Cholecystokinin and pancreatic polypeptide release in diabetic patients with and without autonomic neuropathy

The present study was undertaken to investigate postprandial responses of cholecystokinin (CCK) and pancreatic polypeptide (PP) and their interrelationship in patients with diabetes mellitus (DM) with and without autonomic neuropathy (AN). Twenty-two patients with DM (seven with AN and 15 without AN) and 14 age-matched healthy controls were studied. AN was diagnosed according to several tests of cardiovascular autonomic function. CCK and PP plasma levels were measured by specific radioimmunoassays before and at several time points after the oral administration of a test meal. Basal CCK plasma levels in DM patients were normal, whereas basal PP plasma levels were increased (139±18 vs 72±7 pg/ml;P<0.01). integrated=" postprandial=" cck=" response=" was=" increased=" in=" dm=" patients=" (208±27=" vs=" 110±14=" pmol/liter/2=">P<0.05), mainly=" due=" to=" the=" patients=" with=" an.=" postprandial=" pp=" response=" was=" increased=" in=" dm=" patients=" without=" an=" (37,273±5241=" vs=" 13,418±3299=" pg/ml/2=">P<0.001) but=" not=" in=" those=" with=" an=" (8887±3461=" pg/ml/2=" hr).=" moreover,=" pp=" response=" was=" closely=">P<0.002) correlated=" with=" the=" degree=" of=" an.=" a=" direct=" and=" linear=" correlation=" between=" postprandial=" cck=" and=" pp=" responses=" was=" found=" in=" healthy=" controls=">r=0.78;P<0.005) but=" not=" in=" dm=" patients.=" we=" conclude=" that=" the=" cck=" response=" to=" a=" meal=" is=" increased=" in=" diabetic=" patients=" with=" an,=" whereas=" the=" pp=" response=" is=" increased=" only=" with=" an=" intact=" autonomic=" nervous=" system.=" it=" is=" suggested=" that=" the=" correlation=" between=" postprandial=" hormonal=" responses=" in=" healthy=" subjects=" is=" due=" to=" the=" potency=" of=" cck=" as=" pp=" releasing=" agent=" and=" that=" this=" interaction=" does=" not=" work=" in=" diabetic=">     

Pancreatic polypeptide response to a protein-rich meal in diabetic patients with and without neuropathy

A protein-rich meal and insulin-induced hypoglycemia (ITT) are two of the most important stimuli on pancreatic polypeptide (PP) secretion in diabetic patients. Previous studies have shown a reduced PP response to ITT in diabetic patients with autonomic neuropathy (AN). Twelve patients without AN (mean age 44 +/- 10.8 yr, mean duration of diabetes 11 +/- 5.6 yr), 9 with AN (51.4 +/- 6 yr, 15.8 +/- 6.9 yr) and 9 controls (N) were studied. AN was assessed by the evaluation of the beat-to-beat variation of the heart rate during deep breathing. PP secretion was stimulated by a protein-rich meal (200 g meat, 150 g milk). All insulin-dependent diabetic (IDD) patients lacked circulating PP antibodies. All diabetic patients showed a significant reduction in the early vagal phase compared to controls. This behavior was more evident in diabetic patients with AN and the secondary phase of these two groups overlapped with the response of controls. These data may be explained by the initial alterations of vagal functions not detectable by current methods.     

No response of pancreatic hormones to hypoglycemia in diabetic autonomic neuropathy

The responses of pancreatic hormones (i.e. glucagon, pancreatic polypeptide, and somatostatin) to insulin-induced hypoglycemia were investigated in 18 insulin-dependent diabetics without residual beta-cell function and in 6 normal subjects. Nine of the diabetics had autonomic neuropathy, and 9 had no neuropathy. After hypoglycemia, no significant increase in any of the 3 pancreatic hormones was found in the diabetics with autonomic neuropathy, whereas significant increments were found in the diabetics without neuropathy and in the normal subjects. These results suggest that autonomic nervous activity is of major importance for pancreatic hormone release during hypoglycemia in man.     

Diabetic autonomic neuropathy and impaired human pancreatic polypeptide secretion in response to food

