Download - Diabetes Lancet

Transcript
  • 8/22/2019 Diabetes Lancet

    1/14

    Seminar

    Diabetes mellitus has reached epidemic proportions and

    affects more than 170 million individuals worldwide(figure 1). Global estimates for the year 2010 predict afurther growth of almost 50%, with the greatestincreases in the developing countries of Africa, Asia, andSouth America.1 In more developed societies, theprevalence of diabetes mellitus has reached about 6%, 2

    and, even more alarmingly, among obese whiteadolescents 4% had diabetes and 25% had abnormalglucose tolerance.3 Some 90% of diabetic individualshave type 2 (non-insulin-dependent) diabetes mellitus,and within this category no more than 10% can beaccounted for by monogenic forms such as maturity-onset diabetes of the young4 and mitochondrial diabetes5

    or late-onset autoimmune diabetes of the adult, which isactually a late-onset type 1 diabetes.6 Thus, most diabetesin the world is accounted for by common type 2diabetes, which has a multifactorial pathogenesis causedby alterations in several gene products.

    The medical and socioeconomic burden of the diseaseis caused by the associated complications,79 whichimpose enormous strains on health-care systems. Theincremental costs of patients with type 2 diabetes arisenot only when the diagnosis is established but at least8 years earlier.10 The devastating complications ofdiabetes mellitus are mostly macrovascular and

    microvascular diseases as a consequence of accelerated

    atherogenesis. Cardiovascular morbidity in patients withtype 2 diabetes is two to four times greater than that ofnon-diabetic people.1

    DiagnosisDiabetes mellitus is diagnosed on the basis of WHOrecommendations from 1999, incorporating both fastingand 2-h after glucose load (75 g) criteria into a practicablediagnostic classification that should now be used(table 1).11 Conditions that predispose to overt diabetes,including impaired fasting glucose and impairedglucose tolerance are not merely of academic interest,since, unless treated, about 7% of people with these

    problems will progress to overt diabetes every year.

    12,13

    Furthermore, impaired glucose tolerance itself carriesan increased risk of macrovascular disease.14

    Heredity in type 2 diabetes mellitusAlthough lifestyle and overeating seem to be thetriggering pathogenic factors, genetic elements are alsoinvolved in the pathogenesis of type 2 diabetes. Positivefamily history confers a 24 fold increased risk for type 2diabetes. 1525% of first-degree relatives of patients withtype 2 diabetes develop impaired glucose tolerance ordiabetes.15 The lifetime risk (at age 80 years) for type 2

    Lancet 2005; 365: 133346

    See Personal Account page 1347

    Third Medical Department,

    University of Leipzig, Leipzig,

    Germany (Prof M Stumvoll MD);

    Division of Endocrinology,

    Diabetes and Metabolic

    Diseases, Department of

    Medicine, Jefferson Medical

    College of Thomas Jefferson

    University, Philadelphia, PA,

    USA (Prof B J Goldstein MD); and

    Department of Internal

    Medicine G 02228, University

    Medical Centre Utrecht,

    PO Box 85500, NL 3508 GA

    Utrecht, Netherlands

    (T W van Haeften MD)

    Correspondence to:

    Dr T W van Haeften

    [email protected]

    www.thelancet.com Vol 365 April 9, 2005 1333

    Type 2 diabetes: principles of pathogenesis and therapyMichael Stumvoll, Barry J Goldstein, Timon W v an Haeften

    Type 2 diabetes mellitus has become an epidemic, and virtually no physician is without patients who have thedisease. Whereas insulin insensitivity is an early phenomenon partly related to obesity, pancreas -cell functiondeclines gradually over time already before the onset of clinical hyperglycaemia. Several mechanisms have beenproposed, including increased non-esterified fatty acids, inflammatory cytokines, adipokines, and mitochondrialdysfunction for insulin resistance, and glucotoxicity, lipotoxicity, and amyloid formation for -cell dysfunction.Moreover, the disease has a strong genetic component, but only a handful of genes have been identified so far: genesfor calpain 10, potassium inward-rectifier 62, peroxisome proliferator-activated receptor , insulin receptorsubstrate-1, and others. Management includes not only diet and exercise, but also combinations of anti-hyperglycaemic drug treatment with lipid-lowering, antihypertensive, and anti platelet therapy.

    Glucose concentration in venous plasma (mmol/L)

    Diabetes mellitus Fasting70 or 2-h post-glucose load 111

    Impaired glucose tolerance Fasting (if measured)70 and 2-h post-glucose load 78 and111

    Impaired fasting glucose Fasting61 and70 and 2 h post-glucose load (if measured)78

    Glucose load=75 g glucose orally.10

    Table 1: Diagnostic criteria of diabetes mellitus and other categories of hyperglycaemia

    21

    11

    3

    32

    14

    49

    46

    Figure 1: Estimated numbers (millions) of people aged 2079 years with

    diabetes in 2001Source: International Diabetes Federation (http://www.eatlas.idf.org).

    Search strategy and selection criteria

    We searched PubMed with the terms type 2 diabetes,

    insulin resistance, insulin secretion, beta cell

    dysfunction, sulphonylurea, thiazolidionediones,

    metformin, acarbose, and combinations of these terms.

    We selected the most recent papers and review articles.

  • 8/22/2019 Diabetes Lancet

    2/14

    Seminar

    diabetes has been calculated to be 38% if one parent hadtype 2 diabetes.15 If both parents are affected, theprevalence of type 2 diabetes in the offspring isestimated to approach 60% by the age of 60 years.16

    Since dizygotic twins share the environment (bothintrauterine and extrauterine) but only 50% of theirgenes, concordance rates in monozygotic twins in excessof those in dizygotic twins have been used to distinguishgenetic from non-genetic contributions. In individualsolder than 60 years, concordance rates for diabetes were3558% in monozygotic twins, compared with 1720%in dizygotic twins.17,18 Inclusion of impaired glucosetolerance markedly increased the concordance in

    monozygotic twins to 88%.

    19

    Estimates of heritability ofdiabetes-related traits are summarised in table 2.Nevertheless, concordance rates in monozygotic twins

    might produce an underestimate of genetic effects,because the monochorionic intrauterine nutrition ofmonozygotic twins has been shown to result in growthretardation compared with dizygotic twins.32 And lowbirthweight itself is associated with increased risk of type2 diabetes later in life. 33,34

    Pathophysiology of hyperglycaemia

    To understand the cellular and molecular mechanismsresponsible for type 2 diabetes it is necessary toconceptualise the framework within which glycaemia iscontrolled. Insulin is the key hormone for regulation ofblood glucose and, generally, normoglycaemia ismaintained by the balanced interplay between insulinaction and insulin secretion. Importantly, the normalpancreatic cell can adapt to changes in insulin actionie, a decrease in insulin action is accompanied byupregulation of insulin secretion (and vice versa).Figure 2 illustrates the curvilinear relation betweennormal -cell function and insulin sensitivity.35 Deviationfrom this hyperbola, such as in the patients withimpaired glucose tolerance and type 2 diabetes in figure

    2, occurs when -cell function is inadequately low for aspecific degree of insulin sensitivity. Thus, -celldysfunction is a critical component in the pathogenesisof type 2 diabetes. This concept has been verified not onlyin cross-sectional studies but also longitudinally in PimaIndians progressing from normal to impaired glucosetolerance to type 2 diabetes.36

    However, not only deviation from but also progressionalong the hyperbola affects glycaemia. When insulinaction decreases (as with increasing obesity) the systemusually compensates by increasing -cell function.However, at the same time, concentrations of bloodglucose at fasting and 2 h after glucose load will increase

    mildly.

    37

    This increase may well be small, but over timebecomes damaging because of glucose toxicity, and initself a cause for -cell dysfunction. Thus, even with(theoretically) unlimited -cell reserve, insulinresistance paves the way for hyperglycaemia and type 2diabetes.

    Insulin resistanceInsulin resistance is said to be present when thebiological effects of insulin are less than expected forboth glucose disposal in skeletal muscle and suppressionof endogenous glucose production primarily in the liver.38

    In the fasting state, however, muscle accounts for only asmall proportion of glucose disposal (less than 20%)

    whereas endogenous glucose production is responsiblefor all the glucose entering the plasma. Endogenousglucose production is accelerated in patients with type 2diabetes or impaired fasting glucose.39,40 Because thisincrease occurs in the presence of hyperinsulinaemia, atleast in the early and intermediate disease stages, hepaticinsulin resistance is the driving force of hyperglycaemiaof type 2 diabetes (figure 3).

    ObesityInsulin resistance is strongly associated with obesity andphysical inactivity, and several mechanisms mediatingthis interaction have been identified. A number ofcirculating hormones, cytokines, and metabolic fuels,such as non-esterified (free) fatty acids (NEFA) originate

    1334 www.thelancet.com Vol 365 April 9, 2005

    Heritability, family studies Heritability, twin studies

    Range References Range References

    BMI 042054 19-21 080 22

    WHR 013022 20,21,23 006070 22,24

    Fasting glucose 010072 19-21,23,25 026 22

    2-h glucose 014030 20,25 052 22

    Fasting insulin 008037 19-21,23,25,26 026 22

    2-h insulin 014025 20,25,27

    Secretion index 078 21 050068 22,24,28

    Sensitivity index 008046 19,21,25-27,29-31 037059 24,28

    Heritability is the proportion of a trait attributable to genetic factors; heritability was corrected for body-mass index, sex, and

    age (except assessment for body-mass index itself). WHR=waist-hip ratio.

    Table 2: Heritability of obesity, fasting and 2-h post-glucose load concentrations of glucose and insulin

    in plasma, and measures of insulin secretion and insulin sensitivity

    Insulin sensitivity

    -cellfunction

    T2DM IGT

    Insulin resistance without

    -cell compensation

    Insulin resistance with

    -cell compensation

    NGT

    Figure 2: Hyperbolic relation between -cell function and insulin sensitivity

    In people with normal glucose tolerance (NGT) a quasi-hyperbolic relation exists

    between-cell function and insulin sensitivity. With deviation from this

    hyperbola, deterioration of glucose tolerance (impaired glucose tolerance [IGT],and type 2 diabetes [T2DM]) occurs.

