Insulin resistance:Impact on therapeutic developments in diabetes

Insulin resistance has a broad pathogenic impact affecting metabolic, cardio-renal and other disease areas. Extensive studies to dissect the mechanisms of insulin resistance have provided valuable insights to shape current clinical awareness and advance therapeutic practice. However, the development of direct interventions against insulin resistance has been hindered by its complex and highly variable presentations, especially in type 2 diabetes. Among glucose-lowering agents, metformin and thiazolidinediones provide cellular actions that counter some effects of insulin resistance: reduced glucotoxicity and weight-lowering with antidiabetic therapies also improve insulin action, except that endogenously- or exogenously-created hyperinsulinaemia may partially compromise these benefits. Increasing awareness of the pervasiveness and damaging ramifications of insulin resistance heightens the need for more specifically targeted and more effective therapies

Historical patterns of phytoplankton productivity in Lake Mead

Lake Mead was impounded in 1935 by the construction of Hoover Dam. The Colorado River was unregulated prior to then and therefore was subjected to extreme variations in flows and suspended sediment loads. Hoover Dam stabilized flows and reduced suspended sediment loads downstream, but Lake Mead still received silt-laden inflows from the upper Colorado River Basin. The Colorado River contributed 97% of the suspended sediment inputs to Lake Mead, and up to 140 x 1O6 metric tons (t) entered the reservoir in years of high runoff. Most of the sediments were deposited in the river channel and formed an extensive delta in upper Lake Mead. However, sediments were also transported into the Virgin Basin and Overton Arm by the overflow that occurred during spring runoff. The limnology of Lake Mead is thought to have been strongly influenced by this turbid overflow until Glen Canyon Dam was constructed 450 km upstream in 1963. The construction of Glen Canyon Dam and formation of Lake Powell drastically altered the characteristics of the Colorado River inflow to Lake Mead. The operation of Glen Canyon Dam stabilized flows, reduced river temperatures and cut the suspended sediment loads by 70-80%. Nitrate loads decreased initially during 1963 and 1964, then increased through 1970, but have since decreased again to a lower steady state. Phosphorus loads were decreased due to reductions in suspended sediment inputs. Lake Powell now retains 70% of the dissolved phosphorus and 96% of the total phosphorus inputs that once flowed into Lake Mead. The Colorado River still provides 85% of the inorganic nitrogen to Lake Mead, but Las Vegas Wash now contributes 60% of the phosphorus inputs. Wastewater discharges from Las Vegas Wash into Las Vegas Bay increased steadily during the post-Lake Powell period. The morphometry and hydrodynamics of Lake Mead are such that the Las Vegas Wash inflow is confined to the Lower Basin where historically it has elevated phytoplankton productivity. However, high phosphorus loading and productivity have resulted in decreases in nitrate concentrations, and the Las Vegas Bay and parts of Boulder Basin have become nitrogen limited since 1972. A unique situation has therefore developed in Lake Mead in that the Upper Basin has become more phosphorus limited and the Lower Basin more nitrogen limited since the formation of Lake Powell. Paulson and Baker theorized that these changes in nutrient loading and limitation must also have been accompanied by decreases in reservoir-wide productivity. There is some evidence for this hypothesis in apparent improvements in water quality of Las Vegas Bay since 1968. Chlorophyll-a concentrations in the inner Las Vegas Bay have decreased considerably since the first measurements were made in 1968 and during the period of the Lake Mead Monitoring Program. Improvements in water quality of the bay have confounded efforts to establish water quality standards on effluent discharges and are contrary to predictions made in the early 1970s that water quality would continue to degrade with increased phosphorus loading. The decline in the largemouth bass fishery documented by the Nevada Department of Wildlife could also be a symptom of lower productivity in Lake Mead. In this paper, the hypothesis that algal productivity has declined in Lake Mead as a result of impoundment of Lake Powell is evaluated. The chemical status of six stations in the Upper and Lower Basins of Lake Mead is analyzed and current and past rates of organic carbon and phosphorus sedimentation are calculated. The relationship between algal productivity and accretion of organic carbon in sediment is determined, and this is used to construct a historical record of algal productivity for Lake Mead

