Biosynthesis of Insulin: Insulin is synthesized in significant quantities only in B cells in the pancreas. The insulin mRNA is translated as a single chain precursor called pre proinsulin , and removal of its signal peptide during insertion into the endoplasmic reticulum generates proinsulin. Proinsulin consists of three domains: an amino-terminal B chain, a carboxy-terminal A chain and a connecting peptide in the middle known as the C peptide. Within the endoplasmic reticulum, proinsulin is exposed to several specific endopeptidases which excise the C peptide, thereby generating the mature form of insulin. Insulin and free C peptide are packaged in the Golgi into secretory granules which accumulate in the cytoplasm. When the B cell is appropriately stimulated, insulin is secreted from the cell by exocytosis and diffuses into islet capillary blood. C peptide is also secreted into blood, but has no known biological activity.
Our understanding of the mechanisms behind insulin secretion remain somewhat fragmentary. Nonetheless, certain features of this process have been clearly and repeatedly demonstrated,yielding the following model: Glucose is transported into the B cell by facilitated diffusion through a glucose transporter; elevated concentrations of glucose in extracellular fluid lead to elevated concentrations of glucose within the B cell. Elevated concentrations of glucose within the B cell ultimately leads to membrane depolarization and an influx of extracellular calcium. The resulting increase in intracellular calcium is thought to be one of the primary triggers for exocytosis of insulin-containing secretory granules. The mechanisms by which elevated glucose levels within the B cell cause depolarization is not clearly established, but seems to resuls from metabolism of glucose and other fuel molecules within the cell, perhaps sensed as an alteration of ATP:ADP ratio and transduced into alterations in membrane conductance.
Insulin is secreted in primarily in response to elevated blood concentrations of glucose. This makes sense because insulin is &quot;in charge&quot; of facilitating glucose entry into cells.Some neural stimuli (e.g. site and taste of food) and increased blood concentrations of of the fuel molecules, including amino acids and fatty acids, also promote insulin secretion.
Factors Affecting Insulin Secretion from the Pancreas Stimulatory agents or conditions: Hyperglycemia (high glucose); Amino acids; Fatty acids, especially long-chain; Gastrointestinal hormones, GIP, sepecially gastrin and secretin; Acetylcholine Inhibitory agents or conditions: Somatostatin, Norepinephrine, Epinephrine Inputs to beta cells and effects of insulin, including negative feedback on glucose and animo-acids levels.
A well-known effect of insulin is to decrease the concentration of glucose in blood, which should make sense considering the mechanisms described above. Another important consideration is that, as blood glucose concentrations fall, insulin secretion ceases. In the absense of insulin, a bulk of the cells in the body become unable to take up glucose, and begin a switch to using alternative fuels like fatty acids for energy. Neurons, however, require a constant supply of glucose, which in the short term, is provided from glycogen reserves.
Glucose is liberated from dietary carbohydrate such as starch or sucrose by hydrolysis within the small intestine, and is then absorbed into the blood. Elevated concentrations of glucose in blood stimulate release of insulin, and insulin acts on cells throughout the body to stimulate uptake, utilization and storage of glucose. The effects of insulin on glucose metabolism vary depending on the target tissue. Two important effects are: Insulin facilitates entry of glucose into muscle, adipose and several other tissues. The only mechanism by which cells can take up glucose is by facilitated diffusion through a family of hexose transporters. In many tissues - muscle being a prime example - the major transporter used for uptake of glucose (called GLUT4) is made available in the plasma membrane through the action of insulin. In the absen c e of insulin, GLUT4 glucose transporters are present in cytoplasmic vesicles, where they useless for transporting glucose. Binding of insulin to receptors on such cells leads rapidly to fusion of those vesicles with the plasma membrane and insertion of the glucose transporters, thereby giving the cell an ability to efficienty take up glucose. When blood levels of insulin decrease and insulin receptors are no longer occupied, the glucose transporters are recycled back into the cytoplasm. The animation to the right depicts how insulin signalling leads to translocation of glucose transporters from the cytoplasm into the plasma membrane, allowing glucose (small blue balls) to enter the cell. Click on the &quot;Add Glucose&quot; button to start it. It should be noted here that there are some tissues that do not require insulin for efficient uptake of glucose: important examples are brain and the liver. This is because these cells don't use GLUT4 for importing glucose, but rather, another transporter that is not insulin-dependent.
Figure 3. Molecular mechanism of insulin-stimulated transport. The insulin-dependent glucose transporter 4 (GLUT4) is translocated by a phosphatidylinositol 3-kinase (PI 3K)-dependent pathway including PKB/AKT and PKC stimulation downstream of PI3K [Reproduced with permission from H. U. Häring: Exp Clin Endocrinol Diabetes 107[Suppl 2]:S17—S23, 1999 (7 ).] PI3,4,5P, Phosphatidylinositol 3,4,5-phosphate; PDK, phosphatidylinositol (3 4 5 )-phosphate-dependent kinase; IRS, insulin receptor substrate. The first substrate of the insulin receptor was described by White et al. in 1985 ( 64 ). Subsequently, this intracellular protein was cloned by Sun et al . ( 65 ) and named insulin receptor substrate-1 (IRS-1). IRS-1 and o the r recently cloned IRS proteins (IRS-2, -3, -4) are phosphorylated upon insulin stimulation and have adaptor function between the insulin receptor and o the r cellular substrates such as the phosphatidylinositol 3-kinase (PI 3kinase) ( 65 , 66 , 67 , 68 ). The contribution of IRS-1 and IRS-2 to insulin resistance and diabetes was recently tested by targeted disruption of the respective gene in mice. IRS-1 knockout mice were insulin resistant but not hyperglycemic ( 69 ). It has been shown that the recently cloned IRS-2 was at least partially able to compensate for the lack of IRS-1, which could explain the mild and nondiabetic phenotype of IRS-1 knockout mice ( 70 ). In the meantime, IRS-2 knockout mice have also been generated. Although IRS-1 and IRS-2 are highly homologous proteins and share many signaling properties, the phenotype of IRS-2 knockout mice is markedly different from that of IRS-1 knockout mice ( 71 ). IRS-2-deficient mice are severely hyperglycemic due to abnormalities of peripheral insulin action and failure of ß-cell secretion ( 71 ). This phenotype with severe hyperglycemia as a consequence of peripheral insulin resistance and insufficient insulin secretion due to a significantly reduced ß-cell mass reveals many similarities to type 2 diabetes in man and outlines the role of IRS proteins for the development of cellular insulin resistance and ß-cell function.