In normal subjects, the early human pancreatic polypeptide (hPP) increase induced by food is mainly dependent on vagal activity. Parasympathetic function and plasma hPP response to a standard mixed meal were evaluated in 10 long term insulin-dependent (type I) diabetic patients (group A), 6 age-matched newly diagnosed type I diabetic patients (group B), and 8 normal subjects. The indices of vagal function (beat to beat heart rate variation during deep breathing and the Valsalva maneuver) were uniformly altered in group A, while they were in the normal range in group B, thus excluding in these latter patients the presence of vagal damage. Plasma hPP in response to standard mixed meal was measured at 5, 15, 30, 60, and 120 min. Fasting plasma hPP concentrations (determined by RIA) in groups A and B (mean +/- SEM, 113 +/- 21 and 83 +/- 21 pg/ml, respectively) did not significantly differ from normal (59 +/- 12 pg/ml). In group A, the initial meal-induced hPP increase was significantly lower than normal (5 min, 139 +/- 12; 15 min, 173 +/- 24; 30 min, 137 +/- 17 pg/ml; P less than 0.01 vs. 5 min, 412 +/- 76; 15 min, 446 +/- 57; 30 min, 325 +/- 56 pg/ml). All group B patients had a marked early increase in the peptide, similar to that in the normal subjects. These results suggest that diabetic autonomic neuropathy is associated with dysfunction of hPP secretion, and the evaluation of hPP in response to SMM may be considered a sensitive and nonstressful method for the assessment of parasympathetic impairment in diabetes.     

Pancreatic polypeptide secretion in diabetic patients with delayed gastric emptying and autonomic neuropathy

Measuring postprandial pancreatic polypeptide (PP) plasma concentration is a sensitive method for autonomic nervous system assessment. Delayed gastric emptying (DGE) often does not correlate clearly with cardiac autonomic neuropathy (CAN). This study was conducted to evaluate whether decreased PP secretion (PPS) accompanies DGE and CAN in diabetes. Fourteen long-standing diabetics with DGE assessed by scintigraphy (group A), 14 well-matched diabetics with normal gastric emptying (NGE) (group B), and 12 healthy controls (group C) were the study subjects. CAN and postprandial PPS at 0, 30, and 60 min after test meal ingestion were examined in all the subjects, and the area under curve of PP secretion was calculated. There was no correlation between DGE and CAN (eight diabetics with CAN in A and six in B). Basal PP values were almost the same in all the patients (mean 77.27 ± 11.0 pg/mL). The area under curve of PP secretion values (PP_AUC) after test meal ingestion were significantly higher in B (211.84 ± 36.13 pg/mL/h; p < 0.0001) and C (233.68 ± 23.43 pg/mL/h; p < 0.00001) than in A (147.59 ± 31.77 pg/mL/h). Diabetics with CAN had lower PPS expressed as PP_AUC than those without CAN, which was independent of gastric emptying rate (152.31 ± 37.18 versus 207.12 ± 39.21 pg/mL/h; p < 0.001). There were no significant differences between test meal-stimulated PP_AUC in diabetics without CAN (207.12 ± 39.21 pg/mL/h) and controls (233.68 ± 23.43 pg/mL/h), and this was also independent of gastric emptying rate. In patients with both DGE and CAN, the PPS was completely blunt (PP_AUC 124.04 ± 5.71 versus 233.68 ± 23.43 pg/mL/h in controls; p < 0.001). The PPS in diabetics with CAN and NGE was significantly lower than in controls (PP_AUC 190.0 ± 37.45 versus 233.68 ± 23.43 pg/mL/h; p < 0.01). In conclusion, the PPS in diabetics with CAN was decreased significantly and independently of DGE. The PP secretion was very low in diabetics with both CAN and DGE.     

Pancreatic polypeptide (PP) response to food in type I diabetics with and without diabetic autonomic neuropathy

Nineteen type I diabetics and 15 healthy subjects were given 500 ml of a mixed liquid test meal (flüssige Diabetikerkost, Fresenius, FRG) orally. Furthermore, heart rate variation during deep breathing and Valsalva maneuver was performed in order to test vagus nerve function. PP serum levels were determined before, and 2 to 160 minutes after finishing, the meal. In healthy subjects and in 10 diabetics without any sign of autonomic neuropathy of the vagus nerve a significant rise in PP serum values after the meal could be detected. In 7 type I diabetics with autonomic cardiac neuropathy (abnormal beat-to-beat variation during deep breathing and during the Valsalva maneuver) post-prandial PP levels remained low. Two diabetics without autonomic neuropathy were excluded from the test because endogenic PP antibodies were found in their serum. PP secretion after ingestion of a mixed protein-rich meal is mostly mediated by the vagus nerve or by the extravagal cholinergic system. After vagotomy, no PP secretion after a mixed meal could be detected. Measuring PP serum levels in diabetics after a mixed meal can be useful to check vagus nerve function in the gastrointestinal tract in order to detect autonomic neuropathy.     

