rose twofold at 8:00 A.M. and threefold at 6:00 P.M. (P less than 0.01). Insulin levels did not differ significantly between the two series of tests. Splanchnic glucose balance switched from the net output of the basal state to a net uptake in both morning and afternoon studies. However, this effect was more marked at 6:00 P.M. than at 8:00 A.M. (at 60-120 min, P less than 0.05). The different pattern of splanchnic glucose balance was entirely accounted for by a greater rise in splanchnic glucose uptake in the afternoon, as the suppression of endogenous glucose output by the glucose load was practically complete in both series of studies. In contrast, glucose uptake by leg tissues increased less at 6:00 P.M. than at 8:00 A.M. (at 30-60 min, P less than 0.05; at 75 and 90 min, P less than 0.01; at 105 and 120 min, P less than 0.005). These data indicate that the mechanism responsible for the reduced glucose tolerance later in the day resides in the peripheral tissues whose ability to dispose of a glucose load is drastically decreased.

Long-term correction of hyperglycemia and progression of retinopathy in insulin dependent diabetes. A five-year randomized prospective study.

Thirty-eight patients with insulin dependent diabetes mellitus who had background retinopathy and no residual endogenous insulin secretion as assessed by plasma C-peptide determinations, were randomized to either conventional insulin treatment or to more intensive glucose control using ultralente insulin as basal cover and soluble insulin at mealtimes and were followed for five years. Plasma glucose profile and glycosylated hemoglobin were determined every eight weeks. Eye examinations were performed at the start of the study and after one, three and five years. Age, duration of diabetes, insulin dosage, glycemic control were comparable in the two groups. The mean plasma glucose profile was similar at entry in both groups and did not change in the conventionally-treated group. Mean plasma glucose profile 11.2 +/- 1 mmol/l with glycosylated hemoglobin level 10.7 +/- 0.3% fell to 7.9 +/- 0.4 mmol/l and 8.7 +/- 0.5% respectively during intensive treatment. Retinal morphology deteriorated during the follow-up with no significant differences between patients under unchanged conventional treatment and intensive insulin regimen. Proliferative retinopathy developed in six patients--three of these were under intensive insulin treatment. These data suggest that substantial long-term improvement of glycemic control does not affect progression of background retinopathy even when it is mild. The evolution of established retinopathy in insulin dependent diabetic patients is not only a function of poor glycemic control; other factors, either intrinsic or environmental, must also be important.

Somatostatin response to glucose before and after prolonged fasting in lean and obese non-diabetic subjects.

Insulin, glucagon, and somatostatin concentrations were measured in 7 lean and 7 obese non-diabetic subjects over 7 days of fasting. In addition each subject was given a 75 g oral glucose tolerance test after fasts of 12 h and 7 days. In lean subjects complete food deprivation induced a significant decrease in the circulating levels of both insulin and somatostatin, while glucagon nearly doubled by 48 h and then remained constant for the duration of starvation. Refeeding with oral glucose suppressed the increased plasma glucagon, but insulin and somatostatin responses were enhanced in comparison with the prefast values, as assessed by the integrated areas of change. In obese subjects peripheral insulin and somatostatin levels were significantly lowered, but plasma glucagon level was unchanged at the end of the starvation period. In the same group glucose-induced insulin and somatostatin release were greater than in the fed state. Suppression of plasma glucagon by glucose appeared less complete in obese than in lean subjects. It is concluded that prolonged starvation enhances D-cell responsiveness to glucose in lean and obese subjects.

Circulating somatostatin concentrations in healthy and cirrhotic subjects.

Plasma insulin, glucagon, somatostatin, and glucose concentrations were measured in the fasting state as well as after mixed meals (breakfast, lunch, and dinner) in 10 cirrhotic patients and 10 control subjects during a 24-hour period. Cirrhotic patients had fasting glucose values higher than controls (at -15 min: 5.2 +/- 0.2 mmol/L v 3.9 +/- 0.5 mmol/L, P less than 0.05; at 0 min: 5.5 +/- 0.3 mmol/L v 4.3 +/- 0.5 mmol/L, P less than 0.01). After meals blood glucose values remained higher in cirrhotics than in controls. Insulin levels did not differ between the groups in the fasting state, but cirrhotics showed a lower response to meals. Corresponding glucagon concentrations were greater in cirrhotics than in controls before and after meals throughout the 24-hour period (from -15 min to 24 hour: P less than 0.01). BAsal plasma somatostatin levels in the cirrhotic group were significantly higher than in control subjects (at -15 min and at 0 min: P less than 0.05) and further increased after meals. Plasma somatostatin was heterogeneous in normal and cirrhotic group, but the increase in its concentrations in patients with chronic liver disease was for the most part a consequence of elevations in the 1600 and 3500 molecular weight components. The half-life of exogenously infused somatostatin in cirrhotics was comparable to that of controls. These results indicate that in liver cirrhosis elevated levels of circulating somatostatin are associated with hyperglucagonemia and impaired insulin release. The high plasma somatostatin levels observed in cirrhotic patients are the result of hypersecretion of the D cell rather than impaired removal of the peptide.