Insulin stimulates the liver to store glucose in the form of glycogen. A large fraction of glucose absorbed from the small intestine is immediately taken up by hepatocytes, which convert it into the storage polymer glycogen. Insulin has several effects in liver which stimulate glycogen synthesis. First, it activates the enzyme hexokinase, which phosphorylates glucose, trapping it within the cell. Coincidently, insulin acts to inhibit the activity of glucose-6-phosphatase. Insulin also activates several of the enzymes that are directly involved in glycogen synthesis, including phosphofructokinase and glycogen synthase. The net effect is clear: when the supply of glucose is abundant, insulin &quot;tells&quot; the liver to bank as much of it as possible for use later.
Insulin promotes synthesis of fatty acids in the liver. insulin is stimulatory to synthesis of glycogen in the liver. However, as glycogen accumulates to high levels (roughly 5% of liver mass), further synthesis is strongly suppressed. When the liver is saturated with glycogen, any additional glucose taken up by hepatocytes is shunted into pathways leading to synthesis of fatty acids, which are exported from the liver as lipoproteins. The lipoproteins are ripped apart in the circulation, providing free fatty acids for use in other tissues, including adipocytes, which use them to synthesize triglyceride. Insulin inhibits breakdown of fat in adipose tissue by inhibiting the intracellular lipase that hydrolyzes triglycerides to release fatty acids. Insulin facilitates entry of glucose into adipocytes, and within those cells, glucose can be used to synthesize glycerol. This glycerol, along with the fatty acids delivered from the liver, are used to synthesize triglyceride within the adipocyte. By these mechanisms, insulin is involved in further accumulation of triglyceride in fat cells. From a whole body perspective, insulin has a fat-sparing effect. Not only does it drive most cells to preferentially oxidize carbohydrates instead of fatty acids for energy, insulin indirectly stimulates accumulation of fat is adipose tissue.
Like the receptors for other protein hormones, the receptor for insulin is embedded in the plasma membrane. The insulin receptor is composed of two alpha subunits and two beta subunits linked by disulfide bonds. The alpha chains are entirely extracellular and house insulin binding domains, while the linked beta chains penetrate through the plasma membrane. The insulin receptor is a tyrosine kinase. In other words, it functions as an enzyme that transfers phosphate groups from ATP to tyrosine residues on intracellular target proteins. Binding of insulin to the alpha subunits causes the beta subunits to phosphorylate themselves (autophosphorylation), thus activating the catalytic activity of the receptor. The activated receptor then phosphorylates a number of intracellular proteins, which in turn alters their activity, thereby generating a biological response. Several intracellular proteins have been identified as phosphorylation substrates for the insulin receptor, the best-studied of which is insulin receptor substrate 1 or IRS-1. When IRS-1 is activated by phosphorylation, a lot of things happen. Among other things, IRS-1 serves as a type of docking center for recruitment and activation of other enzymes that ultimately mediate insulin's effects.
Our current knowledge Circulating insulin rapidly reaches the target tissue, where it interacts with its cognate receptor. The IR (IR), which iswidely expressed, is a transmembrane tyrosine (Tyr) kinase that is expressed as a tetramer in an 2ß2 configuration . Insulin binding to specific regions of the subunit leads to a rapid configurational change in the receptor that eventuates in autophosphorylation of specific Tyr residues of the intracellular region of the ß subunits through a transphosphorylation mechanism. Autophosphorylation results in activation of the Tyr kinase activity of the receptor . In the inactive state, the catalytic site of the Tyr kinase is occluded by the &quot;activation-loop,&quot; preventing access of ATP and various substrates. Autophosphorylation of Tyr residues at the activation-loop causes a conformational change that allows ATP and substrates to reach the catalytic site. The activated IR kinase phosphorylates substrate proteins on Tyr residues, and these phosphorylated Tyr residues serve as docking sites for downstream effectors. Molecules such as Shc (not shown), IR substrate (IRS), and Gab-1(not shown) engage the IR directly and provide a docking interface with downstream substrates. IRS proteins contain a conserved pleckstrin homology (PH) domain, located at the NH2-terminus, that serves to localize the IRS proteins in close proximity to the receptor. IRS proteins contain a phosphate-Tyr binding (PTB) domain COOH-terminal to their PH domain. The PTB domain, present in a number of signaling molecules (13), shares 75% sequence identity (14) between IRS-1 and IRS-2 and functions as a binding site to the NPXY motif of the juxtamembrane region of the IR to promote IR/IRS-1 interactions. The COOH-terminal region of IRS proteins is poorly conserved. It contains multiple Tyr phosphorylation motifs that serve as docking sites for SH2 domain–containing proteins, like the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-K), growth factor receptor binding protein-2 (Grb2), Nck, Crk, Fyn, SHP-2, and others, all of which mediate the metabolic and growth-promoting functions of insulin. Insulin-receptor signaling involves two major pathways—the mitogen-activated protein (MAP) kinase and the PI3-K. each pathway could, under certain circumstances, activate the other. Thus, Akt may activate Raf kinase, and conversely, Ras may activate PI3-K. The MAP kinase pathway is activated by the binding of Grb2 to Tyr-phosphorylated Shc or IRS via its SH2 domain. Grb2 is prebound to mammalian Son of Sevenless (mSOS), a nucleotide exchange protein that catalyzes the exchange of GDP for GTP on Ras (a small GTPase protein); this results in activation of Ras. The prenylated form of Ras binds the inner leaflet of the plasma membrane, and on activation, it binds the NH2-terminal region of Raf, recruiting Raf to the plasma membrane. Ras-Raf interaction displaces the 14-3-3 proteins that are bound to Raf and allows the phosphorylation of Raf by a number of (Ser/Thr) kinases, thus disinhibiting Raf kinase. Raf-1 activates a dual-specificity kinase, MEK1, by phosphorylating two regulatory Ser residues. In turn, MEK1 activates extracellular signal-regulated kinase (ERK)-1 and ERK2 by phosphorylating regulatory Tyr and Thr residues Activated ERKs mediate the growth-promoting effects of insulin by phosphorylating transcription factors such as Elk-1, leading to the induction of genes. The metabolic response to insulin is primarily mediated via the PI3-K pathway. Following the association of the p85/p110 complex of PI3-K with the IRS molecules, PI3-K activity results in production of phosphatidylinositol 