Jerome Conn

Jerome W Conn (1907-1994) is best known for his 1955 description of the syndrome of primary aldosteronism which bears his name. However, in the 1940s and 50s he was prominent in the world of diabetes, especially in relation to the glucose tolerance test (GTT). He spent his whole career at the University of Michigan Medical School where, after his residency, he did research on obesity and diabetes with Louis Newburgh (1883-1956). From 1943 to 1973 he was director of the Division of Endocrinology and Metabolism.

Jerome Conn
Jerome Conn
Conn was one of the popularisers of the concept of functional hyperinsulinism or reactive hypoglycaemia, a ‘non disease’ which reached epidemic proportions in the USA in the 1950s and 60s. In a lecture to the Michigan State Medical Society in September 1946, he described it as “by far the most common cause of periodic attacks of spontaneous hypoglycaemia, accounting for about 70% of all cases in which hypoglycaemia is responsible for clinical symptoms.”[1] To him it was a clear cut easily recognisable syndrome with characteristic clinical and laboratory features. Those affected complained of sudden, overwhelming attacks of severe weakness and fatigue, most frequently in the forenoon and late afternoon.

If on further questioning there were other symptoms such as inward trembling, pallor, sweating, palpitation, visual disturbances, loss of mental acuity or syncope, the diagnosis was even more likely. Conn emphasised that attacks never occurred during fasting and fasting blood sugar was always normal. Diagnosis was made by a standard (100gm) GTT with a blood sugar below 2.2 mmol/l being diagnostic, one of 2.7 presumptive and 3.3 being suggestive. Conn believed it was a type of autonomic imbalance which gave rise to an “excessive responsiveness of the islets of Langerhans to the normal stimulus for insulin production.” Whether it was a somatic expression of a psychological disturbance, Conn was not sure and it didn’t matter because treatment with a high protein low carbohydrate diet produced such dramatic relief of symptoms.[2] In 1955, he tried to put the genie back into the bottle in a field where, as he put it, ‘the diagnosis is now being made promiscuously without the supporting evidence necessary to establish it’[3] This was a bit rich because Conn himself had exaggerated the frequency of reactive hypoglycaemia just as he did that of primary aldosteronism.

Conn’s long series of researches using the glucose tolerance test began in 1940 when he showed that a low carbohydrate diet caused deterioration of glucose tolerance.[4] This had actually been known since the late 19th century but for some reason Conn felt impelled to reinvestigate the issue. He did GTTs on 3 malnourished but otherwise normal patients, 3 male medical students and 3 female dietitians after 3 days on a normal diet and 5 days on a low carbohydrate one. Those on the low carbohydrate diet showed dramatic increases in the 1 and 2hr post glucose values. He also described three cases where diabetes had been wrongly diagnosed because of failure to take into account previous carbohydrate restriction. One was a 21 year old woman who had lost 20 pounds in six months because of marital troubles and another a man with renal glycosuria who had been put on a low carbohydrate diet before having a GTT. He had been thought to have diabetes for 20 years! Conn recommended a standard preparatory diet of 300 gm carbohydrate and 80gm protein for at least 3, and preferably 5 days before a GTT and this was religiously followed in American hospitals for the next 20 years – longer in Ann Arbor where Conn worked; it was still being rigidly enforced and taught in 1973 when I was there!

In 1953 Conn was joined by Stefan Fajans (b.1918) and they developed the cortisone-glucose tolerance test. The basis was that if a large enough dose of cortisone was given to normal people their glucose tolerance initially decreased but recovered within a few days presumably because their pancreas could produce enough insulin to overcome the cortisone induced resistance. It seemed that a cortisone primed GTT might be a way of uncovering people who, although not diabetic, had a reduced pancreatic reserve, ie.,were ‘prediabetic’.

The first stage was to establish a dose of cortisone which would not modify carbohydrate tolerance in normals. Eventually they chose 50mg cortisone given as two doses, 8½ hours and 2 hours before the test. In their first publication they tested 152 apparently healthy relatives of diabetic patients and 50 controls.[5] On the baseline non-cortisone primed GTT, 29/152 relatives compared to only 1/50 controls were found to be overtly diabetic. After cortisone, on the basis of a two hour blood sugar over 140 mg/dl (7.8 mmol/l), 24% of relatives showed a positive response compared to only 3% of normals. In 1958 when Conn gave the Banting Memorial Lecture of the American Diabetes Association rates of diabetes (26%) and probable diabetes (9%) were much higher during a seven year follow up in those with positive than negative cortisone GTTs.[6] In retrospect, rates of positivity were strongly related to age and body weight and the original groups had not been poorly matched for these variables.[7]

Nevertheless, the test became widely accepted (mainly in the USA) as a sensitive and specific method of identifying early diabetes. When Fajans and Conn revisited their test in 1961 they concluded that it was still a research procedure. Nevertheless, it spawned numerous other studies and was probably used inappropriately in doctor’s offices in the USA. The best epitaph is that of Kelly West who wrote in 1978 that, ‘after a quarter of a century of rather unproductive application in investigative studies one may also doubt the continuing utility of these tests in research, at least in their present form.’

In 1965 Conn suggested that many cases of diabetes were due to hyperaldosteronism. He thought that 15-25% of patients with ‘essential hypertension’ actually had hyperaldosteronism. Since 50% of people with aldosteronism had abnormal carbohydrate tolerance, it followed for Conn that ‘approximately 1,500,000 diabetics in the USA are potentially curable by adrenal surgery.’ [8] Needless to say, this preposterous suggestion came to nothing.

References

  1. ^ Conn JW. Functional hyperinsulinism:a common and well defined clinical entity amenable to medical management. J Michigan Med Soc 1947;46:451-455.

  2. ^ Conn JW. The advantage of a high protein diet in the treatment of spontaneous hypoglycemia. J Clin Invest 1936;15:673-8.

  3. ^ Conn JW, Seltzer HS. Spontaneous hypoglycemia. Am J Med 1955; 19: 460-478

  4. ^ Conn JW. Interpretation of the glucose tolerance test.The necessity of a standard preparatory diet. Am J Med Sci. 1940; 199: 555-564.

  5. ^ Fajans SS, Conn JW. An approach to the prediction of diabetes mellitus by modification of the glucose tolerance test with cortisone. Diabetes 1954; 3 296-303.

  6. ^ Conn JW. The Prediabetic State in Man: Definition, Interpretation and Implications. Diabetes 1958;7:347-357.

  7. ^ Fajans SS, Conn JW. Comments on the cortisone-glucose tolerance test. Diabetes 1960; 9:83.

  8. ^ Conn JW. Hypertension, the potassium ion and impaired carbohydrate tolerance. N Engl J Med. 1965;273:1135–1143.

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