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2004 Diabetes Research Highlights

Adeli, Khosrow

Division of Clinical Biochemistry

Our research group is involved in both fundamental research as well as clinical laboratory studies in the area of lipid and lipoprotein disorders particularly those affecting paediatric populations. The incidence of obesity in children and adolescents has been increasing at an alarming rate in recent years, mostly as a result of decreased physical activity and increased availability of high calorie foods. This in turn has contributed to higher incidence of insulin resistant syndromes such as type 2 diabetes in this population, which is frequently accompanied with hyperlipidemia and increased risk of cardiovascular disease later in life. A common finding in these conditions is hepatic overproduction of apolipoprotein B (apoB) and thus increased plasma levels of atherogenic lipoproteins. Our research program is aimed at elucidating the key genetic and environmental factors that link insulin resistance, lipoprotein abnormalities, and cardiovascular disease. We are thus investigating the mechanisms that underlie the development of metabolic dyslipidemia in insulin resistant states at the cellular and molecular levels. Diet-induced animal models of insulin resistance and obesity are deployed to investigate the link between the insulin signaling pathway and deregulation of hepatic and intestinal lipoprotein metabolism. These animal models are also applied to the investigation of the mechanisms of action of hypolipidemic and insulin sensitizing drugs at the cellular and molecular level.

  1. Qiu W., Kohen Avramoglu R., Dube N., Chong T.M., Naples M., Au C., Lewis G.F.L., Cohn J.S., Tremblay M.L., and Adeli K. Hepatic PTP-1B Expression Regulates the Assembly and Secretion of ApoB-Containing Lipoproteins: Evidence from PTP-1B overexpression, knockout and RNAi studies. Diabetes 2004, 53(12):3057-662)
  2. Lewis,G.F, Leung,N., Watanabe,T., Uffelman,K., Szeto,L., Adeli, K.. 2004. Intestinal lipoprotein production is stimulated by acute plasma FFA elevation: Studies in insulin resistant and insulin sensitized Syrian Golden hamsters. Endocrinology 2004 145(11):5006-12

Brubaker, Patricia

Departments of Physiology and Medicine

Research in the Brubaker lab is focused on the intestinal glucagon-like peptides, GLP-1 and GLP-2, that are released into the circulation following nutrient ingestion. GLP-1 has therapeutic potential for the treatment of patients with type 2 diabetes, due to its ability to stimulate insulin secretion, enhance beta cell growth and reduce food intake. GLP-2 also has tropic actions, increasing the growth and function of the intestine. A recent study has now demonstrated the intracellular signaling pathway by which GLP-1 exerts its stimulatory effects on beta cell mass, in Glucagon-like peptide-1 regulates proliferation and apoptosis via activation of protein kinase B in pancreatic INS-1 beta cells,and the growth effects of both GLP-1 and GLP-2 have been reviewed in Minireview: Glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system.A review of the factors that regulate the secretion of these peptides is also found in Nutrient, Neural and Endocrine Control of Glucagon-like Peptide Secretion.

Drucker, Daniel J.

Department of Medicine

The Drucker lab is carrying out studies focused on understanding the factors regulating proglucagon gene expression in the gut and pancreas, as well as the actions of the glucagon-like peptides, GLP-1, and GLP-2, on their target tissues. GLP-1 is a promising gut-derived peptide that is being evaluated as a new treatment for subjects with diabetes. Understanding how GLP-1 is produced in the intestine may lead to new therapies designed to increase the synthesis and secretion of GLP-1 in diabetic subjects. Identification of the mechanisms mediating GLP-1 action in different target tissues is being pursued through studies utilizing normal and mutant mice, as exemplified in Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure. Gastroenterology. 2004 Aug;127(2):546-58. and Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors. Diabetes. 2004 May;53(5):1326-35. Similarly, GLP-2, co-secreted together with GLP-1 from gut endocrine cells, is in late stage clinical trials for the treatment of intestinal disorders. The laboratory continues to be interested in delineating the mechanisms mediating GLP-2 action in different cells and tissues as described in Extrahypothalamic expression of the glucagon-like peptide-2 receptor is coupled to reduction of glutamate-induced cell death in cultured hippocampal cells. Endocrinology. 2004 Jul;145(7):3495-506. and Lipid raft-dependent glucagon-like peptide-2 receptor trafficking occurs independently of agonist-induced desensitization.Mol Biol Cell. 2004 Aug;15(8):3673-87