  • 8/22/2019 Diabetes Lancet

    3/14

    Seminar

    in the adipocyte and modulate insulin action. An

    increased mass of stored triglyceride, especially invisceral or deep subcutaneous adipose depots, leads tolarge adipocytes that are themselves resistant to theability of insulin to suppress lipolysis. This results inincreased release and circulating levels of NEFA andglycerol, both of which aggravate insulin resistance inskeletal muscle and liver (figure 3).41

    Excessive fat storage not only in adipocytes butectopically in non-adipose cells also has an importantrole.42 For example, increased intramyocellular lipids areassociated with skeletal muscle insulin resistance undersome circumstances.43 The coupling betweenintrahepatic lipids and hepatic insulin resistance seemsto be even tighter.44,45

    Insulin receptor knock-out modelsTo understand the contribution of insulin resistance in aparticular tissue to whole body glucose homoeostasis,conditional knockouts of the insulin receptor have beencreated using the Cre-lox system. Among the fiveconditional insulin receptor knockouts shown in table 3,only liver47 and -cell specific knockouts50 becameglucose intolerant whereas, unexpectedly, knockoutmodels specific for muscle46 and fat cells48 did not. Thesefindings clearly support a central role of hepatic insulinresistance in the pathogenesis of type 2 diabetes, andsuggest that an adequate insulin signal in the pancreatic

    cell is needed to maintain its function.

    Cellular mechanismsInsulin elicits its pleiotropic metabolic responses bybinding to and activating a specific plasma membranereceptor with tyrosine kinase activity.51 Cellularsubstrates of the insulin receptor kinase, mostprominently the insulin receptor substrate (IRS)proteins, are efficiently tyrosine phosphorylated onseveral sites, which serve as binding scaffolds for variousadaptor proteins and lead to the downstream signallingcascade (figure 4).52 Insulin activates a series of lipid andprotein kinase enzymes linked to the translocation ofglucose transporters to the cell surface, synthesis of

    glycogen, protein, mRNAs, and nuclear DNA, whichaffect cell survival and proliferation.

    Phosphorylation and dephosphorylation of IRS proteinsIn states of insulin resistance, one or more of thefollowing molecular mechanisms to block insulinsignalling are likely to be involved. The positive effects ondownstream responses exerted by tyrosine phospho-rylation of the receptor and the IRS proteins are opposedby dephosphorylation of these tyrosine side-chains bycellular protein-tyrosine phosphatases and by proteinphosphorylation on serine and threonine residues, whichoften occur together.53 Phosphotyrosine phosphatase 1B(PTP1B) is widely expressed and has an important role inthe negative regulation of insulin signalling.54

    Serine/threonine phosphorylation of IRS1 reduces itsability to act as a substrate for the tyrosine kinase activityof the insulin receptor and inhibits its coupling to itsmajor downstream effector systems. Several IRS serinekinases have been identified, including various mitogen-activated protein kinases, c-Jun NH2-terminal kinase,atypical protein kinase C, and phosphatidylinositol3-kinase, among others.52 Signal downregulation canalso occur through internalisation and loss of the insulinreceptor from the cell surface and degradation of IRSproteins.55 Members of the suppressor of cytokinesignalling (SOCS) family of proteins participate in IRSprotein degradation through a ubiquitin-proteosomalpathway (figure 4).56

    Role of adipocyte products and inflammationIncreased concentrations of NEFA and inflammatorycytokines (eg, tumour necrosis factor [TNF] andinterleukin 6) released by expanded visceral adiposetissue adversely affect the insulin signalling cascade.57,58

    www.thelancet.com Vol 365 April 9, 2005 1335

    Tissue without insulin receptor Glucose intolerance Additional features

    Muscle No Moderate obesity, no insulin resistance46

    Liver Yes Severe insulin resistance, hepatic dysfunction47

    Fat tissue No Lean, extended lifespan48

    Neurons No Hyperphagia, obesity, infertility49

    Pancreatic cells Yes Insulin secretion defect50

    Table 3: Mouse models of tissue-specific insulin-receptor knockout

    Liver

    Blood glucose

    Insulin

    Lipolysis

    Fat Muscle

    -cell

    dysfunction

    Pancreas

    Diabetes genes

    Adipokines

    Inflammation

    Hyperglycaemia

    Free fatty acids

    Other factors

    Insulin resistance

    Glucose uptake

    Glucose

    production

    Fatty acids

    Figure 3: Pathophysiology of hyperglycaemia and increased circulating fatty acids in type 2 diabetes

    Insulin secretion from the pancreas normally reduces glucose output by the liver, enhances glucose uptake by

    skeletal muscle, and suppresses fatty acid release from fat tissue. The various factors shown that contribute to the

    pathogenesis of type 2 diabetes affect both insulin secretion and insulin action. Decreased insulin secretion will

    reduce insulin signalling in its target tissues. Insulin resistance pathways affect the action of insulin in each of the

    major target tissues, leading to increased ci rculating fatty acids and the hyperglycaemia of diabetes. In turn, the

    raised concentrations of glucose and fatty acids in the bloodstream will feed back to worsen both insulin secretion

    and insulin resistance.

  • 8/22/2019 Diabetes Lancet

    4/14

    Seminar

    NEFA inhibit insulin-stimulated glucose metabolism inskeletal muscle and stimulate gluconeogenesis inliver.59,60 They activate cellular kinases, including atypicalprotein kinase C isoforms by increasing cellulardiacylglycerol levels, which can activate the inflammatorykinases inhibitor B kinase (IKK) and c-jun N-terminalkinase, increasing serine/threonine phosphorylation ofIRS1 and reducing downstream IRS1 signalling, aspreviously described.6163 TNF enhances adipocytelipolysis, which further increases NEFA, and also elicitsits own direct negative effects on insulin signallingpathways.64 Neutralisation of TNF substantially reverses

    insulin resistance in rodents; however, the magnitude ofits involvement in human insulin resistance is notentirely clear.65 The proinflammatory interleukin 6inhibits the insulin signal by augmenting the expressionof SOCS proteins.66,67

    AdiponectinWhereas circulating NEFA and several adipokines areincreased in visceral obesity, the concentrations of theadipose-specific protein adiponectin are decreased,reducing its insulin-sensitising effects in liver andmuscle.57,68 Adiponectin signals via AMP kinase, a stress-activated signalling enzyme implicated in variousmetabolic responses, including suppression of hepaticgluconeogenesis, glucose uptake in exercising skeletal

    muscle, fatty acid oxidation, and inhibition of lipolysis,

    which might explain its beneficial metabolic effects.

    6872

    AMP kinase has also been implicated in the mechanismof action of metformin,73,74 and possibly of thethiazolidinediones,75 suggesting that it has a role inclinical anti-diabetic responses.

    NFB and IKK activityA close connection between insulin resistance andclassic inflammatory signalling pathways has alsorecently been identified. Nuclear factor B (NFB) isheld in an inactive state in resting conditions by bindingto an inhibitory partner, IB.76 Phosphorylation of IB byits kinase (IKK) leads to IB degradation, releasingNFB for translocation to the nucleus where it can affect

    the transcription of diverse genes involved in theinflammatory response. High doses of salicylates, whichblock IKK activity,77 can ameliorate hyperglycaemia andinsulin resistance in diabetes and obesity.78,79 Moreimportantly, genetic disruption of IKK returnedskeletal muscle insulin resistance caused by NEFA tonormal, through improvement in IRS1 tyrosinephosphorylation and activation of its downstream signalcascade.80 Overall, this evidence suggests that IKK mightbe an important target for the development of newtherapeutics in insulin resistance, especially in thesetting of visceral adiposity.

    In addition to their effects on insulin signalling, the

    circulating adipose tissue factors strongly affectvascular endothelial function, linking the increasedvascular risk in the metabolic syndrome withmechanisms of cellular insulin resistance.68,81 Adiposesecretory factors also recruit and activate inflammatorycells, which can further perpetuate a systemicinflammatory milieu that can strongly affect vascularfunction and atherogenesis.82

    Mitochondrial metabolismThe accumulation of ectopic triglyceride in visceral depots(mainly in the liver) has suggested a defect inmitochondrial lipid oxidation in patients with type 2diabetes, who have impaired oxidative capacity and small

    mitochondria in skeletal muscle.83 PPAR co-activator 1(PGC1), a transcription factor for genes involved inmitochondrial fatty acid oxidation and ATP synthesis, wasdecreased in young, lean, insulin-resistant offspring ofparents with type 2 diabetes, suggesting that an inheriteddefect in mitochondrial oxidative phosphorylation couldlead to cellular lipid accumulation.84 Gene expressionprofiling studies have also shown that decreasedexpression of PGC1 and related gene products couldaffect mitochondrial function in people with insulin-resistance and type 2 diabetes.85,86

    -cell dysfunctionVarious abnormalities in insulin secretion are present inpatients with type 2 diabetes. Basal insulin concentra-

    1336 www.thelancet.com Vol 365 April 9, 2005

    Inhibitory

    triggers

    High glucose

    NEFA

    Interleukin 6

    Inflammatory

    mediators

    TNF

    adipokines

    Signal

    mediators

    Atypical

    PKC

    PTEN

    SOCS -3

    IKK

    PTP1B

    Adiponectin

    Tyrosine

    dephosphorylation

    Inhibitory

    pSer signals

    Lipid

    dephosphorylation

    Deactivation

    pathways

    IRS protein

    degradation

    AMP kinase

    Ameliorative

    pathways

    Insulin receptor

    tyrosine kinase

    PI 3 -kinase

    Glucose/lipid

    metabolism

    Insulin

    Glucose

    homoeostasis

    Stimulatory

    p-Ser signals

    IRS proteins

    Activation

    pathways

    PI 3-P

    c-JUN

    kinase

    Figure 4: Insulin signalling and insulin resistance

    Insulin signalling involves binding of insulin to its receptor followed by a cascade of intracellular events, depicted as

    activation pathways. Negative modulation of insulin action can be mediated via various pathways leading to

    insulin resistance: various inhibitory triggers affect their respective signal modulators (partly via transcription

    factors), which lead through deactivating pathways (tyrosine phosphatases, serine kinases, lipid phosphatases and

    degradation pathways) to inhibitory actions on insulin signalling (activation pathways). Adiponectin has an

    ameliorating function on glucose metabolism apart from insulin signalling. PKC=protein kinase C.

    PTEN=phosphatase and tensin homologue. PI=phospho-inositol.

