Reply to M Manco et al and to MF McCarty

Division of Clinical Epidemiology and Preventive Medicine
Department of Medicine
University of California, Los Angeles
David Geffen School of Medicine
924 Westwood Boulevard
Suite 335
Los Angeles, CA 90024
E-mail: kchiu{at}mednet.ucla.edu

Dear Sir:

We appreciate the interest in our report of the association of hypovitaminosis D with insulin resistance and ß cell dysfunction (1). It is important to reiterate our statement that a strong correlation does not necessarily imply a cause-effect relation. Furthermore, the serum 25-hydroxyvitamin D concentration only independently accounts for 6% of the variation in insulin sensitivity in glucose-tolerant subjects. Type 2 diabetes, as well as the metabolic syndrome, is a multifactorial disease. Thus, if vitamin D per se plays a role in the pathogenesis of the diseases, hypovitaminosis D could only be a contributing factor for type 2 diabetes, the metabolic syndrome, or both.

In response to Manco et al, the association between serum 25-hydroxyvitamin D concentration and insulin sensitivity is independent of obesity, as shown from the multivariate analysis. Because obesity is one of the criteria for the metabolic syndrome, a higher body mass index would be expected in those with the metabolic syndrome than in those without it. It is of great interest whether there is a relation between latitude and insulin sensitivity. However, latitude accounted for 42% of the variation in serum 25-hydroxyvitamin D concentration from a study of 17 countries (2), and serum 25-hydroxyvitamin D explained only 6% of the variation in insulin sensitivity in our study (1). It is not surprising that no association was found between latitude and insulin sensitivity in a study of only 6 centers (3). Furthermore, I cannot find such information in the cited article (3). Although serum 25-hydroxyvitamin D concentrations vary with the seasons, serum 25-hydroxyvitamin D was determined from the fasting samples obtained immediately before the assessment of insulin sensitivity and from ß cell function on the same day in this study (1). Therefore, it is very unlikely that the observed association was biased by the prevalence of subjects studied or seasonal influence. Interestingly, there is a seasonal variation in the prevalence of type 2 diabetes, which peaks in the late winter and is lowest in summer (4, 5). With regard to the improvement in insulin sensitivity after biliopancreatic diversion, it is expected after substantial weight loss despite hypovitaminosis D, which only accounts for 6% of the variation in insulin sensitivity independently (1). It would be very intriguing to determine whether this relation remains in this group of patients after biliopancreatic diversion. A sample size of 135 subjects would be required to show this association with a power of 0.80.

In reply to McCarty's fascinating hypothesis that calcium plays a central role in this association, there is also evidence against it. Although the infusion of parathyroid hormone significantly affects intracellular calcium in human subjects and rats, it does not affect the action of insulin (6, 7). Therefore, neither parathyroid hormone nor calcium is the primary effecter on glucose metabolism. With regard to ß cell function, it has been shown that vitamin D, but not calcium, is essential for normal insulin secretion (8). In addition, treatment with bisphosphonate (eg, parmidraonate) resulting in hypocalcemia with elevated parathyroid hormone concentrations is not associated with an increased incidence of abnormal glucose tolerance or diabetes. Furthermore, it has been shown that glucose significantly elevates intracellular free calcium in a dose- and time-dependent manner (9), and a hyperglycemia-induced increase in intracellular calcium is a fundamental lesion in diabetes (10). However, we agree that our findings need to be examined in other populations and with different study designs.

REFERENCES

1. Chiu KC, Chu A, Go VLW, Saad MF. Hypovitaminosis D is associated with insulin resistance and ß cell dysfunction. Am J Clin Nutr 2004;79:820-5.
2. Lips P, Duong T, Oleksik A, et al. A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial. J Clin Endocrinol Metab 2001;86:1212-21.
3. Ferrannini E, Natali A, Bell P, Cavallo-Perin P, Lalic N, Mingrone G. Insulin resistance and hypersecretion in obesity. European Group for the Study of Insulin Resistance (EGIR). J Clin Invest 1997;100:1166-73.
4. UKPDS. UK Prospective Diabetes Study. IV. Characteristics of newly presenting type 2 diabetic patients: male preponderance and obesity at different ages. Multi-center Study. Diabet Med 1988;5:154-9.
5. Gamble DR, Taylor KW. Seasonal incidence of diabetes mellitus. Br Med J 1969;3:631-3.
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7. Fliser D, Franek E, Fode P, et al. Subacute infusion of physiological doses of parathyroid hormone raises blood pressure in humans. Nephrol Dial Transplant 1997;12:933-8.
8. Kadowaki S, Norman AW. Dietary vitamin D is essential for normal insulin secretion from the perfused rat pancreas. J Clin Invest 1984;73:759-66.
9. Barbagallo M, Shan J, Pang PK, Resnick LM. Glucose-induced alterations of cytosolic free calcium in cultured rat tail artery vascular smooth muscle cells. J Clin Invest 1995;95:763-7.
10. Barbagallo M, Gupta RK, Resnick LM. Cellular ions in NIDDM: relation of calcium to hyperglycemia and cardiac mass. Diabetes Care 1996;19:1393-8.