Given the pleiotropic effect of eicosapentaenoic acid (EPA), it is interesting to know whether EPA is capable of improving obesity. Here we examined the anti-obesity effect of EPA in mice with two distinct models of obesity.

Research Design and Methods:

Male C57BL/6J mice were fed high-fat/high-sucrose diet (HF/HS, 25.0wt% fat, 32.5wt% sucrose) (HF/HS group) or high-fat diet (HF, 38.1wt% fat, 8.5wt% sucrose) (HF group) for 4-20 weeks. Five% EPA was administered by partially substituting EPA for fat in HF/HS+EPA and HF+EPA groups.

Results:

Both HF/HS and HF groups similarly develop obesity. EPA treatment strongly suppresses body weight gain and obesity-related hyperglycemia and insulin hyperinsulinemia in HF/HS-fed mice (HF/HS+EPA group), where hepatic triglyceride content and lipogenic enzymes are increased. There is no appreciable effect of EPA on body weight in HF-fed mice (HF+EPA group) without enhanced expression of hepatic lipogenic enzymes. Moreover, EPA is capable of reducing hepatic triglyceride secretion and changing VLDL fatty acid composition in HF/HS group. By indirect calorimetry analysis, we also found that EPA is capable of increasing energy consumption in HF/HS+EPA group.

Conclusions:

This study is the first demonstration that the anti-obesity effect of EPA in HF/HS-induced obesity is associated with the suppression of hepatic lipogenesis and steatosis. Because the metabolic syndrome is often associated with hepatic lipogenesis and steatosis, the data of this study suggest that EPA is suited for the treatment of the metabolic syndrome.

Cerebral microvascular disease associated with Type 2 diabetes may exacerbate the effects of ageing on cognitive function. With considerable homology existing between the retinal and cerebral microcirculations, a hypothesized association between diabetic retinopathy and cognitive decline was examined in older people with Type 2 diabetes.

Research Design and Methods—

In the population-based Edinburgh Type 2 Diabetes Study, 1046 men and women aged 60 to 75 years with Type 2 diabetes, underwent standard 7-field binocular digital retinal photography and a battery of 7 cognitive function tests. A general cognitive ability score (g) was generated by principal components analysis. The Mill-Hill Vocabulary Scale was used to estimate premorbid cognitive ability. Diabetic retinopathy was graded using a modification of the Early Treatment of Diabetic Retinopathy Scale.

Results—

After age and sex adjustment, a significant relationship was observed with increasing severity of diabetic retinopathy (none, mild, and moderate-severe) for most cognitive measures. Participants with moderate to severe retinopathy had worst performances on ‘g’ and on the individual tests. There was a significant interaction between gender and retinopathy for ‘g’. In males, the associations of retinopathy with g, (and with tests of verbal fluency, mental flexibility and processing speed but not memory and non-verbal reasoning) persisted (p<0.05) when further adjusted for vocabulary (to estimate lifetime cognitive decline), depression, socio-demographic characteristics, cardiovascular risk factors and macrovascular disease.

Conclusions—

Diabetic retinopathy was independently associated with estimated lifetime cognitive decline in older men with Type 2 diabetes, supporting the hypothesis that cerebral microvascular disease may contribute to their observed accelerated age-related cognitive decline. A gender interaction with stronger findings in men requires further confirmation.

Retinoid X receptors (RXRs) are members of the nuclear hormone receptor superfamily and are thought to be key regulators in differentiation, cellular growth, and gene expression. Although several experiments using pancreatic β-cell lines have shown that the ligands of nuclear hormone receptors modulate insulin secretion, it is not clear whether RXRs have any role in insulin secretion.

Research design and methods-

To elucidate the function of RXRs in pancreatic β-cells, we generated a double-transgenic mouse in which a dominant-negative form of RXRβ was inducibly expressed in pancreatic β-cells using the Tet-On system. We also established a pancreatic β-cell line from an insulinoma caused by the β-cell-specific expression of simian virus 40 T antigen in the above transgenic mouse.

