C H A P T E R

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Type 1 Diabetes Mellitus: An OverviewAndrea Gerard Gonzalez, Saleh Adi

Department of Pediatrics, Division of Pediatric Endocrinology, University of California,

San Francisco, CA, USA ved.

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Introduction 3

Definition 4

Epidemiology 4

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utritional and Therapeutic Interventions for Diabetes and Metabolic Syndrome

OI: 10.1016/B978-0-12-385083-6.15001-6 3

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Clinical Presentationl rig

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Management 7. Al

Comorbidities 7Inc

Complications 8

Prevention and Intervention Trials 8

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INTRODUCTION

Diabetes mellitus (DM) is a group of heteroge-neous disorders with distinct genetic, etiologic,and pathophysiologic mechanisms with thecommon elements of glucose intolerance andhyperglycemia, due to insulin deficiency,impaired insulin action, or both. The WorldHealth Organization estimates that more than220 million people worldwide have DM. Themajority of these caseshave type 2DM.Currently,DM is classified on the basis of etiology and clin-ical presentation into four major types:1

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(I) Type 1 DM: characterized by a gradual

loss of insulin-producing b-cells, due toautoimmune destruction.

(II) Type 2 DM: caused predominantly bysevere insulin resistance and subsequentb-cell failure.

(III) Gestational DM: defined ashyperglycemia with onset or firstrecognition during pregnancy.

(IV) Other Specific types: includingmonogenic forms of DM (neonatal DMand maturity onset diabetes of the young,or MODY), and DM that is attributable to

Copyright � 2012 Elsevier Inc. All rights reserved.

1. TYPE 1 DIABETES MELLITUS: AN OVERVIEW4

diseases of exocrine pancreas, otherendocrinopathies, and drug-induced DM.

This overview will focus on the autoimmunetype 1 DM; definition and criteria for diagnosis,epidemiology, pathophysiology, clinical presen-tation, management, comorbidities, and newdevelopments in the treatment and preventionof type 1 DM.

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DEFINITION

Type 1 DM results from deficiency of insulinsecretion due to a gradual autoimmune, T-cellmediated destruction of the b-cells in peoplewith genetic predisposition to this disease.Recently, more evidence has accumulated thatB-cell autoimmunity also has a major role in thepathogenesis of type 1 DM.2 In 85e95% of casesof type 1 DM, at least one serum marker of auto-immunity is detected in the form of autoanti-bodies against insulin, islet cells, the proteintyrosine phosphatase IA2, the 65-kD form ofglutamate decarboxylase (GAD-65), and thezinc transporter ZnT8.3 This subgroup of type1 DM (with positive antibodies) is designated astype 1A, while the remaining 5e15% of cases ofphenotypic type 1 DM but no detectable anti-bodies are referred to as “idiopathic” or type1B.2e5 This does not necessarily mean that indi-viduals with type 1B DM do not manifestmarkers of autoimmunity, but rather reflectsour lack of knowledge of what these antibodiesmight be. Future discoveries of yet unidentifiedislet autoantigens may prove that in fact all casesof type 1 DM are autoimmune in nature. Therehave been limited efforts to further understandthepathophysiology behind this particular groupof antibody-negative patients, with some datasuggesting an increased incidence in individualswith African or Asian ancestry. This group tendsto demonstrate a tendency for recurrent episodesof diabetic ketoacidosis (DKA) with varyingdegrees of insulin deficiency between episodes.This type of diabetes is strongly inherited and

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does not appear to have a geneticHLA-type asso-ciation.6 There are also reports of a more fulmi-nant form of b-cell destruction primarily inJapanese patients, with T-cell infiltration of theislets but no measurable autoantibodies.7e9

Type 1 diabetes is generally thought of as“childhood or juvenile” diabetes, although itcan be diagnosed at any age, with a peak inci-dence in the early teen years, around the timeof puberty.10 Worldwide, the incidence ofT1DM has been steadily increasing at anaverage annual rate of 3%.11,12

EPIDEMIOLOGY

Worldwide, it is estimated that approxi-mately 5.9%, or 246 million adults had diabetesin 2007. These estimates are expected to increaseto some 380 million, or 7.1% of the adult popu-lation, by the year 2025. About 80% of theselive in the developing countries where thelargest increases will also take place.13

In the United States, the National DiabetesFact Sheet estimates that 23.6 million childrenand adults had diabetes in 2007, accountingfor 7.8% of the population. Of those, around5.7 million were undiagnosed, making DM oneof the most prevalent chronic diseases thatcarries an economic burden of around US$174billion per year.14 However, type 1 DM accountsfor only 5e15% of these cases.

In the United States, approximately 30,000new cases of type 1 DM are diagnosed eachyear; about two-thirds of them are in childrenunder the age of 19 years.12,15

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PATHOPHYSIOLOGY

The autoimmune trigger in type 1 DM is theresult of certain environmental exposures ingenetically susceptible individuals. This geneticsusceptibility is strongly linked to specific HLAgeneswhich encode themajor histocompatibility

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complex (MHC) proteins. These proteins playa critical role in regulating immune responsesand recognition of self vs non-self cells. CertainHLA types are associated with much higherrisk for developing type 1 DM, with theHLA-DR3 and DR4, and HLA-DQ being themost common in people with type 1 DM, whileother types (e.g., HLA-DR2) appear to be protec-tive against developing autoimmunity againstb-cells.4,16 The inheritance of particular HLAalleles can account for over half of the geneticrisk for developing type 1 DM.16,17 Other geneticloci have been also identified.

While the genetics of type 1 DM continue to becarefully examined, identifying the environ-mental factors involved in developing type1DM remain largely uncertain.18,19 The increas-ing incidence of type 1 DM over the past fewdecades adds further evidence that environ-mental factors are of importance since it is notlikely that genetic changes could take place insuch a short period of time. Most of the findingsin this field have been based on strong associa-tions between the incidence of type 1 DM andcertain environmental elements, but no definitivestudies have clearly demonstrated a cause andeffect with any of these factors.18,19 Examples ofthese associations have linked type 1 DM to die-tary habits, vitamin deficiencies, exposure tocertain viruses, and the so-called “hygienehypothesis”.18e28 Population-based observa-tional studies have found that children whowere breastfed have a lower risk of type 1 DMthan those who were not, and that exposure tocow’s milk before the age of 6 months doublesthe risk of developing type 1 DM, particularlyin individuals with high-risk HLA types.28,31

However, a recent report from Finlandconcluded that early exposure to cow’s milk isnot a risk factor for developing type 1 DM.32

The EURODIAB Substudy-2 group suggestedthat rapid growth, rather than cow’s milk orearly introduction of solid foods, may explainthe increased risk for type 1 DM.33 Similar asso-ciations (although also controversial) have been

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found with intake of glutens, and foods rich inproteins, carbohydrates, and nitrosaminecompounds.34e36

In animals, a number of viruses can causea diabetes-like syndrome. In humans, epidemicsof mumps, rubella and coxsackie viral infectionshave been associated with increases in the inci-dence of type 1 DM.22e25,27,38,39 The virusesmay act directly to destroy the b-cells, or by trig-gering a widespread immune response againstseveral endocrine tissues including theb-cells.37e41 Some investigators postulate thatthis is an example of molecular mimicrybetween these viruses and the antigenic deter-minants on the surface of the b-cells.42