Gaisano, Herbert

Departments of Medicine and Physiology

The Gaisano laboratory investigates the mechanisms by which SNARE proteins, originally described to mediate exocytosis in neurons, regulate insulin secretion. The central working hypothesis is that SNARE proteins act to link together the distal components of insulin secretion, including not only exocytosis of the insulin granule, but also the membrane ion channels which regulate K+ and Ca2+ fluxes, and the priming and mobilization of insulin granule pools, into the fine sequence of events leading to secretion. His lab recently reported that SNARE proteins can bind and regulate the dominant K+ channels in islet beta-cells which mediate membrane depolarization (K-ATP, JBC 279:4234, 2004; JBC 279:47125, 2004; JBC 279:53259, 2004) and repolarization (Kv2.1, JBC 279:24685, 2004, Biochem J in press). As well, his lab showed that the key receptor acted upon by diacylglycerol to prime insulin secretion is not protein kinase C as broadly believed, but rather a novel protein called Munc13-1 (JBC 278:27556, 2003), and further studies are directed at examining other novel priming proteins, and those which mediate compound exocytosis. This work may identify potential interaction sites between the SNARE proteins and the distinct secretory steps, which could be targeted for therapeutic intervention. His lab has in place state-of-the-art single cell patch clamp and exocytic imaging assays (epifluorescence, evanescent and confocal microscopy), complementary biochemical and molecular biology tools, and genetically-modified mouse models to unequivocally dissect these complicated secretory pathways.

Hanley, Anthony

Departments of Medicine and Public Health Sciences

  1. Obesity has many health consequences, including diabetes, hypertension, and heart disease. Recently, a novel liver complication of obesity, called non-alcoholic fatty liver disease (NAFLD) has been described. It has been proposed that NAFLD may be related to insulin resistance and the development of diabetes, although few studies have looked at this issue. We studied the relationship of blood markers of NAFLD, including the liver enzymes ALT and AST, with risk of developing type 2 diabetes in a large multi-ethnic cohort. We found that subjects in the upper quartiles of ALT and AST had a 2-fold increased risk of developing diabetes after 5 years, even after taking into account other diabetes risk factors including central adiposity and insulin resistance. The results were essentially identical when we excluded former and heavy drinkers from the analysis (Hanley et al. Diabetes 2004;53:2623-2632).
  2. Both diabetes and heart disease are characterized and predicted by a cluster of cardiovascular risk factors. For many years this list of factors has included hypertension, obesity and elevations of glucose and blood lipids. More recently, the list has been expanded to include newer risk factors such as chronic, low-level activation of the immune system (also known as sub-clinical inflammation). This cluster of risk factors is referred to as the metabolic syndrome. The interrelationships among all of these risk factors make it difficult to understand the primary disorder underlying the metabolic syndrome. We used a statistical technique known as factor analysis to help shed light on the common thread underlying this cluster of disorders. From a set of 12 heart disease and diabetes risk variables in subjects free of diabetes, we found 3 independent factors: a "Metabolic" factor, an "Inflammation" factor, and a "Blood Pressure" factor. Each of these factors was a significant predictor of new-onset diabetes after 5 years (Hanley et al. Diabetes 2004;53:1773-81).

Irwin, David M.

Department of Laboratory Medicine and Pathobiology

The Irwin lab is investigating the expression and evolution of the proglucagon gene. The proglucagon gene encodes several hormones that are important in regulating metabolism, including glucagon, glucagon-like peptide 1 (GLP-1), and glucagon-like peptide 2 (GLP-2). While the regulation of expression of the rat proglucagon gene has been extensively studied, we have found that comparable regulatory gene sequences previously identified for the rat proglucagon gene do not appear to be important in regulating the human proglucagon gene. Recent advances in Genome projects have generated huge amounts of sequence data from many vertebrate species. We are using these resources to better understand the origin, evolution, and expression of proglucagon genes as well as other genes for receptors for these peptides.

