Acylation stimulating protein stimulates insulin secretion

Acylation stimulating protein (ASP) is a hormone produced by adipocytes and is of importance for the storage of energy as fat. We examined whether ASP might also have effects on islet function. In clonal INS-1 cells, ASP dose-dependently augmented glucose-stimulated insulin secretion. The lowest effective dose of ASP at 10 mmol/l glucose was 5 micro mol/l. The effect was glucose-dependent because ASP did not increase insulin secretion at 1 mmol/l glucose but had clear effect at 10 and 20 mmol/l glucose. Similarly, ASP augmented glyceraldehyde-induced insulin secretion but the hormone did not enhance insulin secretion in response to depolarization by 20 mmol/l of KCl. ASP-induced insulin secretion was completely abolished by competitive inhibition of glucose phosphorylation by glucokinase with 5-thio-glucose and was partially inhibited by the calcium channel blocker, nifedipine, and by the protein kinase C inhibitor, GF109203. Furthermore, thapsigargin, an inhibitor of Ca(2+)-ATPase in the endoplasmic reticulum, did not affect ASP-induced insulin secretion. ASP (>5 micro mol/l) also augmented glucose-stimulated insulin secretion from islets isolated from C57BL/6J mice, and intravenous administration of ASP (50 nmol/kg) augmented the acute (1 and 5 min) insulin response to intravenous glucose (1 g/kg) in C57BL/6J mice. This was accompanied by an increased rate of glucose disposal. Minimal model analyses of data derived from the intravenous glucose tolerance test revealed that whereas ASP augmented insulin secretion, the hormone did not affect insulin sensitivity (S(I)) or glucose effectiveness (S(G)). We conclude that ASP augments glucose-stimulated insulin secretion through a direct action on the islet beta cells. The effect is dependent on glucose phosphorylation, calcium uptake and protein kinase C. Stimulation of insulin secretion by ASP in vivo results in augmented glucose disposal

Disruption of TBP-2 ameliorates insulin sensitivity and secretion without affecting obesity

Type 2 diabetes mellitus (T2DM) is characterized by defects in both insulin sensitivity and glucose-stimulated insulin secretion (GSIS) and is often accompanied by obesity. In this study, we show that disruption of thioredoxin binding protein-2 (TBP-2, also called Txnip) in obese mice (ob/ob) dramatically improves hyperglycaemia and glucose intolerance, without affecting obesity or adipocytokine concentrations. TBP-2-deficient ob/ob mice exhibited enhanced insulin sensitivity with activated insulin receptor substrate-1/Akt signalling in skeletal muscle and GSIS in islets compared with ob/ob mice. The elevation of uncoupling protein-2 (UCP-2) expression in ob/ob islets was downregulated by TBP-2 deficiency. TBP-2 overexpression suppressed glucose-induced adenosine triphosphate production, Ca2+ influx and GSIS. In β-cells, TBP-2 enhanced the expression level and transcriptional activity of UCP-2 by recruitment of peroxisome proliferator-activated receptor-γ co-activator-1α to the UCP-2 promoter. Thus, TBP-2 is a key regulatory molecule of both insulin sensitivity and GSIS in diabetes, raising the possibility that inhibition of TBP-2 may be a novel therapeutic approach for T2DM

Activation of hypothalamic ATP-sensitive K⁺ channels by the aminoguanidine carboxylate BVT.12777

Derivatives of 3-guanidinopropionic acid, such as leptin, reduce body weight in obese, diabetic mice. We have assessed whether one of these analogues, BVT.12777 activates intracellular signalling pathways in the arcuate nucleus in a manner analogous to leptin and insulin. In addition, because these hormones have been shown to activate K-ATP channels in a subset of arcuate neurones, we examined whether this channel is also a functional endpoint for BVT.12777 in the arcuate nucleus. BVT.12777 transiently increased phosphorylation of MAPK, STAT3, PKB and GSK3, in a manner identical to that observed for leptin and insulin. BVT.12777 also hyperpolarized glucose-responsive neurones by increasing the activity of K-ATP channels. The increase in K-ATP activity driven by BVT.12777 was PI3-kinase independent, unlike leptin and insulin activation of this channel, and could also be elicited in isolated patches. However, K-ATP activity induced by BVT.12777 was dependent on actin filament dynamics, both in intact neurones and isolated patches. Thus, BVT.12777 modulates arcuate neurone K-ATP activity by re-organization of the cytoskeleton, a mechanism that has also been ascribed to leptin and insulin. Consequently, BVT.12777 appears to act as a leptin and insulin mimetic with respect to at least some elements of arcuate neurone intracellular signalling and the activation of K-ATP channels. Resistance to leptin and insulin, associated with obesity has, at least in part, been postulated to be due to aberrant intracellular signalling in arcuate neurones. The data presented here indicate that it may be possible to develop drugs, which by-pass up-stream signalling components associated with adiposity hormone resistance, such as PI3-kinase, but can still induce functional outputs from arcuate neurones by targeting downstream components of the leptin and insulin signalling cascades

Missense glucokinase mutation in maturity-onset diabetes of the young and mutation screening in late-onset diabetes

We describe a codon 299 mutation in the glucokinase gene in a British pedigree with maturity-onset diabetes of the young (MODY) resulting in a substitution of glycine to arginine. One out of fifty patients diagnosed with classical late-onset type 2 diabetes mellitus was also found to have this mutation. All nine relatives of this patient who have inherited the mutation have type 2 diabetes, although six others without the mutation are also present with diabetes. The discovery that glucokinase mutations can cause MODY and was also found in ten affected members of a pedigree with type 2 diabetes in which MODY had not previously been considered indicates that diagnosis based on molecular pathology will be helpful in understanding the aetiology of type 2 diabetes