There is increasing evidence that inadequatevitamin D increases the risk for type 1 andtype 2 DM and other autoimmune con-ditions.43e47 This is supported by epidemiolog-ical findings of higher incidence of type 1 DMat higher latitudes and in other conditionswith decreased sun exposure,43,51 and by thefact that vitamin D receptors are expressed inb-cells and in immune cells.43,52e54 Further-more, certain polymorphisms within thevitamin D receptor gene are associated withdevelopment of type 1 DM, at least in some pop-ulations.55,56 In animal models, pharmacologicaldoses of the active form, 1,25-dihydroxyvitaminD3, have been shown to modulate the immunesystem and delay the onset of diabetes.22,59

The hygiene hypothesis suggests that avoid-ance to pathogen exposure secondary toimproved living conditions leads to inadequatematuration of the immune system. The hypoth-esis is based on the increased incidence ofdiseases like asthma or other atopic disorders inchildren, in addition to the fact that type 1DM ismore prevalent in developed societies.27,61

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DIAGNOSIS

In general, DM is diagnosed when one ormore of the following criteria are met 1,61:

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1. Symptoms of diabetes plus casual plasmaglucose concentration� 200mg/dl(11.1 mmol/l); or

2. Fasting plasma glucose� 126 mg/dl(7.0 mmol/l). Fasting is defined as no caloricintake for at least 8 h; or

3. Two-hour post load glucose� 200 mg/dl(11.1 mmol/l) during an OGTT. The testshould be performed as described byWHO,62 using a glucose load containing theequivalent of 75 g anhydrous glucosedissolved in water or 1.75 g/kg of bodyweight to a maximum of 75 g.

Recently, both the WHO and the AmericanDiabetes Association have added the 4th crite-rion of hemoglobin A1c� 6.5% as beingdiagnostic of DM.1

As noted above, the presence of diabetes-related autoantibodies confirms the classifica-tion of type 1,while the presence of obesity, acan-thosis nigricans, family history of type 2DM, andother risk factors for insulin resistance such asthe lack of physical activity or the ethnicity ofHispanic or African American origin, stronglypoint towards type 2 DM. However, type 1 DMcan occur in obese individuals with one ormore risk factors for insulin resistance, thereforescreening formarkers of autoimmunity is recom-mended in all cases of new onset DM.01

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CLINICAL PRESENTATION

Type 1 DMhas four major clinical phases: pre-clinical diabetes, overt diabetes, partial remissionphase (honeymoon), and the chronic phase.

In general, autoimmune destruction of theb-cells is a slow process that can take yearsbefore causing sufficient b-cell loss to causeinsulin deficiency. Under normal physiologicalconditions, it is estimated that less than 50% ofthe b-cell mass is sufficient to maintain euglyce-mia in humans. Typically, in individuals whoare “developing” type 1 DM, a transient stateof insulin resistance occurs, mostly due to a viral

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or bacterial illness, leading to increased require-ments for insulin production which cannot bemet because of the ongoing loss of b-cells. Thisleads to hyperglycemia, which itself has a detri-mental effect on b-cell function leading tofurther hyperglycemia and its manifestations,leading eventually to the diagnosis of DM. It isestimated that only between 10% and 40% ofthe insulin-producing b-cells are still func-tioning by the time someone develops clinicalmanifestations of DM.63,64

Thesymptomsandsignsare related to thepres-ence of hyperglycemia and the resulting effects ofwater and electrolyte imbalance. They generallyinclude polyuria, polydipsia, polyphagia, weightloss and blurry vision. Onset of symptoms canbe very variable from insidious to acute.65

It is also not uncommon that new onsetdiabetes presents with a more serious and life-threatening diabetic ketoacidosis (DKA) withsevere dehydration. The occurrence of DKA ismore commonly seen in children younger than 4years of age, and is less common in adolescentsand young adults.64e66 Despite the increasedawareness of diabetes in the public and amonggeneral practitioners, the incidence of initialDKA at diagnosis remains relatively high andvaries between 15% and 29%.64e68 Typically thepatient is acidotic with acetone fruity odor, respi-ratory distress, abdominal pain, nausea, vomit-ing, and polyuria and polydipsia. Laboratoryfindings include hyperglycemia, glucosuria,ketonemia, and ketonuria. Without timelymanagement, severe fluid and electrolyte deple-tion develops with signs of hypoperfusion andaltered mental status that may lead to coma anddeath.66,67

Once the diagnosis ismade, fluid resuscitationand insulin replacement can begin immediately.This reverses the metabolic derangements andhyperglycemia,which togetherwith the recoveryfrom the precipitating infectious process, leads torelative recovery of b-cell function and return tonear-adequate insulin production to maintaineuglycemia, heralding the honeymoon period.

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This remission phase can last from a fewmonthsto 2 years in some cases.69 However, the processof b-cell destruction continues, eventually result-ing in a gradual decrease in insulin secretion andensuing hyperglycemia, marking the chronicphase of type 1 DM.

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MANAGEMENT

The cornerstone of type 1 DM management isproviding insulin at all times. This can beachieved by administration of one to two dosesof long-acting insulin, and frequent prandialrapid-acting insulin. A series of modified humaninsulins with altered dynamics of absorptionafter subcutaneous injection have been intro-duced since 1996 and are now standard inclinical care including the long-acting insulinsGlargine and Detemir, and the rapid-acting insu-lins Lispro, Aspart, and Glulisine.70e74 These“custom-designed” insulins provide excellenttools to try to mimic the physiologic patterns ofendogenous insulin secretion and action, whileminimizing the range of blood glucose excur-sions and the risk of hypoglycemia, two of themain obstacles to achieving more aggressiveand optimal glucose control in patients withdiabetes.70,72,74

In most practices, newly diagnosed patientsare started on multiple daily injection (MDI) ofsubcutaneous insulin, while those who presentwith DKA are treated initially with intravenousinsulin infusion then switched to MDI. It iswidely accepted that replacement of insulin inall patients with type 1 DM should consist ofa combination of “basal and bolus” insulin. Typi-cally, the dose of long-acting, basal insulin isunchanged from day to day and should provideabout half of the total daily insulin requirements.However, the dosing of rapid-acting insulin isdifferent for each time, and follows certainformulas to calculate the insulin dose for eachmeal based on the blood glucose (BG) valueand the carbohydrate content in each meal

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(and snack). Alternatively, a continuous subcuta-neous insulin infusion (CSII) pump is used toprovide frequent small doses of rapid-actinginsulin as basal insulin in lieu of the long-actinginsulin, and user-administered boluses of rapid-acting insulin for meals and high BG. Because ofthis, management of type 1 DM requires self-monitoring of BG and a certain degree of compe-tency in carbohydrate counting. Type 1 DM isrecognized as a primarily self-managed disease,and to achieve the recommended glycemictargets patients need to receive ongoing nutri-tional counseling and training in self-manage-ment of their insulin regimen. In mostpractices, clinic visits with a team of physicians,diabetes educators, and nutritionists are recom-mended every 3e4 months.