  • 8/22/2019 Diabetes Lancet

    5/14

    Seminar

    tions may be raised to roughly double the usual value,

    especially in obese hyperglycaemic patients, but thisfinding is presumably due to increased plasma glucose.Similarly, after a meal, concentrations of insulin inplasma can appear higher than normal, because ofsubstantially raised plasma glucose. Indeed,hyperglycaemic glucose clamp studies understandardised conditions of identical glycaemia haveshown that insulin secretion is markedly diminishedcompared with non-diabetic individuals with similaranthropometric characteristics.87 But even before thedevelopment of overt hyperglycaemia, which in itselfadversely affects -cell function, secretory defects havebeen shown, for example in individuals with impairedglucose tolerance and impaired fasting glucose.88

    Moreover, both normoglycaemic offspring of type 2diabetic parents and non-diabetic twin-siblings ofdiabetic patients have reduced insulin secretion.87 Thus,in predisposed individuals, an insulin secretory defectis present, possibly on a genetic basis. 89 Obesity, acuteillness, or simply ageing might further expose oraggravate the underlying defect, ultimately leading toovert diabetes.87

    In Pima Indians, a group known for their insulinresistance, prospective studies have shown that lowinsulin release determines the transition from normalto impaired glucose tolerance; conversely, PimaIndians who do not progress to the diabetic state were

    found to be able to increase their insulin secretion overtime.36

    Normal insulin secretionGlucose is rapidly taken up by the pancreatic cell viathe glucose transporter 2 (GLUT2), upon which it isphosphorylated via glucokinase, which is the rate-limiting step of -cell glucose metabolism (figure 5).Further degradation leads to formation of pyruvate,which is then taken up in the mitochondria in whichfurther metabolism leads to ATP formation. ATP isnecessary for the delivery of energy needed for therelease of insulin, but it is also involved in the cellmembrane depolarisation. The ADP/ATP ratio leads to

    activation of the sulphonylurea receptor 1 (SUR1)protein which will lead to closure of the adjacentpotassium channel (potassium inward rectifier [KIR]62 channel). The closure of the potassium channelswill alter the membrane potential and open calciumchannels, which triggers the release of preformedinsulin-containing granules (figure 5).

    Glucose toxicityThe notion that hyperglycaemia itself can decreaseinsulin secretion has led to the concept of glucosetoxicity, which implies the development of irreversibledamage to cellular components of insulin productionover time.90,91 Indeed, deterioration of insulin secretionover time is the usual course in most patients, and

    many patients will end with more or less severe insulindeficiency after about 10 years of diabetes.92

    In cells, oxidative glucose metabolism will alwayslead to production of reactive oxygen species, normallydetoxified by catalase and superoxide dismutase. cells

    are equipped with a low amount of these proteins andalso of the redox-regulating enzyme glutathioneperoxidase.90 Hyperglycaemia has been proposed to leadto large amounts of reactive oxygen species in cells,with subsequent damage to cellular components(figure 6). Loss of pancreas duodenum homeobox 1(PDX-1), a critical regulator of insulin promoter activity,has also been proposed as an important mechanismleading to -cell dysfunction.90 The finding in thediabetes-prone Zucker Diabetic Fatty rat that loss ofpancreas duodenum homeobox-1 could be diminishedby various manoeuvres preventing hyperglycaemiasupports this. Additionally, reactive oxygen species areknown to enhance NFB activity, which potentially

    induces -cell apoptosis.

    LipotoxicityMore recently, the concept of lipotoxicity involving the cell has been put forward. Generally, in both non-diabetic and diabetic obese patients, NEFAconcentrations are raised as a result of enhancedadipocyte lipolysis. Fatty acids lead to enhanced insulinsecretion in acute studies, but after 24 h they actuallyinhibit insulin secretion. In the presence of glucose,fatty acid oxidation in cells is inhibited andaccumulation of long-chain acyl coenzyme A occurs. 93

    This mechanism has been proposed to be an integralpart of the normal insulin secretory process. However,long-chain acyl coenzyme A itself can also diminish the

    www.thelancet.com Vol 365 April 9, 2005 1337

    ATP

    SUR1

    KIR 62

    channel

    Calcium

    channel

    Mitochondria

    ATP

    Acetyl-CoA

    Glucokinase G-6-P

    GLUT2

    Glucose

    DNA

    Insulin

    IAPP

    IAPP

    Insulin

    Ca2+

    Ca2+

    Figure 5: Schematic representation of normal glucose-induced insulin secretion

    IAPP=islet amyloid polypeptide. G-6-P=glucose-6-phosphate. CoA=coenzyme A. GLUT2=glucose transporter 2.

  • 8/22/2019 Diabetes Lancet

    6/14

    Seminar

    insulin secretory process by opening -cell potassiumchannels (figure 6). A second mechanism might beincreased expression of uncoupling protein-2, whichwould lead to reduced ATP formation and, hence,

    decreased insulin secretion. A third mechanism mightinvolve apoptosis of cells, possibly via fatty acid ortriglyceride-induced ceramide synthesis or generation ofnitric oxide.

    Islet amyloidIslet amyloid consists of deposits of islet amyloidpolypeptide, also known as amylin, which is co-secretedwith insulin at a more than tenfold lower rate. Thephysiological role of islet amyloid polypeptide is unclear,and diverse roles such as inhibition of insulin action,inhibition of insulin secretion, and inhibition of glucagonsecretion have been proposed. It has been suggested thatsmall aggregates are cytotoxic,94 possibly related to radical

    production. NEFA may add to the cytotoxicity of theaggregates.95 Amyloid deposits are found in most but notall individuals with type 2 diabetes.96

    It is possible that early in the disease, increaseddemands of insulin secretion lead to islet amyloidpolypeptide aggregates, especially in the presence ofraised concentrations of NEFA. The finding that first-degree relatives of patients with type 2 diabetes havedecreased islet amyloid polypeptide (and insulin)responses to intravenous glucose, however, challengesthis speculation.96 Also, amyloid is not observed inmiddle-aged insulin-resistant individuals. Thus, the roleof amyloid deposits (a post-mortem finding) in pancreaticislets in the pathophysiology of type 2 diabetes remainsunclear.

    Genetic factors

    Although there is little doubt as to the importance ofgenetic factors in type 2 diabetes (table 2), it should beborne in mind that this disease is very heterogeneous.Genetic studies have therefore given very diverseresults. In general, two methods are used for studyinggenetic factors involved in a specific disease: the so-called candidate gene approach and the genome-widescan approach.

    The candidate gene approach examines specific geneswith a plausible role in the disease process. For thispurpose the statistical association of a given allele and aphenotype (eg, type 2 diabetes, or insulin resistance) istested in unrelated individuals. The genome-wide scanor linkage approach is not based on assumptions but

    locates genes through their genomic position and isbased on the rationale that family members sharing aspecific phenotype will also share chromosomal regionssurrounding the gene involved.

    Candidate genesThe candidate gene approach in attempts to identify acausative factor among the obvious biological candidatesfor insulin resistance has been largely disappointing(table 4). Variants in many candidate genes wereextensively studied over the past two decades, such asthe Gly972Arg polymorphism in IRS1, the Gly1057Asppolymorphism in IRS2, the Trp64Arg polymorphism in

    the

    3 adrenergic receptor, the 308 G/A promotervariant in TNF, or variants in the adiponectin gene. Inmost instances the initial association was not replicatedin subsequent analyses and, currently, the most robustsingle candidate variant is the highly prevalent Pro12Alapolymorphism in peroxisome proliferator-activatedreceptor (PPAR).97,98

    PPARPPAR is a transcription factor that is activated bycertain fatty acids, prostanoids, and thiazo-lidinediones.99,100 Whereas the isoform PPAR1 isexpressed in most tissues, PPAR2 is specific for adiposetissue, where it has a key role in regulation of

    adipogenic differentiation.101 The high risk proline alleleof the Pro12Ala PPAR polymorphism has a prevalenceof 75% in white people. In 333 Scandinavian parent-offspring trios with abnormal glucose tolerance, among16 candidate gene variants only the P12A polymorphismin the PPAR gene (PPARG) was significant.102 Resultsof two meta-analyses and a large prospective analysishave shown a risk reduction between 21% and 27% forthe alanine allele.97,98,103 The alanine genotype presumablyresults in greater insulin sensitivity.104106 The prolinevariant has lower transcriptional activity andheterozygous PPAR knockout mice are more insulinresistant. Since PPAR2 is exclusively expressed inadipose tissue, a primary mechanism in this tissue witha secondary effect on hepatic insulin sensitivity and

    1338 www.thelancet.com Vol 365 April 9, 2005

    NEFA

    ?

    Inhibitory triggers Signal mediatorsMechanism of

    dysfunction

    High glucose Reactive

    oxygen

    species

    PDX-1

    NFB

    IAPP

    aggregates

    Other?

    Ceramide

    UCP-2?

    ?

    LC-CoA

    IAPP

    secretion

    Insulin gene

    transcription

    Apoptosis

    Mitochondrial

    ATP generation

    K channel

    Transcription of genes

    (growth/development)Disturbed insulin/IGF signalling?

    TNF?

    Inflammatory

    mediators

    Figure 6: Possible negative effects of hyperglycaemia, increased NEFA, and various modulators involved in

    insulin resistance on -cell dysfunction

    IAPP=islet amyloid polypeptide. LC-CoA=long-chain acetyl coenzyme A. PDX-1=pancreas duodenum

    homeobox-1. UCP-2=uncoupling protein-2.

  • 8/22/2019 Diabetes Lancet

    7/14

    Seminar

    insulin clearance can be invoked.107 Interestingly, inPima Indians, insulin suppression of glucoseproduction was 40% more efficient in carriers of the Alaallele whereas insulin-stimulated glucose uptake did notdiffer.106

    IRS1 and PGC1The Gly972Arg polymorphism in IRS1, a variantintuitively associated with insulin resistance, may havea weak association with type 2 diabetes,97 althoughpossibly through -cell dysfunction rather than insulinresistance.108,109 The Gly483Ser polymorphism inPGC1, a transcriptional co-factor, might also be

    associated with type 2 diabetes via as yet unknownmechanisms.110

    Sulphonylurea receptor-1/potassium inward rectifier 62Among the many candidate genes for insulin secretorydysfunction, those encoding SUR1 and KIR62 havebeen most extensively studied. The two genesABCC8and KCNJ11, respectivelyare adjacent to one anotheron chromosome 11. There is insufficient evidence forassociation of two widely studied SUR1 polymorphisms(exon 163t/c, exon 18 T759T) with type 2 diabetes.111

    Meta-analyses on the E23K variant in the KIR62 geneare more robust, suggesting that the risk of type 2diabetes increased by about 15% for the K allele, 111

    probably through decreased insulin secretion. A recenthaplotype analysis using an independent datasetconfirmed the association with the KIR62 variant andfurther substantiated the notion that genetic variationin the SUR1/KIR62 region is associated with type 2diabetes.112 However, because the E23K polymorphismis in strong linkage disequilibrium with a nearby codingvariant in the SUR1 gene (A1369S), it is difficult todistinguish the roles of the two polymorphisms.