  1. Zhou L, Irwin DM. Fish proglucagon genes have differing coding potential. Comp Biochem Physiol B Biochem Mol Biol. 2004 Feb;137(2):255-64.
  2. Yue S, Irwin DM. Structure and expression of the chicken proglucagon gene. Mol Cell Endocrinol. 2005 Jan 31;230(1-2):69-76.

Lewis, Gary

Departments of Medicine and Physiology

Dr. Lewis, in collaboration with Dr. Khosrow Adeli (HSC, Department of Laboratory Medicine and Pathobiology), has used the fructose and fat fed Syrian Golden hamster as models of insulin resistance that develop many of the lipoprotein abnormalities that are typical of insulin resistant humans. Lewis and Adeli have used this model to investigate the molecular mechanisms that underlie the overproduction of triglyceride-rich lipoproteins by the liver and intestine of these nutritionally induced insulin resistant animal models. The major novel finding from these studies is that the intestine, in addition to the liver, overproduces lipoproteins in insulin resistant states. The intestinal abnormalities that underlie this overproduction of triglyceride-rich lipoproteins closely resemble the abnormalities that Lewis, Adeli and others have previously described in the liver of insulin resistant animals and humans. In addition they showed that that a key enzyme involved in the regulation of plasma lipoproteins, hepatic lipase, is upregulated at the mRNA level in insulin resistance. Many of these abnormalities can be reversed or ameliorated with insulin sensitizing therapies.

  1. Leung N, Haidari M, Uffelman K, Szeto L, Buckingham R, Adeli K, Lewis GF. Rosiglitazone improves intestinal lipoprotein overproduction in the fat-fed Syrian Golden hamster, an animal model of nutritionally-induced insulin resistance. Atherosclerosis 174:235-241, 2004.
  2. Lewis GF, Murdoch S, Uffelman K, Leung N, Szeto L, Albers A, Adeli K, Brunzell JD. Hepatic lipase mRNA, protein and plasma enzyme activity is increased in the insulin-resistant fructose-fed Syrian Golden hamster and is partially normalized by the insulin sensitizer, rosiglitazone. Diabetes 53:2893-2900, 2004.
  3. Lewis GF, Naples M, Uffelman K, Leung N, Szeto L, Watanabe T, Adeli A. Intestinal Lipoprotein production is stimulated by acute elevation of plasma free fatty acids: Studies in insulin resistant and insulin sensitized Syrian Golden hamsters. Endocrinology 145(11):5006-12, 2004. Epub 2004 Jul 22.
  4. Lewis GF, Uffelman K, Naples M, Szeto L, Haidari M, Adeli K. Intestinal lipoprotein overproduction, a newly recognized component of insulin resistance, is ameliorated by the insulin sensitizer, rosiglitazone: studies in the fructose-fed Syrian Golden hamster. Endocrinology Jan;146(1):247-55, 2005. Epub 2004 Oct 14.

van der Kooy, Derek

Department of Medical Genetics

We have found a novel adult mouse pancreatic precursor cell. These single adult cells can proliferate clonaally to produce all of the cell types present in the pancreas, including the insulin producing beta cells. Seaberg, R.M., Smukler, S.R., Kieffer, T.J., Enikolopov, G., Asghar, Z., Wheeler, Korbutt, G., and van der Kooy, D. Clonal identification of multipotent progenitors from adult pancreas that generate neural andpancreatic lineages. Nature Biotechnology 22 (2004) 1115-1124.

Vranic, Mladen / Matthews, Stephen G.