In addition, a series of devices are now avail-able for the continuous measurement of glucoseconcentration in the subcutaneous interstitialfluids, which reflects, with some time lag, theglucose concentration in the blood. These contin-uous glucose monitors (CGMs) can be operatedalone or can be integrated with an insulin pump.The current devices provide predictive alarmsfor high and low BG, as well as continuous read-ings of glucose concentrations. Intense studiesare ongoing for the development of the “closedloop” in which a CGM will control the operationof an insulin pump in response to changes in BGlevels. Recent studies have shown improved gly-cemic control with the use of CGMs in type1DM.75e80Using these tools, the goals of diabetesmanagement in adults is to achieve a HgA1c of< 7.0% with preprandial BG of 70e130 mg/dl(3.9e7.2 mmol/l) and a peak postprandial BG of< 180 mg/dl (< 10.0 mmol/l).1 These goalsshould be invidualized in all patients and mustbe less stringent in children with type 1 DM.1

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COMORBIDITIES

The same genetic factors that pre-disposepatients to type 1 DM make them more likely

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to develop other autoimmune diseases.81e83 Themost common of these are thyroid autoimmu-nity, celiac disease, gastric autoimmunity, andAddison’s disease.

Autoimmune thyroid disease occurs in17e30% of patients with type 1 DM. It is morecommon in females and is often associatedwith the presence of anti-thyroperoxidase(aTPO) and anti-thyroglobulin (aTG) anti-bodies.82e84 The current recommendations arefor screening for aTPO and aTG at or shortlyafter diagnosis of type 1 DM, and measurementof TSH concentrations after metabolic controlhas been established. If normal, TSH should bere-checked every 1e2 years, or if the patientdevelops symptoms of thyroid dysfunction, thy-romegaly, or an abnormal growth rate.1

Celiac disease is an autoimmune enteropathywith a variable reported incidence of 1e10% inpatients with type 1 DM, and is more commonin children with the risk of developing celiacdisease being about 10 times higher than thegeneral population, especially in the first 5 yearsafter diagnosis with type 1 DM.87 Celiac diseasecan manifest with non-gastroenterologic signs,includingpoorgrowth,delayedpuberty, amenor-rhea, erratic blood glucose concentrations, andeven psychiatric problems.88e90 Therefore a highindex of suspicion must be kept and periodicscreening for serum levels of tissue transglutami-nase (tTG) or anti-endomysial antibodies is rec-ommended along with screening for thyroiddisease in patients with type 1 DM.1,84,88,91 Somestudies suggest that celiac disease is more likelyto develop in the first 5 years after diagnosis oftype 1 DM91 and is more likely in children diag-nosed with type 1 DM before the age of 4 yearsthan in those diagnosed as teenagers.92

Also associated with type 1 DM is antigastricparietal cell and antiadrenal autoimmunity.These, however, are more rare than thyroidand celiac disease, such that routine screeningis not currently recommended. However,because of the potential higher risk of devel-oping pernicious anemia and gastric carcinoid

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tumors and adenocarcinomas,92 De Blocket al. recently recommended periodic screeningfor antiparietal cell antibodies especially inadolescents with longer duration of diabetes,positive GAD-65 antibodies, and anti-TPOantibodies.94,95

COMPLICATIONS

Chronic hyperglycemia and poor control oftype 1 DM can lead to several long-termcomplications including hyperlipidemia,cardiovascular disease, peripheral neuropathy,and renal disease. These complications aresimilar to those seen in type 2 DM and arediscussed in other chapters in this book.res

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PREVENTION ANDINTERVENTION TRIALS

As mentioned earlier, the pathophysiology oftype 1 DM encompasses several stages, begin-ning by activation of the immune system ingenetically susceptible individuals, which leadsto b-cell injury, impaired insulin secretion, andeventually frank hyperglycemia and clinical dia-betes. This process is relatively slow and can takeup to 2 years or more. By the time the diagnosisof type 1 DM is made, only 10e50% of islet cellmass remains intact but continues to be gradu-ally destroyed over time.96e100 Therefore theprincipal challenge in any effort towards preven-tion of type 1 DM is the identification of at-riskindividuals well before they lose a substantialb-cell mass. Currently, the best predictor of type1 DM development is the presence of b-cell-directed autoantibodies, combined with carryinghigh-risk HLA alleles.101 In such individuals,several interventions have been tried, with littlesuccess in preventing the progression to overtdiabetes. However, in the past few years, signifi-cant efforts have shifted towards strategies thataim at modulating the autoimmune response to

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halt the destruction of pancreatic islets andpreserving the remaining b-cells immediatelyafter diagnosis of type 1 DM.96e100 Such strate-gies fall into two main categories: the first isantigen-specific, with interventions aimed atinducing tolerance to the specific antigen that istargeted, and the second is non-antigen specific,which aims to alter the function of componentsof the immune system, specifically T-cells andB-cells.97,100 Preliminary results have showndecreased insulin dependence at least in the firstyear after treatment and current extended phase2 and 3 trials are being carried out.102e104 Oncethese studies have shown sufficient safety andefficacy in newly diagnosed patients, they willthen be tested in at-risk individuals before theylose significant b-cell mass and become clinicallyhyperglycemic.

More recently, the role of vitamin D in regu-lating the immune system has gained muchattention.21,43,105,106 A meta-analysis of recentlypublished results suggested that vitamin Dsupplement given to children may reduce therisk for type 1 DM, particularly with doses of2000 IU/day.107

In the meantime, much effort is focusing onstem cell therapy by generating new b-cellsfrom autologous umbilical cord blood cellsand gene-engineered dendritic cells.108,109

Other, more tertiary interventions such aswhole-organ pancreatic transplant and transferof isolated islet cells, combined with ongoingimmune suppression, have both proven to besuccessful in terms of restoring glycemic leveland insulin independence,110,111 but they remainlimited by the availability of viable donor organ.

In parallel, there is continued strong interestin linking an insulin pumpwith a CGM to createan artificial pancreas.

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50. Chiu KC, Chu A, Go VL, Saad MF. HypovitaminosisD is associated with insulin resistance and beta celldysfunction. Am J Clin Nutr 2004;79:820e5.

51. Staples JA, Ponsonby AL, Lim LL, McMichael AJ.Ecologic analysis of some immune-related disorders,including type 1 diabetes, in Australia: latitude,regional ultraviolet radiation, and disease prevalence.Environ Health Perspect 2003;111(4):518e23.

52. Bruce D, Cantorna MT. Intrinsic requirement for thevitamin D receptor in the development of CD8al-phaalpha-expressing T cells. J Immunol 2011;186(5):2819e25.

53. Bhalla AK, Amento EP, Clemens TL, Holick MF,Krane SM. Specific high-affinity receptors for 1,25-dihydroxyvitamin D3 in human peripheral bloodmononuclear cells: presence in monocytes andinduction in T lymphocytes following activation.J Clin Endocrinol Metab 1983;57:1308e10.

54. Lee S, Clark SA, Gill RK, Christakos S. 1,25-Dihy-droxyvitamin D3 and pancreatic beta-cell function:vitamin D receptors, gene expression, and insulinsecretion. Endocrinology 1994;134:1602e10.

55. Maestro B, Davila N, Carranza MC, Calle C. Identi-fication of a vitamin D response element in thehuman insulin receptor gene promoter. J Steroid Bio-

chem Mol Biol 2003;84:223e30.56. Mimbacas A, Trujillo J, Gascue C, Javiel G,

Cardoso H. Prevalence of vitamin D receptor genepolymorphism in a Uruguayan population and itsrelation to type 1 diabetes mellitus. Genet Mol Res2007;6(3):534e42.