    Insulin-like growth factorGenes involved in embryonic -cell development, suchas components of the insulin-like growth factorpathways, have also been studied. Although intactinsulin/insulin-like growth factor signalling is clearly

    essential for -cell growth and development,113 thepotential role of genetic variants remains an area ofresearch.

    Genome-wide scansSeveral findings of positive associations of genomicregions with type 2 diabetes have been replicated in oneor more studies (1q2124, 1q31q42, 9q21, 10q23,11p15, 11q1314, 12q12, 19q13, and 20q11q13 ).114

    Generally, such findings are followed by positionalcloning of the causative gene, which to date has not beensuccessful for most regions.

    Calpain-10The first common diabetes gene cloned in this waywas CAPN10 in the NIDDM1 region ofchromosome 2.115,116 It encodes for calpain-10, a cysteineprotease which is ubiquitously expressed.117,118 Originally,the G allele of a non-coding single nucleotidepolymorphism (UCSNP-43) was reported to beassociated with type 2 diabetes, while specific haplotypecombinations of several single nucleotidepolymorphisms (UCSNP-19, 43, 63) seemed to increasethe risk of diabetes in selected populations.116 In laterstudies, this finding could not be replicated119,120 butanother single nucleotide polymorphism (UCSNP-44)was found to be associated with type 2 diabetes.121124

    Genetic variants in calpain-10 might affect insulinsensitivity,125 or insulin secretion,126 or the relationbetween the two (table 4).127

    HNF4AAbnormalities in the HNF4A gene cause maturity-onsetdiabetes of the young type 1. Genetic variation near or inthe P2-promoter of the MODY-1 gene HNF4A gene(chromosome 20q) has been proposed to relate tocommon type 2 diabetes,128 but this finding requiresindependent confirmation.

    Insulin gene variable number tandem repeatA peculiar possibility is the relation of diabetes toimprinted genesie, genes for which expression varies

    www.thelancet.com Vol 365 April 9, 2005 1339

    Encoded protein Function of protein Rare variant Diabetes risk, odds ratio Putative mechanism

    (allele /genotype ) f or rare all ele (p )

    PPARG Peroxisome proliferator-activated receptor Nuclear receptor (transcription factor) Ala12 079 (p00001) Insulin resistance

    GYS1 Glycogen synthase Enzyme A2 (XbaI) 060 (p=002) Alteration of glycogen storage

    IRS1 Insulin receptor substrate 1 Docking protein (insulin signalling) Arg972 127 (p=0005) Probably-cell dysfunction

    INS Proinsulin Hormone class III VNTR 121 (p=001) -cell dysfunction

    KCJN11 Potassium-inward rectifier 62 Potassium channel Lys23 112 (p=0002) -cell or-cell dysfunction

    ABCC8 Sulfonylurea receptor 1 Potassium channel (subunit) T761 (exon 18) 228 (p005) Probably-cell dysfunction

    SLC2A1 Glucose transporter 1 Facilitated transport 62 kB allele (XbaI) 176 (p005) Unclear

    PPARGC1 PPAR-coactivator-1 Transcriptional cofactor Ser482 121 (p0001) Unclear, possibly pleiotropic

    CAPN10 Calpain-10 Cystein protease Intronic SNP43, G 115 (p=0002) Unclear, possibly pleiotropic

    Intronic SNP44, C 117 (p=00003)

    Significant positive associations extracted from a series of meta-analyses by Parikh and Groop97 and from Lohmueller and colleagues.98 VNTR=variable number tandem repeat.

    Table 4: Candidate genes and genetic polymorphisms associated with type 2 diabetes

  • 8/22/2019 Diabetes Lancet

    8/14

    Seminar

    depending on the sex of the transmitting parent. Theclass III allele of the variable number tandem repeatnear the insulin gene (chromosome 11p15) might relateto type 2 diabetes.129 The class III allele is associated withdecreased amounts of insulin mRNA. Only paternallytransmitted class III alleles were found to be associatedwith diabetes in one study.130

    Management of hyperglycaemiaIn making therapeutic choices (figure 7) in themanagement of type 2 diabetes, the major goal ofprotecting patients from the long-term complications ofthe disease must be considered. Because insulin

    resistance plays a fundamental role in the pathogenesis oftype 2 diabetes and especially its adverse cardiovascularoutcomes, interventions should initially be aimed towardsimprovement in tissue insulin sensitivity. This ofteninvolves lifestyle intervention, with modest exercise andweight loss, which clearly reduces the risk of progressionof impaired glucose tolerance to overt diabetes12,13 and canimprove many of the cardiovascular risk parameters ofthe metabolic syndrome.

    ThiazolidinedionesDrugs that enhance insulin sensitivity are primarilythose of the thiazolidinedione class, which not onlyreduce glycaemia, but also enhance vascular functionand ameliorate the dyslipidaemia and inflammatory

    milieu of type 2 diabetes.131 Thiazolidinediones primarily

    activate PPAR

    receptors in adipose tissue and alteradipose metabolism and distribution. The redistributionof tissue triglyceride from visceral stores reduces levelsof circulating NEFA apparently by sequestration in aless lipolytic subcutaneous compartment.132 Thiazoli-dinediones also reduce circulating concentrations ofpro-inflammatory cytokines that promote insulinresistance (eg, TNF and interleukin 6) and at the sametime increase concentrations of adiponectin, which hasinsulin-sensitising and anti-inflammatory properties.The multiple effects of thiazolidinediones on adiposetissue metabolism and cross-talk of these signals withliver and skeletal muscle, as well as pancreatic cellsand the vascular endothelium, might account for the

    enhancement of insulin action and improvement ininsulin secretion with these agents, as well as severalbeneficial effects on vascular function.133 The action ofthe thiazolidinediones to redistribute visceraltriglyceride can reduce hepatic lipid content in non-alcoholic steatohepatosis, which is closely related toobesity and insulin resistance.131 Ongoing studies willdetermine if these agents can reduce the risk ofinflammation leading to cirrhosis in this condition. Therenal and vascular benefits of thiazolidinediones havebeen demonstrated in controlled studies, for example,showing significant improvement in albumin excretionabove that observed with a similar degree of glycaemic

    lowering with sulfonylureas.

    134

    Unlike metformin, the thiazolidinediones can be usedin patients with reduced renal function, and they arebetter tolerated without significant gastrointestinal side-effects. A major adverse effect associated with clinicaluse of the thiazolidinediones is weight gain, whichseems to be coupled to the effects of the drugs onadipose cell differentiation and triglyceride storage.Fluid retention is also linked to the PPAR-agonistactivity of the thiazolidinediones, leading to peripheraloedema and a mild haemodilution in some patients.Fortunately, congestive heart failure is quite rare withuse of thiazolidinediones, but remains a seriousconcern that requires caution in selection of patients to

    receive these agents.135 The ability of thiazolidinedionesto ameliorate risk of atherosclerotic events is beingassessed in several large outcomes studies.

    MetforminMetformin is a highly effective antihyperglycaemic drugthat works independently of the pancreas, sparinginsulin. It decreases hepatic glucose output and hasbeen shown to have a beneficial effect on cardiovascularoutcomes.136138 Metformin has less robust effects oninsulin resistance, inflammatory markers, and vascularfunction compared with the thiazolidinediones, but itsbenefit in abrogating some of the weight gain commonlyobserved with insulin-sensitisers and insulin secretionenhancers adds important value to this drug.

    1340 www.thelancet.com Vol 365 April 9, 2005

    Tissue site Mechanism Drug

    Delay of gastric emptying Pramlintide

    -glucosidase inhibitors

    Sulfonylureas

    Meglitinides

    GLP1/DPP-IV-inhibitors

    Metformin

    Thiazolidinediones

    Inhibition of glucagon release

    Inhibition of glucose absorption

    Stimulation of GLP-1 release

    Acute stimulation of insulin release

    Stimulation of insulin biosynthesis

    Inhibition of-cell apoptosis

    Stimulation of-cell differentiation

    Suppression of NEFA release

    Fat redistribution (visceral to subcutaneous)

    Modulation of adipokine release

    Inhibition of glucose production

    Increase in hepatic insulin sensitivity

    Increase in muscle insulin sensitivity

    Gastrointestinal tract

    Pancreatic cell

    Liver

    Muscle

    Adipose tissue

    Figure 7: Pharmacological treatment of hyperglycaemia according to site of action

    GLP1=glucagon-like peptide 1. DPP-IV=dipeptidyl peptidase IV.

  • 8/22/2019 Diabetes Lancet

    9/14

    Seminar

    -glucosidase inhibitors

    The

    -glucosidase inhibitor acarbose has been shown toreduce glycaemic excursions and protect against thedevelopment of diabetes and cardiovascular disease.139

    Sulfonylurea derivativesAs inadequate -cell insulin secretion is fundamental tothe development of hyperglycaemia in diabetes, insulinsecretion enhancers also play an important role incontrol of blood glucose. Sulfonylurea derivatives act byclosing pancreatic cell potassium channels, which leadsto enhanced insulin secretion. The results of the UKProspective Diabetes Study8 showed a clear riskreduction for the occurrence of microvascularcomplications by the use of sulfonylurea derivatives,

    while the risk reduction of macrovascular disease wasaround 16%. Antihypertensive therapy diminished therisk of macrovascular complications by around 20%.Combined management with both sulfonylureaderivatives and antihypertensives improves the riskreduction even more.

    The mode of action of sulfonylurea derivatives impliesthat they also act at low concentrations of plasmaglucose, which explains the potential of (occasionallysevere) hypoglycaemia. Whereas tolbutamide, gliclazide,and glipizide have a relatively short durations of action,glimepiride and glibenclamide (glyburide) are longacting (24 h), adding to the risk of hypoglycaemia. 140 The

    risk of hypoglycaemia in the other sulfonylureaderivatives is lower, with a possible advantage ofgliclazide in patients with decreased kidney function.141

    Sulfonylurea derivatives will lead to moderate decreasesin concentrations of plasma glucose in most patientswith type 2 diabetes, and concentrations of glycosylatedhaemoglobin will generally decrease by about 12%.