Professor of Physiology and Medicine / Department of Physiology, Obstetrics and Gynaecology

  1. Our work analyzed the mechanisms of decreased counterregulation to hypoglycemia in diabetic rats. Normally hypoglycemia stimulates a coordinated response of glucocorticoids, sympathoadrenal discharge, and release of glucagon. This coordination is disrupted by chronic stress. Diabetes increases activity of the hypothalamo-pituitary-adrenal (HPA) axis, which has a negative effect on glucoregulation and can decrease neurogenesis in the nervous system. The increase in HPA activity results from low plasma insulin and not from chronic hyperglycemia. On the other hand, the deficient response of the HPA axis to hypoglycemia results from chronic hyperglycemia and not from insulin deficiency. Even in euglycemia, insulin can activate HPA activity both in normal and diabetic rats. This response is augmented in hypoglycemia in normal but not in diabetic rats. We postulated that the defect in diabetes is mainly due to dysregulation of mineralocorticoid receptors in the hippocampus (Diabetes lowers the ceiling for maximal activation of the hypothalamo-pituitary-adrenal axis in response to stress. Endocrinology 2005, first published online Nov. 24, 2004). We postulated that the poor response of epinephrine is due to a reduced expression of genes encoding enzymes responsible for epinephrine synthesis. This defect is augmented with antecedent hypoglycemia (Effects of diabetes and recurrent hypoglycemia on the regulation of the sympathoadrenal system and the hypothalamo-pituitary-adrenal (HPA) axis. Am J Physiol Endocrinol Metab 288: E422-429, 2005, first published online October 19, 2004).
  2. We studied the progression of diabetes in Zucker Diabetic Fatty rats. To our surprise, not only exercise training, but also chronic intermittent neurogenic stress markedly improved glucose homeostasis. The mechanism is studied by the molecular analysis of pancreatic hormones, their regeneration and apoptosis.

Wang, Qinghua

Departments of Physiology and Medicine

We are studying the mechanism by which growth factors induce islet cell growth, in particular, how they affect the capacity for pancreatic insulin storage and secretion. The lab's investigations also include targeting and identify new compositions and methods that can prevent the development of diabetes. To this end, the nature of cross-talking between insulin-secreting beta cells and glucagon-secreting alpha cells is currently being studied, with emphasis on identifying novel mechanisms by which glucose stimulates insulin secretion and suppresses glucagon release in the islet cells. Findings from these studies may provide new therapeutic strategies to combat diabetic hyperglycemia. Glucagon-like peptide-1 regulates proliferation and apoptosis via activation of protein kinase B in pancreatic INS-1 beta cells.

Wolever, Thomas

Department of Nutritional Sciences

We continue to be interested in the effects of dietary carbohydrates in the body, and particularly how diet is related to the development of diabetes and insulin resistance. Last year we were the first to show that a high fiber cereal affects insulin responses differently in normal and insulin resistant subjects. High-fiber cereal reduces postprandial insulin responses in hyperinsulinemic but not normoinsulinemic subjects. Diabetes Care 2004;27:1281-85. We published two studies related to our interest in the how the breakdown (fermentation) of undigested carbohydrate in the large intestine can affect metabolism in the body L-rhamnose raises serum propionate in humans. Am J Clin Nutr 2004;80:89-94 and L-Ramnose increases serum propionate after long-term supplementation, but lactulose does not raise serum acetate. Am J Clin Nutr 2004;80:1254-61. Also, we found that a variation in the gene which makes a protein involved in fat absorption, intestinal fatty acid binding protein, which is present in about 20% of the population, was associated with potentially beneficial alterations in insulin metabolism in lean healthy subjects after a high fat meal. Postprandial lipemia in subjects with the T54 variant of fatty acid-binding protein 2 (FABP2) gene is dependent on the type of fat ingested. Am J Clin Nutr 2004:79:1110-17. The glycaemic index is a classification of the blood glucose raising potential of the glycaemic (or available) carbohydrate in foods. We continue to be interested in improving the methods used to measure the glycaemic index of foods. Effect of blood sampling schedule and method calculating the area under the curve on validity and precision of glycaemic index values. Brit J Nutr 2004;91:295-300.