57. Eerligh P, Koeleman BP, Dudbridge F, Jan BG,Roep BO, Giphart MJ. Functional genetic poly-morphisms in cytokines and metabolic genes asadditional genetic markers for susceptibility todevelop type 1 diabetes. Genes Immun 2004;5:36e40.

58. Mathieu C, Waer M, Laureys J, Rutgeerts O,Bouillon R. Prevention of autoimmune diabetes inNOD mice by 1,25 dihydroxyvitamin D3. Diabetologia

1994;37:552e8.59. Zella JB, McCary LC, Deluca HF. Oral administration

of 1,25-dihydroxyvitamin D3 completely protectsNOD mice from insulin-dependent diabetes mellitus.Arch Biochem Biophys 2003;417:77e80.

60. D’Angeli MA, Merzon E, Valbuena LF, Tirschwell D,Paris CA, Mueller BA. Environmental factors

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associated with childhood-onset type 1 diabetesmellitus: an exploration of the hygiene and overloadhypotheses. Arch Pediatr Adolesc Med2010;164(8):732e8.

61. Craig ME, Hattersley A, Donaghue KC. Definition,epidemiology and classification of diabetes in chil-dren and adolescents. Pediatr Diabetes 2009;10(Suppl. 12):3e12.

62. World Health Organization. Definition, Diagnosisand Classification of Diabetes Mellitus and itsComplications, Part 1: Diagnosis and Classification ofDiabetes Mellitus. Geneva: WHO/NCD/NCS/99.2;1999. Ref Type: Report.

63. Knip M, Korhonene S, Kulmala P, Veijola R. Predic-tion of type 1 diabetes in the general population.Diabetes Care 2010;6:1206e12.

64. Hekkala A, Knip M, Veijola R. Ketoacidosis at diag-nosis of type 1 diabetes in children in northernFinland, temporal changes over 20 years.Diabetes Care

2007;30:861e6.65. Maniatis AK, Goehrig SH, Gao D, Rewers A,

Walravens P, Klingensmith GJ. Increased incidenceand severity of diabetes ketoacidosis among unin-sured children with newly diagnosed type 1 diabetes.Pediatr Diabetes 2005;6:79e83.

66. Neu A, Willasch A, Ehehalt S, Hub R, Ranke MB.DIARY Group Baden-Wuerttemberg. Ketoacidosisat onset of type 1 diabetes mellitus inchildrenefrequency and clinical presentation. PediatrDiabetes 2003;4(2):77e81.

67. Sundaram PC, Day E, Kirk JM. Delayed diagnosis intype 1 diabetes mellitus. Arch Dis Child

2009;94(2):151e2.68. Rewers A, Klingensmith G, Davis C, Petitti DB,

Pihoker C, Rodriguez B, Schwartz ID, Imperatore G,Williams D, Dolan LM, Dabelea D. Presence of dia-betic ketoacidosis at diagnosis of diabetes mellitus inyouth: the SEARCH for Diabetes in Youth Study.Pediatrics 2008;121(5):e1258e66.

69. Bowden SA, Duck MM, Hoffman RP. Young children(<5 yr) and adolescents (>12 yr) with type 1 diabetesmellitus have low rate of partial remission: diabeticketoacidosis is an important risk factor. Pediatr

Diabetes 2008;9:197e201.70. Eckardt K, Eckel J. Insulin analogues: action profiles

beyond glycaemic control. Arch Physiol Biochem

2008;114(1):45e53.71. Hartman I. Insulin analogs: impact on treatment

success, satisfaction, quality of life, and adherence.Clin Med Res 2008;6(2):54e67.

72. Freeman JS. Insulin analog therapy: improving thematch with physiologic insulin secretion. J Am Oste-opath Assoc 2009;109(1):26e36.

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73. Jensen MG, Hansen M, Brock B, Rungby J. Differencesbetween long-acting insulins for the treatment oftype 2 diabetes. Expert Opin Pharmacother2010;11(12):2027e35.

74. Brunton SA. Nocturnal hypoglycemia: answering thechallenge with long-acting insulin analogs. Med Gen

Med 2007;9(2):38.75. Currie CJ, Poole CD, Papo NL. An overview and

commentary on retrospective, continuous glucosemonitoring for the optimisation of care for people withdiabetes. Curr Med Res Opin 2009;25(10):2389e400.

76. Chetty VT, Almulla A, Odueyungbo A, Thabane L.The effect of continuous subcutaneous glucosemonitoring (CGMS) versus intermittent whole bloodfinger-stick glucose monitoring (SBGM) on hemo-globin A1c (HBA1c) levels in Type I diabetic patients:a systematic review. Diabetes Res Clin Pract

2008;81(1):79e87.77. Carchidi C, Holland C, Minnock P, Boyle D. New

technologies in pediatric diabetes care. MCN Am

J Matern Child Nurs 2011;36(1):32e9.78. Davey RJ, Jones TW, Fournier PA. Effect of short-term

use of a continuous glucose monitoring system witha real-time glucose display and a low glucose alarmon incidence and duration of hypoglycemia in a homesetting in type 1 diabetes mellitus. J Diabetes SciTechnol 2010;4(6):1457e64.

79. Cooke D, Hurel SJ, Casbard A, Steed L, Walker S,Meredith S, Nunn AJ, Manca A, Sculpher M,Barnard M, Kerr D, Weaver JU, Ahlquist J,Newman SP. Randomized controlled trial to assessthe impact of continuous glucose monitoring onHbA(1c) in insulin-treated diabetes (MITRE Study).Diabet Med 2009;26(5):540e7.

80. Satish Garg K, Mary Voelmle K, Christie Beatson R,Hayley Miller A, Lauren Crew B, Brandon Freson J,Rachel Hazenfield M. Use of continuous glucosemonitoring in subjects with type 1 diabetes onmultiple daily injections versus continuous subcuta-neous insulin infusion therapy: A prospective6-month study. Diabetes Care 2011;34:574e9.

81. Triolo TM, Armstrong TK, McFann K, Yu L,Rewers MJ, Klingensmith GJ, Eisenbarth GS,Barker JM. One-third of patients have evidence for anadditional autoimmune disease at type 1 diabetesdiagnosis. Diabetes Care 2011 Mar 23 [Epub ahead ofprint].

82. Barker JM. Clinical review: Type 1 diabetes-associatedautoimmunity: natural history, genetic associations,and screening. J Clin Endocrinol Metab

2006;91(4):1210e7.83. De Block CE, De Leeuw IH, Vertommen JJ,

Rooman RP, Du Caju MV, Van Campenhout CM,

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Weyler JJ, Winnock F, Van Autreve J, Gorus FK.Belgian Diabetes Registry. Beta-cell, thyroid, gastric,adrenal and coeliac autoimmunity and HLA-DQtypes in type 1 diabetes. Clin Exp Immunol

2001;126(2):236e41.84. Kordonouri O, Maguire AM, Knip M, Schober E,

Lorini R, Holl RW, Donaghue KC. Other complica-tions and conditions associated with diabetes inchildren and adolescents. Pediatric Diabetes

2009;10(Suppl. 12):204e10.85. Kordonouri O, Klinghammer A, Lang EB,

Gruters-Kieslich A, Grabert M, Holl RW. Thyroidautoimmunity in children and adolescents with type1 diabetes: a multicenter survey. Diabetes Care2002;25(8):1346e50.