Prevalence of diabetes mellitus and impaired glucose tolerance in a rural area of Italy.

The prevalence of diabetes in subjects aged 18 yr and over was evaluated in a rural community of Southern Italy (Sanza). Among the 1,154 participants examined by using a 75 g oral glucose load according to the recent WHO diagnostic criteria, the diabetes prevalence was 6.6% in men and 6.8% in women; impaired glucose tolerance occurred in 5.1% of men and 7.9% of women. The frequency of positive family history of diabetes was no higher in subjects with diabetes and impaired glucose tolerance, than in controls. Obesity was clearly related to diabetes (p less than 0.05 in men and p less than 0.01 in women 40 yr old and over). The level of physical activity was significantly lower in subjects with diabetes than in normal subjects. The results suggest that a remarkable reduction in physical activity, along with an increased caloric intake, may have importance in determining the prevalence and time of appearance of non-insulin-dependent diabetes.

Soybean protein diets in the management of type II hyperlipoproteinaemia.

The efficacy of soybean protein treatment of stable type II hyperlipoproteinaemia was evaluated in 57 patients assigned to the following protocols: (i) substitution of animal protein with soybean protein (19 subjects) and (ii) addition of soybean protein to a standard low-lipid diet (38 subjects). After 16 weeks of treatment, plasma cholesterol was reduced by 29.5% in the first group, and by 29.9% in the second; the difference was not significant. Similarly the reduction in LDL cholesterol was not significantly different between the 2 groups (39% in the first group and 36% in the second). Plasma triglycerides fell by 11.8% and 18.2%, respectively. HDL cholesterol was not modified to any significant extent by soybean protein regimens. These results provide that the addition of soybean protein to a standard low-lipid diet is effective in inducing a significant cholesterol decrease in patients with type II hyperlipoproteinaemia.

Prolactin response to sulpiride in non insulin dependent diabetes mellitus.

Blood glucose, insulin and prolactin concentrations were determined before and after sulpiride injection (50 mg i.m.) in 20 non-insulin-dependent diabetic patients (10 with retinopathy and 10 without evidence of retinal damage) and 10 subjects with normal glucose tolerance. Prolactin response to sulpiride was significantly higher in diabetics than in controls (at 20 min., p less than 0.01; at 30 and 60 min., p less than 0.005; at 90 min., p less than 0.01; at 120 min., p less than 0.05). The sulpiride induced hyperprolactinemia did not influence blood glucose and plasma insulin levels in controls as well as in diabetic patients. Prolactin response to sulpiride was the same in diabetics with and in those without retinal changes. We conclude that acute hyperprolactinemia seems to have no influence on glucose homeostasis in normal and non insulin-dependent diabetic subjects.

Circadian variation in glucose tolerance and associated changes in plasma insulin and somatostatin levels in normal volunteers.

The day-time variations of blood sugar and associated changes in plasma insulin and somatostatin levels in response to glucose-glucagon load were investigated in eight healthy volunteers. The glucose-glucagon test was performed in the same subjects at 9.00 a.m., at 5.00 p.m. and at midnight after 10 hrs of fasting. The blood sugar values were higher in the midnight while the corresponding plasma insulin levels were significantly lower. Plasma somatostatin levels did not differ at the different times of the day. These results suggest that the circadian variations of the glucose tolerance are correlated to a simultaneous circadian rhythmicity in the insulin response in the sense of a decreased insulin release later in the day. Somatostatin does not seem involved in the circadian variation of beta cell responsiveness observed in healthy volunteers.

Prevalence of impaired glucose tolerance, diabetes mellitus and ischemic heart disease in an Italian rural community. The Sanza Survey.

Coronary heart disease rates were estimated in three groups of people participating in the Sanza Survey - newly diagnosed non insulin dependent diabetics, subjects with impaired glucose tolerance and control subjects with normal glucose tolerance. The prevalence of Minnesota-coded ECG abnormalities showed a significant gradient with an approximately twofold excess in both the newly detected diabetic and impaired glucose tolerance cases over the subjects with normal glucose tolerance. The doubling of ECG ischemic changes found in subjects with impaired glucose tolerance and diabetes mellitus appeared to operate almost equally in the absence or presence of several other recognized risk factors for coronary ischemic damage. It is concluded that a relatively low degree of glucose intolerance alone may be important in determining coronary heart disease.