Z', new fermions and flavor changing processes, constraints on E6_6 models from μ\mu --> eee

We study a new class of flavor changing interactions, which can arise in models based on extended gauge groups (rank $>$4) when new charged fermions are present together with a new neutral gauge boson. We discuss the cases in which the flavor changing couplings in the new neutral current coupled to the $Z^\prime$ are theoretically expected to be large, implying that the observed suppression of neutral flavor changing transitions must be provided by heavy $Z^\prime$ masses together with small $Z$-$Z^\prime$ mixing angles. Concentrating on E$_6$ models, we show how the tight experimental limit on $\mu \rightarrow eee$ implies serious constraints on the $Z^\prime$ mass and mixing angle. We conclude that if the value of the flavor changing parameters is assumed to lie in a theoretically natural range, in most cases the presence of a $Z^\prime$ much lighter than 1 TeV is unlikely.Comment: plain tex, 22 pages + 2 pages figures in PostScript (appended after `\bye'), UM-TH 92-1

Chemical and biological structure of Lake Mead sediments

Lake Mead has undergone a serious decline since Glen Canyon Dam was constructed 450 km upstream in 1963. State fisheries management agencies are concerned that the decline was caused by water level fluctuations and more severe drawdowns during the bass spawning season, when the operation of Hoover Dam was altered during the post-Lake Powell period. The construction of Glen Canyon Dam and formation of Lake Powell in 1963 drastically altered the natural discharge and temperature cycles and decreased suspended sediment and nutrient loading in the Colorado River inflow to Lake Mead. Recent studies indicate that these changes in nutrient loading have caused a decrease in the fertility and productivity of Lake Mead, and this, in turn, could have contributed to the decline in the largemouth bass fishery. The Water and Power Resources Service initiated a detailed investigation of the chemical and biological properties of Lake Mead sediments in order to: (i) resolve questions regarding historical changes in fertility and productivity of the reservoir, (ii) better assess the cause(s) for the decline in the largemouth bass fishery and (iii) predict future impacts associated with the proposed power modifications to Hoover Dam and operation of pump-storage hydroelectric units. Sediment cores were collected with a Vibra-corer by a commercial, oceanographic drilling firm in non-delta areas of the inner Las Vegas Bay, middle Las Vegas Bay, Boulder Basin, Virgin Basin, Bonelli Bay and the Overton Arm. Sediments were dated by 137Cs assays and analyzed for organic content, organic carbon, total nitrogen, total phosphorus, organic phosphorus, NaOH -extractable phosphorus, calcium carbonate, bulk density and water of hydration. Individual-basin (Lower and Upper Basins) and reservoir-wide sedimentation rates were estimated for autochthonous and allochthonous organic carbon and calcium carbonate, nitrogen and phosphorus and dry weight during three periods (\u3c1954, 1955-1962, \u3c1963) of Lake Mead history. Autochthonous organic carbon sedimentation in the post-Lake Powell period was used with recent measurements of phytoplankton productivity to develop a regression model for predicting historic rates of productivity. Reservoir-wide sedimentation rates and productivity in Lake Mead were relatively low during the period prior to 1954. Increased nutrient loading in years of high runoff during the 1955-1962 period caused a sharp increase in reservoir-wide sedimentation and productivity. The Upper Basin was especially productive during this period due to large inputs of suspended sediments and phosphorus. Phosphorus loading in the Colorado River decreased by over 90% in the post-Lake Powell period and caused a severe reduction in productivity in the Upper Basin. Increased phosphorus loading from the discharges of secondary-treated sewage effluents into Las Vegas Bay, combined with relatively high nitrogen loading from the Colorado River, elevated productivity in the Lower Basin. However, this was not sufficient to offset reductions that occurred in the Upper Basin, and reservoir-wide productivity decreased by 77% during the post-Lake Powell period and was equivalent to productivity in the period prior to 1954. This decline in productivity was accompanied by a decrease in abundance of zooplankton, which comprise the principal food source for largemouth bass fry. Survival of bass fry appears to have decreased in the face of low zooplankton abundance, and this may be the cause for the historic decline of the largemouth bass fishery. The fertility and productivity of Lake Mead could be improved to benefit the bass fishery if: (i) Hoover Dam were operated from a surface, rather than deep, discharge, (ii) pump-storage hydroelectric units were operated to recirculate nutrients in the reservoir, (iii) nutrient loading from Las Vegas Wash were maintained at current levels or allowed to increase with some type of diffuser system to minimize the point source problem in the inner Las Vegas Bay

