Inhibition of Hepatic Glucose Production by SDZ 51641

Young, Douglas A.; Ho, Robert S.; Bell, Philip; Cohen, Diana K; McIntosh, Raymond H; Nadelson, Jeffrey; Foley, James E.

doi:10.2337/diab.39.11.1408

Cited by 26 publications

(3 citation statements)

References 20 publications

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“…51 Mixed anhydrides represent original attempts for preparing prodrugs of carboxylic or phosphonic acid. 54 Primary amides of carboxylic acids are easily converted in humans to the corresponding acid (e.g. They are more lipophilic than the parent clodronate, stable against chemical hydrolysis, and hydrolyzed enzymatically to clodronate in human serum.…”

Section: Derivatization Of Drugs Containing a Carboxylic Acid Functmentioning

confidence: 99%

Designing Prodrugs and Bioprecursors

Wermuth¹

2008

The Practice of Medicinal Chemistry

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Section: Derivatization Of Drugs Containing a Carboxylic Acid Functmentioning

confidence: 99%

Designing Prodrugs and Bioprecursors

Wermuth¹

2008

The Practice of Medicinal Chemistry

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“…After incubation, the muscle specimens were rapidly removed and frozen in liquid nitrogen. The 95 % 02/5 % CO2 gas line was removed, and the liberated 14CO2 was collected (1 h; 35°C) in a hanging centre well situated in the resealed flask [15]. The samples were then processed for total liberated 14CO2 as described by Young et al [15].…”

Section: Determination Of Oxidation Of [U-4c]fructose and Glycogen Smentioning

confidence: 99%

“…Skeletal-muscle strips were incubated as described above in KHB medium containing unlabelled glucose (concentrations given in the Tables) and [U-_4C]glucose (0.3 ,uCi/ml). After incubation, the muscle specimens were removed, and the liberated 14CO2 was collected as described above for the muscles exposed to [U-14C]fructose [15]. The muscle specimens were then processed for the estimation of glycogen synthesis [16,17].…”

Section: Determination Of Oxidation Of [U-14c]giucose and Glycogen Symentioning

confidence: 99%

Carrier-mediated fructose uptake significantly contributes to carbohydrate metabolism in human skeletal muscle

Zierath

Nolte

Wahlström

et al. 1995

Biochemical Journal

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To determine whether fructose can be utilized as a metabolic substrate for skeletal muscle in man, we investigated its incorporation into glycogen, its oxidation and lactate production in isolated human skeletal muscle. Rates of fructose oxidation and incorporation into glycogen increased in the presence of increasing fructose concentrations (0.1-1.0 mM). Lactate production increased 3-fold when extracellular fructose was increased from 0.1 to 0.5 mM. Cytochalasin B, a competitive inhibitor of hexose transport mediated by the GLUT1 and GLUT4 facilitative glucose transporters, completely inhibited insulin-stimulated glucose incorporation into glycogen and glucose oxidation (P < 0.01), but did not alter fructose incorporation into glycogen or fructose oxidation. Insulin (1000 mu-units/ml) increased glucose incorporation into glycogen 2.7-fold and glucose oxidation 2.3-fold, whereas no effect on fructose incorporation into glycogen or fructose oxidation was noted. A physiological concentration of glucose (5 mM) decreased the rate of 0.5 mM fructose incorporation into glycogen by 60% (P < 0.001), whereas fructose oxidation was not altered in the presence of 5 mM glucose. Irrespective of fructose concentration, the majority of fructose taken up underwent non-oxidative metabolism. Lactate production accounted for approx. 80% of the fructose metabolism in the basal state and approx. 70% in the insulin (1000 mu-units/ml)-stimulated state. In the presence of 5 mM glucose, physiological concentrations of fructose could account for approximately 10-30% of hexose (glucose + fructose) incorporation into glycogen under non-insulin-stimulated conditions. In conclusion, fructose appears to be transported into human skeletal muscle via a carrier-mediated system that does not involve GLUT4 or GLUT1. Furthermore, under physiological conditions, fructose can significantly contribute to carbohydrate metabolism in human skeletal muscle.

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Pathophysiology of Type 2 Diabetes and Modes of Action of Therapeutic Interventions

Dagogo‐Jack¹

1997

Arch Intern Med

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At least 90% of the 12 to 15 million persons with diabetes mellitus in the United States, half of whose condition remains undiagnosed, have type 2 diabetes. Type 2 diabetes is preceded by a long period of impaired glucose tolerance, a reversible metabolic state associated with increased prevalence of macrovascular complications. Thus, at the time of diagnosis, long-term complications have developed in almost one fourth of patients. Susceptibility to type 2 diabetes requires genetic (most likely polygenic) and acquired factors, and its pathogenesis involves an interplay of progressive insulin resistance and beta-cell failure. The ideal treatment of type 2 diabetes should reverse insulin resistance and beta-cell dysfunction in most treated patients and prevent, delay, or reverse long-term complications. Current strategies are aimed at amelioration of insulin resistance (diet, exercise, weight loss, and metformin and troglitazone therapy), augmentation of insulin supply (sulfonylurea and insulin therapy), or limitation of postprandial hyperglycemia (acarbose therapy). Future therapies probably will target (1) insulin resistance, using a multifaceted approach; (2) hepatic glucose production, using gluconeogenesis inhibitors; (3) excess nonesterified fatty acid production, using lipolysis inhibitors; and (4) fat oxidation, using carnitine palmitoyltransferase I and II inhibitors. Attempts also could be made to stimulate energy expenditure and increase nonoxidative glucose disposal by means of beta 3-adrenoceptor agonists. One promising strategy is an attack on multiple pathophysiological processes by combining antidiabetic agents with disparate mechanisms of action. Thus, we now have unprecedented resources for drug therapy for diabetes, with great opportunity for innovative combinations. It is hoped that these expanded choices will provide the tools necessary for a more efficient management of type 2 diabetes and prevention of its long-term complications.

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Inhibition of Hepatic Glucose Production by SDZ 51641

Cited by 26 publications

References 20 publications

Designing Prodrugs and Bioprecursors

Designing Prodrugs and Bioprecursors

Carrier-mediated fructose uptake significantly contributes to carbohydrate metabolism in human skeletal muscle

Pathophysiology of Type 2 Diabetes and Modes of Action of Therapeutic Interventions

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