86. Kordonouri O, Hartmann R, Deiss D, Wilms M,Gruters-Kieslich A. Natural course of autoimmunethyroiditis in type 1 diabetes: association with gender,age, diabetes duration, and puberty. Arch Dis Child

2005;90(4):411e4.87. Collin P, Kaukinen K, Valimaki M, Salmi J. Endocri-

nological disorders and celiac disease. Endocr Rev2002;23:464e83.

88. Holmes GK. Screening for coeliac disease in type 1diabetes. Arch Dis Child 2002;87(6):495e8.

89. Mohn A, Cerruto M, Lafusco D, Prisco F, Tumini S,Stoppoloni O, Chiarelli F. Celiac disease in childrenand adolescents with type I diabetes: importance ofhypoglycemia. J Ped Gastroent Nutr 2001;32:37e40.

90. Barker JM, Liu E. Celiac disease: pathophysiology,clinical manifestations, and associated autoimmuneconditions. Adv Pediatr 2008;55:349e65.

91. Larsson K, Carlsson A, Cederwall E, Jonsson B,Neiderud J, Jonsson B, Lernmark A, Ivarsson SA.Skane Study Group. Annual screening detects celiacdisease in children with type 1 diabetes. Pediatr

Diabetes 2008;9:354e9.92. Cerutti F, Bruno G, Chiarelli F, Lorini R, Meschi F,

Sacchetti C.Diabetes StudyGroupof the Italian Societyof Pediatric Endocrinology and Diabetology. Youngerage at onset and sex predict celiac disease in childrenand adolescents with type 1 diabetes: an Italianmulticenter study. Diabetes Care 2004;27(6):1294e8.

93. Kakkola A, Sjoblom SM, Haapiainen R, Sipponen P,Puolakkainen P, Jarvinen H. The risk of gastriccarcinoma and carcinoid tumours in patients withpernicious anemia: a prospective follow-up study.Scand J Gastroenterol 1998;33:88e92.

94. De Block CE, De Leeuw IH, Van Gaal LF. Autoim-mune gastritis in type 1 diabetes: A clinically orientedreview. J Clin Endocrinol Metab 2008;93(2):363e71.

95. De Block CE, De Leeuw IH, Rooman RP, Winnock F,Du Caju MV, Van Gaal LF. Gastric parietal cell

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antibodies are associated with glutamic acid decar-boxylase-65 antibodies and the HLA DQA1)0501-DQB1)0301 haplotype in Type 1 diabetes mellitus.Belgian Diabetes Registry. Diabet Med

2000;17(8):618e22.96. Zhang L, Eisenbarth GS. Prediction and prevention of

Type 1diabetesmellitus. JDiabetes.2011Mar;3(1):48e57.97. Cernea S, Dobreanu M, Raz I. Prevention of type 1

diabetes: today and tomorrow. Diabetes Metab Res Rev

2010;26(8):602e5.98. Rewers M, Gottlieb P. Immunotherapy for the

prevention and treatment of type 1 diabetes: humantrials and a look into the future. Diabetes Care

2009;32:1769e82.99. Haller MJ, Atkinson MA, Schatz D. Type 1 diabetes

mellitus: etiology, presentation, and management.Pediatr Clin North Am 2005;52:1553e78.

100. Sherr J, Sosenko J, Skyler JS, Herold KC. Prevention oftype 1 diabetes: the time has come. Nat Clin Pract

Endocrinol Metab 2008;4:334e43.101. Verge CF, Gianani R, Kawasaki E, et al. Number of

autoantibodies (against insulin, GAD or ICA512/IA2)rather than particular autoantibody specificitiesdetermines risk of type I diabetes. J Autoimmun

1996;9:379e83.102. Herold KC, Gitelman SE, Masharani U, et al. A single

course of anti-CD3 monoclonal antibody hOKT3g1(Ala-Ala) results in improvement in C-peptideresponses and clinical parameters for at least 2 yearsafter onset of type 1 diabetes. Diabetes

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103. Keymeulen B, Vandemeulebroucke E, Ziegler AG,et al. Insulin needs after CD3- antibody therapy innew-onset type 1 diabetes. N Engl J Med2005;352:2598e608.

104. Herold KC, Gitelman S, Greenbaum C, et al. ImmuneTolerance Network ITN007AI Study Group. Treat-ment of patients with new onset type 1 diabetes witha single course of anti-CD3 mAb teplizumabpreserves insulin production for up to 5 years. ClinImmunol 2009;132:166e73.

105. Borges MC, Martini LA, Rogero MM. Currentperspectives on vitamin D, immune system, andchronic diseases. Nutrition 2011;27(4):399e404.

106. Mathieu C, Gysemans C, Giulietti A, Bouillon R.Vitamin D and diabetes. Diabetologia

2005;48(7):1247e57.107. Zipitis CS, Akobeng AK. Vitamin D supplementation

in early childhood and risk of type 1 diabetes:a systematic review and meta-analysis. Arch Dis Child

2008;93(6):512e7.108. Madsen OD. 2005 Stem cells and diabetes treatment.

APMIS 2005;113:858e75.109. Zhao Y, Mazzone T. Human cord blood stem cells and

the journey to a cure for type 1 diabetes. Autoimmun

Rev 2010;10(2):103e7.110. Wen Y, Chen B, Ildstad ST. Stem cell-based strategies

for the treatment of type 1 diabetes mellitus. ExpertOpin Biol Ther 2011;11(1):41e53.

111. Krishna KA, Rao GV, Rao KS. Stem cell-based therapyfor the treatment of Type 1 diabetes mellitus. RegenMed 2007;2(2):171e7.

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C H A P T E R

2

Overview of Type 2 DiabetesJonathan Pinkney*, Julie Tomlinsony, Elizabeth Stenhouse**

*Peninsula College of Medicine and Dentistry, University of Plymouth, UK yPeninsula College of

Medicine and Dentistry, University of Plymouth and Cornwall & Isles of Scilly Primary Care Trust, UK** Faculty of Health, University of Plymouth, UK

O U T L I N E

Definition and Diagnostic Criteria 15

Epidemiology of Type 2 Diabetes and ItsComplications 17

Prevalence and Incidence 17Complications 17

Genetic Risk Factors for Type 2 Diabetes 18

Risk Factors and Screening for Type 2Diabetes 18

Diabetes in Pregnancy: Implications forMother and Offspring 19

Evidence for Metabolic Programming ofDiabetes in Early Life 20

Early Intervention in Type 2 Diabetes 21

Clinical Management of Type 2 Diabetes 21

Treatment Guidelines 21

Nutrition and Lifestyle Intervention 22

Pharmacological Treatments 22

Bariatric Surgery 23

Economic Impact of Type 2 Diabetes 23

Future Directions 23

DEFINITION AND DIAGNOSTICCRITERIA

Adiagnosis of type 2diabetes (T2DM) requiresbothbiochemical criteria andetiological consider-ations. The World Health Organization (WHO)

has recommended fasting and 2-h oral glucosetolerance tests (OGTT) for the diagnosis ofT2DM (Table 2.1),1 and this classification of dia-betes and impaired glucose regulation (IGR) isrecognizedby theAmericanDiabetesAssociation(ADA).2,3 Although the ADA revised their

Nutritional and Therapeutic Interventions for Diabetes and Metabolic Syndrome

DOI: 10.1016/B978-0-12-385083-6.00002-4 Copyright � 2012 Elsevier Inc. All rights reserved.15