α/β-Hydrolase Domain 6 Deletion Induces Adipose Browning and Prevents Obesity and Type 2 Diabetes

SummarySuppression of α/β-domain hydrolase-6 (ABHD6), a monoacylglycerol (MAG) hydrolase, promotes glucose-stimulated insulin secretion by pancreatic β cells. We report here that high-fat-diet-fed ABHD6-KO mice show modestly reduced food intake, decreased body weight gain and glycemia, improved glucose tolerance and insulin sensitivity, and enhanced locomotor activity. ABHD6-KO mice also show increased energy expenditure, cold-induced thermogenesis, brown adipose UCP1 expression, fatty acid oxidation, and white adipose browning. Adipose browning and cold-induced thermogenesis are replicated by the ABHD6 inhibitor WWL70 and by antisense oligonucleotides targeting ABHD6. Our evidence suggests that one mechanism by which the lipolysis derived 1-MAG signals intrinsic and cell-autonomous adipose browning is via PPARα and PPARγ activation, and that ABHD6 regulates adipose browning by controlling signal competent 1-MAG levels. Thus, ABHD6 regulates energy homeostasis, brown adipose function, and white adipose browning and is a potential therapeutic target for obesity and type 2 diabetes

Regulation of lipolytic activity by long-chain acyl-coenzyme A in islets and adipocytes

Intracellular lipolysis is a major pathway of lipid metabolism that has roles, not only in the provision of free fatty acids as energy substrate, but also in intracellular signal transduction. The latter is likely to be particularly important in the regulation of insulin secretion from islet beta-cells. The mechanisms by which lipolysis is regulated in different tissues is, therefore, of considerable interest. Here, the effects of long-chain acyl-CoA esters (LC-CoA) on lipase activity in islets and adipocytes were compared. Palmitoyl-CoA (Pal-CoA, 1-10 mu M) stimulated lipase activity in islets from both normal and hormone-sensitive lipase (HSL)-null mice and in phosphatase-treated islets, indicating that the stimulatory effect was neither on HSL nor phosphorylation dependent. In contrast, we reproduced the previously published observations showing inhibition of HSL activity by LC-CoA in adipocytes. The inhibitory effect of LC-CoA on adipocyte HSL was dependent on phosphorylation and enhanced by acyl-CoA-binding protein (ACBP). In contrast, the stimulatory effect on islet lipase activity was blocked by ACBP, presumably due to binding and sequestration of LC-CoA. These data suggest the following intertissue relationship between islets and adipocytes with respect to fatty acid metabolism, LC-CoA signaling, and lipolysis. Elevated LC-CoA in islets stimulates lipolysis to generate a signal to increase insulin secretion, whereas elevated LC-CoA in adipocytes inhibits lipolysis. Together, these opposite actions of LC-CoA lower circulating fat by inhibiting its release from adipocytes and promoting fat storage via insulin action

Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling.