3,4,5-phosphate (PIP3). PIP3 binds to the PH domains of PI3-K–dependent kinase (PDK)-1and Akt (protein Ser/Thr kinase B). This leads to the activation of PDK1, which in turn phosphorylates and activates Akt. Akt has been implicated in regulating the translocation of GLUT4, an insulin-sensitive glucose transporter expressed by muscle and fat cells. Interestingly, Akt may not be the only downstream kinase to regulate GLUT4 translocation to the cell surface. Protein kinase C (PKC) isoforms and are also activated by PI3-K and PDK1 and regulate GLUT4 translocation (rev. in 20). Indeed, overexpression of wild-type PKC increases, whereas overexpression of a dominant-negative PKC decreases basal and insulin-stimulated glucose transport in adipocytes and muscle cells. Stimulation of glycogen synthesis is another key metabolic effect of insulin. Glycogen synthase kinase-3 (GSK-3) mediates, at least in part, the activation of glycogen synthase in response to insulin. Activation of Akt by insulin results in the phosphorylation and inactivation of GSK-3, rendering it incapable of inhibiting glycogen synthase activity (23). GSK-3 also inactivates the protein synthesis eukaryotic initiation factor (eIF)-2B (the guanine nucleotide exchange factor) by phosphorylation. Insulin-mediated activation of Akt reverses these processes, thereby enhancing protein synthesis (24). Insulin can also activate protein synthesis at the translational level by phosphorylation of p70S6 kinase and 4E-BP1 via the kinase mammalian Target of Rapamycin (mTOR). In fact, increased 4E-BP1 phosphorylation is controlled by a parallel signaling pathway that immediately bifurcates upstream of p70s6k, with the two pathways sharing a common rapamycin-sensitive activator. The phosphorylation of 4E-BP causes it to disassociate from the eIF-4E, thus enhancing its ability to initiate protein synthesis (25). The importance of nuclear transport of signaling molecules Signaling substrates of the Tyr kinase receptors can be grouped into three levels, depending on their proximity to the receptor. Level I represents proximal substrates such as the IRS proteins and SHC and the proteins that directly interact with them. Level II represents downstream intermediates, including MAP kinases, Akt, and related substrates, and level III molecules affect the final biological responses (Fig. 1). Whereas level I and II molecules function primarily at the plasma membrane or in the cytosol, many of the level III molecules are transported into the nucleus, because their specific function involves the regulation of gene transcription. A prerequisite for the nuclear translocation of these molecules is often phosphorylation by upstream kinases. For example, overexpression of membrane-bound forms of ERK1 and ERK2 results in their homodimerization with the endogenous ERKs’ isoforms, thus preventing them from entering the nucleus after activation of the receptor Tyr kinase. As a result, transcriptional activation of c-fos is inhibited; this strongly supports the idea that nuclear translocation is an essential component of the signaling cascade (26). Recently, insulin and IGF-1 have been shown to inhibit nuclear translocation of transcription factors in a process that involves the activation of Akt, a downstream effector of the insulin and IGF-I receptor Tyr kinases. Akt phosphorylates a family of transcription factors called the Forkhead family (FH), which includes FKHR, FKHRL1, and AFX, and represents the mammalian counterparts of DAF16 in the nematodes (27). Phosphorylation of FKHR by Akt, after stimulation by insulin or IGF-1, inhibits the expression of several genes encoding for proteins, such as the IGF binding protein-1 (28). Phosphorylation of other members of the FH family by Akt may similarly inhibit the expression of other insulin-regulated genes, such as phosphoenol pyruvate carboxy kinase (PEPCK). Akt phosphorylates the FH family of proteins on Ser residues in a consensus site, RXRXXS/T (29). This creates a phosphoserine motif capable of binding members of the 14-3-3 family of proteins (30). The interaction of FKHR with 14-3-3 leads to retention of FKHR in the cytoplasm and prevents FKHR from translocating to the nucleus. Consequently, the expression of a number of genes is inhibited. Similar effects were observed with IGF-I receptor-induced phosphorylation of FKHRL1, which normally induces FAS, partially explaining IGF’s antiapoptotic effects (30). Serum and glucocorticoid-inducible kinase (SGK) is another recently described target of the insulin and IGF-I receptor signaling cascades involving PI3-K. SGK is apparently involved in amplifying the mitogenic signal, because it demonstrates cytoplasmic-nuclear shuttling dependent on the phase of the cell cycle (31). SGK ishyperphosphorylated in serum-stimulated cells and localizes to the nucleus, and inhibition of PI3-K results in inhibition of this hyperphosphorylated state of the protein and inhibition of the nuclear localization of SGK (32). Thus, an important paradigm has recently been described in the signaling pathways of the Tyr kinase receptors that involves phosphorylation of signaling molecules, which in turn determines their cytoplasmic or nuclear localization and their ability to perform their function(s).
In the ß-cell, glucose enters cell via GLUT2 transporter and is metabolized by glucokinase (GK) to glucose 6-phosphate (G6P)/xylulose 5-phosphate (X5P), leading to activation of glucose/insulin responsive (GIR) genes. In liver, activation of insulin receptor initiates expression of purely insulin-responsive (pIR) genes such as GK, which is required for metabolism of glucose. In adipose tissues, insulin stimulates translocation of GLUT4 transporter to plasma membrane, which promotes uptake of glucose into cell. In adipocytes, glucose is metabolized to G6P/X5P by hexokinase (HK).
Potential signaling pathways involved in transcriptional regulation of insulin gene () in ß-cell. WM, wortmannin. In ß-cell, glucose is metabolized to G6P (which may act as a signaling metabolite), prompting an increase in intracellular ATP concentration, which then inhibits an ATP-sensitive K+ channel in plasma membrane. Subsequent lowering of membrane potential promotes uptake of Ca2+ into cell via a voltage-sensitive Ca2+ channel, and this in turn stimulates secretion of insulin from intracellular stores. Binding of insulin to its receptor in plasma membrane may then initiate a signaling cascade ultimately activating expression of insulin gene.
The effect on potassium is clinically important. Insulin activates sodium-potassium ATPases in many cells, causing a flux of potassium into cells. Under certain circumstances, injection of insulin can kill patients because of its ability to acutely suppress plasma potassium concentrations.
Glucagon has a major role in maintaining normal concentrations of glucose in blood, and is often described as having the opposite effect of insulin. That is, glucagon has the effect of increasing blood glucose levels.
