The Hypoglycemic Action of Ketones. II. Evidence for a Stimulatory Feedback of Ketones on the Pancreatic Beta Cells *

Abstract

The effects of alterations in carbohydrate metabolism induced by starvation and insulin deprivation on hepatic ketone production and peripheral ketone utilization have been the subject of intensive investigation (1-12). Only scant attention, however, has been paid to the effects that hyperketonemia, in turn, might have on carbohydrate and fat metabolism. The conflicting results from such studies (13-17) have been reviewed recently (18). Studies in this laboratory, designed to define the effects of induced hyperketonemia on carbohydrate and fat metabolism (18,19), showed that iv infusions of ,8-hydroxybutyric acid, acetoacetic acid, or their sodium salts produced the following immediate changes in glucose and nonesterified fatty acid (NEFA) metabolism: 1) blood glucose concentration fell promptly, at times to distinctly hypoglycemic levels, 2) hepatic glucose output decreased sharply to less than 50% of control values, a reduction accounting entirely for the decrease in arterial glucose concentration, and 3) these changes in glucose metabolism were accompanied simultaneously by a greater than 50% fall in arterial plasma NEFA concentration. The qualitative similarity between ketone infusion and the slow iv administration of insulin (20) only on blood glucose concentration and hepatic glucose output but also on plasma NEFA concentration suggested the possibility that ketones produce these effects via stimulation of endogenous insulin secretion.The present studies were designed specifically to determine whether ketone bodies stimulate the pancreatic 8-cells, directly or indirectly, to secrete increased amounts of insulin. Two types of studies were performed: in the first group, the effects of hyperketonemia produced by infusions of 8-hydroxybutyrate and acetoacetate on blood glucose concentrations were compared in depancreatized dogs and in dogs with alloxan diabetes; in the second group of studies, the changes in pancreatic venous insulin concentrations were determined by immunoassay during infusions of ketones either into a femoral vein or into a branch of the pancreatic artery. MethodsIn the studies designed to compare the effects of ,3-hydroxybutyrate and acetoacetate on the arterial glucose concentration of totally diabetic depancreatized and partially diabetic alloxanized dogs, experiments were performed at least 2 weeks after alloxanization (21)

Long-term elevation of β-hydroxybutyrate in dairy cows through infusion: Effects on feed intake, milk production, and metabolism

“…This finding is consistent with other reports of decreased plasma glucose concentration associated with elevated BHBA in pregnant sheep Harmeyer 2003, 2004), dogs (Felts et al, 1964;Madison et al, 1964), and pigs (Müller et al, 1984). However, our findings are in contrast to other reports that described a hyperglycemia in rabbits (Mirsky and Broh-Kahn, 1937) induced by ketone bodies infusion.…”

“…Infusion of BHBA increases insulin secretion in pigs (Müller et al, 1984). Madison et al (1964) suggested that pancreatic beta cells respond to the high plasma BHBA concentration with increased insulin secretion in dogs. It appears that insulin suppresses the glucose production throughout an inhibitory effect on the regulatory enzymes of gluconeogenesis (Brockman and Larrveld, 1986;Hayirli, 2006).…”

“…Intravenous BHBA infusion led to decreased plasma concentration of glucose in dogs (Madison et al, 1964), pigs (Müller et al, 1984), and ewes Harmeyer, 2003, 2004). The reason for declined glucose during the infusion of BHBA remains unclear, but those authors suggested that infusion of BHBA induced hypoglycemia through direct or indirect inhibition of gluconeogenesis, or by a change in the insulin concentration in pig and sheep (Müller et al, 1984;Schlumbohm and Harmeyer, 2004).…”

Glucagon stimulates ketone utilization by rat brain slices.

“…23 We observed that giving BHB-ketotic mice glucose not only increased the animals' blood glucose levels (Group #5), it elevated their HST (Group # 4 and #5) as compared to ketotic animals who did not receive glucose (Group #3). Our data, therefore, are consistent with the idea that increased substrate availability enhances hypoxic tolerance.…”

“…One explanation for the proposed inhibition of glucose metabolism may be that GG has recently been shown to inhibit the activity of phosphofructokinase by decreasing the level of fructose 2,6-biphosphate in intact cells. 23 This inhibition would then suppress glucose utilization but not adversely effect BHB utilization since BHB does not utilize the glycolytic pathway. This contrasts with earlier studies of Lefebvre and Luyckx 24 who reported that GG had no direct effect on the peripheral glucose utilization.…”