Pioglitazone Decreases Fasting and Postprandial Endogenous Glucose Production in Proportion to Decrease in Hepatic Triglyceride Content

Balasubramanian, Ravikumar; Gerrard, J; Man, Chiara Dalla; Firbank, Michael; Lane, Annette; English, Philip; Cobelli, Claudio; Taylor, Roy

doi:10.2337/db07-1828

Cited by 66 publications

(68 citation statements)

References 58 publications

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“…Hepatic insulin sensitivity is known to be impaired by increased liver triacylglycerol (17,29). Short-term carbohydrate overfeeding can induce liver triacylglycerol accumulation (30), and furthermore, weight loss with a consequent reduction in liver fat is associated with improvements in insulin sensitivity and fasting plasma glucose levels (16,31). The current study demonstrates a greater reduction in liver fat content post-RYGB in individuals with T2DM compared with NGT, with normalization of hepatic insulin sensitivity.…”

Section: Discussionmentioning

confidence: 48%

“…Fasting plasma glucose concentration is determined by the rate of hepatic glucose production (16), which in turn is controlled by insulin (28). Hepatic insulin sensitivity is known to be impaired by increased liver triacylglycerol (17,29).…”

Section: Discussionmentioning

confidence: 99%

“…[6969-2H] glucose (98% enriched; Cambridge Isotope Laboratories, Andover, MA) was used to determine hepatic glucose production (16). Basal rates were calculated during the last 30 min of the 150-min basal period.…”

Section: Hepatic Glucose Production and Insulin Sensitivitymentioning

confidence: 99%

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Weight Loss Decreases Excess Pancreatic Triacylglycerol Specifically in Type 2 Diabetes

et al. 2015

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OBJECTIVEThis study determined whether the decrease in pancreatic triacylglycerol during weight loss in type 2 diabetes mellitus (T2DM) is simply reflective of whole-body fat or specific to diabetes and associated with the simultaneous recovery of insulin secretory function. RESEARCH DESIGN AND METHODSIndividuals listed for gastric bypass surgery who had T2DM or normal glucose tolerance (NGT) matched for age, weight, and sex were studied before and 8 weeks after surgery. Pancreas and liver triacylglycerol were quantified using inphase, out-of-phase MRI. Also measured were the first-phase insulin response to a stepped intravenous glucose infusion, hepatic insulin sensitivity, and glycemic and incretin responses to a semisolid test meal. RESULTSWeight loss after surgery was similar (NGT: 12.8 6 0.8% and T2DM: 13.6 6 0.7%) as was the change in fat mass (56.7 6 3.3 to 45.4 6 2.3 vs. 56.6 6 2.4 to 43.0 6 2.4 kg). Pancreatic triacylglycerol did not change in NGT (5.1 6 0.2 to 5.5 6 0.4%) but decreased in the group with T2DM (6.6 6 0.5 to 5.4 6 0.4%; P = 0.007). Firstphase insulin response to a stepped intravenous glucose infusion did not change in (P = 0.005). No differential effect of incretin secretion was observed after gastric bypass, with more rapid glucose absorption bringing about equivalently enhanced glucagon-like peptide 1 secretion in the two groups. CONCLUSIONSThe fall in intrapancreatic triacylglycerol in T2DM, which occurs during weight loss, is associated with the condition itself rather than decreased total body fat.Type 2 diabetes mellitus (T2DM) has reached epidemic proportions, affecting 9.2% of the U.S. population and costing the country $322 billion in 2012 (1). The condition is widely recognized to be caused by a combination of insulin resistance and insulin secretory failure. However, insulin resistance alone does not cause blood glucose to rise (2), and T2DM occurs only when the acute insulin response of pancreatic b-cells becomes inadequate to control blood glucose (3,4). The etiologic process underlying this is still uncertain. Inhibition by excess intracellular fatty acids or their metabolites is a potential mechanism (5-7). We have previously demonstrated in people with T2DM that weight loss over 8 weeks can normalize the acute insulin response and

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Section: Discussionmentioning

confidence: 48%

Section: Discussionmentioning

confidence: 99%

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Weight Loss Decreases Excess Pancreatic Triacylglycerol Specifically in Type 2 Diabetes

et al. 2015

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“…Because hepatic triglyceride has been reported to be a significant independent predictor of fasting endogenous glucose production (19,20) and platensimycin reduced liver TG levels after chronic dosing, we next examined the effect of PTM treatment on plasma glucose levels of overtly diabetic db/db mice. Mice were orally gavaged with platensimycin twice daily for 2 wk at doses of 3 or 30 mpk.…”