Results-

In the transgenic mouse, expression of the dominant-negative RXR enhanced the insulin secretion with high glucose stimulation. In the pancreatic β-cell line, the suppression of RXRs also enhanced glucose-stimulated insulin secretion at a high glucose concentration, while 9-cis-retinoic acid, an RXR agonist, repressed it. High-density oligonucleotide microarray analysis showed that expression of the dominant-negative RXR affected the expression levels of a number of genes, some of which have been implicated in the function and/or differentiation of β-cells.

Conclusions-

These results suggest that endogenous RXR negatively regulates the glucose-stimulated insulin secretion. Given these findings, we propose that the modulation of endogenous RXR in β-cells may be a new therapeutic approach for improving impaired insulin secretion in type 2 diabetes mellitus.

Several clinical studies have shown the benefits of renin-angiotensin system (RAS) blockade in the development of diabetes and a local RAS has been identified in pancreatic islets. Angiotensin-I Converting Enzyme (ACE) 2, a new component of the RAS has been identified in the pancreas but its role in β-cells function remains unknown. Using 8 and 16-week old obese diabetic (db/db) mice, we examined the ability of ACE2 to alter pancreatic β-cell function and thereby modulate hyperglycemia.

Research design and methods—

Both db/db and non-diabetic lean control (db/m) mice were infected with an adenovirus expressing human ACE2 (Ad-hACE2-eGFP) or the control virus (Ad-eGFP), via injection into the pancreas. Glycemia and β-cell function were assessed 1 week later, at the peak of viral expression.

Results—

In 8-week old db/db mice, Ad-hACE2-eGFP significantly improved fasting glycemia, enhanced intra-peritoneal (IP) glucose tolerance, increased islet insulin content and β-cell proliferation and reduced β-cell apoptosis when compared to Ad-eGFP. ACE2 over-expression had no effect on insulin sensitivity in comparison to Ad-eGFP treatment in diabetic mice. Angiotensin-(1-7) receptor blockade by D-Ala⁷-Ang-(1-7) prevented the ACE2-mediated improvements in IP glucose tolerance, glycemia and islet function and also impaired insulin sensitivity in both Ad-hACE2-eGFP and Ad-eGFP treated db/db mice. D-Ala⁷-Ang-(1-7) had no effect on db/m mice. In 16-week old diabetic mice, Ad-hACE2-eGFP treatment improved fasting blood glucose but had no effect on any of the other parameters.

Conclusions—

These findings identify ACE2 as a novel target for the prevention of β-cell dysfunction and apoptosis occurring in type 2 diabetes.

Given the pleiotropic effect of eicosapentaenoic acid (EPA), it is interesting to know whether EPA is capable of improving obesity. Here we examined the anti-obesity effect of EPA in mice with two distinct models of obesity.

Research Design and Methods:

Male C57BL/6J mice were fed high-fat/high-sucrose diet (HF/HS, 25.0wt% fat, 32.5wt% sucrose) (HF/HS group) or high-fat diet (HF, 38.1wt% fat, 8.5wt% sucrose) (HF group) for 4-20 weeks. Five% EPA was administered by partially substituting EPA for fat in HF/HS+EPA and HF+EPA groups.

Results:

Both HF/HS and HF groups similarly develop obesity. EPA treatment strongly suppresses body weight gain and obesity-related hyperglycemia and insulin hyperinsulinemia in HF/HS-fed mice (HF/HS+EPA group), where hepatic triglyceride content and lipogenic enzymes are increased. There is no appreciable effect of EPA on body weight in HF-fed mice (HF+EPA group) without enhanced expression of hepatic lipogenic enzymes. Moreover, EPA is capable of reducing hepatic triglyceride secretion and changing VLDL fatty acid composition in HF/HS group. By indirect calorimetry analysis, we also found that EPA is capable of increasing energy consumption in HF/HS+EPA group.

Conclusions:

This study is the first demonstration that the anti-obesity effect of EPA in HF/HS-induced obesity is associated with the suppression of hepatic lipogenesis and steatosis. Because the metabolic syndrome is often associated with hepatic lipogenesis and steatosis, the data of this study suggest that EPA is suited for the treatment of the metabolic syndrome.