    The recently introduced class of meglitinides consistsof nateglinide, which binds to the same site ofsulphonylurea receptor 1 as do the sulfonylureaderivatives, and repaglinide, which binds to a nearby siteof the receptor, both leading to insulin release. Theseagents cannot further stimulate insulin release inpatients on maximal doses of sulfonylurea derivatives.

    Both agents have a shorter action than sulfonylureaderivatives, are therefore associated with lower risk ofhypoglycaemia, and can also be used in patients withdecreased renal function.140

    Exogenous insulinReplacing circulating concentrations of insulin isessential to support the clinical effects of metformin andthe thiazolidinediones, which are ineffective withoutadequate insulin availability, and may also haveimportant beneficial effects in reducing inflammatoryprocesses, especially in the vasculature.142 Thus, it isessential to initiate insulin injections when required toachieve glycaemic targets in type 2 diabetes, possibly incombination with oral insulin sensitisers. However,

    combined use of insulin and thiazolidinediones seems

    to infer an increased risk of oedema and cardiac failure.Therefore, this combination is not allowed in mostEuropean countries.

    Glucagon-like peptide 1A novel insulin secretagogue concept has been builtaround glucagon-like peptide 1. This incretin hormonehas potent glucose-dependent insulinotropic properties,trophic effects on cells, and inhibitory effects onintestinal motility, all of which reduce plasma glucose.However, because circulating glucagon-like peptide 1 isimmediately inactivated by dipeptidyl peptidase IV, it istherapeutically impractical. Dipeptidyl peptidaseIV-resistant analogues and selective dipeptidyl peptidase

    IV inhibitors have been developed and are in the finalstages of approval (figure 7).143

    Experimental approachesAs specific drug targets are identified through improvedunderstanding of the molecular pathogenesis ofdiabetes, novel therapeutics will become available in thefuture. For example, PTP1B is a negative regulator ofinsulin signalling, and inhibition of its activity withspecific pharmaceutical agents, or reduction of itsprotein concentrations with novel antisense oligonu-coleotides, has been shown to enhance insulin action inpre-clinical models.144

    Controlling excessive secretion of TNF

    or interleukin6 or blocking their action mediated by serine/threoninekinases would be expected to enhance insulin sensitivityin patients with visceral adiposity. Conversely,increasing adiponectin secretion or administration of anadiponectin receptor agonist would probably enhanceglucose metabolism in skeletal muscle and liver and alsoconfer beneficial effects in the endothelium. Recentevidence for amelioration of insulin resistance bysalicylates by favourable interference with theinflammatory kinase cascade in insulin signalling mightlead to entirely novel therapeutic approaches.

    Management of other cardiovascular risk factors

    A complete discussion of this topic is outside the scopeof this paper and the metabolic syndrome is discussed ina separate Seminar.145 Hypertension, coronary arterydisease, and cerebrovascular disease, occur more oftenin type 2 diabetes than in matched controls.146 The UKProspective Diabetes Study8 has convincingly shown thebenefit of vigorous antihypertensive therapy in patientswith type 2 diabetes. The benefit of antihypertensivetherapy is larger in diabetic than in non-diabetichypertensive patients. To lower blood pressure to thelevels recently proposed by the American DiabetesAssociation (less than 130/80 mm Hg), many patientswill need two or three different antihypertensive drugs. blockers, diuretics, angiotensin-converting enzyme(ACE) inhibitors, calcium channel antagonists, and

    www.thelancet.com Vol 365 April 9, 2005 1341

  • 8/22/2019 Diabetes Lancet

    10/14

    Seminar

    angiotensin receptor blockers can all effectively decrease

    blood pressure in type 2 diabetes, while

    blockers areprobably less effective.146

    ACE inhibitionThe results of the HOPE study,147 in which use oframipril was associated with a markedly lower risk ofmyocardial infarction, stroke, and death, favour use ofthe ACE inhibitor in diabetic patients with one additionalrisk factor, even if they do not have hypertension.Losartan may have an advantage over the blockeratenolol in decreasing cardiovascular mortality.146

    Whether angiotensin receptor blockers will show greaterbenefit than ACE inhibitors, or whether these two classesof drugs should be used together, as suggested by lower

    blood pressure during combination therapy148 is yet to beascertained.

    StatinsThe benefit of lipid-lowering drugs has now been firmlyestablished, since the Scandinavian Simvastatin SurvivalStudy showed a reduction in total mortality of 43%.Similarly, the Heart Protection Study showed a 25%lower risk in end points for simvastatin use.149 The AdultTreatment Panel III of the National CholesterolEducation Program in the USA sets the LDL-cholesterolgoal at less than 26 mmol/L. It also aims for triglycerideconcentrations of less than 17 mmol/L, and for HDL

    cholesterol concentrations of greater than 10 mmol/L.

    150

    Fibric acid derivatives might benefit diabetic patientsbecause they raise concentrations of HDL cholesterol andreduce triglyceride levels. They can decrease endothelialcell activation possibly because of their capacity forbinding PPAR. They have been shown to reduce therisk for myocardial infarction by 24%.146 Nicotinic acidmight also raise HDL cholesterol, but could lead tohigher glycaemia.151

    AspirinThe management of other risk factors remains underdebate. Antiplatelet treatment (generally aspirin) hasbeen shown to decrease the risk of atherosclerotic

    manifestations by 19%.146 The American DiabetesAssociation recommends to prescribe low-dose aspirinas a secondary prevention strategy after manifestations

    of atherosclerotic disease, and to use aspirin as primary

    prevention in patients with a high risk for atheroscleroticdisease, especially patients older than 40 years, or withan additional risk factor such as family history ofcardiovascular disease, hypertension, smoking,dyslipidaemia or albuminuria.152 There is stilluncertainty about the dose of aspirin that is needed.

    Whether therapy should be given for other risk factorssuch as hyperhomocysteinaemia (treated with folic acid),and whether antioxidants are of use, is still unclearbecause of the absence of studies with hard endpoints inpatients with type 2 diabetes.

    Diabetes preventionThe goal of ultimately reducing the population burden of

    diabetes by early treatment and prevention is clearly ofpivotal importance. A number of studies have shownthat diabetes can be delayed or prevented in individualsat high risk undergoing an intensive diet and exerciseprogramme, and intervention with medicationsincluding metformin, acarbose or thiazolidinedioneshas also shown to be effective (table 5). The interestingobservation that improvement in one or more majorpathogenic factors offsets the progression of impairedglucose tolerance to diabetes underscores thecontribution of each of these factors to the developmentof the disease, including insulin sensitivity, -cellfunction, and actual glucose excursions. Thus, careful

    attention needs to be applied to determine appropriatepublic interventions for the varied populations of theworld. Lifestyle modification has been difficult tomaintain over a long term, and has costs associated withregular visits to various health-care professionals andlifestyle coaches. Medications may have unwanted side-effects. Further clinical trials comparing these andnewer medications that may affect diabetespathogenesis (such as glucagon-like peptide 1analogues) are needed to balance safety and efficacy withthe costs of these different agents in various regions.

    Future aspectsA more complete understanding of the molecular

    mechanisms of diabetes will enable the identification ofindividuals at highest risk, which could lead to novelpharmacological concepts, risk stratification, anddevelopment of more targeted preventive measures. Along-term goal is to develop drugs that restorenormoglycaemia by targeting specific pathogenicdefects. One example would be to advance thethiazolidinedione concept to design compounds thatcould restore defects in individuals with a defectivePPAR regulatory system. Similarly, the understandingof the role of the SUR1/KIR62 complex in -celldysfunction might foster the development of a newgeneration of sulphonylurea-like agents. Antisenseinhibition of PTP1B, a tyrosine phosphatase, currentlyundergoing phase II trials, could become the treatment

    1342 www.thelancet.com Vol 365 April 9, 2005

    Co ho rt In te rve nt ion D ura ti on R is k re duc ti on (%) N NT

    (years)

    DaQing (China)153 IGT Lifestyle 6 42 45

    TRIPOD (USA)154 GDM Troglitazone 25 56 6

    Diabetes Prevention Program (DPP; USA)12 IGT Lifestyle 3 58 7

    Metformin 3 31 14

    Diabetes Prevention Study (DPS; Finland)13 IGT Lifestyle 4 58 8

    STOP-NIDDM (international)155 IGT Acarbose 4 25 11

    IGT=impaired glucose tolerance. GDM=gestational diabetes. NNT=number needed to treat.

    Table 5: Diabetes prevention trials

  • 8/22/2019 Diabetes Lancet

    11/14

    Seminar

    of choice for patients with a genetic variant in PTP1B. 156

    Generally, with an optimised risk-benefit ratio, patientswho respond to treatment may also benefit from specificdrugs in a preventive approach. Until that day, diet andexercise remain the pillars of prevention and treatmentof type 2 diabetes. The implementation and sensible useof the available pharmacological agents, includinginsulin, and the management of other cardiovascularrisk factors, remain the practical challenge to theclinician.

    Conflict of interest statement

    M Stumvoll has acted as a consultant for Pfizer and GlaxoSmithKline.B J Goldstein has obtained research grants from GlaxoSmithKline,NovoNordisk, Pfizer, Takeda, Aventis, has acted as a consultant forGlaxoSmithKline, and has received honoraria from Aventis andGlaxoSmithKline. T W van Haeften has acted as a consultant for

    Aventis.

    Acknowledgments

    B J Goldstein is supported by NIH grants DK RO1063018, DKRO143396, and DK UO1048468. Timon W van Haeften has obtainedsupport from Diabetes Research Foundation, Amersfoort, Netherlands.The sponsors of the study had no role in the writing of the manuscript.The corresponding author had final responsibility for the decision tosubmit for publication.

    References1 Zimmet P, Alberti KG, Shaw J. Global and societal implications of

    the diabetes epidemic. Nature 2001; 414: 78287.

    2 King H, Aubert RE, Herman WH. Global burden of diabetes,19952025: prevalence, numerical estimates, and projections.Diabetes Care 1998; 21: 141431.

    3 Sinha R, Fisch G, Teague B, et al. Prevalence of impaired glucosetolerance among children and adolescents with marked obesity.

    N Engl J Med2002; 346: 80210.4 Fajans SS, Bell GI, Polonsky KS. Molecular mechanisms and

    clinical pathophysiology of maturity-onset diabetes of the young.N Engl J Med2001; 345: 97180.