Cardiac autonomic neuropathy in the diabetic patient

The importance of cardiac autonomic neuropathy (CAN) derives from its remarkable frequency and its clinical impact. The clinical features are postural hypotension and resting tachycardia, these abnormalities may be overlooked in a high number of patients asymptomatic. Although rarely life threatening, CAN causes considerable morbidity, which can be ameliorated by its identification and appropriate treatment. Circulatory reflexes were studied in 48 diabetic patients and 14 normal control subjects. Twenty-six of the diabetic patients had normal response. The remaining 22 had evidence of neuropathy and abnormal cardiac response during these tests. Only one patient had postural syncope but he had severe orthostatic hypotension. The others remained asymptomatic. All the control subjects had normal reflexes. Beat-to-beat variation with deep breathing (sinus arrhythmia), carotid body massage and mental stress, were important for the detection of CAN (86, 90 and 90% sensitivity respectively). The Valsalva maneuver and sinus arrhythmia showed 82 and 92% of specificity for the diagnosis of CAN. Our findings suggest that CAN in diabetic patients can be detected by these relatively simple test. We propose a rational approach to the diagnosis. Our method is applicable as a clinical routine examination for cardiac neuropathy.     

Parotid salivary secretion in diabetic autonomic neuropathy

Parotid salivary flow rates and amylase concentrations were measured in three groups of eight subjects each (normal control, non-neuropathic diabetic, and neuropathic diabetic). Flow rates were significantly reduced in neuropathic diabetic patients as compared with normal controls (p < 0.001) and non-neuropathic diabetic patients (p < 0.02). Amylase concentrations were similar. These data are consistent with parasympathetic denervation of the parotid gland in diabetic neuropathy and provide evidence for a widespread distribution of autonomic denervation in diabetes.     

Gastric emptying in diabetic autonomic neuropathy.

Gastric emptying was studied in 12 diabetic patients, six with and six without objective evidence of autonomic neuropathy and in 20 non-diabetic controls, using a double isotope scinti-scanning technique which differentiated between solid and liquid emptying. Three patients with autonomic neuropathy exhibited gastric stasis, although this was detected by conventional radiology in only one. Neither the patients with stasis nor those without exhibited abnormally rapid early gastric emptying. In patients without stasis, the normal differentiation between solid and liquid emptying was impaired, suggesting an abnormality of antral peristalsis not attributable to vagal denervation. Both intravenous and oral metoclopramide produced symptomatic improvement in two patients with gastric stasis and restored their gastric emptying to normal.     

Cardiorespiratory arrest in a patient with advanced diabetic autonomic neuropathy

A 53-year-old diabetic woman who had been diabetic for 14 years had recurrent episodes of cardiorespiratory arrest, which were easily resuscitated by a few chest massages. In 2 of 4 episodes a radial pulse was detected, so respiratory arrest was thought to be a primary event. Pentazocine was injected several hours prior to each of the 3 episodes. This was considered to be a precipitating factor. From the first episode of cardiorespiratory arrest, she received oxygen inhalation. When oxygen inhalation was withdrawn for 5-10 min, she became cyanotic. This was considered to be a sign of lack of hypoxic drive mediated by peripheral chemoreceptors. Ventilatory responses to hypercapnia was markedly decreased, indicating impaired central chemosensitivity. The possibility that impaired chemosensitivity could be a cause of respiratory arrest was suggested.     

The problem of autonomic neuropathy in diabetic pregnancy

The hazards of pregnancy for both the mother and the fetus in diabetic women with severe retinopathy and nephropathy are well reported. We wish to highlight a poorly recognized problem in the obstetric management of the diabetic mother, that of pregnancy in a patient with autonomic neuropathy. Two such cases are reported where the presence of autonomic neuropathy severely jeopardized the health of the mother, with the loss of the fetus in one, due to occurrence of severe and intractable vomiting. The presence of moderate to severe symptomatic diabetic autonomic neuropathy, particularly with evidence of gastroparesis, may be a relative contraindication to pregnancy.     

Diagnosis and treatment of diabetic autonomic neuropathy

Diabetic autonomic neuropathy (DAN) is associated with a markedly reduced quality of life and poor prognosis. The manifestations of DAN cause multiple symptoms and involve the 1) cardiovascular system: resting tachycardia, reduced heart rate variability and circadian rhythm of heart rate and blood pressure, painless myocardial ischemia/ infarction, orthostatic hypotension, exercise intolerance, perioperative instability, sudden death; 2) respiratory system: reduced ventilatory drive to hypercapnia/ hypoxemia, sleep apnea; 3) gastrointestinal tract: esophageal motor dysfunction, diabetic gastroparesis, gallbladder atony, diabetic enteropathy, colonic hypomotility, anorectal dysfunction; and 4) genitourinary tract: diabetic cystopathy, erectile dysfunction. Treatment is based on four cornerstones: 1) causal treatment aimed at near-normoglycemia; 2) treatment based on pathogenetic mechanisms; 3) symptomatic treatment; and 4) avoidance of risk factors and complications. Pharmacologic treatment of symptomatic DAN may be difficult, due to limited efficacy and frequent adverse reactions. First-line treatments include midodrine for orthostatic hypotension, prokinetic drugs for gastroparesis, broad-spectrum antibiotics for diabetic diarrhea, and sildenafil for erectile dysfunction. Prior to an adequate symptomatic treatment a thorough risk-benefit estimate, aimed at maintaining the patient’s quality of life, is required.     

