Bariatric surgery in obese patients is a highly effective method of preventing or resolving type 2 diabetes mellitus (T2DM); however, the remission rate is not the same among different surgical procedures. We compared the effects of 20% weight loss induced by laparoscopic adjustable gastric banding (LAGB) or Roux-en-Y gastric bypass (RYGB) surgery on the metabolic response to a mixed meal, insulin sensitivity, and β cell function in nondiabetic obese adults. The metabolic response to meal ingestion was markedly different after RYGB than after LAGB surgery, manifested by rapid delivery of ingested glucose into the systemic circulation, by an increase in the dynamic insulin secretion rate, and by large, early postprandial increases in plasma glucose, insulin, and glucagon-like peptide-1 concentrations in the RYGB group. However, the improvement in oral glucose tolerance, insulin sensitivity, and overall β cell function after weight loss were not different between surgical groups. Additionally, both surgical procedures resulted in a similar decrease in adipose tissue markers of inflammation. We conclude that marked weight loss itself is primarily responsible for the therapeutic effects of RYGB and LAGB on insulin sensitivity, β cell function, and oral glucose tolerance in nondiabetic obese adults.

BackgroundThere are at least two phases of β-cell death during the development of autoimmune diabetes: an initiation event that results in the release of β-cell-specific antigens, and a second, antigen-driven event in which β-cell death is mediated by the actions of T lymphocytes. In this report, the mechanisms by which the macrophage-derived cytokine interleukin (IL)-1 induces β-cell death are examined. IL-1, known to inhibit glucose-induced insulin secretion by stimulating inducible nitric oxide synthase expression and increased production of nitric oxide by β-cells, also induces β-cell death.Methods and FindingsTo ascertain the mechanisms of cell death, the effects of IL-1 and known activators of apoptosis on β-cell viability were examined. While IL-1 stimulates β-cell DNA damage, this cytokine fails to activate caspase-3 or to induce phosphatidylserine (PS) externalization; however, apoptosis inducers activate caspase-3 and the externalization of PS on β-cells. In contrast, IL-1 stimulates the release of the immunological adjuvant high mobility group box 1 protein (HMGB1; a biochemical maker of necrosis) in a nitric oxide-dependent manner, while apoptosis inducers fail to stimulate HMGB1 release. The release of HMGB1 by β-cells treated with IL-1 is not sensitive to caspase-3 inhibition, while inhibition of this caspase attenuates β-cell death in response to known inducers of apoptosis.Patient SummaryBackgroundType 1 diabetes (also called autoimmune diabetes or juvenile diabetes) is an autoimmune disease. For unknown reasons, at some point in childhood or adolescence, the body's own immune system starts attacking and destroying the insulin-producing islet cells in the pancreas. Once the majority of islet cells are destroyed, patients can no longer produce insulin to regulate their blood sugar and must depend on strict diets and insulin injections. Scientists are trying to understand the early events during the development of the disease. There are two fundamentally different kinds of cell death in cells of higher animals and humans, called apoptosis and necrosis. Apoptosis (also called programmed cell death) is an organized, clean way in which cells die without spilling their contents and without causing an inflammatory immune response. They are simply gobbled up by other cells that serve as the body's garbage collectors. Necrosis, on the other hand, is a more messy process and one that does activate the immune system and cause local inflammation.Why Was This Study Done?The scientists who did this study are interested in the early stages of islet cell death. Specifically, they wanted to know whether islet cells during the early events of autoimmune diabetes die via apoptosis or necrosis. Earlier experiments to address this question had yielded no clear-cut results.What Did the Researchers Do and Find?All the experiments for this study were done in cultured cells in the laboratory. For the most part, the researchers used rodent islet cells, and then they confirmed the crucial finding in human islet cells. They ...

Background: Thiazolidinediones may have insulin-sensitizing effects independent of the nuclear receptor PPAR␥. Results: A novel PPAR␥-sparing thiazolidinedione ameliorated insulin resistance and inflammation in obese mice. Conclusion:The insulin-sensitizing effects of thiazolidinediones are separable from the ability to bind PPAR␥. Significance: Identification of other molecular targets of thiazolidinediones may generate new therapeutics for treatment of insulin resistance and diabetes.

SUMMARY Carrier-facilitated pyruvate transport across the inner mitochondrial membrane plays an essential role in anabolic and catabolic intermediary metabolism. The mitochondrial pyruvate carrier 2 (Mpc2) is believed to be a component of the complex that facilitates mitochondrial pyruvate import. Complete MPC2 deficiency resulted in embryonic lethality in mice. However, a second mouse line expressing an N-terminal truncated MPC2 protein (Mpc2Δ16) was viable, but exhibited reduced capacity for mitochondrial pyruvate oxidation. Metabolic studies demonstrated exaggerated blood lactate concentrations after pyruvate, glucose, or insulin challenge in Mpc2Δ16 mice. Additionally, compared to WT controls, Mpc2Δ16 mice exhibited normal insulin sensitivity, but elevated blood glucose after bolus pyruvate or glucose injection. This was attributable to reduced glucose-stimulated insulin secretion and was corrected by sulfonylurea KATP channel inhibitor administration. Collectively, these data are consistent with a role for MPC2 in mitochondrial pyruvate import and suggest that Mpc2 deficiency results in defective pancreatic beta cell glucose sensing.

Monoacylglycerol acyltransferase (MGAT) enzymes convert monoacylglycerol to diacylglycerol (DAG), a lipid that has been linked to the development of hepatic insulin resistance through activation of protein kinase C (PKC). The expression of genes that encode MGAT enzymes is induced in the livers of insulin-resistant human subjects with nonalcoholic fatty liver disease, but whether MGAT activation is causal of hepatic steatosis or insulin resistance is unknown. We show that the expression of Mogat1, which encodes MGAT1, and MGAT activity are also increased in diet-induced obese (DIO) and ob/obmice. To probe the metabolic effects of MGAT1 in the livers of obese mice, we administered antisense oligonucleotides (ASOs) against Mogat1 to DIO and ob/ob mice for 3 weeks. Knockdown of Mogat1 in liver, which reduced hepatic MGAT activity, did not affect hepatic triacylglycerol content and unexpectedly increased total DAG content. Mogat1 inhibition also increased both membrane and cytosolic compartment DAG levels. However, Mogat1 ASO treatment significantly improved glucose tolerance and hepatic insulin signaling in obese mice. In summary, inactivation of hepatic MGAT activity, which is markedly increased in obese mice, improved glucose tolerance and hepatic insulin signaling independent of changes in body weight, intrahepatic DAG and TAG content, and PKC signaling.