    5 Maassen JA, t Hart LM, Van Essen E, et al. Mitochondrial diabetes:molecular mechanisms and clinical presentation. Diabetes 2004;53 (suppl 1): S10309.

    6 Pozzilli P, Di Mario U. Autoimmune diabetes not requiring insulinat diagnosis (latent autoimmune diabetes of the adult): definition,characterization, and potential prevention. Diabetes Care 2001; 24:146067.

    7 Wei M, Gaskill SP, Haffner SM, Stern MP. Effects of diabetes andlevel of glycemia on all-cause and cardiovascular mortality. The SanAntonio Heart Study. Diabetes Care 1998; 21: 116772.

    8 UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared withconventional treatment and risk of complications in patients with

    type 2 diabetes (UKPDS 33). Lancet1998; 352: 83753.9 UK Prospective Diabetes Study (UKPDS) Group. Effect of intensiveblood-glucose control with metformin on complications inoverweight patients with type 2 diabetes (UKPDS 34). Lancet1998;352: 85465.

    10 Nichols GA, Glauber HS, Brown JB. Type 2 diabetes: incrementalmedical care costs during the 8 years preceding diagnosis. DiabetesCare 2000; 23: 165459.

    11 World Health Organization Expert Committee. Definition,diagnosis and classification of diabetes mellitus and itscomplications. Report of a WHO consultation, part 1: diagnosisand classification of diabetes mellitus. Geneva: World HealthOrganization, 1999.

    12 Diabetes Prevention Program Research Group. Reduction in theincidence of type 2 diabetes with lifestyle intervention ormetformin. N Engl J Med2002; 346: 393403.

    13 Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention oftype 2 diabetes mellitus by changes in lifestyle among subjects

    with impaired glucose tolerance. N Engl J Med2001; 344:134350.

    www.thelancet.com Vol 365 April 9, 2005 1343

    14 DECODE Study Group. Glucose tolerance and mortality:comparison of WHO and American Diabetes Association

    diagnostic criteria. The DECODE study group. EuropeanDiabetes Epidemiology Group. Diabetes Epidemiology:Collaborative analysis of diagnostic criteria in Europe. Lancet1999; 354: 61721.

    15 Pierce M, Keen H, Bradley C. Risk of diabetes in offspring ofparents with non-insulin-dependent diabetes. Diabet Med1995;12: 613.

    16 Tattersal RB, Fajans SS. Prevalence of diabetes and glucoseintolerance in 199 offspring of thirty-seven conjugal diabeticparents. Diabetes 1975; 24: 45262.

    17 Kaprio J, Tuomilehto J, Koskenvuo M, et al. Concordance for type 1(insulin-dependent) and type 2 (non-insulin-dependent) diabetesmellitus in a population-based cohort of twins in Finland.Diabetologia 1992; 35: 106067.

    18 Newman B, Selby JV, King MC, Slemenda C, Fabsitz R,Friedman GD. Concordance for type 2 (non-insulin-dependent)diabetes mellitus in male twins. Diabetologia 1987; 30: 76368.

    19 Henkin L, Bergman RN, Bowden DW, et al. Genetic epidemiologyof insulin resistance and visceral adiposity. The IRAS Family Studydesign and methods. Ann Epidemiol2003; 13: 21117.

    20 Hsueh WC, Mitchell BD, Aburomia R, et al. Diabetes in the OldOrder Amish: characterization and heritability analysis of theAmish Family Diabetes Study. Diabetes Care 2000; 23: 595601.

    21 Mills GW, Avery PJ, McCarthy MI, et al. Heritability estimates forbeta cell function and features of the insulin resistance syndromein UK families with an increased susceptibility to type 2 diabetes.Diabetologia 2004; 47: 73238.

    22 Poulsen P, Kyvik KO, Vaag A, Beck Nielsen H. Heritability of typeII (non-insulin-dependent) diabetes mellitus and abnormal glucosetolerancea population-based twin study. Diabetologia 1999; 42:13945.

    23 Freeman MS, Mansfield MW, Barrett JH, Grant PJ. Heritability offeatures of the insulin resistance syndrome in a community-basedstudy of healthy families. Diabet Med2002; 19: 99499.

    24 Lehtovirta M, Kaprio J, Forsblom C, Eriksson J, Tuomilehto J,

    Groop L. Insulin sensitivity and insulin secretion in monozygoticand dizygotic twins. Diabetologia 2000; 43: 28593.

    25 Watanabe RM, Valle T, Hauser ER, et al. Familiality of quantitativemetabolic traits in Finnish families with non-insulin-dependentdiabetes mellitus. Finland-United States Investigation of NIDDMGenetics (FUSION) Study investigators. Hum Hered1999; 49:15968.

    26 Bergman RN, Zaccaro DJ, Watanabe RM, et al. Minimal model-based insulin sensitivity has greater heritability and a differentgenetic basis than homeostasis model assessment or fastinginsulin. Diabetes 2003; 52: 216874.

    27 Hanson RL, Imperatore G, Narayan KM, et al. Family and geneticstudies of indices of insulin sensitivity and insulin secretion inPima Indians. Diabetes Metab Res Rev2001; 17: 296303.

    28 Jenkins AB, Samaras K, Carey DG, Kelly P, Campbell LV.Improved indices of insulin resistance and insulin secretion for usein genetic and population studies of type 2 diabetes mellitus. TwinRes 2000; 3: 14851.

    29 Elbein SC, Hasstedt SJ, Wegner K, Kahn SE. Heritability ofpancreatic beta-cell function among nondiabetic members ofCaucasian familial type 2 diabetic kindreds.J Clin Endocrinol Metab1999; 84: 1398403.

    30 Hong Y, Weisnagel SJ, Rice T, et al. Familial resemblance forglucose and insulin metabolism indices derived from anintravenous glucose tolerance test in Blacks and Whites of theHERITAGE Family Study. Clin Genet2001; 60: 2230.

    31 Sakul H, Pratley R, Cardon L, Ravussin E, Mott D, Bogardus C.Familiality of physical and metabolic characteristics that predict thedevelopment of non-insulin-dependent diabetes mellitus in PimaIndians. Am J Hum Genet1997; 60: 65156.

    32 Beck-Nielsen H, Vaag A, Poulsen P, Gaster M. Metabolic andgenetic influence on glucose metabolism in type 2 diabeticsubjectsexperiences from relatives and twin studies.Best Pract Res Clin Endocrinol Metab 2003; 17: 44567.

    33 Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabetesmellitus: the thrifty phenotype hypothesis. Diabetologia 1992; 35:

    595601.

  • 8/22/2019 Diabetes Lancet

    12/14

    Seminar

    34 Hattersley AT, Tooke JE. The fetal insulin hypothesis: analternative explanation of the association of low birthweight with

    diabetes and vascular disease. Lancet1999; 353: 178992.35 Bergman RN. Lilly lecture 1989. Toward physiological

    understanding of glucose tolerance. Minimal-model approach.Diabetes 1989; 38: 151227.

    36 Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history ofinsulin secretory dysfunction and insulin resistance in thepathogenesis of type 2 diabetes mellitus.J Clin Invest1999; 104:78794.

    37 Stumvoll M, Tataranni PA, Stefan N, Vozarova B, Bogardus C.Glucose allostasis. Diabetes 2003; 52: 90309.

    38 Dinneen S, Gerich J, Rizza R. Carbohydrate metabolism in non-insulin-dependent diabetes mellitus. N Engl J Med1992; 327: 70713.

    39 Weyer C, Bogardus C, Pratley RE. Metabolic characteristics ofindividuals with impaired fasting glucose and/or impaired glucosetolerance. Diabetes 1999; 48: 2197203.

    40 Meyer C, Stumvoll M, Nadkarni V, Dostou J, Mitrakou A, Gerich J.Abnormal renal and hepatic glucose metabolism in type 2 diabetes

    mellitus.J Clin Invest1998; 102: 61924.41 Boden G. Role of fatty acids in the pathogenesis of insulinresistance and NIDDM. Diabetes 1997; 46: 310.

    42 Danforth E Jr. Failure of adipocyte differentiation causes type IIdiabetes mellitus? Nat Genet2000; 26: 13.

    43 Machann J, Haring H, Schick F, Stumvoll M. Intramyocellularlipids and insulin resistance. Diabetes Obes Metab 2004; 6: 23948.

    44 Seppala-Lindroos A, Vehkavaara S, Hakkinen AM, et al. Fataccumulation in the liver is associated with defects in insulinsuppression of glucose production and serum free fatty acidsindependent of obesity in normal men.J Clin Endocrinol Metab2002; 87: 302328.

    45 Bajaj M, Suraamornkul S, Pratipanawatr T, et al. Pioglitazonereduces hepatic fat content and augments splanchnic glucoseuptake in patients with type 2 diabetes. Diabetes 2003; 52: 136470.

    46 Bruning JC, Michael MD, Winnay JN, et al. A muscle-specificinsulin receptor knockout exhibits features of the metabolicsyndrome of NIDDM without altering glucose tolerance. Mol Cell

    1998; 2: 55969.47 Michael MD, Kulkarni RN, Postic C, et al. Loss of insulin signaling

    in hepatocytes leads to severe insulin resistance and progressivehepatic dysfunction. Mol Cell2000; 6: 8797.

    48 Bluher M, Kahn BB, Kahn CR. Extended longevity in mice lackingthe insulin receptor in adipose tissue. Science 2003; 299: 57274.

    49 Bruning JC, Gautam D, Burks DJ, et al. Role of brain insulinreceptor in control of body weight and reproduction. Science 2000;289: 212225.

    50 Kulkarni RN, Bruning JC, Winnay JN, Postic C, Magnuson MA,Kahn CR. Tissue-specific knockout of the insulin receptor inpancreatic beta cells creates an insulin secretory defect similar tothat in type 2 diabetes. Cell1999; 96: 32939.

    51 Kido Y, Nakae J, Accili D. Clinical review 125: The insulin receptorand its cellular targets.J Clin Endocrinol Metab 2001; 86: 97279.

    52 White MF. IRS proteins and the common path to diabetes.Am J Physiol Endocrinol Metab 2002; 283: E413E422.

    53 Zick Y. Insulin resistance: a phosphorylation-based uncoupling ofinsulin signaling. Trends Cell Biol2001; 11: 43741.

    54 Goldstein BJ. Protein-tyrosine phosphatases and the regulation ofinsulin action. In: LeRoith D, Taylor SI, Olefsky JM, eds. Diabetesmellitus: a fundamental and clinical text. Philadelphia: Lippincott,2003: 25568.

