Insulin resistance in obese individuals may arise from various causes. The primary factors contributing to obesity-induced insulin resistance are as follows:
1. Skeletal muscle exhibits reduced responsiveness to insulin's ability to facilitate glucose uptake through the GLUT4 transporter. This impairment in glucose metabolism regulation is likely due to the excessive accumulation of triglycerides (TG) in muscle tissues. Hyperinsulinemia, resulting from excessive caloric intake, initially promotes excessive glucose uptake in skeletal muscle. However, similar to the liver, the surplus glucose encourages lipogenesis and suppresses fatty acyl-CoA oxidation via malonyl-CoA generation. The byproducts of fatty acid and TG synthesis, such as diacylglycerol and ceramide, may accumulate and activate signaling pathways (e.g., protein kinase C-dependent pathways). These pathways antagonize signaling from the insulin receptor (InsR) or insulin receptor substrate (IRS) proteins, or both, thereby contributing to insulin resistance in skeletal muscle.
2. Insulin's ability to suppress hepatic glucose production is impaired in insulin-resistant individuals. The liver synthesizes glucose through glycogenolysis in the short term and gluconeogenesis in the long term. Insulin resistance in the liver may also result from lipotoxicity observed in obese individuals, such as fatty liver or hepatic steatosis. Visceral adipose tissue likely affects insulin signaling at the liver through multiple mechanisms, including lipotoxicity. For instance, visceral adipose tissue releases the cytokine tumor necrosis factor (TNF)-α, which has been shown to antagonize insulin signaling pathways. Additionally, the high turnover rate of triglycerides (TG) in visceral adipose tissue, possibly due to rich sympathetic innervation, exposes the liver to elevated levels of free fatty acids (FFAs), further exacerbating hepatic lipotoxicity.
3. Insulin's ability to suppress hormone-sensitive lipase (HSL) or increase lipoprotein lipase (LPL) in adipose tissue, or both, is impaired in insulin resistance. High levels of HSL and low levels of LPL contribute to the dyslipidemia associated with insulin resistance and diabetes. The factors responsible for resisting insulin's action on HSL and LPL are not completely understood, but evidence suggests increased production of paracrine diabetogenic factors in adipose tissue, such as TNF-α. Dyslipidemia in insulin resistance is characterized by hypertriglyceridemia with the liver producing large TG-rich very low-density lipoprotein (VLDL) particles. Due to their high TG content, these large VLDL and intermediate-density lipoprotein (IDL) particles are efficiently digested, resulting in small, dense low-density lipoprotein (LDL) particles that are highly atherogenic. Furthermore, high-density lipoprotein (HDL) acquires excess TG in exchange for cholesterol esters, which shortens the circulating half-life of HDL and ApoA proteins. Consequently, lower levels of HDL particles, which normally play a protective role against vascular disease, are observed.
Type 1 diabetes mellitus (T1DM) is characterized by the destruction of beta cells, predominantly through an autoimmune mechanism. T1DM is also known as insulin-dependent diabetes mellitus and exhibits the following characteristics:
1. Individuals with T1DM require exogenous insulin for survival and to prevent ketosis since the pancreas produces virtually no insulin.
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Theunderlyingcausesofinsulinresistancedifferamongpatients.Threemajorunderlyingcausesofobesity-inducedinsulinresistanceare: 1.Decreased ability of insulin to increase GLUT4-mediated uptake of glucose, especially by skeletal muscle. Thisfunction,whichisspecificallyapartofglucometabolic regulation by insulin, maybeduetoexcessiveaccumulationofTGinmuscleinobeseindividuals.Excessivecaloricintakeinduceshyperinsulinemia.Initiallythisleadstoexcessiveglucoseuptakeintoskeletalmuscle.Justasintheliver,excessivecaloriesintheformofglucosepromotelipogenesisand,throughgenerationofmalonylCoA,repressionoffattyacylCoAoxidation.ByproductsoffattyacidandTGsynthesis(e.g.,diacylglycerol,ceramide)mayaccumulateandstimulatesignalingpathways(e.g.,proteinkinaseC–dependentpathways)thatantagonizesignalingfromtheInsRorIRSproteins,orboth.Thusinsulinresistanceintheskeletalmuscleofobeseindividualsmaybeduetolipotoxicity.
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Decreased ability of insulin to repress hepatic glucose production. Thelivermakesglucosebyglycogenolysisintheshorttermandbygluconeogenesisinthelongterm.Theabilityofinsulintorepresskeyhepaticenzymesinboththesepathwaysisattenuatedininsulin-resistantindividuals.Insulinresistanceinthelivermayalsobeduetolipotoxicityinobeseindividuals(e.g.,fatty liver orhepatic steatosis).Visceraladiposetissueislikelytoaffectinsulinsignalingattheliverinseveralways,inadditiontotheeffectsoflipotoxicity.Forexample,visceraladiposetissuereleasesthecytokinetumor necrosis factor (TNF)-α, whichhasbeenshowntoantagonizeinsulinsignalingpathways.Also,TGinvisceraladiposetissuehasahighrateofturnover(possiblybecauseofrichsympatheticinnervation),sotheliverisexposedtohighlevelsofFFAs,whichfurtherexacerbateshepaticlipotoxicity.
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Inability of insulin to repress hormone-sensitive lipase or increase LPL in adipose tissue (or both). HighHSLandlowLPLaremajorfactorsinthedyslipidemiaassociatedwithinsulinresistanceanddiabetes.AlthoughthefactorsthatresisttheactionsofinsulinonHSLandLPLarenotcompletelyunderstood,thereisevidenceforincreasedproductionofparacrinediabetogenicfactorsinadiposetissue,suchasTNF-α.ThedyslipidemiaischaracterizedashypertriglyceridemiawithlargeTG-richVLDLparticlesproducedbytheliver.BecauseoftheirhighTGcontent,largeVLDLsandIDLsaredigestedveryefficiently,therebygivingrisetosmall,denseLDLparticlesthatareveryatherogenic.Inaddition,HDLtakesonexcessTGinexchangeforcholesterolesters,whichappearstoshortenthecirculatinghalf-lifeofHDLandApoAproteins.ThustherearelowerlevelsofHDLparticles,whichnormallyplayaprotectiveroleagainstvasculardisease.T1DM ischaracterizedbydestructionofbetacells,almost alwaysbyanautoimmunemechanism.T1DMisalsotermedinsulin-dependent diabetes mellitus. CharacteristicsofT1DMare: 1.
PeoplewithT1DMneedexogenousinsulintomaintainlifeandpreventketosis;virtuallynopancreaticinsulinisproduced.
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