Aims/hypothesis The aim of this study was to determine the role of fatty acid signalling in islet beta cell compensation for insulin resistance in the Zucker fatty fa/fa (ZF) rat, a genetic model of severe obesity, hyperlipidaemia and insulin resistance that does not develop diabetes. Materials and methods NEFA augmentation of insulin secretion and fatty acid metabolism were studied in isolated islets from ZF and Zucker lean (ZL) control rats. Results Exogenous palmitate markedly potentiated glucose-stimulated insulin secretion (GSIS) in ZF islets, allowing robust secretion at physiological glucose levels (5-8 mmol/l). Exogenous palmitate also synergised with glucagon-like peptide-1 and the cyclic AMP-raising agent forskolin to enhance GSIS in ZF islets only. In assessing islet fatty acid metabolism, we found increased glucose-responsive palmitate esterification and lipolysis processes in ZF islets, suggestive of enhanced triglyceride-fatty acid cycling. Interruption of glucose-stimulated lipolysis by the lipase inhibitor Orlistat (tetrahydrolipstatin) blunted palmitate-augmented GSIS in ZF islets. Fatty acid oxidation was also higher at intermediate glucose levels in ZF islets and steatotic triglyceride accumulation was absent. Conclusions/interpreation The results highlight the potential importance of NEFA and glucoincretin enhancement of insulin secretion in beta cell compensation for insulin resistance. We propose that coordinated glucose-responsive fatty acid esterification and lipolysis processes, suggestive of triglyceride-fatty acid cycling, play a role in the coupling mechanisms of glucose-induced insulin secretion as well as in beta cell compensation and the hypersecretion of insulin in obesity

Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells

Diabetes is a global health problem caused primarily by the inability of pancreatic β-cells to secrete adequate levels of insulin. The molecular mechanisms underlying the progressive failure of β-cells to respond to glucose in type-2 diabetes remain unresolved. Using a combination of transcriptomics and proteomics, we find significant dysregulation of major metabolic pathways in islets of diabetic βV59M mice, a non-obese, eulipidaemic diabetes model. Multiple genes/proteins involved in glycolysis/gluconeogenesis are upregulated, whereas those involved in oxidative phosphorylation are downregulated. In isolated islets, glucose-induced increases in NADH and ATP are impaired and both oxidative and glycolytic glucose metabolism are reduced. INS-1 β-cells cultured chronically at high glucose show similar changes in protein expression and reduced glucose-stimulated oxygen consumption: targeted metabolomics reveals impaired metabolism. These data indicate hyperglycaemia induces metabolic changes in β-cells that markedly reduce mitochondrial metabolism and ATP synthesis. We propose this underlies the progressive failure of β-cells in diabetes.Peer reviewe

Carriers of Loss-of-Function Mutations in ABCA1 Display Pancreatic β-Cell Dysfunction

OBJECTIVE: Abnormal cellular cholesterol handling in islets may contribute to beta-cell dysfunction in type 2 diabetes. beta-Cell deficiency for the ATP binding cassette transporter A1 (ABCA1), which mediates the efflux of cellular cholesterol, leads to altered intracellular cholesterol homeostasis and impaired insulin secretion in mice. We aimed to assess the impact of ABCA1 dysfunction on glucose homeostasis in humans. RESEARCH DESIGN AND METHODS: In heterozygous carriers of disruptive mutations in ABCA1 and family-based noncarriers of similar age, sex, and BMI, we performed oral glucose tolerance tests (OGTTs) (n = 15 vs. 14) and hyperglycemic clamps (n = 8 vs. 8). RESULTS: HDL cholesterol levels in carriers were less than half those in noncarriers, but LDL cholesterol levels did not differ. Although fasting plasma glucose was similar between groups, glucose curves after an OGTT were mildly higher in carriers than in noncarriers. During hyperglycemic clamps, carriers demonstrated lower first-phase insulin secretion than noncarriers but no difference in insulin sensitivity. The disposition index (a measure of beta-cell function adjusted for insulin sensitivity) of the carriers was significantly reduced in ABCA1 heterozygotes. CONCLUSIONS: Carriers of loss-of-function mutations in ABCA1 show impaired insulin secretion without insulin resistance. Our data provide evidence that ABCA1 is important for normal beta-cell function in human