Treatment of Streptozotocin Diabetes with Di-isopropylammonium Dichloroacetate (DIPA)

Abstract

Streptozotocin-diabetic rats were treated with di-isopropylammonium dichloroacetate (DIPA) via an orogastric tube in doses of 25 or 50 mg./l kg. twice daily for one week. In nonketotic animals, mean blood glucose concentration decreased significantly during treatment with either DIPA or its acid moiety, sodium dichloroacetate. Neither di-isopropylammonium hydrochloride nor saline reduced hyperglycemia in the diabetic rats. There was no change in the blood glucose of nondiabetic rats in response to DIPA. In ketotic diabetes produced by streptozotocin, 63 per cent of DIPA-treated animals survived after one week, compared to 24 per cent of those given saline. DIPA did not influence glucose absorption in isolated everted jejunal sacs from diabetic and normal rats, while phenformin inhibited transport by more than 50 p_er cent Thus DIPA, which only partially mimics insulin in its actions and does not stimulate insulin release as do the sulfonylureas, also fails to duplicate the effects of phenformin and appears to have a unique mode of action. DIPA is an effective oral hypoglycemic agent in streptozotocin-diabetic rats. DIABETES 25: 179-82, March, 1974.

Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1

“…DCA and some other halogenated acetic acid derivatives were found to activate PDC by inhibiting PDK, which was up-regulated by diabetes and other conditions in which fatty acid beta-oxidation was increased (Stacpoole, 1989). By activating PDC, DCA lowers circulating glucose independently of insulin, as illustrated in insulin-deficient streptozotocin- or alloxan-induced diabetic rats, in which DCA reduced both blood glucose and ketone bodies and decreased mortality (Blackshear, et al, 1974; Eichner, et al, 1974). In patients with non-ketotic type 2 diabetes, oral DCA reduced circulating levels of lactate and alanine, which are in equilibrium with pyruvate and glucose, while modestly raising beta-hydroxybutyrate concentrations (Stacpoole, et al, 1978).…”

Pharmacogenetic Considerations with Dichloroacetate Dosing

“…Second, DCA inhibits de novo hepatic triglyceride synthesis in nondiabetic rodents [5] and decreases circulating triglyc eride and very low density lipoprotein levels in patients with Type 2 diabetes mellitus [4]. It also decreases blood ketone bodies in rats with experimentally induced diabetic ketoacidosis [8,9]. The precise mechanisms underlying these effects on lipid synthesis and oxidation are unknown.…”

AZD7545, a novel inhibitor of pyruvate dehydrogenase kinase 2 (PDHK2), activates pyruvate dehydrogenase in vivo and improves blood glucose control in obese (fa/fa) Zucker rats

“…Diabetes is also associated with elevated hepatic glucose production, so activation of PDH may have the potential to decrease blood glucose, not only by increasing glucose oxidation, but also reducing the supply of the gluconeogenic substrates lactate and alanine. DCA (dichloroacetate) is a non-specific inhibitor of PDHK which has been shown to increase both muscle and liver PDH activity in a number of rat models of diabetes: streptozotocin- [2] and alloxan-induced [3] insulin-deficient states and models of type 2 diabetes such as the dexamethasone-induced [4] and the ZDF (Zucker diabetic fatty) rat [5]. In these models, with the exception of alloxandiabetes, DCA causes a decrease in blood glucose.…”