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diagnostic criteria in 2010, allowing theuse of gly-cosylated hemoglobin (HbA1c) (Table 2.2), thissuggestion remains controversial. An etiologicalclassification of diabetes is described by theADA,3 and is summarized in Table 2.3. Themain problems with this classification are thatmany individuals with “T2DM” are atypical,

and so etiology may be hard to determine. Someindividuals with T2DM exhibit features such asketosis or islet autoimmunity, which leads toconfusion with type 1 diabetes (T1D). Moreover,whereas once most children diagnosed with dia-betes were considered to have T1D, now up to45% of new cases in somepopulations of children

TABLE 2.1 Values for Diagnosis of Diabetes and Other Categories of Hyperglycemia

Glucose concentration, mmol.lL1 (mg.dlL1)

Diagnosis Venous Capillary Plasma venous

Diabetes Mellitus

Fasting (or) � 6.1 (� 110) � 6.1 (� 110) � 7.0 (� 126)

2-h post glucose load � 10.0 (� 180) � 11.1(� 200) � 11.1(� 200)

Impaired Glucose Tolerance (IGT):

Fasting (if measured) and < 6.1 (< 110) and < 6.1 (< 110) and < 7.0 (< 126) and

2-h post glucose load � 6.7 (� 120) � 7.8 (� 140) � 7.8 (� 140)

Impaired Fasting Glucose (IFG):

Fasting � 5.6 (� 100) and � 5.6 (� 100) and � 6.1 (� 110) and

and (if measured) < 6.1 (< 110) < 6.1 (< 110) < 7.0 (< 126)

2-h post glucose load < 6.7 (< 120) < 7.8 (< 140) < 7.8 (< 140)

For epidemiological or population screening purposes, the fasting or 2-h value after 75 g oral glucose load may be used alone. For clinical

purposes, the diagnosis of diabetes should always be confirmed by repeating the test on another day unless there is an unequivocal hyper-

glycemia with acute metabolic decompensation or obvious symptoms.

Reproduced from: World Health Organization (1999) Definition, Diagnosis & Classification of Diabetes Mellitus and its complications: Part 1 Diagnosis &

Classification of Diabetes. Geneva WHO.

TABLE 2.2 American Diabetes Association Diagnostic Criteria for Diabetes

American diabetes association criteria for the diagnosis of diabetes

1 HbA1c 6.5%. The test should be performed in a laboratory using a method that is NGSP certified and standardized to theDCCT assay.* OR

2 FPG 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.* OR

3 Two-hour plasma glucose 200 mg/dl (11.1 mmol/l) during an Oral Glucose Tolerance Test.The test should be performed as described by the World Health Organization, using a glucose load containing theequivalent of 75 g anhydrous glucose dissolved in water.* OR

4 In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose 200 mg/dl(11.1 mmol/l).

* In the absence of unequivocal hyperglycemia, criteria 1e3 should be confirmed by repeat testing.

Reproduced from: American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care (2011) 34: 9(Suppl. 1), S11.

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have T2DM,4 resulting in diagnostic uncertainty.The etiological diagnosis of T2DM also requiresexclusion of other forms of diabetes, includingmonogenic forms. Therefore,whilst the classifica-tion is useful to assess newpatientswithdiabetes,it does not provide a watertight definition ofT2DM. The etiological classification could beimproved with better recognition of the hetero-geneity and polygenic nature of the disease.

EPIDEMIOLOGY OF TYPE 2DIABETES AND ITSCOMPLICATIONS

Prevalence and Incidence

More than 220 million people worldwidehave diabetes and 80% live in low- to middle-

income countries.5 The majority of these peoplehave T2DM. In the US, 25.8 million people(8.3%) have diabetes, of which 90e95% haveT2DM.6 Of these, 18.8 million (73%) are diag-nosed and 7 million (27%) are undiagnosed.Amongst the > 65 year age group, 10.9 millionhave diabetes, representing a prevalence of26.9%. A further 50% of this age group(79 million) have prediabetes.6 Similarly, inthe UK, where T2DM accounts for 92% of allregistered diabetics,7 approximately 30% ofpeople with diabetes remain undiagnosed inEngland and the actual prevalence was pre-dicted to be 7.4% in 2010, rising to 8.5% by2020 and 9.5% by 2030.7 By 2025, 300 millionpeople worldwide will have diabetes.8 Thus,diabetes prevalence rates of 10e50% will becommonplace by 2030. Towards the end of the20th century, especially high prevalences wereobserved in indigenous populations. Notably,in populations such as Native Americans,9

Pacific Islanders10 and Aboriginal Australians,11

this high prevalence is linked to rapid transi-tions from traditional to modern lifestyles,major changes in diet and physical activity,and with excessive weight gain. Since much ofthat work, it has been apparent that the preva-lence of diabetes is high and rising in mostworld populations.8 In China, the increasingaffluence and changing lifestyles have seendramatic increases in T2DM prevalence, partic-ularly in urban populations. The numbers ofadults with diabetes is projected to rise from53.1 million in 2009 to 76.1 million in 2016.This represents a prevalence of 3.9% (urban5.2%, rural 2.9%) in 2009, increasing to 5.4%(urban 6.9%, rural 3.8%) in 2016.12 In summary,T2DM poses a serious escalating public healthproblem, irrespective of gender, society, race,or age.

Complications

In 2005, there were 1.1 million deaths world-wide attributed to diabetes, almost half of which

TABLE 2.3 American Diabetes Association EtiologicalClassification of Diabetes

1. Type 1 diabetes (b-cell destruction, usually leading toabsolute insulin deficiency): (a) Immune mediated. (b)Idiopathic

2. Type 2 diabetes (ranging from predominant insulinresistance with relative insulin deficiency topredominantly secretory defect with insulin resistance)

3. Other specific forms of diabetes:

1. Genetic defects of b-cell function

2. Genetic defects in insulin action

3. Diseases of the exocrine pancreas

4. Endocrinopathies

5. Drug or chemical induced

6. Infections

7. Uncommon forms of immune-mediated diabetes

8. Other genetic syndromes sometimes associated withdiabetes

4. Gestational diabetes mellitus

Abbreviated from American Diabetes Association. Standards of Medical

Care in Diabetes. Diabetes Care (2011) 34: 9(Suppl. 1), S62.

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were below the age of 70 years and 55% werewomen. It is predicted that worldwide diabetesdeaths will double between 2005 and 2030.5 USdata report diabetes as the seventh-highestleading cause of death, with heart disease listedas the highest and cerebrovascular disease asthe third leading cause. However, only 35e40%of deceased people with diabetes have thiscondition listed on their death certificate.Furthermore, as a high percentage of diabetesremains undiagnosed, it is likely that diabetesas a cause of death is grossly underreported.Many of the cardiovascular deaths are likely tobe associated with underlying diabetes.13 Simi-larly, macrovascular disease is the commonestcause of premature death in people withT2DM, and has been shown to reduce life expec-tancy of middle-aged males with T2DM inEngland by about 8 years.14,15 For individualswho develop uncomplicated T2DM in later life,there is likely to be less risk of progression ofmicrovascular complications compared withindividuals who develop this condition ata younger age, although risks vary between indi-viduals. In general, younger patientswith T2DMare likely to have high lifetime risks of both mac-rovascular and microvascular disease. A clearrelationship between glycemic control andmicrovascular andmacrovascular complicationswas shown in the UKPDS study.16 A 1% reduc-tion in HbA1c was associated with 21% reduc-tion in risk of any diabetes-related end point ordeath. Specifically, myocardial infarction risk isreduced by 14% and microvascular disease riskby 37% by reducing HbA1c from 7.9% to 7.0%.Long-term follow-up of patients with tighterglycemic control showed lasting reductions inmacrovascular and microvascular disease.17

