The following discussion is from pages 258-260 of the NRC’s report’s “Fluoride in Drinking Water: A Scientific Review of EPA’s Standards.”

Animal Studies (Normal Animals)

Turner et al. (1997) reported a 17% increase in serum glucose in female rabbits given fluoride in drinking water at 100 mg/L for 6 months. IGF-1 was also significantly increased (40%) in these rabbits, but other regulators of serum glucose, such as insulin, were not measured. The authors suggested that IGF-1 concentrations might have changed in response to changes in serum glucose concentrations. Dunipace et al. (1995, 1998) found no significant differences with chronic fluoride treatment in mean blood glucose concentrations in rats; specific data by treatment group were not reported, and parameters such as insulin and IGF-1 were not measured.

Suketa et al. (1985) and Grucka-Mamczar et al. (2005) have reported increases in blood glucose concentrations following intraperitoneal injections of NaF; Suketa et al. (1985) attributed these increases to fluoride stimulation of adrenal function. Rigalli et al. (1990, 1992, 1995), in experiments with rats, reported decreases in insulin, increases in plasma glucose, and disturbance of glucose tolerance associated with increased plasma fluoride concentrations. The effect of high plasma fluoride (0.1-0.3 mg/L) appeared to be transient, and the decreased response to a glucose challenge occurred only when fluoride was administered before (as opposed to together with or immediately after) the glucose administration (Rigalli et al. 1990). In chronic exposures, effects on glucose metabolism occurred when plasma fluoride concentrations exceeded 0.1 mg/L (5 µmol/L) (Rigalli et al. 1992, 1995). The in vivo effect appeared to be one of inhibition of insulin secretion rather than one of insulin-receptor interaction (Rigalli et al. 1990). Insulin secretion (both basal and glucose-stimulated) by isolated islets of Langerhans in vitro was also inhibited as a function of fluoride concentrations (Rigalli et al. 1990, 1995). Rigalli et al. (1990) pointed out that recommended plasma fluoride concentrations for treatment of osteoporosis are similar to those shown to affect insulin secretion.

Jackson et al. (1994) reported no differences in mean fasting blood glucose concentrations between osteoporosis patients treated with fluoride and untreated controls, although 3 of 25 treated individuals had values outside the normal range (versus 1 of 38 controls). No significant differences were found between groups of older adults with different fluoride concentrations in drinking water in studies in China (Li et al. 1995; subjects described as “healthy” adults) and the United States (Jackson et al. 1997), and all mean values were within normal ranges. Glucose tolerance tests were not conducted in these studies.

Trivedi et al. (1993) reported impaired glucose tolerance in 40% of young adults with endemic fluorosis, with fasting serum glucose concentrations related to serum fluoride concentrations; the impaired glucose tolerance was reversed after 6 months of drinking water with “acceptable” fluoride concentrations (<1 mg/L). It is not clear whether individuals with elevated serum fluoride and impaired glucose tolerance had the highest fluoride intakes of the group with endemic fluorosis or a greater susceptibility than the others to the effects of fluoride. For all 25 endemic fluorosis patients examined, a significant positive correlation between serum fluoride and fasting serum immunoreactive insulin (IRI) was observed, along with a significant negative correlation between serum fluoride and fasting glucose/ insulin ratio (Trivedi et al. 1993).

The finding of increased IRI contrasts with findings of decreased insulin in humans after exposure to fluoride (Rigalli et al. 1990; de la Sota et al. 1997) and inhibition of insulin secretion by rats, both in vivo and in vitro (Rigalli et al. 1990, 1995). However, the assay for IRI used by Trivedi et al. (1993) could not distinguish between insulin and proinsulin, and the authors suggested that the observed increases in both IRI and serum glucose indicate either biologically inactive insulin—perhaps elevated proinsulin—or insulin resistance. Inhibition of one of the prohormone convertases (the enzymes that convert proinsulin to insulin) would result in both elevated proinsulin secretion and increased blood glucose concentrations and would be consistent with the decreased insulin secretion reported by Rigalli et al. (1990, 1995) and de la Sota et al. (1997). Although Turner et al. (1997) suggested fluoride inhibition of insulin-receptor activity as a mechanism for increased blood glucose concentrations, Rigalli et al. (1990) found no difference in response to exogenous insulin in fluoride-treated versus control rats, consistent with no interference of fluoride with the insulin-receptor interaction.

More than one mechanism for diabetes or impaired glucose tolerance exists in humans, and a variety of responses to fluoride are in keeping with variability among strains of experimental animals and among the human population. The conclusion from the available studies is that sufficient fluoride exposure appears to bring about increases in blood glucose or impaired glucose tolerance in some individuals and to increase the severity of some types of diabetes. In general, impaired glucose metabolism appears to be associated with serum or plasma fluoride concentrations of about 0.1 mg/L or greater in both animals and humans (Rigalli et al. 1990, 1995; Trivedi et al. 1993; de al Sota et al. 1997). In addition, diabetic individuals will often have higher than normal water intake, and consequently, will have higher than normal fluoride intake for a given concentration of fluoride in drinking water. An estimated 16-20 million people in the United States have diabetes mellitus (Brownlee et al. 2002; Buse et al. 2002; American Diabetes Association 2004; Chapter 2); therefore, any role of fluoride exposure in the development of impaired glucose metabolism or diabetes is potentially significant.

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