    55 Zhande R, Mitchell JJ, Wu J, Sun XJ. Molecular mechanism ofinsulin-induced degradation of insulin receptor substrate 1.Mol Cell Biol2002; 22: 101626.

    56 Rui L, Yuan M, Frantz D, Shoelson S, White MF. SOCS-1 andSOCS-3 block insulin signaling by ubiquitin-mediated degradationof IRS1 and IRS2.J Biol Chem2002; 277: 4239498.

    57 Rajala MW, Scherer PE. Minireview: the adipocyteat thecrossroads of energy homeostasis, inflammation, andatherosclerosis. Endocrinology2003; 144: 376573.

    58 Ravussin E, Smith SR. Increased fat intake, impaired fat oxidation,and failure of fat cell proliferation result in ectopic fat storage,insulin resistance, and type 2 diabetes mellitus. Ann N Y Acad Sci

    2002; 967: 36378.

    59 Boden G, Shulman GI. Free fatty acids in obesity and type 2diabetes: defining their role in the development of insulin

    resistance and b-cell dysfunction. Eur J Clin Invest2002;32 (suppl 3): 1423.

    60 Shulman GI. Cellular mechanisms of insulin resistance.J Clin Invest2000; 106: 17176.

    61 Griffin ME, Marcucci MJ, Cline GW, et al. Free fatty acid-inducedinsulin resistance is associated with activation of protein kinase Ctheta and alterations in the insulin signaling cascade. Diabetes1999; 48: 127074.

    62 Itani SI, Ruderman NB, Schmieder F, Boden G. Lipid-inducedinsulin resistance in human muscle is associated with changes indiacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 2002;51: 200511.

    63 Gao Z, Zhang X, Zuberi A, et al. Inhibition of insulin sensitivity byfree fatty acids requires activation of multiple serine kinases in3T3-L1 adipocytes. Mol Endocrinol2004; 18: 202434.

    64 Hotamisligil GS. Molecular mechanisms of insulin resistance andthe role of the adipocyte. Int J Obes Relat Metab Disord2000; 24(suppl 4): S2327.

    65 Moller DE. Potential role of TNF-alpha in the pathogenesis ofinsulin resistance and type 2 diabetes. Trends Endocrinol Metab2000; 11: 21217.

    66 Senn JJ, Klover PJ, Nowak IA, et al. Suppressor of cytokinesignaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes.J Biol Chem2003; 278:1374046.

    67 Krebs DL, Hilton DJ. A new role for SOCS in insulin action.Suppressor of cytokine signaling. Sci STKE2003; 2003: E6.

    68 Goldstein BJ, Scalia R. Adiponectin: a novel adipokine linkingadipocytes and vascular function.J Clin Endocrinol Metab 2004; 89:256368.

    69 Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulatesglucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med2002; 8: 128895.

    70 Tomas E, Tsao TS, Saha AK, et al. Enhanced muscle fat oxidationand glucose transport by ACRP30 globular domain: acetyl-CoA

    carboxylase inhibition and AMP-activated protein kinase activation.Proc Natl Acad Sci USA 2002; 99: 1630913.

    71 Wu X, Motoshima H, Mahadev K, Stalker TJ, Scalia R, GoldsteinBJ. Involvement of AMP-activated protein kinase in glucose uptakestimulated by the globular domain of adiponectin in primary ratadipocytes. Diabetes 2003; 52: 135563.

    72 Ruderman NB, Cacicedo JM, Itani S, et al. Malonyl-CoA and AMP-activated protein kinase (AMPK): possible links between insulinresistance in muscle and early endothelial cell damage in diabetes.Biochem Soc Trans 2003; 31: 20206.

    73 Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinasein mechanism of metformin action.J Clin Invest2001; 108:116774.

    74 Zou MH, Kirkpatrick SS, Davis BJ, et al. Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin invivo: Role of mitochondrial reactive nitrogen species.J Biol Chem2004; 279: 4394051.

    75 Fryer LG, Parbu-Patel A, Carling D. The anti-diabetic drugs

    rosiglitazone and metformin stimulate AMP-activated proteinkinase through distinct signaling pathways.J Biol Chem2002; 277:2522632.

    76 Karin M, Delhase M. The I kappa B kinase (IKK) and NF-kappa B:key elements of proinflammatory signalling. Semin Immunol2000;12: 8598.

    77 Yin MJ, Yamamoto Y, Gaynor RB. The anti-inflammatory agentsaspirin and salicylate inhibit the activity of I(kappa)B kinase-beta.Nature 1998; 396: 7780.

    78 Kim JK, Kim YJ, Fillmore JJ, et al. Prevention of fat-induced insulin resistance by salicylate.J Clin Invest2001; 108:43746.

    79 Yuan M, Konstantopoulos N, Lee J, et al. Reversal of obesity- anddiet-induced insulin resistance with salicylates or targeteddisruption of Ikkbeta. Science 2001; 293: 167377.

    80 Shoelson SE, Lee J, Yuan M. Inflammation and the IKK beta/Ikappa B/NF-kappa B axis in obesity- and diet-induced insulin

    resistance. Int J Obes Relat Metab Disord2003; 27 (suppl 3):S4952.

    1344 www.thelancet.com Vol 365 April 9, 2005

  • 8/22/2019 Diabetes Lancet

    13/14

    Seminar

    81 Havel PJ. Control of energy homeostasis and insulin action byadipocyte hormones: leptin, acylation stimulating protein, and

    adiponectin. Curr Opin Lipidol2002; 13: 5159.82 Wellen KE, Hotamisligil GS. Obesity-induced inflammatory

    changes in adipose tissue.J Clin Invest2003; 112: 178588.

    83 Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction ofmitochondria in human skeletal muscle in type 2 diabetes.Diabetes 2002; 51: 294450.

    84 Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impairedmitochondrial activity in the insulin-resistant offspring of patientswith type 2 diabetes. N Engl J Med2004; 350: 66471.

    85 Patti ME, Butte AJ, Crunkhorn S, et al. Coordinated reduction ofgenes of oxidative metabolism in humans with insulin resistanceand diabetes: Potential role of PGC1 and NRF1. Proc Natl Acad SciUSA 2003; 100: 846671.

    86 Mootha VK, Lindgren CM, Eriksson KF, et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation arecoordinately downregulated in human diabetes. Nat Genet2003;34: 26773.

    87 Gerich JE. The genetic basis of type 2 diabetes mellitus: impairedinsulin secretion versus impaired insulin sensitivity. Endocr Rev1998; 19: 491503.

    88 Van Haeften TW, Pimenta W, Mitrakou A, et al. Disturbances inbeta-cell function in impaired fasting glycemia. Diabetes 2002;51 (suppl 1): S26570.

    89 Bonadonna RC, Stumvoll M, Fritsche A, et al. Altered homeostaticadaptation of first- and second-phase beta-cell secretion in theoffspring of patients with type 2 diabetes: studies with a minimalmodel to assess beta-cell function. Diabetes 2003; 52: 47080.

    90 Robertson RP, Harmon J, Tran PO, Tanaka Y, Takahashi H.Glucose toxicity in beta-cells: type 2 diabetes, good radicals gonebad, and the glutathione connection. Diabetes 2003; 52: 58187.

    91 Yki-Jrvinen H. Glucose toxicity. Endocr Rev1992; 13: 41531.

    92 Wallace TM, Matthews DR. Coefficient of failure: a methodologyfor examining longitudinal beta-cell function in Type 2 diabetes.Diabet Med2002; 19: 46569.

    93 Robertson RP, Harmon J, Tran PO, Poitout V. Beta-cell glucose

    toxicity, lipotoxicity, and chronic oxidative stress in type 2 diabetes.Diabetes 2004; 53 (suppl 1): S11924.

    94 Janson J, Ashley RH, Harrison D, McIntyre S, Butler PC. Themechanism of islet amyloid polypeptide toxicity is membranedisruption by intermediate-sized toxic amyloid particles. Diabetes1999; 48: 49198.

    95 Hull RL, Westermark GT, Westermark P, Kahn SE. Islet amyloid:a critical entity in the pathogenesis of type 2 diabetes.J Clin Endocrinol Metab 2004; 89: 362943.

    96 Knowles NG, Landchild MA, Fujimoto WY, Kahn SE. Insulinand amylin release are both diminished in first-degree relativesof subjects with type 2 diabetes. Diabetes Care 2002; 25: 29297.

    97 Parikh H, Groop L. Candidate genes for type 2 diabetes.Rev Endocr Metab Disord2004; 5: 15176.

    98 Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN.Meta-analysis of genetic association studies supports a contributionof common variants to susceptibility to common disease. Nat Genet2003; 33: 17782.

    99 Olefsky JM. Treatment of insulin resistance with peroxisomeproliferator-activated receptor gamma agonists.J Clin Invest2000;106: 46772.

    100 Schoonjans K, Auwerx J. Thiazolidinediones: an update. Lancet2000; 355: 100810.

    101 Auwerx J. PPARgamma, the ultimate thrifty gene. Diabetologia1999; 42: 103349.

    102 Altshuler D, Hirschhorn JN, Klannemark M, et al. The commonPPARg Pro12Ala polymorphism is associated with decreased riskof type 2 diabetes. Nat Gen 2000; 26: 7680.

    103 Memisoglu A, Hu FB, Hankinson SE, et al. Prospective study ofthe association between the proline to alanine codon 12polymorphism in the PPARgamma gene and type 2 diabetes.Diabetes Care 2003; 26: 291517.

    104 Deeb SS, Fajas L, Nemoto M, et al. A Pro12Ala substitution inPPARg2 associated with decreased receptor activity, lower bodymass index and improved insulin sensitivity. Nat Genet1998; 20:

    28487.

    105 Ek J, Andersen G, Urhammer SA, et al. Studies of the Pro12Alapolymorphism of the peroxisome proliferator-activated receptor-2

    (PPAR-2) gene in relation to insulin sensitivity among glucosetolerant Caucasians. Diabetologia 2001; 44: 117076.

    106 Muller YL, Bogardus C, Beamer BA, Shuldiner AR, Baier LJ.A functional variant in the peroxisome proliferator-activatedreceptor gamma2 promoter is associated with predictors ofobesity and type 2 diabetes in Pima Indians. Diabetes 2003; 52:186471.

    107 Stumvoll M, Hring H. The Pro12Ala polymorphism in theperoxisome proliferator-activated receptor . Diabetes 2002; 51:234147.