The relationship between glycosylated haemoglobin levels and various degrees of glucose intolerance.

To assess the use of glycosylated haemoglobin to discriminate between various degrees of glucose intolerance, glycosylated haemoglobin levels were determined in 107 subjects (48 males and 59 females, age range 18-80 years). Following a 75 g oral glucose tolerance test and according to World Health Organization criteria, subjects were classified as normal (n = 32), diabetic (n = 46) or as having impaired glucose tolerance (n = 29). Mean glycosylated haemoglobin levels were 5.8 +/- 1.3% (range 4%-9%) in normal subjects, 7.1 +/- 1.7% in subjects with impaired glucose tolerance (range 4.1%-10.1%) and 10.1 +/- 2.6% (range 4.7%-18.8%) in diabetic patients. The difference between the groups was highly significant (p less than 0.01). Twelve per cent of normal subjects exceeded and 52% of subjects with impaired glucose tolerance fell below 7.4% (mean +/- 2SD, considered as the upper limit of normal values). A significant correlation was observed between glycosylated haemoglobin values and fasting blood glucose (r = 0.68, p less than 0.01). These results provide evidence that glycosylated haemoglobin levels are influenced by slightly reduced carbohydrate tolerance. Glycosylated haemoglobin may be a useful test to improve the specificity of the oral glucose load to select and to follow-up subjects with impaired glucose tolerance.

Epidemiology of diabetes mellitus in an Italian rural community.

To evaluate the prevalence of diabetes in a rural community, 589 subjects in Laurino, Southern Italy, were submitted to a 50 g oral glucose tolerance test. Two hours later, blood glucose levels revealed 453 normal subjects, 36 diabetics and 100 borderline subjects. The borderline subjects were re-examined with 75 g OGTT and, according to criteria recommended by the National Diabetes Data Groups (NDDG), 29 subjects were found normal, 35 with impaired glucose tolerance (IGT) and 36 with diabetes. Final figures showed 72 diabetics (12.2%) and 35 IGT cases (5.9%). Obesity appeared strongly related to diabetes (p less than 0.05 in males and p less than 0.01 in females 40 years old and over). Diabetes was more prevalent in subjects with a positive family history (p less than 0.01). No significant difference in number was observed between male and female diabetics, nor between big babies delivered by normal women and big babies by diabetic women. The high diabetes prevalence might be partly explained by the changes created by an industrially-established dietetic influence on the rural communities in Southern Italy.

Effect of somatostatin on the potentiating action of glucagon, cyclic adenosine monophosphate and theophylline on glucose-induced insulin release.

The effect of glucagon on the inhibition of the insulin response to glucose induced by somatostatin was investigated in humans and in the isolated perfused rat pancreas. Both in vivo and in vitro somatostatin suppressed glucose-induced insulin release. This inhibitory effect of somatostatin was overcome by glucagon. Similar results have been observed in vitro by the infusion of theophylline or cyclic adenosine monophosphate.

Diurnal variation in blood sugar and serum insulin in response to glucose and/or glucagon in healthy subjects.

The role of insulin secretion in the diurnal variation of glucose tolerance has been investigated. In ten healthy subjects, at 08.00 and at 18.00 after 10 hrs of fasting, a combination test of glucose and glucagon was performed. 1 mg glucagon was injected intravenously 40 min after the intravenous infusion of glucose (0.5 g/kg b.w.). Samples for blood sugar (BS) and serum immunoreactive insulin (IRI) were taken before and 2-5 min following the glucose and glucagon loads, and thereafter at 10 min intervals up to 85 min. In the afternoon test, the mean blood sugar values were higher, the differences in the 20-85 min values being statistically significant: the IRI values were statistically lower after glucose, while after glucagon, the increase of serum IRI was apparently similar in both morning and afternoon tests. However, the insulin/glucose ratio (I/G) was significantly lower at 18.00 at 55-85 men. Corresponding results were obtained in six additional healthy subjects when only glucagon (1 mg i.v.) was injected. In this case also, the mean insulin levels were lower in the afternoon after 5 min, while the BS values during the maximal insulin release (2-30 min) were comparable in both the morning and afternoon tests. In the 40-60 min interval, the BS levels were significantly higher in the afternoon. The existence of a diurnal variation in the blood sugar after intravenous glucose load, as well as after glucagon, seems to be correlated to a simultaneous diurnal variation in the insulin response, suggesting decreased pancreatic beta-cell activity in the afternoon.