Increased lipid oxidation but normal muscle glycogen response to epinephrine in humans with IDDM

Abstract

The effects of physiological increments in epinephrine and insulin on glucose production (GP), skeletal muscle glycogen metabolism, and substrate oxidation were studied in eight insulin-dependent diabetes mellitus (IDDM) and nine control subjects. Epinephrine was coinfused for the final 120 min of a 240-min euglycemic, hyperinsulinemic clamp. In both groups, insulin increased glucose uptake, glycogen synthesis, and whole body carbohydrate (CHO) oxidation and inhibited GP (by 70-80%) and lipid oxidation (by approximately 50%), whereas epinephrine antagonized the effect of insulin on glucose uptake and glycogen synthesis. In contrast, GP increased in IDDM subjects (P < 0.02) but remained suppressed by insulin in controls. CHO oxidation fell (1.37 +/- 0.25 vs. 2.08 +/- 0.32 mg.kg-1.min-1) and lipid oxidation increased to baseline in IDDM subjects, with increments in plasma free fatty acids (FFA) and glycerol. In contrast, in controls, plasma FFA and glycerol remained suppressed and lipid oxidation decreased further with epinephrine (P < 0.005). Epinephrine completely reversed insulin's activation of muscle glycogen synthase in both groups. Thus, during hyperinsulinemia, the hepatic response to epinephrine in IDDM subjects may be dependent on activation of lipid oxidation. Skeletal muscle glycogen metabolism is exquisitely sensitive to epinephrine despite the presence of hyperinsulinemia.

Induction of Hepatic Glucose-6-Phosphatase Gene Expression by Lipid Infusion

“…It is suggested that prolonged hyperlipidemia may contribute to the increased production of glucose via increased expression of this protein. Taken together with numerous other reports on the impact of lipids on carbohydrate metabolism in skeletal muscle (7)(8)(9), liver (8)(9)(10)12,13), and pancreatic (3-cells (11,38,39), our finding provides experimental support for the role of hyperlipidemia in the pathogenesis of NIDDM (40,41).…”

“…It also suggests that the mechanism(s) by which a sustained increase in the availability of lipids might affect hepatic glucose output involves more than the short-term increase in the rate of gluconeogenesis (15). Indeed, increased hepatic glucose production is an early (~1 week) consequence of high-fat feeding in rodents (34), and the plasma FFA levels are closely related to the rate of endogenous glucose production in humans (8)(9)(10)12,13). Furthermore, most patients with NIDDM display increased concentrations of plasma FFA throughout the day (14).…”

“…In particular, numerous studies have shown that the rate of endogenous glucose production is closely related to the circulating plasma FFA concentrations ER, endoplasmic reticulum; FFA, free fatty acid; PMSF, phenylmethylsulfonyl fluoride; SSC, sodium chloride-sodium citrate. (9,10,12,13) and that the majority of individuals with NIDDM have increased 24-h plasma FFA profiles (14). While the acute effects of an increase in plasma FFA availability are likely to be largely caused by its known stimulatory effect on gluconeogenesis (15), much less is known regarding the long-term consequences of increased hepatic availability of FFAs.…”

Fibroblasts From Type 1 Diabetics Exhibit Enhanced Ca2+ Mobilization after TNF or Fat Exposure

“…Even in non-ketotic states, type 1 diabetics have dyslipidemia, or elevated levels of FFA in serum [17]. Following insulin-induced hypoglycemia, stimulation of type 1 diabetics with epinephrine results in increases in FFA greater than in controls subjected to the same maneuver [18], [19]. Short term ketosis in type 1 diabetics is associated with almost doubled plasma FFA concentrations [20].…”

Antecedent hypoglycemia does not alter increased epinephrine-induced lipolysis in type 1 diabetes mellitus

“…Some studies found no differences in response to direct adrenergic stimulation [24,28] or response to hypoglycemic adrenergic counterregulation, whereas others have found significant increases in lipolytic [29] or ketogenic [30] responses to epinephrine infusion or hypoglycemia-induced epinephrine secretion in type 1 diabetes mellitus [31,32]. Differences in metabolic control, method of b-adrenergic stimulation, and metabolic conditions likely account for the differences.…”