Insulin Clearance In Liver Research Articles

Novel aspects of the role of the liver in carbohydrate metabolism

Malfunction of the liver is a central factor in metabolic disease. Glucose production by liver is complex and controlled via indirect mechanisms; insulin regulates adipose tissue lipolysis, and free fatty acids in turn regulate liver glucose output. This latter concept is confirmed by studies in L-Akt-Foxo1 knockout mice. The adipocyte is a likely locus of hepatic insulin resistance. Also, kidneys play a role in regulating glucose production; denervated kidneys abrogate the effect of fat feeding to cause insulin resistance. Glucose itself is an important regulator of liver metabolism (“glucose effectiveness”); after entering liver, glucose is phosphorylated and can be exported as lactate. Using the dynamic glucose/lactate relationship, we have been able to estimate glucose effectiveness in intact animals and human subjects. Families have been identified with a glucokinase regulatory protein defect; modeling demonstrates elevated glucokinase activity. Insulin clearance by liver is highly variable among normal individuals, and is under environmental control: high fat diet reduces clearance by 30%. Liver insulin clearance is significantly lower in African American (AA) adults and children compared to European American participants, accounting for fasting hyperinsulinemia in AA. We hypothesize that reduced hepatic insulin clearance causes peripheral insulin resistance and increased Type 2 diabetes in AA.

PPARα (Peroxisome Proliferator-activated Receptor α) Activation Reduces Hepatic CEACAM1 Protein Expression to Regulate Fatty Acid Oxidation during Fasting-refeeding Transition

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is expressed at high levels in the hepatocyte, consistent with its role in promoting insulin clearance in liver. CEACAM1 also mediates a negative acute effect of insulin on fatty acid synthase activity. Western blot analysis reveals lower hepatic CEACAM1 expression during fasting. Treating of rat hepatoma FAO cells with Wy14,643, an agonist of peroxisome proliferator-activated receptor α (PPARα), rapidly reduces Ceacam1 mRNA and CEACAM1 protein levels within 1 and 2 h, respectively. Luciferase reporter assay shows a decrease in the promoter activity of both rat and mouse genes by Pparα activation, and 5'-deletion and block substitution analyses reveal that the Pparα response element between nucleotides -557 and -543 is required for regulation of the mouse promoter activity. Chromatin immunoprecipitation analysis demonstrates binding of liganded Pparα toCeacam1promoter in liver lysates ofPparα(+/+), but notPparα(-/-)mice fed a Wy14,643-supplemented chow diet. Consequently, Wy14,643 feeding reduces hepatic Ceacam1 mRNA and CEACAM1 protein levels, thus decreasing insulin clearance to compensate for compromised insulin secretion and maintain glucose homeostasis and insulin sensitivity in wild-type mice. Together, the data show that the low hepatic CEACAM1 expression at fasting is mediated by Pparα-dependent mechanisms. Changes in CEACAM1 expression contribute to the coordination of fatty acid oxidation and insulin action in the fasting-refeeding transition.

Enhanced insulin clearance in mice lacking TRPM8 channels

Blood glucose concentration is tightly regulated by the rate of insulin secretion and clearance, a process partially controlled by sensory neurons serving as metabolic sensors in relevant tissues. The activity of these neurons is regulated by the products of metabolism which regulate transmitter release, and recent evidence suggests that neuronally expressed ion channels of the transient receptor potential (TRP) family function in this critical process. Here, we report the novel finding that the cold and menthol-gated channel TRPM8 is necessary for proper insulin homeostasis. Mice lacking TRPM8 respond normally to a glucose challenge while exhibiting prolonged hypoglycemia in response to insulin. Additionally, Trpm8-/- mice have increased rates of insulin clearance compared with wild-type animals and increased expression of insulin-degrading enzyme in the liver. TRPM8 channels are not expressed in the liver, but TRPM8-expressing sensory afferents innervate the hepatic portal vein, suggesting a TRPM8-mediated neuronal control of liver insulin clearance. These results demonstrate that TRPM8 is a novel regulator of serum insulin and support the role of sensory innervation in metabolic homeostasis.