Section: Platensimycin Causes a Net Reduction Of Liver Triglyceride Lmentioning

confidence: 99%

Antidiabetic and antisteatotic effects of the selective fatty acid synthase (FAS) inhibitor platensimycin in mouse models of diabetes

Wu¹,

Singh

Wang³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

140

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Platensimycin (PTM) is a recently discovered broad-spectrum antibiotic produced by Streptomyces platensis. It acts by selectively inhibiting the elongation-condensing enzyme FabF of the fatty acid biosynthesis pathway in bacteria. We report here that PTM is also a potent and highly selective inhibitor of mammalian fatty acid synthase. In contrast to two agents, C75 and cerulenin, that are widely used as inhibitors of mammalian fatty acid synthase, platensimycin specifically inhibits fatty acid synthesis but not sterol synthesis in rat primary hepatocytes. PTM preferentially concentrates in liver when administered orally to mice and potently inhibits hepatic de novo lipogenesis, reduces fatty acid oxidation, and increases glucose oxidation. Chronic administration of platensimycin led to a net reduction in liver triglyceride levels and improved insulin sensitivity in db/+ mice fed a high-fructose diet. PTM also reduced ambient glucose levels in db/db mice. These results provide pharmacological proof of concept of inhibiting fatty acid synthase for the treatment of diabetes and related metabolic disorders in animal models.

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“…Third, thiazolidinediones increase insulin sensitivity and decrease insulin secretion rates. These agents bring about a 54% decrease in liver fat content [32,33]. Finally, use of subcutaneous insulin in type 2 diabetes brings about decreases in portal insulin delivery and liver fat [34].…”

Section: The Effect Of Modifying Plasma Insulin Levels On Fatty Livermentioning

confidence: 99%

Pathogenesis of type 2 diabetes: tracing the reverse route from cure to cause

2008

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The metabolic abnormalities of type 2 diabetes can be reversed reproducibly by bariatric surgery. By quantifying the major pathophysiological abnormalities in insulin secretion and insulin action after surgery, the sequence of events leading to restoration of normal metabolism can be defined. Liver fat levels fall within days and normal hepatic insulin sensitivity is restored. Simultaneously, plasma glucose levels return towards normal. Insulin sensitivity of muscle remains abnormal, at least over the weeks and months after bariatric surgery. The effect of the surgery is explicable solely in terms of energy restriction. By combining this information with prospective observation of the changes immediately preceding the onset of type 2 diabetes, a clear picture emerges. Insulin resistance in muscle, caused by inherited and environmental factors, facilitates the development of fatty liver during positive energy balance. Once established, the increased insulin secretion required to maintain plasma glucose levels will further increase liver fat deposition. Fatty liver causes resistance to insulin suppression of hepatic glucose output as well as raised plasma triacylglycerol. Exposure of beta cells to increased levels of fatty acids, derived from circulating and locally deposited triacylglycerol, suppresses glucose-mediated insulin secretion. This is reversible initially, but eventually becomes permanent. The essential time sequence of the pathogenesis of type 2 diabetes is now evident. Muscle insulin resistance determines the rate at which fatty liver progresses, and ectopic fat deposition in liver and islet underlies the related dynamic defects of hepatic insulin resistance and beta cell dysfunction. These defects are capable of dramatic reversal under hypoenergetic feeding conditions, completely in early diabetes and to a worthwhile extent in more established disease.

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Pioglitazone Decreases Fasting and Postprandial Endogenous Glucose Production in Proportion to Decrease in Hepatic Triglyceride Content

Cited by 66 publications

References 58 publications

Weight Loss Decreases Excess Pancreatic Triacylglycerol Specifically in Type 2 Diabetes

Weight Loss Decreases Excess Pancreatic Triacylglycerol Specifically in Type 2 Diabetes

Antidiabetic and antisteatotic effects of the selective fatty acid synthase (FAS) inhibitor platensimycin in mouse models of diabetes

Pathogenesis of type 2 diabetes: tracing the reverse route from cure to cause

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