Research Notes: Insulin

Status in PWS

• Generally lower than expected, especially in those that are significantly overweight.
  • Fasting insulin level was significantly lower in the obese PWS subjects compared with subjects with simple obesity, and insulin sensitivity (QUICKI) was significantly higher in PWS subjects with obesity. (Talebizadeh 2005)
  • Before [GH] treatment, insulin levels in children with PWS were lower (p < 0.01) than in healthy obese children. During GH treatment, fasting insulin levels increased in children with PWS (p < 0.001). Glucose levels were similar for PWS and obese children before treatment. Children with PWS showed a slow glucose disappearance rate (k = 1.7%) which deteriorated (k = 1.3%, p < 0.001) during GH treatment. HbA1c and fasting glucose levels remained normal. (Lindgren 1999)

What it does

• "Pessin's group has shown that the promoter of the GLUT4 gene contains a MEF2 binding site that is essential for activation of transcription and that MEF2A binds to this element as a MEF2A-MEF2D heterodimer. They also found that insulin deficiency, which results in a marked decrease of GLUT4 in insulin-sensitive tissues, causes a selective down-regulation of MEF2A. The addition of MEF2A to nuclear extracts from insulin-deficient, diabetic rat muscle reversed a reduction in binding to the MEF2 element, leading Thai et al. to conclude that MEF2A is necessary for expression of GLUT4 in striated muscle and is responsible for hormonal/metabolic regulation of the GLUT4 gene." [ cite ] (See also NRF-1)
• Stimulates long-chain fatty acid (LCFA) esterification in skeletal muscle and cardiac myocytes. (cite)

Can J Physiol Pharmacol. 2007 Mar-Apr.
Insulin withdrawal induces apoptosis via a free radical-mediated mechanism.
Ricci C, Pastukh V, Mozaffari M, Schaffer SW.
University of South Alabama, College of Medicine, Department of Pharmacology, Mobile, AL, USA.

Diabetes is characterized by chronic hyperglycemia as well as insulin deficiency or resistance. However, the majority of research has focused on the consequences of hyperglycemia in development of diabetic complications, whereas the effects of insulin deficiency or resistance, independent of hyperglycemia, have received little attention. Since insulin is a well known cytoprotective factor, we hypothesized that its removal could significantly impact cell survival. To examine this possibility, cultured neonatal cardiomyocytes were subjected to insulin withdrawal and examined for apoptosis. Insulin deficient cells succumbed to apoptosis, an effect associated with impaired PI3-kinase/Akt signaling and reduction in the Bcl-2 to Bax ratio. Perhaps more importantly, superoxide generation was altered in cells subjected to insulin withdrawal. Removal of insulin caused a significant increase in reactive oxygen species production and resulted in oxidative mitochondrial DNA damage the latter effect is associated with impaired expression of mitochondrially encoded proteins that make up the electron transport chain. Significantly, the effects of insulin withdrawal could be mitigated by treatment with the antioxidant, Tiron. Collectively, these data demonstrate that insulin deficiency leads to apoptosis and suggest a role for oxidative mitochondrial DNA damage in this cascade.

Biochem Soc Trans. 2006 Nov.
Regulation of insulin secretion by uncoupling protein.
Chan CB, Kashemsant N.
Department of Biomedical Sciences, University of Prince Edward Island, 550 University Avenue, Charlottetown, PE, Canada.

UCPs (uncoupling proteins) can regulate cellular ATP production by uncoupling oxidative phosphorylation. UCP2 is expressed in islet beta-cells and its induction reduces glucose-stimulated insulin secretion. Under physiological conditions, superoxide, formed as a by-product of respiration, activates UCP2. This leads to reduced ATP production, which impairs closure of the ATP-dependent K+ channels to prevent insulin secretion. It is suggested that the physiological role of UCP2 is to prevent excessive superoxide generation through a feedback loop. UCP2 induction may also alter fatty acid metabolism by altering NAD/NADH or by facilitating cycling of fatty acid anions. Recently, UCP2 has been proposed to keep insulin secretion low during starvation, a function under the control of the transcription co-repressor, surtuin-1, which has been shown to bind to the UCP2 promoter. Pathological UCP2 expression or activation may suppress glucose-stimulated insulin secretion to the extent that diabetes onset is hastened. In ob/ob mice, induction of UCP2 at age 5 weeks precedes development of insulin secretion defects and hyperglycaemia. Activating protein kinase A-dependent pathways can normalize insulin secretion in UCP2-overexpressing islets. Conversely, lowering UCP2 expression may promote increased insulin secretion. UCP2 knockout mice were protected from the diabetogenic effects of a high-fat diet and their islets exhibited increased sensitivity to glucose and elevated ATP/ADP. These results support a role for UCP2 as a gene contributing to the pathogenesis of Type 2 diabetes.