The major effect of glucagon is to stimulate an increase in blood concentration of glucose. T he brain in particular has an absolute dependence on glucose as a fuel, because neurons cannot utilize alternative energy sources like fatty acids to any significant extent. When blood levels of glucose begin to fall below the normal range, it is imperative to find and pump additional glucose into blood. Glucagon exerts control over two pivotal metabolic pathways within the liver, leading that organ to dispense glucose to the rest of the body:
Glucagon stimulates breakdown of glycogen stored in the liver. When blood glucose levels are high, large amounts of glucose are taken up by the liver. Under the influence of insulin, much of this glucose is stored in the form of glycogen. Later, when blood glucose levels begin to fall, glucagon is secreted and acts on hepatocytes to activate the enzymes that depolymerize glycogen and release glucose. Glucagon activates hepatic gluconeogenesis. Gluconeogenesis is the pathway by which non-hexose substrates such as amino acids are converted to glucose. As such, it provides another source of glucose for blood. This is especially important in animals like cats and sheep that don't absorb much if any glucose from the intestine - in these species, activation of gluconeogenic enzymes is the chief mechanism by which glucagon does its job. Glucagon also appears to have a minor effect of enhancing lipolysis of triglyceride in adipose tissue, which could be viewed as an addition means of conserving blood glucose by providing fatty acid fuel to most cells.
Inputs to alpha cells and effects of glucagon, including negative feedback, which increases plasma glucose levels.
Developed by Derek Le Roith, M.D., Ph.D. Aventis Dinner 2000 Borrowed from: Derek Le Roith, M.D., Ph.D. CMEA ADA ISS June 9, 2000 WO: 3035 syllabus
Relationship of Nutrition to Blood Glucose Control
Lesson 3.2 : Relationship of Nutrition to Blood Glucose Control
Insulin peptides C peptide Insulin ER Golgi Pre/pro -hormone (11,500 kDa) Pro -insulin (9,000 kDa) ER Insulin (6,000kDa) + Peptide C Golgi Enter the secretory granules Exit by exocytosis Blood (t 1/2 = 6 min) Action: via insulin receptors Proinsulin
General actions and regulation of insulin Insulin Secretion Lipoprotein lipase activated Cellular transport activated Catabolic enzymes inhibited Anabolic enzymes activated Glucagon secretion inhibited Gastrin Parasympatetic activity Amino Acids CCK Glucagon Glucose
Role of insulin during absorptive metabolic states (feeding) Glucose Fatty acids Amino acids Liver Most cells Adipose Muscle Insulin Intestine Glycogen Triglycerides Glycogen Triglycerides Proteins Proteins
The post-absorptive metabolic states (fasting ) Neurons Muscle Most cells Adipose Liver Proteins Proteins Glycogen Proteins Glycogen Triglycerides Triglycerides Energy Glucose Ketones Fatty Acids
Glucose-Insulin Relationship <ul><li>I nsulin decrease s the concentration of glucose in the blood , and a s soon as the blood glucose concentration fall s the insulin secretion ceases ( they regulate each other ). </li></ul><ul><li>In the absence of insulin, most cells switch to alternative fuels like fatty acids and proteins. </li></ul><ul><ul><li>CNS , however, require a constant supply of glucose, which is provided from glycogen degradation . </li></ul></ul>
Effects of insulin on GLUT4 in the muscle and fat <ul><li>S timulat ion of uptake, utilization and storage of glucose . </li></ul><ul><li>T he major transporter for uptake of glucose is GLUT4 . </li></ul><ul><li>GLUT4 is translocated to the plasma membrane through the action of insulin. </li></ul><ul><li>I nsulin stimulates the fusion of GLUT4 vesicles with the plasma membrane . </li></ul><ul><li>When blood levels of insulin decrease, the GLUT4 transporters are recycled back into the cytoplasm . </li></ul>
Insulin receptor Plasma membrane GLUT4 vesicle mobilization to plasma membrane Glucose Insulin Intracellular signaling cascades Insulin Action in Muscle and Fat Cells Mobilization of GLUT4 to the Cell Surface GLUT4 vesicle integration into plasma membrane Glucose entry into cell via GLUT4 vesicle Intracellular GLUT4 vesicles GLUT4=glucose transporter 4
Insulin in the liver: stimulation of glucose storage by glycogenesis <ul><li>Insulin stimulates glucose storage </li></ul><ul><ul><li>Glucose uptake </li></ul></ul><ul><ul><li>Glucose phopshorylation (glucokinase) </li></ul></ul><ul><ul><li>Enzymes involved in glycogenesis, including glycogen synthase. </li></ul></ul><ul><li>Insulin inhibits glycogen degradation </li></ul><ul><ul><li>glucose-6-phosphatase </li></ul></ul>
Insulin and Lipids: promotion of FA synthesis and lipid storage <ul><li>When the liver become saturated with glycogen , insulin </li></ul><ul><li>promotes synthesis of fatty acids . </li></ul><ul><ul><li>lipids are exported as lipoproteins . </li></ul></ul><ul><li>inhibits breakdown of lipids in adipose tissue s </li></ul><ul><ul><li>by inhibiting the hormone-sensitive lipase </li></ul></ul><ul><li>facilitates entry of glucose to synthesize glycerol </li></ul><ul><ul><li>glycerol and fatty acid form triglyceride stores in fat cells . </li></ul></ul>glucose
From the whole body perspective <ul><li>I nsulin has a fat-sparing effect : </li></ul><ul><li>It drive s most cells to preferentially oxidize glucose instead of fatty acids for energy . </li></ul><ul><li>It stimulates accumulation of lipids i n adipose tissue. </li></ul>