Skeletal muscle protein metabolism is resistant to the anabolic action of insulin in healthy, non-diabetic older adults. This defect is associated with impaired insulin-induced vasodilation and mTORC1 signaling. We hypothesized that, in older subjects, pharmacological restoration of insulin-induced capillary recruitment would improve the response of muscle protein synthesis and anabolism to insulin.

Research Design and Methods.

Twelve healthy, non-diabetic older subjects (71±2 yrs) were randomized to two groups. Subjects were studied at baseline and during local infusion in one leg of insulin alone (Control) or insulin plus sodium nitroprusside (SNP) at variable rate to double leg blood flow. We measured leg blood flow by dye dilution; muscle microvascular perfusion with contrast enhanced ultrasound; Akt/mTORC1 signaling by Western blotting; and muscle protein synthesis, amino acid and glucose kinetics using stable isotope methodologies.

Results.

There were no baseline differences between groups. Blood flow, muscle perfusion, phenylalanine delivery to the leg, and intracellular availability of phenylalanine increased significantly (P<0.05) in SNP only. Akt phosphorylation increased in both groups, but increased more in SNP (P<0.05). Muscle protein synthesis and net balance (NB) (nmol·min^–1·100ml leg^–1) increased significantly (P<0.05) in SNP (Synthesis: 43±6 to 129±25; NB: –16±3 to 26±12), but not in Control (Synthesis: 41±10 to 53±8, NB: –17±3 to –2±3).

Conclusion.

Pharmacological enhancement of muscle perfusion and amino acid availability during hyperinsulinemia improves the muscle protein anabolic effect of insulin in older adults.

The effect of diabetes on mild cognitive impairment (MCI) and its conversion to dementia remains controversial. We sought to examine whether diabetes and pre-diabetes are associated with MCI, and accelerate the progression from MCI to dementia.

Research design and methods:

In the Kungsholmen Project, 963 cognitively intact participants and 302 subjects with MCI (120 amnestic MCI [aMCI] and 182 other cognitive impairment no dementia [oCIND]) aged ≥ 75 years were identified at baseline. The two cohorts were followed for 9 years to detect incident MCI and dementia following international criteria. Diabetes was ascertained based on medical examination, hypoglycaemic medication use, and random blood glucose level ≥ 11.0 mmol/l. Pre-diabetes was defined as random blood glucose level of 7.8-11.0 mmol/l in diabetes-free participants. Data were analyzed using standard and time-dependent Cox proportional-hazards models.

Results:

During the follow-up period, in the cognitively intact cohort, 182 people developed MCI (42 aMCI and 140 oCIND), and 212 developed dementia. In the MCI cohort, 155 subjects progressed to dementia, the multi-adjusted hazard ratio (95% confidence interval) of dementia was 2.87 (1.30-6.34) for diabetes, and 4.96 (2.27-10.84) for pre-diabetes. In Kaplan-Meier survival analysis, diabetes and pre-diabetes accelerated the progression from MCI to dementia by 3.18 years. Diabetes and pre-diabetes were neither cross-sectionally nor longitudinally associated with MCI.

Conclusions:

Diabetes and pre-diabetes substantially accelerate the progression from MCI to dementia, and anticipate dementia occurrence by more than three years in people with MCI. The association of diabetes with the development of MCI is less evident in old people.

To gain a greater understanding of the cause of fasting and postprandial hyperglycemia in people with type 2 diabetes.

Overview:

Endogenous glucose production is excessive before eating and fails to appropriately suppress after eating in people with type 2 diabetes. This is due in part to impaired insulin induced suppression of endogenous glucose production which is observed early in the evolution of type 2 diabetes. Increased rates of gluconeogenesis and perhaps glycogenolysis contribute to hepatic insulin resistance. Insulin induced stimulation of hepatic glucose uptake and hepatic glycogen synthesis are reduced in people with type 2 diabetes primarily due to decreased uptake of extracellular glucose presumably because of inadequate activation of hepatic glucokinase. Delayed insulin secretion results in higher peak glucose concentrations particularly when suppression of glucagon is impaired whereas, insulin resistance prolongs the duration of hyperglycemia which can be marked when both hepatic and extra-hepatic insulin resistance are present

