Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes. Despite its relationship to an increased risk of cardiovascular mortality and its association with multiple symptoms and impairments, the significance of DAN has not been fully appreciated. The reported prevalence of DAN varies widely depending on the cohort studied and the methods of assessment. In randomly selected cohorts of asymptomatic individuals with diabetes, 20% had abnormal cardiovascular autonomic function. DAN frequently coexists with other peripheral neuropathies and other diabetic complications, but DAN may be isolated, frequently preceding the detection of other complications. Major clinical manifestations of DAN include resting tachycardia, exercise intolerance, orthostatic hypotension, constipation, gastro- paresis, erectile dysfunction, sudomotor dysfunction, impaired neurovascular function, "brit- tle diabetes," and hypoglycemic autonomic failure. DAN may affect many organ systems throughout the body (e.g., gastrointestinal (GI), genitourinary, and cardiovascular). GI distur- bances (e.g., esophageal enteropathy, gastroparesis, constipation, diarrhea, and fecal inconti- nence) are common, and any section of the GI tract may be affected. Gastroparesis should be suspected in individuals with erratic glucose control. Upper-GI symptoms should lead to con- sideration of all possible causes, including autonomic dysfunction. Whereas a radiographic gastric emptying study can definitively establish the diagnosis of gastroparesis, a reasonable approach is to exclude autonomic dysfunction and other known causes of these upper-GI symptoms. Constipation is the most common lower-GI symptom but can alternate with episodes of diarrhea. Diagnostic approaches should rule out autonomic dysfunction and the well-known causes such as neoplasia. Occasionally, anorectal manometry and other specialized tests typically performed by the gastroenterologist may be helpful. DAN is also associated with genitourinary tract disturbances including bladder and/or sexual dysfunction. Evaluation of bladder dysfunc- tion should be performed for individuals with diabetes who have recurrent urinary tract infec- tions, pyelonephritis, incontinence, or a palpable bladder. Specialized assessment of bladder dysfunction will typically be performed by a urologist. In men, DAN may cause loss of penile erection and/or retrograde ejaculation. A complete workup for erectile dysfunction in men should include history (medical and sexual); psychological evaluation; hormone levels; mea- surement of nocturnal penile tumescence; tests to assess penile, pelvic, and spinal nerve func- tion; cardiovascular autonomic function tests; and measurement of penile and brachial blood pressure. Neurovascular dysfunction resulting from DAN contributes to a wide spectrum of clinical disorders including erectile dysfunction, loss of skin integrity, and abnormal vascular reflexes. Disruption of microvascular skin blood flow and sudomotor function may be among the earliest manifestations of DAN and lead to dry skin, loss of sweating, and the development of fissures and cracks that allow microorganisms to enter. These changes ultimately contribute to the development of ulcers, gangrene, and limb loss. Various aspects of neurovascular function can be evaluated with specialized tests, but generally these have not been well standardized and have limited clinical utility. Cardiovascular autonomic neuropathy (CAN) is the most studied and clinically important form of DAN. Meta-analyses of published data demonstrate that reduced cardiovascular autonomic function as measured by heart rate variability (HRV) is strongly (i.e., relative risk is doubled) associated with an in- creased risk of silent myocardial ischemia and mortality. The determination of the presence of CAN is usually based on a battery of auto- nomic function tests rather than just on one test. Proceedings from a consensus conference in 1992 recommended that three tests (R-R variation, Valsalva maneuver, and postural blood pressure testing) be used for longitudi- nal testing of the cardiovascular autonomic system. Other forms of autonomic neuropathy can be evaluated with specialized tests, but these are less standardized and less available than commonly used tests of cardiovascular autonomic function, which quantify loss of HRV. Interpretability of serial HRV testing re- quires accurate, precise, and reproducible procedures that use established physiological maneuvers. The battery of three recom- mended tests for assessing CAN is readily per- formed in the average clinic, hospital, or diagnostic center with the use of available technology. Measurement of HRV at the time of diagnosis of type 2 diabetes and within 5 years after diagnosis of type 1 diabetes (unless an individual has symptoms suggestive of au- tonomic dysfunction earlier) serves to estab- lish a baseline, with which 1-year interval tests can be compared. Regular HRV testing pro- vides early detection and thereby promotes timely diagnostic and therapeutic interven- tions. HRV testing may also facilitate differen- tial diagnosis and the attribution of symptoms (e.g., erectile dysfunction, dyspepsia, and diz- ziness) to autonomic dysfunction. Finally, knowledge of early autonomic dysfunction can encourage patient and physician to im- prove metabolic control and to use therapies such as ACE inhibitors and -blockers, proven to be effective for patients with CAN. Diabetes Care 26:1553-1579, 2003