Insulin Receptor <ul><li>a tyrosine kinase </li></ul><ul><li>b inding of insulin causes autophosphorylat ion </li></ul><ul><li>t he activated receptor then phosphorylates intracellular proteins </li></ul><ul><li>the best known substrate: insulin receptor substrate 1 or IRS-1 </li></ul>
INSULIN signaling downstream of IRS: Sos Grb Ras Grb Insulin receptor IRS Sos Gene expression PTEN PI3 kinase Akt Insulin PIP3 Forkhead TF
Glucose and insulin regulate insulin gene expression C ell a signaling metabolite PI3K SAPK Insulin receptor substrates Inhibitors Insulin receptor Glucose Wortmanin Insulin Insulin
Other Effects of Insulin <ul><li>Insulin stimulates the uptake of amino acids </li></ul><ul><li>(an anabolic effect) (+) </li></ul><ul><li>At low insulin ( fasting state ), the metabolism is pushed toward protein degradation. </li></ul><ul><li>I n sulin in crease s the cellular uptake of K, Mg and P </li></ul><ul><ul><li>K influx is clinically important in diabetics </li></ul></ul><ul><ul><ul><li>Insulin activates Na/K pumps and decreases K in plasma </li></ul></ul></ul>
Physiologic Effects of Glucagon <ul><li>S t imulat ion of glucose production in the liver. </li></ul>
W hen blood glucose levels begin to fall , glucagon <ul><li>stimulat es glycogenolysis in the liver by activat ing enzymes that hydrolyze glycogen and release glucose. </li></ul><ul><li>activates hepatic gluconeogenesis - the conversion of amino acids to glucose . </li></ul><ul><li>enhanc es lipolysis of triglyceride in adipose tissue as an addition al way of conserving blood glucose . </li></ul>
General actions and regulation of glucagon cells Glucagon secretion Sympathetic activity Fatty acids and ketones Gluconeogenesis Glycogenolysis Inhibition of anabolism Secretion of Insulin Secretin CCK Parasymathetic activity Insulin Amino Acids Glucose
Abnormalities in Blood Glucose Control <ul><li>Fasting hyperinsulinemia & hyperglycemia </li></ul><ul><li>Fasting hyperinsulinemia </li></ul><ul><li>Fasting or postprandial hypoglycemia </li></ul>
Consequences of Hyperinsulinemia and Hyperglycemia <ul><li>Hyperinsulinemia </li></ul><ul><ul><li>increased SNS activity </li></ul></ul><ul><ul><li>altered smooth muscle cell Ca ++ transport </li></ul></ul><ul><ul><li>increased renal sodium retention </li></ul></ul><ul><ul><li>mitogenic effects on smooth muscle cells </li></ul></ul><ul><ul><li>increases plasminogen activator inhibitor-type 1 </li></ul></ul><ul><li>Hyperglycemia </li></ul><ul><ul><li>responsible for cellular injury/tissue damage underlying complications of poorly controlled diabetes </li></ul></ul>
Role of Diet in Control of Blood Glucose Abnormalities <ul><li>Prevention </li></ul><ul><ul><li>inhibits </li></ul></ul><ul><ul><li>delays </li></ul></ul><ul><li>Contribution </li></ul><ul><ul><li>accelerates </li></ul></ul><ul><ul><li>exacerbates </li></ul></ul><ul><li>Management </li></ul><ul><ul><li>primary treatment </li></ul></ul><ul><ul><li>adjunct treatment </li></ul></ul>
Dietary modifications to control blood glucose are involved in management of : <ul><ul><li>diabetes mellitus </li></ul></ul><ul><ul><li>hypertension </li></ul></ul><ul><ul><li>hyperlipidemia </li></ul></ul><ul><ul><li>liver disease </li></ul></ul><ul><ul><li>renal disease </li></ul></ul><ul><ul><li>cancer </li></ul></ul><ul><ul><li>obesity </li></ul></ul><ul><ul><li>trauma </li></ul></ul><ul><ul><li>sepsis </li></ul></ul><ul><ul><li>medication side effects </li></ul></ul><ul><ul><ul><li>hydrochlorothiazide </li></ul></ul></ul><ul><ul><ul><li>prednisone </li></ul></ul></ul><ul><ul><ul><li>chlorpropamide </li></ul></ul></ul><ul><ul><ul><li>propranolol </li></ul></ul></ul>
Blood Glucose Response to Different Sources of Carbohydrate
Steps in Development of Insulin Resistance from High Glycemic Load Rapidly digested & absorbed CHO with high energy density Rapid rise in blood glucose to high levels Release of corresponding high amount of insulin Insulin peaks at level consistent with blood glucose levels Downregulation of insulin receptors Repeated bouts of high insulin levels
Summary of Presentation <ul><li>Introduction: </li></ul><ul><li>Insulin Resistance/Metabolic Dyslipidemia </li></ul><ul><li>Recent Observations </li></ul><ul><li>Animal Model of Insulin Resistance </li></ul><ul><li>(Fructose-Fed Syrian Golden Hamster) </li></ul><ul><li>Evidence for Hepatic VLDL Overproduction </li></ul><ul><li>Evidence for Hepatic Insulin Resistance </li></ul><ul><li>Evidence for Intestinal Lipoprotein Overproduction </li></ul>
Insulin Resistance The diverse biological manifestations of the insulin resistant state arise as a consequence of both a blunted insulin action as well as the compensatory hyperinsulinemia per se. Insulin resistant peripheral tissues Insulin Increased insulin action in more sensitive tissues or biochemical pathways Pancreas
Clinical spectrum of insulin resistant states <ul><li>Rare (genetic) forms of insulin resistance </li></ul><ul><li>Obesity (central, abdominal, visceral, android) </li></ul><ul><li>Fasting hyperglycemia/Impaired glucose tolerance </li></ul><ul><li>Type 2 diabetes mellitus </li></ul>
Features of Metabolic Dyslipidemia • • Hypertriglyceridemia Hypertriglyceridemia TG, TG, ApoB ApoB VLDL-TG and VLDL-apoB secretion VLDL-TG and VLDL-apoB secretion Small Dense LDL Small Dense LDL ( LDL particle density) ( LDL particle density) • • Reduced HDL-C Reduced HDL-C • • Increase FFA Increase FFA
FFA FA VLDL DNL Adipose tissue Muscle Liver Intestine TG mobilization by tissue lipases TG, CE ApoB Cytosolic TG stores Oxidation Lipases LPL Mechanisms of VLDL overproduction in Insulin Resistance Hepatic Insulin Resistance Adeli K. et al. (2000) J. Biol. Chem. 275: 8416-8425. Adeli K. et al. (2002) J. Biol. Chem. 277:793-803.