However, there has been controversy about tightglycemic targets. A meta-analysis of studies ofintensive glycemic control suggested that riskreduction for major cardiovascular events wasjust 9%, accompanied by significant risk of hypo-glycemia.18 Furthermore, there is evidence thatlower levels of HbA1c are associated with

increased mortality.19 Therefore, a current wide-spread view of glycemic control in T2DM is thatthis is best tailored to the individual. It has beensuggested that younger patients with greater lifeexpectancy merit more aggressive treatmentthan older patients with established cardiovas-cular complications and limited life expectancy.2

GENETIC RISK FACTORS FORTYPE 2 DIABETES

An early breakthrough in unravelling thecomplexity of T2DM came from the analysisof DNA from families with autosomal domi-nant diabetes, so-called Maturity Onset Dia-betes of the Young (MODY).20 This family ofdisorders accounts for a few per cent of dia-betes in some populations, and if not consid-ered the diagnosis is missed.21 Nearly 30susceptibility genes have now been identified,mainly influencing aspects of insulin secre-tion.22 Currently known genes appear toexplain only a small fraction of inheritedrisk.23 While the mechanisms causing associa-tions with T2DM remain unclear for most ofthese genes, the majority of the genes areexpressed in islet b-cells. Thus, whilst obesityis an important cause of insulin resistance,and is a powerful risk factor for T2DM,24,25

genetic factors will protect some obese patientsthrough b-cell compensation.

RISK FACTORS AND SCREENINGFOR TYPE 2 DIABETES

The ADA2 advocates screening in high-risk,asymptomatic individuals, so that early diag-nosis and treatment can prevent and delaycomplications. Common risk factors for T2DMand features to prompt screening are shown inTable 2.4. There remains controversy regardingthe optimal testing strategy, and several testsare currently recognized. The two main tests

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are fasting plasma glucose (FPG) or the 2-hplasma glucose (2-h PG) level after a 75 gOGTT. The adoption of HbA1c as a diagnostictest has been more controversial26 but was sug-gested by the ADA in 2010.27 No currentscreening or diagnostic test is completely inter-changeable, since FPG and 2-h PG identifydifferent individuals,28 many of whom are alsomissed with HbA1c.29 In women with poly-cystic ovary syndrome (PCOS) for example,the diagnosis of T2DM is usually missed withan FPG.30 The choice of test is also affected bywhether the intention is to screen for IGR suchas impaired fasting glucose (IFG) and impairedglucose tolerance (IGT), which are currentlyessential if “prediabetes” is to be identified byblood glucose measures. HbA1c also fails toidentify many individuals with IGR.31

Currently, screening has not been widely imple-mented in many risk groups, including thosewith obesity, women with PCOS or a history ofgestational diabetes.

DIABETES IN PREGNANCY:IMPLICATIONS FOR MOTHER

AND OFFSPRING

Gestational Diabetes Mellitus (GDM) hasbeen widely defined as carbohydrate intoler-ance of variable severity with onset duringpregnancy which returns to normal afterdelivery. Maternal hyperglycemia causes fetalhyperglycemia, fetal hyperinsulinemia andmacrosomia, resulting in excess perinatalmorbidity and mortality. Maternal risks includethe need for induction of labor and caesareansection, and long-term risks of T2DM andpossibly cardiovascular disease. The definition,diagnosis and importance of GDM have beencontroversial however. The Hyperglycemiaand Adverse Pregnancy Outcomes Study(HAPO), found a clear association betweenmaternal glucose levels below the thresholdfor diagnosis of diabetes and adverse outcomesin 25,000 pregnant women.32 In 2010, after years

TABLE 2.4 Criteria for Diabetes Screening in Asymptomatic Adult Individuals at High Risk of Type 2 Diabetes

Testing should be considered in all adults who are overweight (BMI� 25 kg/m2 or lower in high-risk ethnic groups) and haveadditional risk factors:

Physical inactivity

First degree relative with diabetes

High-risk ethnic group

Women with previous GDM or macrosomic baby

Blood pressure > 140/90 or treated hypertension

HDL cholesterol < 35 mg/dl (0.9 mmol/l) and/or triglycerides > 250 mg/dl (2.82 mmol/l)

Women with polycystic ovary syndrome

Previous IFG, IGT or HbA1c � 5.7%

Other clinical condition associated with insulin resistance (e.g., acanthosis nigricans)

History of cardiovascular disease

In the absence of the above criteria testing should begin at age 45 years.

If results are normal testing should be repeated at intervals of at least 3 years, with consideration of more frequent testingbased on initial results and risk status.

Modified from: American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care (2011) 34: 9(Suppl. 1), S11.

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of variation controversy, the International Asso-ciation of Diabetes and Pregnancy StudyGroups recommended the approach summa-rized in Table 2.5.33 These criteria recognizethat standard criteria for the diagnosis of dia-betes are inadequate for identifying levels ofhyperglycemia (i.e. GDM) that affect the fetus.This study influenced the US change fromscreening based on GDM risk factors (such asBMI> 30, previous GDM, a previous macroso-mic baby, diabetes in a first degree relative, ormaternal origin from a high-risk ethnicgroup)2,34 to universal screening at24e28 weeks’ gestation.2 However, the conse-quences of this are greatly increased screeningof “low-risk” women.

Whether GDM requires active treatment wascontroversial for many years. The aim of treat-ment for women with GDM is to reducematernal and neonatal morbidity with treat-ment options including diet and exercise, oralhypoglycemic agents and insulin. Recentstudies show that pregnancy outcomes areimproved by active treatment35e37 but thata high proportion of women with maternalhyperglycemia maintain good glycemic controlwithout drug therapy. A recent systematicreview and meta-analysis of major trialsconcluded that there were few differences inmost outcomes when comparing metforminwith insulin, but that metformin led to lessmaternal weight gain.38

Maternal hyperglycemia has importantlong-term implications for both mother andchild. The incidence of maternal T2DM afterGDM is as high as 70% after 10 years.39 Finally,maternal GDM also results in increased long-term metabolic risk in their adolescentoffspring.40 The consequences of GDM for thenext generation are therefore an importantemerging concern.

EVIDENCE FOR METABOLICPROGRAMMING OF DIABETES IN

EARLY LIFE

Neither traditional theories of genetic norenvironmental causation account for increasedrisk of T2DM in adults who were of low birth-weight for gestational age. Barker and Halesobserved increased risks of IGT and T2DM inmales who were of low birthweight.41 Theseand other findings led them to formulate theconcept of the “thrifty phenotype”,42 drawingon the earlier ideas of Neel.43 The hypothesisof “thrifty” metabolism postulates that evolu-tionary pressure from scarcity of food led tothe selection of highly efficient insulin secretionand action and that fuel starvation during intra-uterine life leads to adaptation to ensuresurvival but also results in permanent“programming” of metabolism. Neel proposedthat this evolutionarily thrifty metabolism had

TABLE 2.5 Procedures for Screening and Diagnosis of GDM

Perform a 75 g oral glucose tolerance test (OGTT) with plasma glucose measurement fasting, at 1 and 2 h, at 24e28 weeks ofgestation in women not previously diagnosed with overt diabetes.