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Diabetic Autonomic Neuropathy

We studied the effects of a long-acting analogue of somatostatin (SMS 201–995, Sandoz) in 25 patients with histologically proved metastatic carcinoid tumors and the carcinoid syndrome. Thi...

https://www.nejm.org/doi/pdf/10.1056/NEJM198609113151102?listPDF=true

Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue.

https://www.carcinoid.org/wp-content/uploads/2015/10/Current-Status.pdf

Current status of gastrointestinal carcinoids.

Radioimmunoassay of gastrin

RELEASING factors1 and other brain peptides2 have been the subject of extensive studies and the high sensitivity of modern measurement techniques has led to the discovery, in various tissues3,4 and in the nervous system5–9, of new, unpredicted locations for otherwise well known peptides. Evidence for the presence in the vertebrate nervous system of a hitherto undescribed brain gastrin immunoassayable peptide (BGP) is presented here.

New peptide in the vertebrate CNS reacting with antigastrin antibodies.

A radioiodine-immunoassay technic was used to measure fasting serum gastrin levels in four patients with the Zollinger-Ellison syndrome and 24 patients without gastrointestinal diseases. Serum gastrin levels in all the patients with the Zollinger-Ellison syndrome exceeded by approximately tenfold or greater the mean serum gastrin level of 425 μμg per milliliter in the control population. Gastrin was identified immunochemically in an extract derived from a pancreatic islet-cell tumor from one of the patients with the Zollinger-Ellison syndrome.

Immunochemical measurement of elevated levels of gastrin in the serum of patients with pancreatic tumors of the Zollinger-Ellison variety.

https://www.gastrojournal.org/article/0016-5085(80)90933-6/pdf

Secretin injection test in the diagnosis of gastrinoma

Fasting and postprandial (two hour) venous gastrin concentrations were measured in serums from a population of 29 patients with pernicious anemia and compared with a control population of patients. Mean fasting and postprandial gastrin concentrations for the patients with pernicious anemia were 997 (± 182 S.E.) and 1007 (± 303 S.E.) pg per milliliter respectively, whereas fasting and postprandial serum gastrin levels for the control patients were 165 (± 28 S.E.) and 209 (± 55 S.E.) pg per milliliter. The differences are significant (p less than 0.025). Among the patients with pernicious anemia nine of 29 (31 per cent) had serum gastrin levels sufficiently elevated to be considered in the hypergastrinemic range characteristic of the Zollinger — Ellison syndrome.

Serum Gastrin Concentrations in Pernicious Anemia

THE carcinoid syndrome is characterized by episodes of flushing that appear to be secondary to the secretion of one or more substances by a tumor of enterochromaffin-cell origin.1 2 3 Flushing can ...

The carcinoid flush. Provocation by pentagastrin and inhibition by somatostatin.

Serum gastrin levels were repeatedly measured in a patient with a total gastrectomy and hypergastrinemia associated with the Zollinger—Ellison syndrome. Fasting serum concentrations determined on consecutive days, and also at four-hour intervals during a 24-hour period, revealed persistent hypergastrinemia that varied within a relatively narrow range. Serum gastrin levels were found to relate directly to plasma calcium concentrations, falling by a factor of 20 with the development of hypocalcemia after parathyroidectomy for hypercalcemic hyperparathyroidism. Marked increases in serum gastrin concentration were induced by calcium infusion (12 and 20 mg per kilogram of body weight) but not by infusion of parathormone. The previously demonstrated effects of calcium in the control and stimulation of gastric acid secretion may be mediated by the polypeptide hormone gastrin.

James E. McGuigan

Papers

Immunochemical measurement of elevated levels of gastrin in the serum of patients with pancreatic tumors of the Zollinger-Ellison variety.

Secretin injection test in the diagnosis of gastrinoma

Serum Gastrin Concentrations in Pernicious Anemia

The carcinoid flush. Provocation by pentagastrin and inhibition by somatostatin.

Effects of Calcium on Serum Gastrin Levels in the Zollinger–Ellison Syndrome