Diet and Insulin Resistance <ul><li>Diet -induced/responsive </li></ul><ul><li>adaptive response to repeated exposure to postprandial hyperinsulinemia </li></ul><ul><ul><li>downregulation of insulin receptors </li></ul></ul><ul><li>decreased hepatic insulin clearance </li></ul><ul><li>Diet-responsive </li></ul><ul><li>post-receptor defect in signal transduction </li></ul><ul><ul><li>glucose transporter synthesis/activity </li></ul></ul><ul><ul><li>changes in membrane fluidity and integrity </li></ul></ul><ul><li>increase in stress hormones </li></ul><ul><ul><li>injury </li></ul></ul><ul><ul><li>sepsis </li></ul></ul>
Characteristics of Insulin Resistance Obesity vs DM2 <ul><li>Obesity </li></ul><ul><ul><li>peripheral effects </li></ul></ul><ul><ul><li>hepatic glucose output unaffected </li></ul></ul><ul><ul><li>nonoxidative glucose disposal decreased </li></ul></ul><ul><li>DM2 </li></ul><ul><ul><li>peripheral effects </li></ul></ul><ul><ul><li>hepatic glucose output not suppressed </li></ul></ul><ul><ul><li>adipocyte lipogenesis and oxidative glucose metabolism affected </li></ul></ul>
Glycemic Load <ul><li>Described by the area under the curve (AUC) of blood glucose vs time after ingestion </li></ul><ul><li>Characteristic of type of carbohydrate </li></ul><ul><li>A function of energy intake </li></ul><ul><li>Influenced by rate of gastric emptying </li></ul><ul><li>Reflects efficiency of digestion </li></ul><ul><li>Reflects rate of absorption </li></ul>
The Glycemic Index <ul><li>Physiological measure of effects of foods on blood glucose </li></ul><ul><li>Calculated as the AUC of a test food expressed as a percentage of the AUC of a glucose standard </li></ul><ul><li>Compares foods based on equivalent amounts of available CHO </li></ul><ul><li>Characteristic of foods, not individuals </li></ul>
Glycemic Index of Mixed Meals <ul><li>Glycemic indexes calculated for individual foods </li></ul><ul><li>Individual foods weighed by a factor based on percentage of carbohydrate contributed by the food to the total carbohydrate content of the meal </li></ul><ul><li>Accurately predicts differences in blood glucose responses to different meals </li></ul>
Glycemic Indexes of Various Foods (Equivalent Amounts of Available CHO)
Clinical Significance of Glycemic Index <ul><li>Low Gl Foods </li></ul><ul><ul><li>decrease insulin secretion </li></ul></ul><ul><ul><li>improve blood glucose control in DM2/DM1 </li></ul></ul><ul><ul><li>normalize blood glucose, insulin & amino acid levels in cirrhosis </li></ul></ul><ul><li>Low GI Foods/Meals </li></ul><ul><ul><li>increase satiety </li></ul></ul><ul><ul><li>enhance performance </li></ul></ul>
Carbohydrate and Blood Glucose Control <ul><li>Simple Sugars </li></ul><ul><li>high solubility = high load </li></ul><ul><li>liquids > solids </li></ul><ul><li>diminished by fiber </li></ul><ul><li>enhanced by high energy intake </li></ul><ul><li>enhanced by Na + </li></ul><ul><li>Starches </li></ul><ul><li>high digestibility = high load </li></ul><ul><li>amylopectin > amylose </li></ul><ul><li>amylose > resistant starch </li></ul><ul><li>refined starch > simple sugars + fiber </li></ul>
Viscous (Soluble) Dietary Fiber and Blood Glucose Control <ul><li>Decreases rate of digestion </li></ul><ul><ul><li>slows access of digestive enzymes </li></ul></ul><ul><li>Decreases rate of absorption </li></ul><ul><ul><li>slows rate of diffusion across unstirred layer </li></ul></ul><ul><li>Found in small amounts in all plant foods </li></ul><ul><li>Richest source are oats, barley, citrus fruit, legumes, psyllium </li></ul>
Energy Intake and Blood Glucose Control <ul><li>Contributes to weight gain/loss </li></ul><ul><li>Contributes nutrients that affect insulin </li></ul><ul><li>Contributes to abdominal fat deposition </li></ul><ul><ul><li>high portal concentration of free fatty acids inhibits hepatic insulin clearance </li></ul></ul><ul><ul><li>higher insulin requirement for glucose uptake </li></ul></ul>
Exercise and and Blood Glucose Control <ul><ul><li>inhibits weight gain </li></ul></ul><ul><ul><li>increases muscle mass/fat mass ratio </li></ul></ul><ul><ul><li>mobilizes free fatty acids from adipocytes </li></ul></ul><ul><ul><li>increases skeletal muscle uptake of FFA </li></ul></ul><ul><ul><ul><li>enhances glycogenesis for 24-48 hours </li></ul></ul></ul>
Fat and Blood Glucose Control <ul><li>Total Fat </li></ul><ul><li>slows gastric motility/emptying </li></ul><ul><li>predisposes to weight gain </li></ul><ul><li>effects exaggerated if abdominal obesity present </li></ul><ul><li>Type of Fat </li></ul><ul><li>saturated fat </li></ul><ul><ul><li> membrane fluidity </li></ul></ul><ul><ul><li> number of glucose transporters </li></ul></ul><ul><li>polyunsaturated fat </li></ul><ul><ul><li> -3 insulin sensitivity </li></ul></ul><ul><li>monounsaturated fat </li></ul><ul><ul><li>stimulates insulin release </li></ul></ul>
Protein and Blood Glucose Control <ul><li>Influences insulin/glucagon ratio </li></ul><ul><ul><li>blood glucose </li></ul></ul><ul><ul><li>tissue protein accretion </li></ul></ul><ul><ul><li>cholesterol synthesis </li></ul></ul><ul><ul><ul><li>HMG-CoA reductase </li></ul></ul></ul><ul><li>High arginine/lysine ratio stimulates insulin </li></ul>
Meal Patterns and Blood Glucose Control <ul><li>Favorable Effects </li></ul><ul><ul><li>frequent small meals </li></ul></ul><ul><ul><li>low-moderate glycemic loads </li></ul></ul><ul><ul><li>low energy density </li></ul></ul><ul><ul><li>consumed prior to or following periods of activity </li></ul></ul><ul><li>Unfavorable Effects </li></ul><ul><ul><li>few large meals </li></ul></ul><ul><ul><li>frequent meals contributing high glycemic loads </li></ul></ul><ul><ul><li>consumed prior to period of inactivity </li></ul></ul>
Summary <ul><li>Diet can affect short-term insulin response </li></ul><ul><li>Diet can affect long-term insulin response </li></ul><ul><li>Glycemic response is not a simple function of amount and type of carbohydrate </li></ul><ul><li>Glycemic response can be affected by nutrients other than carbohydrate </li></ul>
Comparison of Insulin Responses with Different Patterns of Blood Glucose
Diabetes and Obesity - Type 2 diabetes (90% of diabetes cases) is strongly linked to obesity - >80% of sufferers are obese - Insulin is less able to promote the uptake of glucose into muscles and fat, and to inhibit the production of glucose by the liver - How increased energy storage in adipocytes promotes insulin resistance in other organs is not known
Adipose Tissue: An Endocrine Organ Role in Insulin resistance, Obesity & Diabetes Adiponectin Angiotensinogen etc Resistin IL-6 TNF- Leptin
