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
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
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
Evidence for Intestinal Lipoprotein Overproduction
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
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.
Glycemic response is not a simple function of amount and type of carbohydrate
Glycemic response can be affected by nutrients other than carbohydrate
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
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
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
Possible Reasons For Increased Leptin In Obese Individuals
Differences in the fat production rate of leptin
Some obese people may make leptin at greater rate to compensate for faulty signaling process or action
Resistance to leptin at its site of action
If resistance is partial, not complete, more leptin may be required for action
A combination of both could influence eating behaviors and energy use to cause obesity
All these possibilities indicate that obese individuals are in a state of percieved starvation
Leptin responsible for adaptation to low energy intake rather than a brake on over-consumption and obesity
Regulated by insulin induced changes of adipocyte metabolism
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
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
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.
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)
There is a possibility that testosterone in men might have a suppressive effect on production of leptin by the adipocyte
What we know about Leptin- A key factor is body energy status
Short-term energy restriction leads to a marked fall in circulating leptin levels, even after adjusting for changes in adipose mass
Fall is associated with increased hunger, which may be an early impediment to compliance with a low-energy diet to achieve weight loss
While a number of potential signals could mediate the acute fall in leptin with energy restriction
Plasma insulin concentrations decline in parallel with leptin levels in this condition
Leptins dual action of reducing appetite while increasing energy expenditure makes it a good candidate for weight regulation
Has applications for both dieters and obese individuals
Prevent reduced energy expenditure normally associated with decreased food intake
Prevent the regaining of weight
The lower leptin levels associated with dieting are said to make the body respond as if in period of starvation
Administering leptin will decrease cravings and speed up metabolism to prevent weight from returning to set point
Prevent health problems associated with obesity
high blood pressure, heart attack, arthritis, stroke, etc
Reduce WAT mass for both groups
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