Conclusions:

The premise of these, as well as studies performed by many other investigators, is that an understanding of the pathogenesis of type 2 diabetes will enable the development of targeted therapies that are directed toward correcting specific metabolic defects in a given individual. I, as well as many other investigators believe that such therapies are likely to be more effective and to have a lower risk than would occur if everyone were treated the same regardless of the underlying cause of their hyperglycemia. While we do not yet have sufficient knowledge to truly individualize therapy, in my opinion this approach will be the norm in the not too distant future.

Based on the premise that postabsorptive patients with type 1 diabetes receiving intravenous insulin in a dose that maintains stable euglycemia are receiving biologically optimal insulin replacement, we tested the hypothesis that glucagon supports the postabsorptive plasma glucose concentration in humans.

Research design and methods –

Fourteen patients with type 1 diabetes were studied after an overnight fast on up to five occasions. Insulin was infused intravenously to hold plasma glucose concentrations at ~100 mg/dL (5.6 mmol/L) overnight and fixed from –60 through +240 minutes the following morning. From 0 through 180 minutes the patients also received 1) saline, 2) octreotide 30 ng·kg^–1·min.^–1 (with growth hormone replacement), or octreotide (with growth hormone) plus glucagon in doses of 3) 0.5 ng·kg^–1·min.^–1, 4) 1.0 ng·kg^–1·min.^–1, and 5) 2.0 ng·kg^–1·min.^–1.

Results –

Compared with a mean (±SE) of 98±5 mg/dL (5.4±0.3 mmol/L) at 180 minutes during saline, mean plasma glucose concentrations declined to 58±1 mg/dL (3.2±0.1 mmol/L) (P<0.001) at 180 minutes during octreotide plus saline and were 104±16 mg/dL (5.8±0.9 mmol/L) (ns), 143±13 mg/dL (7.9±0.7 mmol/L) (P=0.004) and 160±15 mg/dL (8.9±0.8 mmol/L) (P<0.001) at 180 minutes during octreotide plus glucagon in doses of 0.5, 1.0 and 2.0 ng·kg^–1·min.^–1 respectively.

Conclusions –

In the setting of biologically optimal insulin replacement suppression of glucagon secretion with octreotide caused a progressive fall in the plasma glucose concentration that was prevented by glucagon replacement. These data document that glucagon supports the postabsorptive glucose concentration in humans.

the pathogenesis of diabetic nephropathy is complex and involves activation of multiple pathways leading to kidney damage. An important role for altered lipid metabolism via sterol regulatory element binding proteins (SREBPs) has been recently recognized in diabetic kidney disease. Our previous studies have shown that the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor, modulates renal SREBP-1 expression. The purpose of the present study was then to determine if FXR deficiency accelerates type 1 diabetic nephropathy in part by further stimulation of SREBPs and related pathways and conversely if a selective FXR agonist can prevent the development of type 1 diabetic nephropathy.

Research design and methods—

insulin deficiency and hyperglycemia were induced with streptozotocin (STZ) in C57BL/6 FXR KO mice. Progress of renal injury was compared to nephropathy-resistant wild-type C57BL/6 mice treated with STZ. DBA/2J mice with STZ-induced hyperglycemia were treated with the selective FXR agonist INT-747 for 12 weeks. To accelerate disease progression, all mice were placed on western diet after hyperglycemia development.

Results—

the present study demonstrates accelerated renal injury in diabetic FXR KO mice. In contrast, treatment with the FXR agonist INT-747 improves renal injury by decreasing proteinuria, glomerulosclerosis and tubulointerstitial fibrosis and modulating renal lipid metabolism, macrophage infiltration and renal expression of SREBPs, profibrotic growth factors and oxidative stress enzymes in diabetic DBA/2J strain.

Conclusions—

our findings indicate a critical role for FXR in the development of diabetic nephropathy and show that FXR activation prevents nephropathy in type 1 diabetes.