What is Leptin? <ul><li>A peptide hormone which is coded for by the obese gene (ob) </li></ul><ul><li>Influences the quantity of food consumed relative to the amount of energy expended </li></ul><ul><ul><li>When leptin levels are high, appetite is reduced and energy expenditure is increased </li></ul></ul><ul><li>Leptin has been found in gastric epithelium, placenta and adipose tissue </li></ul><ul><ul><li>Most abundant in white adipose tissue </li></ul></ul>
White Adipose Tissue (WAT) <ul><li>Composed mainly of adipocytes (fat cells) </li></ul><ul><ul><li>Store energy in the form of triglycerides in times of nutritional affluence </li></ul></ul><ul><ul><li>Release free fatty acids during nutritional deprivation </li></ul></ul><ul><li>WAT mass is determined by the balance between energy intake and expenditure </li></ul><ul><ul><li>This is influenced by genetic, neuroendocrine, and environmental factors </li></ul></ul><ul><li>Under normal conditions this system is carefully regulated so that WAT mass remains constant and close to well defined ‘set point’ </li></ul><ul><li>Disruption of the steady state can lead to chronic decreases or increases in the quantity of WAT </li></ul><ul><ul><li>Decreaased amounts are associated with weight alterations during peroids of diet, malnutrition, eating disorders, etc </li></ul></ul><ul><ul><li>Increased amounts indicate obesity </li></ul></ul>
Regulating Food Intake and Energy Expenditure <ul><li>Leptin binds to its receptor which is expressed primarily in the brains hypothalamus region </li></ul><ul><li>In turn the hypothalamus modulates food intake and energy expenditure </li></ul><ul><li>When low leptin levels are detected, the body is warned of limited energy supplies </li></ul><ul><li>If high leptin levels are detected, the hypothalamus senses the body as being overweight </li></ul><ul><ul><li>This then trigger the body to eat less and expend more energy </li></ul></ul><ul><li>When energy intake and output are equal, leptin reflects the amount of triglyceride stored in the bodies adipose tissue </li></ul>
Metabolic Affects of Leptin <ul><li>Decreases intracellular lipid concentration through reduction of fatty acid and triglyceride synthesis and a concomitant increase in lipid oxidation </li></ul><ul><li>It has been postulated that leptin inhibits acetyl-CoA carboxylase </li></ul><ul><ul><li>Enzyme involved in the committed step of fatty acid synthesis </li></ul></ul><ul><li>This inhibition leads to decrease in malonyl-CoA levels </li></ul><ul><ul><li>Together the inhibition of acetyl-CoA to malonyl-CoA encourages the mobilization of fatty acids from storage sites and simultaneously discourages synthesis </li></ul></ul><ul><li>Carnitine acyl transferase I, which is normally inhibited by malonyl-CoA, is then available to aid in lipid oxidation </li></ul><ul><ul><li>This enzyme is required for the transport of Acyl CoA molecules across the inner mitochondrial membrane </li></ul></ul><ul><ul><li>Without this step, fatty acid breakdown is inhibited </li></ul></ul>
Leptin deficiency and receptor defects in rodents cause marked obesity as well as hyperglycemia and hyperinsulinemia
Experimentation on Mice <ul><li>Mice leptin has an 84% resemblance to human analog </li></ul><ul><li>Some obese mice have been found to have mutation in ob gene caused by premature stop codon </li></ul><ul><ul><li>Results in absolute lack of leptin which leads to severe obesity </li></ul></ul><ul><li>Experimentation done on both obese and normal mice </li></ul><ul><li>Intravenous, intraperitoneal, an intracerebroventricular injections were given </li></ul><ul><li>Results most significant for intracerebroventricular injections </li></ul><ul><ul><li>All mice showed affected </li></ul></ul><ul><ul><li>Lower dosages required </li></ul></ul><ul><li>Varying degrees of body weight loss related to dosage and time </li></ul><ul><li>Decreased food intake and metabolic rate increased </li></ul><ul><li>Significant amounts of WAT mass lost </li></ul>
Experimentation on Humans <ul><li>Few experiments done at this point </li></ul><ul><li>Leptin is said to circulate freely or attached to a binding protein </li></ul><ul><ul><li>It has been found that obese individuals have more circulating bound leptin than lean individuals </li></ul></ul><ul><li>The greater the initial level, the more it declines with dieting </li></ul><ul><li>Levels tend to vary greatly from person to person </li></ul><ul><li>Typically females have more leptin than males </li></ul><ul><ul><li>Adipose tissue accounts for 20-25% of weight in females and only 15-20% in males </li></ul></ul><ul><li>In general the greater the body mass and percent body fat, the higher the levels </li></ul><ul><ul><li>People suffering from obesity have extremely high levels </li></ul></ul>
How does Leptin work in Obesity <ul><li>Appears that leptin is primarily a signal that is active in response to insufficient energy supply rather than one that is activated to prevent an oversupply of energy </li></ul><ul><li>Apparent ineffectiveness of leptin in obese persons despite high circulating levels raises questions of whether "leptin resistance" is operating in these individuals & whether it can be overcome to benefit overweight patients </li></ul>
Possible Reasons For Increased Leptin In Obese Individuals <ul><li>Differences in the fat production rate of leptin </li></ul><ul><ul><li>Some obese people may make leptin at greater rate to compensate for faulty signaling process or action </li></ul></ul><ul><li>Resistance to leptin at its site of action </li></ul><ul><ul><li>If resistance is partial, not complete, more leptin may be required for action </li></ul></ul><ul><li>A combination of both could influence eating behaviors and energy use to cause obesity </li></ul><ul><li>All these possibilities indicate that obese individuals are in a state of percieved starvation </li></ul><ul><li>Leptin responsible for adaptation to low energy intake rather than a brake on over-consumption and obesity </li></ul><ul><ul><li>Regulated by insulin induced changes of adipocyte metabolism </li></ul></ul><ul><ul><li>Fat & fructose intake do not initiate insulin secretion – reduce leptin levels leading to overeating and weight gain in population with high intake of these macronutrients </li></ul></ul>
