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May 29, 1999

Research: Causes and Prevention

Question from Chicago, Illinois, USA:

I am a 31 year old, fit, thin (5'4" -- 114 lbs) woman who has always had a healthy diet. My only health problem prior to diabetes was frequent kidney stones for which I took hydrochlorothiazide (HCTZ) for 6 years until several months ago. Two weeks after ceasing HCTZ, on a routine blood test right after a high-carbohydrate meal, I had a blood glucose level of over 500. My doctor then performed two fasting blood glucose tests which were 219 and 220 respectively. I showed no Islet Cell Antibodies and two separate C-peptide tests were completely normal. My Hemoglobin A1c was 10. During the week and a half that I was monitoring my blood before I went on insulin (I was on no medication), my blood sugars ranged between 100 and 250 (with all 200s happening post-meal). My doctors put me on insulin instead of oral medications because I want to have a child as soon as possible. Initially, I was taking 5 units of Ultralente at night and 2 units of Humalog with meals (with a few insulin reactions happening post-meal). I then went down to 5 units of Ultralente at night and 1 unit of Humalog with meals. In the last two weeks, I have gone down again and I have been completely controlled with only 4 units of Ultralente at night and no meal-time insulin at all. My doctors have not been able to tell me if I am Type 1 or Type 2. In fact, three endocrinologists (from two different academic institutions) have told me that I am somewhat of an academic mystery. On the one hand, they say that I am fairly young and thin to have Type 2 diabetes (although they have told me about MODY but say that my ethnic background -- white -- weighs against that). However, the lack of islet cell antibodies, the normal C-peptides, the little and decreasing amounts of insulin which are controlling my blood sugars, and the blood glucose levels the week and a half before I went on insulin may weigh in favor of Type 2 (although I have been cautioned that there is a chance that I may be Type 1 and honeymooning despite the negative islet cell antibody test). I am wondering whether the HCTZ could have caused the diabetes. I have read a few studies from 1989-90 which associate thiazide drugs with the development of diabetes. See, for example, N.Eng.J.Med. 1989; 321:868-873. The studies concluded that thiazide drugs cause insulin resistance -- and may cause or significantly increase the risk for developing Type 2 diabetes. Subsequent articles criticized the studies' conclusions because the studies involved mostly overweight, older individuals who were taking HCTZ for high blood pressure (not for kidney stones). Thus, the critics concluded that most of the subjects who developed diabetes or glucose intolerance during HCTZ therapy would have developed it anyway and that the thiazides may have merely unmasked latent diabetes that was already in existence. However, despite these criticisms, the recently published Johns Hopkin Guide to Diabetes discusses thiazides as though they may cause diabetes. I am wondering if you know the current state of thinking on thiazides and diabetes. Could the HCTZ have caused me to become insulin resistant -- thus explaining the fact that I look as though I may be a Type 2 diabetic despite my age and weight. Additionally, the 1989 study indicated that in another thiazide study, 60% of the individuals who had elevated blood glucose levels during thiazide therapy (this time, the study involved bendrofluathiazide rather than HCTZ) had normal glucose levels within 6 months to a year after ceasing the drug. I have been off HCTZ for two months and my insulin needs keep coming down. Could I be going back to normal? (My doctors are cautious but hopeful.)


I have to be honest and say that I have not researched the hydrochlorthiazide literature though you seem to have done a pretty good job of this yourself. You might however still enjoy a further explore using PubMed. It is often the most up-to-date instrument to access MEDLINE. I have not in any case come accross ths asociation personally and in fact I think there is a more probably explanation for the fact that you have an insulin dependent, antibody negative form of Diabetes. MODY is a possibility of course; but not very likely and a major laboratory problem to diagnose each of the many forms specifically. Recently a type of Diabetes called Type 1B has come to be recognised. It presents in children or young adults who are then found to be antibody negative. In many of them after a few weeks they can be managed without insulin and with diet and excecise alone. This occurs in less than 10% of Caucasian people in North Ameria and at the moment the basic problem is not yet specifically known although some are chromosonal.

One important reassurance is that meticulous control is everything and the precise laboratory diagnosis does not affect treatment although in time it may be helpful for genetic counselling.

Additional comments from Dr. Quick:

I also must plead ignorance of any understanding of the role of the HCTZ in precipitating your diabetes. But, as Dr. O’Brien points out in his last paragraph, the most important issue for you at this time is maintaining meticulous control in preparation for pregnancy. Low dose insulin, frequent monitoring of blood sugar, exercise and meal planning are to be advised no matter whether you have Type 1 or Type 2 or MODY diabetes, considering your present circumstances and plans.

If you haven’t had a battery of diabetes-related antibodies done in a major reference lab (such as the Barbara Davis Center in Denver), you should. Many commercial labs have difficulty in performing these very difficult assays. And, even if you have negative antibodies now, I’d also suggest that your physicians arrange to deep-freeze some of your blood for future analysis when someday even better tests are available.