Stimulation of proinsulin biosynthesis and insulin release by pyruvate and lactate

Abstract

Increasing concentrations of pyruvate failed to stimulate proinsulin biosynthesis and insulin release in freshly isolated islets. Glycolytic flux (3H2O from [5-3H]glucose) decreased by 80-85%, but decarboxylation of [1(-14)C]pyruvate was unaffected in islets tested immediately after alloxan exposure. This strongly suggested that in freshly isolated islets, beta-cells, in relation to other islet cells, hardly contribute to the decarboxylation of pyruvate. Non-alloxan-treated cultured islets decarboxylated 2-2.5 times as much pyruvate as did alloxan-treated islets cultured for 15-18h. Thus the contribution of beta-cells to the metabolism of pyruvate after culturing markedly increased. Concomitantly beta-cells became responsive to pyruvate. At 20mM-pyruvate, release of prelabelled proinsulin and insulin and incorporation of [3H]leucine into proinsulin reached values approximately half of those obtained with 20mM-glucose. Lactate was as effective as pyruvate in inducing responses in cultured islets. The experiments indicate that a critical degree of substrate utilization is necessary for the generation of signals for insulin release and proinsulin biosynthesis.

A distinct difference in the metabolic stimulus–response coupling pathways for regulating proinsulin biosynthesis and insulin secretion that lies at the level of a requirement for fatty acyl moieties

“…Glucose-induced insulin secretion and proinsulin biosynthesis share a common requirement for glycolysis [7], as indicated by inhibition with mannoheptulose and lack of any effect of nonmetabolizable glucose analogues (Figure 1) [5,7]. Pyruvate, the end product of glycolysis and a substrate for the citric acid cycle and oxidative mitochondrial metabolism [9,25], modestly increases proinsulin biosynthesis and insulin secretion in cultured pancreatic islets [33]. In MIN6 cells, pyruvate stimulated both proinsulin biosynthesis and insulin secretion as effectively as glucose in MIN6 cells.…”

“…Pyruvate entry into the mitochondria provides increased levels of intermediates for the citric acid cycle (i.e. anaplerosis) via pyruvate carboxylase production of oxaloacetate and production of acetyl-CoA by pyruvate dehydrogenase [8,33]. The notion that increased anaplerosis leads to generation of secondary signals for stimulation of insulin release and biosynthesis [8] is supported by the observation that α-KIC, in the presence of glutamine, was as effective as glucose and pyruvate in providing a stimulus for both proinsulin biosynthesis and insulin secretion in MIN6 cells, as found in islets [8,26].…”

2-Oxocarboxylic acids and function of pancreatic islets in obese–hyperglycaemic mice. Insulin secretion in relation to 45Ca uptake and metabolism

“…found for rat islets (30mM) (Sener et al, 1978) and the extremely high rates of 300 mmol/h per kg dry wt. found for rat islets (15 mM) by Jain et al (1978). We adopted a special technique for arresting metabolism of oxocarboxylic acids in small tissue samples (see the Experimental section).…”

Influence of [alpha]-ketoisocaproate on growth, carcass composition and protein metabolism in cattle and sheep

“…Hormones that are known to alter and control growth and metabolism have been demonstrated to be affected by KIC. Insulin secretion has been shown by several researchers to be increased by KIC (Grill, 1982;Hutton and Malaisse, 1977;Biden and Taylor, 1983;Hutton et al, 1974;Jain et al, 1978;Zawalich et al, 1978;Leclercq-Meyer et al, 1979a, b;Zawalich et al, 1979;Leclercq-Meyer et al, 1981;Lebrun et al, 1982;Lenzen et al, 1982;. Conversely, KIC has been demonstrated to inhibit glucagon secretion (Leclercq-Meyer et al,, 1979a, b;.…”