Impaired catecholamine secretion as a cause of diabetic autonomic neuropathy

Human and animal studies were performed to investigate the causes of diabetic autonomic neuropathy. Human diabetics, with and without autonomic neuropathy, were measured for plasma catecholamine response to insulin hypoglycemia and for urinary catecholamine excretion. In streptozotocin-diabetic rats, plasma catecholamine response and tissue catecholamine concentrations were measured at various stages of the disease. As the duration of the diabetic state lengthens in rats, there is a time-proportional stepwise decrease in plasma catecholamine response. This is similar to the clinical course observed in human diabetics, which also includes a reduction of catecholamine excretion after the appearance of autonomic neuropathy. After 6 weeks of diabetes, rat tissue is found to have an increased concentration of catecholamines; this may represent a compensatory reaction to the difficulties of secretion. At 13 weeks of diabetes, tissue catecholamine concentrations return to almost normal, when plasma responses have disappeared. These results suggest that the impaired secretion of catecholamines in diabetics may be a cause of diabetic autonomic neuropathy.     

Dissociated sensory loss in diabetic autonomic neuropathy.

Aims: Clinical observation has led to the idea that there might be a distinctive form of selective sensory and autonomic neuropathy affecting patients with Type 1 diabetic mellitus with severe symptomatic autonomic neuropathy (Type 1-DAN) and this study was conducted to evaluate the presence of such a neuropathy in Type 1-DAN. METHODS: Nineteen Type 1 diabetic patients presenting for treatment of severe symptomatic autonomic neuropathy were examined (all had > or = 2 autonomic symptoms; age 39.3 +/- 10.2 years; duration of disease 25.6 +/- 10.5 years). For comparison, 19 Type 1 diabetic patients with neuropathic foot ulcers (age 44.5 +/- 6.6 years; duration of disease 26.7 +/- 9.2 years), 14 clinically uncomplicated Type 1 diabetic patients (age 39.9 +/- 5.6 years; duration of disease 22.9 +/- 9.3 years) and 16 non-diabetic healthy people as controls (age 39.3 +/- 10.7 years) were also examined. Results The large fibre modalities (light touch and vibration perception) were better preserved in the Type 1-DAN group than in the foot ulcer group. Thus, light touch sensation was normal in 11 out of 19 Type 1-DAN patients compared to only three out of 19 foot ulcer patients (P < 0.01), and vibration perception was 24.9 +/- 15.0 V and 40.5 +/- 7.9 V, respectively (P < 0.002) with some of the Type 1-DAN patients in the normal range. In contrast, the small fibre modalities, thermal perception and autonomic function, were grossly abnormal in both groups (hot thermal perception 14.1 +/- 2.5 degrees C and 12.6 +/- 3.7 degrees C; cold thermal perception 13.8 +/- 2.7 degrees C and 10.9 +/- 4. 7 degrees C; heart rate variation 2.9 +/- 1.5 beats/min and 4.8 +/- 4.0 beats/min, respectively). CONCLUSIONS: There is indeed a subgroup of Type 1 diabetic neuropathy patients who suffer from severe autonomic symptoms associated with a selective small fibre sensory and autonomic loss with relatively preserved large fibre sensory modalities.     

Ergotamine use in severe diabetic autonomic neuropathy.

BACKGROUND: Symptomatic postural hypotension in diabetes is uncommon. When it does occur, it can prove debilitating and difficult to treat. We report here the therapeutic challenges encountered in managing a patient with severe postural hypotension secondary to diabetes-related autonomic neuropathy. CASE REPORT: A 69-year-old gentleman with a 23-year history of Type 1 diabetes mellitus and multiple microvascular complications was admitted with symptoms of severe postural hypotension. Cardiovascular autonomic testing confirmed the presence of severe autonomic neuropathy. He failed to respond to non-pharmacological measures, fludrocortisone, midodrine, octreotide, erythropoietin and increased caffeine intake. Eventually he was commenced on half a Cafergot suppository (giving him a dose of ergotamine 1 mg and caffeine 50 mg) which resulted in dramatic clinical improvement. CONCLUSION: Ergotamine may be considered in refractory cases of postural hypotension.     

Painful myocardial infarction in severe diabetic autonomic neuropathy

Summary Two cases are reported of painful myocardial infarction in diabetics with severe autonomic neuropathy confirmed by abnormal autonomic function tests. Painless myocardial infarction in diabetics has traditionally been attributed to damage of cardiac pain fibres by autonomic neuropathy but other factors such as microangiopathy in the myocardium may be responsible. It may simply be that diabetics come into hospital more often for other reasons and a silent myocardial infarction diagnosed incidentally.