Obesity, insulin resistance, and the pathway to type 2 diabetes

The increase in obesity in the U.S. and elsewhere can be explained by a variety of factors, as outlined by David Allison and his colleagues. Not only is the fast food diet a factor, but also are changes in ambient temperature, obesity-causing psychoactive molecules, associative sorting, changes in smoking habits, and reduction in sleep. In particular is the increase in visceral fat, which is associated with insulin resistance. We have shown in experimental animals that omentectomy increases insulin sensitivity implicating visceral fat per se as an important factor. We have followed longitudinally changes in organ function and crosstalk in a large animal model, rendered overweight by a high fat, hypercaloric diet. In normal animals, like in normal humans, there is a wide range of adiposity as well as visceral and subcutaneous fat deposition. Feeding fat increases visceral and subcutaneous fat with little change in body weight. Physiologic changes occur with absolutely no change in fasting glucose: most predictive of insulin resistance is relative reduction in metabolic clearance of insulin by liver, and a modest increase in beta cell sensitivity to glucose. The latter changes result in hyperinsulinemia. Change in insulin sensitivity is also predicted by change in liver insulin clearance, implicating metabolic clearance of insulin as the primary factor in development of the insulin resistance syndrome.

Decreased osteoclastogenesis and high bone mass in mice with impaired insulin clearance due to liver-specific inactivation to CEACAM1

Type 2 diabetes is associated with normal-to-higher bone mineral density (BMD) and increased rate of fracture. Hyperinsulinemia and hyperglycemia may affect bone mass and quality in the diabetic skeleton. In order to dissect the effect of hyperinsulinemia from the hyperglycemic impact on bone homeostasis, we have analyzed L-SACC1 mice, a murine model of impaired insulin clearance in liver causing hyperinsulinemia and insulin resistance without fasting hyperglycemia. Adult L-SACC1 mice exhibit significantly higher trabecular and cortical bone mass, attenuated bone formation as measured by dynamic histomorphometry, and reduced number of osteoclasts. Serum levels of bone formation (BALP) and bone resorption markers (TRAP5b and CTX) are decreased by approximately 50%. The L-SACC1 mutation in the liver affects myeloid cell lineage allocation in the bone marrow: the (CD3 −CD11b −CD45R −) population of osteoclast progenitors is decreased by 40% and the number of (CD3 −CD11b −CD45R +) B-cell progenitors is increased by 60%. L-SACC1 osteoclasts express lower levels of c-fos and RANK and their differentiation is impaired. In vitro analysis corroborated a negative effect of insulin on osteoclast recruitment, maturation and the expression levels of c-fos and RANK transcripts. Although bone formation is decreased in L-SACC1 mice, the differentiation potential and expression of the osteoblast-specific gene markers in L-SACC1-derived mesenchymal stem cells (MSC) remain unchanged as compared to the WT. Interestingly, however, MSC from L-SACC1 mice exhibit increased PPARγ2 and decreased IGF-1 transcript levels. These data suggest that high bone mass in L-SACC1 animals results, at least in part, from a negative regulatory effect of insulin on bone resorption and formation, which leads to decreased bone turnover. Because low bone turnover contributes to decreased bone quality and an increased incidence of fractures, studies on L-SACC1 mice may advance our understanding of altered bone homeostasis in type 2 diabetes.

Carcinoembryonic antigen-related cell adhesion molecule 1: a link between insulin and lipid metabolism.

OBJECTIVE—Liver-specific inactivation of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) by a dominant-negative transgene (l-SACC1 mice) impaired insulin clearance, caused insulin resistance, and increased hepatic lipogenesis. To discern whether this phenotype reflects a physiological function of CEACAM1 rather than the effect of the dominant-negative transgene, we characterized the metabolic phenotype of mice with null mutation of the Ceacam1 gene (Cc1−/−).RESEARCH DESIGN AND METHODS—Mice were originally generated on a mixed C57BL/6x129sv genetic background and then backcrossed 12 times onto the C57BL/6 background. More than 70 male mice of each of the Cc1−/− and wild-type Cc1+/+ groups were subjected to metabolic analyses, including insulin tolerance, hyperinsulinemic-euglycemic clamp studies, insulin secretion in response to glucose, and determination of fasting serum insulin, C-peptide, triglyceride, and free fatty acid levels.RESULTS—Like l-SACC1, Cc1−/− mice exhibited impairment of insulin clearance and hyperinsulinemia, which caused insulin resistance beginning at 2 months of age, when the mutation was maintained on a mixed C57BL/6x129sv background, but not until 5–6 months of age on a homogeneous inbred C57BL/6 genetic background. Hyperinsulinemic-euglycemic clamp studies revealed that the inbred Cc1−/− mice developed insulin resistance primarily in liver. Despite substantial expression of CEACAM1 in pancreatic β-cells, insulin secretion in response to glucose in vivo and in isolated islets was normal in Cc1−/− mice (inbred and outbred strains).CONCLUSIONS—Intact insulin secretion in response to glucose and impairment of insulin clearance in l-SACC1 and Cc1−/− mice suggest that the principal role of CEACAM1 in insulin action is to mediate insulin clearance in liver.

