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  • 8/22/2019 Diabetes Lancet



    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.


    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


    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








    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



    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%.


    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



    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