    108 Porzio O, Federici M, Hribal ML, et al. The Gly972Arg aminoacid polymorphism in IRS-1 impairs insulin secretion inpancreatic beta cells.J Clin Invest1999; 104: 35764.

    109 Stumvoll M, Fritsche A, Volk A, et al. The Gly972Argpolymorphism in the insulin receptor substrate-1 gene contributesto the variation in insulin secretion in normal glucose toleranthumans. Diabetes 2001; 50: 88285.

    110 Ek J, Andersen G, Urhammer SA, et al. Mutation analysis ofperoxisome proliferator-activated receptor-gamma coactivator-1(PGC-1) and relationships of identified amino acidpolymorphisms to Type II diabetes mellitus. Diabetologia 2001;44: 222026.

    111 Gloyn AL, Weedon MN, Owen KR, et al. Large-scale associationstudies of variants in genes encoding the pancreatic beta-cellKATP channel subunits Kir62 (KCNJ11) and SUR1 (ABCC8)confirm that the KCNJ11 E23K variant is associated with type 2diabetes. Diabetes 2003; 52: 56872.

    112 Florez JC, Burtt N, de Bakker PI, et al. Haplotype structure andgenotype-phenotype correlations of the sulfonylurea receptor andthe islet ATP-sensitive potassium channel gene region. Diabetes2004; 53: 136068.

    113 Rhodes CJ, White MF. Molecular insights into insulin action andsecretion. Eur J Clin Invest2002; 32 (suppl 3): 313.

    114 McCarthy MI. Growing evidence for diabetes susceptibility genesfrom genome scan data. Curr Diab Rep 2003; 3: 15967.

    115 Cox NJ. Challenges in identifying genetic variation affectingsusceptibility to type 2 diabetes: examples from studies of thecalpain-10 gene. Hum Mol Genet2001; 10: 2301305.

    116 Horikawa Y, Oda N, Cox NJ, et al. Genetic variation in the geneencoding calpain-10 is associated with type 2 diabetes mellitus.Nat Genet2000; 26: 16375.

    117 Ma H, Fukiage C, Kim YH, et al. Characterization and expressionof calpain 10. A novel ubiquitous calpain with nuclear localization.J Biol Chem2001; 276: 2852531.

    118 Suzuki K, Hata S, Kawabata Y, Sorimachi H. Structure, activation,and biology of calpain. Diabetes 2004; 53 (suppl 1): S1218.

    119 Rasmussen SK, Urhammer SA, Berglund L, et al. Variants withinthe calpain-10 gene on chromosome 2q37 (NIDDM1) andrelationships to type 2 diabetes, insulin resistance, and impairedacute insulin secretion among Scandinavian Caucasians. Diabetes2002; 51: 356167.

    120 Horikawa Y, Oda N, Yu L, et al. Genetic variations in calpain-10gene are not a major factor in the occurrence of type 2 diabetes in

    Japanese.J Clin Endocrinol Metab 2003; 88: 24447.121 Evans JC, Frayling TM, Cassell PG, et al. Studies of association

    between the gene for calpain-10 and type 2 diabetes mellitus in theUnited Kingdom. Am J Hum Genet2001; 69: 54452.

    122 Bosque-Plata L, Aguilar-Salinas CA, Tusie-Luna MT, et al.Association of the calpain-10 gene with type 2 diabetes mellitus ina Mexican population. Mol Genet Metab 2004; 81: 12226.

    123 Song Y, Niu T, Manson JE, Kwiatkowski DJ, Liu S. Are variants inthe CAPN10 gene related to risk of type 2 diabetes? A quantitativeassessment of population and family-based association studies.Am J Hum Genet2004; 74: 20822.

    124 Weedon MN, Schwarz PE, Horikawa Y, et al. Meta-analysis and alarge association study confirm a role for calpain-10 variation intype 2 diabetes susceptibility. Am J Hum Genet2003; 73: 120812.

    125 Baier LJ, Permana PA, Yang X, et al. A calpain-10 genepolymorphism is associated with reduced muscle mRNA levels andinsulin resistance.J Clin Invest2000; 106: R6973.

    126 Sreenan SK, Zhou YP, Otani K, et al. Calpains play a role in insulinsecretion and action. Diabetes 2001; 50: 201320.

    www.thelancet.com Vol 365 April 9, 2005 1345

  • 8/22/2019 Diabetes Lancet

    14/14

    Seminar

    127 Tripathy D, Eriksson KF, Orho-Melander M, Fredriksson J,Ahlqvist G, Groop L. Parallel manifestation of insulin resistance

    and beta cell decompensation is compatible with a common defectin Type 2 diabetes. Diabetologia 2004; 47: 78293.

    128 Silander K, Mohlke KL, Scott LJ, et al. Genetic variation near thehepatocyte nuclear factor-4 alpha gene predicts susceptibility totype 2 diabetes. Diabetes 2004; 53: 114149.

    129 Ong KK, Phillips DI, Fall C, et al. The insulin gene VNTR, type 2diabetes and birth weight. Nat Genet1999; 21: 26263.

    130 Huxtable SJ, Saker PJ, Haddad L, et al. Analysis of parent-offspringtrios provides evidence for linkage and association between theinsulin gene and type 2 diabetes mediated exclusively throughpaternally transmitted class III variable number tandem repeatalleles. Diabetes 2000; 49: 12630.

    131 Yki-Jarvinen H. Thiazolidinediones. N Engl J Med2004; 351:110618.

    132 Ye JM, Dzamko N, Cleasby ME, et al. Direct demonstration of lipidsequestration as a mechanism by which rosiglitazone preventsfatty-acid-induced insulin resistance in the rat: comparison withmetformin. Diabetologia 2004; 47: 130613.

    133 Meriden T. Progress with thiazolidinediones in the management oftype 2 diabetes mellitus. Clin Ther2004; 26: 17790.

    134 Einhorn D, Aroda VR, Henry RR. Glitazones and the managementof insulin resistance: what they do and how might they be used.Endocrinol Metab Clin North Am2004; 33: 595616.

    135 Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione use, fluidretention, and congestive heart failure: a consensus statement fromthe American Heart Association and American DiabetesAssociation. October 7, 2003. Circulation 2003; 108: 294148.

    136 Bailey CJ, Turner RC. Metformin. N Engl J Med1996; 334: 57479.

    137 Cusi K, Consoli A, DeFronzo RA. Metabolic effects of metforminon glucose and lactate metabolism in noninsulin-dependentdiabetes mellitus.J Clin Endocrinol Metab 1996; 81: 405967.

    138 Mamputu JC, Wiernsperger NF, Renier G. Antiatherogenicproperties of metformin: the experimental evidence. Diabetes Metab2003; 29: 6S7176.

    139 Chiasson JL, Gomis R, Hanefeld M, Josse RG, Karasik A,

    Laakso M. The STOP-NIDDM Trial: an international study on theefficacy of an alpha-glucosidase inhibitor to prevent type 2 diabetesin a population with impaired glucose tolerance: rationale, design,and preliminary screening data. Study to Prevent Non-Insulin-Dependent Diabetes Mellitus. Diabetes Care 1998; 21: 172025.

    140 Rendell M. The role of sulphonylureas in the management of type2 diabetes mellitus. Drugs 2004; 64: 133958.

    141 Schernthaner G, Grimaldi A, Di Mario U, et al. GUIDE study:double-blind comparison of once-daily gliclazide MR andglimepiride in type 2 diabetic patients. Eur J Clin Invest2004; 34:53542.

    142 Dandona P, Aljada A, Dhindsa S, Garg R. Insulin as an anti-inflammatory and antiatherosclerotic hormone. Clin Cornerstone2003; suppl 4: S1320.

    143 Deacon CF. Therapeutic strategies based on glucagon-like peptide1. Diabetes 2004; 53: 218189.

    144 Liu G. Technology evaluation: ISIS-113715, Isis. Curr Opin MolTher2004; 6: 33136.

    145 Eckel RH, Grundy SM, Zimmer PZ. The metabolic syndrome.Lancet(in press).

    146 Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis:epidemiology, pathophysiology, and management.JAMA 2002;287: 257081.

    147 HOPE Study Group. Effects of ramipril on cardiovascular andmicrovascular outcomes in people with diabetes mellitus: results ofthe HOPE study and MICRO-HOPE substudy. Heart OutcomesPrevention Evaluation Study Investigators. Lancet2000; 355:25359.

    148 Mogensen CE, Neldam S, Tikkanen I, et al. Randomised controlledtrial of dual blockade of renin-angiotensin system in patients withhypertension, microalbuminuria, and non-insulin dependentdiabetes: the candesartan and lisinopril microalbuminuria (CALM)study. BMJ2000; 321: 144044.

    149 Heart Protection Study Collaborative Group. MRC/BHF HeartProtection Study of cholesterol lowering with simvastatin in 20 536high-risk individuals: a randomised placebo-controlled trial. Lancet2002; 360: 722.

    150 Expert Panel on Detection Evaluation, and Treatment of HighBlood Cholesterol in Adults. Executive Summary of The ThirdReport of The National Cholesterol Education Program (NCEP)Expert Panel on Detection, Evaluation, And Treatment of HighBlood Cholesterol In Adults (Adult Treatment Panel III).JAMA2001; 285: 248697.

    151 Grundy SM, Vega GL, McGovern ME, et al. Efficacy, safety, andtolerability of once-daily niacin for the treatment of dyslipidemiaassociated with type 2 diabetes: results of the assessment ofdiabetes control and evaluation of the efficacy of niacin trial.Arch Intern Med2002; 162: 156876.

    152 Colwell JA. Aspirin therapy in diabetes. Diabetes Care 2004;27 (suppl 1): S7273.

    153 Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in

    preventing NIDDM in people with impaired glucose tolerance. TheDa Qing IGT and Diabetes Study. Diabetes Care 1997; 20: 53744.

    154 Buchanan TA, Xiang AH, Peters RK, et al. Preservation ofpancreatic beta-cell function and prevention of type 2 diabetes bypharmacological treatment of insulin resistance in high-riskhispanic women. Diabetes 2002; 51: 2796803.

    155 Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A,Laakso M. Acarbose for prevention of type 2 diabetes mellitus: theSTOP-NIDDM randomised trial. Lancet2002; 359: 207277.

    156 Di Paola R, Frittitta L, Miscio G, et al. A variation in 3 UTR ofhPTP1B increases specific gene expression and associates withinsulin resistance. Am J Hum Genet2002; 70: 80612.