No Take Backs: Mice that can't get rid of insulin develop signs of diabetes (Insulin resistance; Diabetes)

If the remnants of a meal aren't tidied, they can turn into a big mess, whether it's in your kitchen or your body. Insulin normally coordinates the cleanup of leftovers in the bloodstream. But cells can turn recalcitrant and ignore the hormone's directives. Researchers have blamed overproduction of insulin for this state, known as insulin resistance, which becomes increasingly common as people age and can lead to diabetes. But new work in mice suggests that ineptitude at getting rid of insulin after a sugar surge can also cause the trouble. Eat a Krispy Kreme doughnut, and feel your blood sugar soar. In response, the pancreas produces insulin, which tells muscle, fat, and liver cells to soak up the sweets. Insulin sets off a chain reaction when it attaches to a cell surface receptor. The receptor adds a phosphate group to other proteins, which enables them to prod cells to absorb sugar and store it. As sugar concentration in the blood falls, liver cells take up insulin to shut off this response. Previous work hinted at a player involved in this insulin clearance pathway. Researchers had determined that a protein called CEACAM1 receives a phosphate group when cultured liver cells are treated with insulin and that cultured cells lacking CEACAM1 can't reabsorb the signaling molecule. But they didn't know whether CEACAM1 helps intact animals soak up insulin. To answer that question, Poy and colleagues engineered a mutant mouse whose liver cells produce a version of CEACAM1 that lacks the site where phosphate attaches. The creatures are chubbier and carry more tummy fat than control animals do; in addition, two to five times the normal amount of insulin courses through the mutants' blood. To find out whether the mice produce extra insulin or can't get rid of what they make, the team injected radioactively labeled insulin into the animals' tails. After 1 hour, the mutant mice retained two to three times as much insulin in their blood as wild-type mice did. These and other experiments suggest that CEACAM1-defective mice can't efficiently remove insulin from the bloodstream. The mutant mice also exhibit hallmarks of insulin resistance. They have abnormally large amounts of glucose in their blood and recover unusually slowly when the researchers inject them with the sugar. In addition, liver cells from mutant mice display fewer insulin receptors than do those from their wild-type siblings. Muscle and fat cells, however, retain their insulin sensitivity, indicating that the animals do not develop diabetes. Together, the results suggest that problems in insulin uptake can stimulate insulin resistance, although additional deficiencies are needed to trigger diabetes. The results are provocative, says cell biologist Morris Birnbaum of the University of Pennsylvania in Philadelphia. But he cautions that the experiments on mice are "a far cry from showing that this ever really happens in people, much less is related to human disease." The work suggests, however, that telling the cleaning crew to go home once the job is done might be good for your health. --R. John Davenport M. N. Poy, Y. Yang, K. Rezaei, M. A. Fernström, A. D. Lee, Y. Kido, S. K. Erickson, S. M. Najjar, CEACAM1 regulates insulin clearance in liver. Nature Genet. , 19 February 2002 [e-pub ahead of print]. [Abstract] [Full Text]

CEACAM1 regulates insulin clearance in liver.

We hypothesized that insulin stimulates phosphorylation of CEACAM1 which in turn leads to upregulation of receptor-mediated insulin endocytosis and degradation in the hepatocyte. We have generated transgenic mice over-expressing in liver a dominant-negative, phosphorylation-defective S503A-CEACAM1 mutant. Supporting our hypothesis, we found that S503A-CEACAM1 transgenic mice developed hyperinsulinemia resulting from impaired insulin clearance. The hyperinsulinemia caused secondary insulin resistance with impaired glucose tolerance and random, but not fasting, hyperglycemia. Transgenic mice developed visceral adiposity with increased amounts of plasma free fatty acids and plasma and hepatic triglycerides. These findings suggest a mechanism through which insulin signaling regulates insulin sensitivity by modulating hepatic insulin clearance.

Central Role of the Adipocyte in the Metabolic Syndrome

Insulin resistance is associated with a plethora of chronic illnesses, including Type 2 diabetes, dyslipidemia, clotting dysfunction, and colon cancer. The relationship between obesity and insulin resistance is well established,...