What research has told us about Leptin <ul><li>It was quickly apparent that leptin is generally ineffective as signal for excessive body fat, since obese people generally have higher, not lower, levels of leptin, but yet remain obese </li></ul><ul><li>Probably more important role of leptin is to signal to body that body fat has fallen to dangerously low levels (for example during starvation) & thus signal that appropriate metabolic changes should occur to preserve metabolic resources. This current view of leptin was supported by the results of clinical trials of leptin on overweight individuals. </li></ul>
What research has told us about Leptin <ul><li>Over 200 candidate genes for obesity-most remain unidentified in humans </li></ul><ul><li>Considerable amount of research has focused on hypothetical link between obesity & type 2 diabetes in region of leptin receptor gene </li></ul><ul><li>But sequence variations that have been detected have not yet been linked to body fat mass </li></ul>
What we know about Leptin <ul><li>Women have higher leptin levels than men, even after accounting for estrogen status (e.g., there are no consistent differences among premenopausal women, postmenopausal women, and postmenopausal women on estrogen replacement) </li></ul><ul><li>There is a possibility that testosterone in men might have a suppressive effect on production of leptin by the adipocyte </li></ul>
What we know about Leptin- A key factor is body energy status <ul><li>Short-term energy restriction leads to a marked fall in circulating leptin levels, even after adjusting for changes in adipose mass </li></ul><ul><li>Fall is associated with increased hunger, which may be an early impediment to compliance with a low-energy diet to achieve weight loss </li></ul><ul><li>While a number of potential signals could mediate the acute fall in leptin with energy restriction </li></ul><ul><li>Plasma insulin concentrations decline in parallel with leptin levels in this condition </li></ul>
What we know about Leptin-Dietary Composition <ul><li>Dietary composition can affect leptin production by the adipocyte </li></ul><ul><li>High-fat diet reduces leptin levels more than a high-carbohydrate diet does </li></ul><ul><li>Fructose reduces leptin levels more than glucose does </li></ul><ul><li>These findings have obvious implications for the relation of dietary composition-specifically high-fat diets-to weight gain </li></ul>
Latest Research Finding about Leptin <ul><li>Researchers have successfully used hormone leptin to treat patients suffering from lipodystrophy-rare & difficult-to-treat disorder that shares some characteristics of typical type 2 diabetes </li></ul><ul><li>People with lipodystrophy have few or no fat cells & thus lack leptin, a hormone produced by & stored in fat cells </li></ul>
Latest Research Finding about Leptin – What is lipodystrophy? <ul><li>Because they have no fat cells, people with condition usually store huge amounts of lipids (fat) in inappropriate places like muscle or liver & have extremely high levels of lipids in their blood </li></ul><ul><li>They are likely to be insulin resistant-meaning their bodies don't readily respond to insulin-hormone that allows muscle & fat cells to properly use glucose. </li></ul>
Another Latest Research Finding <ul><li>Establishes a new connection in metabolic machinery, tying leptin to crucial pathway in fat metabolism in muscle </li></ul><ul><li>Pathway suggests a role for leptin in clearing fat out of cells and sheds light on connection between diabetes & obesity. </li></ul>
Another Latest Research Finding <ul><li>In light of new knowledge about leptin's role in fuel metabolism, it makes sense to revisit idea of targeting leptin's actions to treat obesity </li></ul><ul><li>Obese people develop resistance to leptin, so ability to target downstream pathway & bypass leptin resistance may be more beneficial than treating with leptin itself </li></ul>
Future Treatment in Weight Regulation <ul><li>Leptins dual action of reducing appetite while increasing energy expenditure makes it a good candidate for weight regulation </li></ul><ul><li>Has applications for both dieters and obese individuals </li></ul><ul><li>Dieters: </li></ul><ul><ul><li>Prevent reduced energy expenditure normally associated with decreased food intake </li></ul></ul><ul><ul><li>Prevent the regaining of weight </li></ul></ul><ul><ul><ul><li>The lower leptin levels associated with dieting are said to make the body respond as if in period of starvation </li></ul></ul></ul><ul><ul><ul><li>Administering leptin will decrease cravings and speed up metabolism to prevent weight from returning to set point </li></ul></ul></ul><ul><li>Obese Individuals: </li></ul><ul><ul><li>Prevent health problems associated with obesity </li></ul></ul><ul><ul><ul><li>high blood pressure, heart attack, arthritis, stroke, etc </li></ul></ul></ul><ul><li>Reduce WAT mass for both groups </li></ul>
Diabetes and Obesity Levels of fatty acids are higher in obese people Fatty acids can induce insulin resistance by unknown mechanism Adipocytes secrete tumor-necrosis factor (TNF ) and leptin TNF is involved in insulin resistance but does not account for full insulin resistance Leptin ? Its absence causes obesity in rodents and returning reverses resistance. However, leptin levels are high in obese people Other factors must be involved
Diabetes and Obesity The missing link with obesity? Steppan et al. Hormone resistin links obesity to diabetes. (2001) Nature, 409, 307-312 Resistin - for resistance to insulin (anti-insulin) Expressed in adipocytes, overexpressed in obese animals Secreted into bloodstream Anti-diabetic drugs (thiazoladinediones) reduce its expression Administration of the protein reduces obesity, antibodies against the protein decrease the effect Resistin suppresses insulin’s ability to stimulate glucose uptake
Diabetes and Obesity <ul><li>Adiponectin </li></ul><ul><ul><li>Adipocyte derived peptide </li></ul></ul><ul><ul><li>Anti-inflammatory and insulin sensitizing effect </li></ul></ul><ul><ul><ul><li>Increases tissue fatty acid oxidation therefore reducing FFA and triglycerides </li></ul></ul></ul><ul><ul><li>High concentrations associated with reduction of risk for developing DM2 </li></ul></ul><ul><ul><li>PPAR (peroxisome proliferating activator receptor- - new oral anti diabetic therapy) increase levels of adiponectin – exert insulin sensitizing effect via this mechanism ? </li></ul></ul>
References <ul><li>Journal of Endocrinological Investigation : 25(10); 855-861 Nov 2002 </li></ul><ul><li>Diabetes Metabolism Research and Reviews : 18(5); 345-356 Sep-Oct 2002 </li></ul><ul><li>Current Opinion in Lipidology : 13(1); 51-59 Feb 2002 </li></ul><ul><li> : 13(3); 201-256 June 2002 </li></ul>