The OGTT should be performed in the morning after an overnight fast of at least 8 h.

The diagnosis of GDM is made when any of the following glucose values are exceeded:

Fasting � 92 mg/dl (5.1 mmol/l).

1 h � 180 mg/dl (10.0mmol/l).

2 h� 153 mg/dl (8.5 mmol/l).

Reproduced from: American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care (2011) 34: 9(Suppl. 1), S11.

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maladaptive consequences in the modernworld, leading to T2DM.43 This concept is sup-ported by experimental data showing that tran-sient nutritional deficiencies in early life lead topermanent metabolic programming.44 Themechanism for programming of disease riskmay involve inherited non-DNA, epigeneticmodification through methylation and otherchemical changes to DNA and histone proteins.If so, this could explain the well-known inter-ethnic differences in the risk of diabetes.

EARLY INTERVENTION IN TYPE 2DIABETES

T2DM is often present years before diag-nosis.45,46 Early diagnosis and treatment aim toreduce progression of cardiovascular diseaseand hyperglycemia. The need for targetedscreening and early intervention in high-riskgroups is not therefore in doubt.2 A range ofdrug-based interventions have demonstratedimproved metabolic control and slower diseaseprogression47,48 and data are emerging for thelong-term effects of lifestyle intervention.49

Clearly, the earlier these interventions are insti-tuted, the greater the potential reduction oflong-term health risks. The risk of T2DM canbe reduced substantially by weight reductionand drug interventions in high-risk individualswith IGT50,51 or obesity.52 These studies haveprovided a powerful impetus for diabetesprevention programs. However, it remains tobe determined whether public health programscan afford to target the vast numbers who nowmeet criteria for diabetes screening, such assedentary individuals with BMI > 25 kg/m2.2

CLINICAL MANAGEMENTOF TYPE 2 DIABETES

Key aims of T2DM clinical managementare to reduce associated health risks, control

symptoms and restore or maintain quality oflife. This is achieved by a variety of interven-tions that include weight reduction throughdiet and exercise and using drug treatment tocontrol risk factors for complications (i.e. levelsof blood glucose, blood pressure and choles-terol). The underlying state of insulin resis-tance53 and insulin secretory failure54 providethe principles for these treatment options.Whilst the beneficial metabolic effects of weightloss are long established,55 it is comparativelyrecently that large-scale research into lifestyleand weight loss interventions has been takenseriously.49 Likewise, for selected patients withsevere obesity, bariatric surgery offers a potentialoption.56 Other requirements considered neces-sary for effective T2DM treatment includepatient education programs, a multidisciplinaryteam approach and regular recall for screeningand monitoring. Favorable effects on quality oflife and cost-effectiveness of care are alsoessential.

TREATMENT GUIDELINES

Medical treatment priorities are to achieveblood glucose levels as near to normal aspossible and to lower cholesterol and bloodpressure to reduce microvascular and macro-vascular complications.2,57,58 The importanceof tight glycemic control and treatment ofhypertension is largely based on the findingsof the UKPDS59e61 and post-trial follow-up.17

The ADA guidelines also include a significantfocus on nutrition, exercise, weight loss andmore recently the potential role of bariatricsurgery in treating T2DM.27 In the wake ofrecent trials,27 however, there has beenincreasing recognition that targets for bloodglucose lowering are best individualized, withless strict glycemic control being safer andmore appropriate for older, frailer people withexisting complications with relatively lowerlife expectancy. Based on some of these data,

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along with recent safety concerns related to tightglycemic control,62 blood pressure and choles-terol targets will be the main focus of treatmentfor many.63

NUTRITION AND LIFESTYLEINTERVENTION

Over the years, the importance of nutritionand lifestyle modification to treat T2DMhas often been neglected. Increasing BodyMass Index (BMI) is associated with worse gly-cemic control and increased complications.64

However, definitive data are lacking and nutri-tional guidance and targets for physicalactivity have been controversial. The ADAclearly acknowledges the importance of nutri-tion and physical activity in the preventionand management of diabetes.27 This consensusstatement highlights both nutrient-specific andobesity-related issues. The aim of modestweight loss is to improve glycemic controland reduce cardiovascular risk, based upondata from the Diabetes Prevention Program50

and the Look Ahead study.49 The ADA high-lights the importance of reduced dietary fats,trans fatty acids and cholesterol. Furthermore,despite evidence of short-term weight lossand improved glycemic control with low-carbohydrate diets (< 130 g/day carbohy-drate), the long-term performance and safetyof these diets have been controversial.27

Current ADA recommendations are to take atleast 150 min/week of moderate-intensityaerobic physical activity, and unless contrain-dicated to perform resistance training threetimes per week.27

PHARMACOLOGICALTREATMENTS

Themainstays of treatment have traditionallybeen insulin, sulfonylureas and metformin.

The impact of improved glycemic controlusing these three treatments was describedby the UKPDS.59,60 The use of thiazolidine-diones prompted treatment targeting insulinresistance. Pioglitazone was found to reducemacrovascular disease in high-risk patients,65

however cardiovascular concerns were encoun-tered with other members of this class. The mostrecent additions to hypoglycemic drug thera-pies are Glucagon-Like-Peptide-1 (GLP-1)agonists66 and inhibitors of dipeptidyl pepti-dase-4 (DPP-4),67 both of which enhance insulinsecretion.Whilst drug options for achieving gly-cemic control have broadened, the optimumorder and combination of these treatmentsremains debatable. Latterly, tight glycemiccontrol as the prime objective in treatingT2DM has been questioned.18 The main comor-bidity of T2DM is cardiovascur disease andtherefore the treatment aim should be to reducethis risk. This is more readily achieved by treat-ments that target blood pressure and low-density lipoprotein (LDL) cholesterol.63

Weight-loss drugs and weight-neutral hypo-glycemic agents are a significant consideration,however no firm recommendation is yetpossible without long-term data. Unfortunately,antiobesity drugs such as sibutramine and rimo-nabant have proven unsafe, although orlistathas demonstrated a modest effect on T2DM.68

Currently, GLP-1 agonists are promising forweight loss in T2DM.66 It appears appropriatetherefore to consider these drugs in conjunctionwith active weight management programs suchas that described in the Look Ahead study,49

although this remains to be explored. Whetherthe benefits of insulin, thiazolidinediones andsulfonylureas are offset by weight gain isunclear. The recognition of the benefits ofweight loss in treating T2DM is an importantfactor in the mounting interest in bariatricsurgery as a treatment for some patients. Insummary, these trends indicate increasingacceptance of the significant need for targetingobesity in T2DM.

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BARIATRIC SURGERY

Bariatric surgery came to prominence asa means to control T2DM in 199569 and has sinceattracted increasing attention.56 A range ofsurgical procedures is increasingly used toenhance the control of T2DM in obese individ-uals. The main operations currently usedinclude roux-en-Y gastric bypass (RYGB),adjustable gastric banding (AGB), biliopancre-atic diversion (BPD), and recently sleeve gastrec-tomy (SG). These procedures appear to improveblood glucose levels through changes in guthormones and afferent neural signalling.However, whilst these operations convey manybenefits, their long-term role in treating T2DMhas not been compared. A meta-analysis sug-gested T2DM “remission” in 78% of patients,70

with different rates with each procedure,although patient selection makes most of thepatients unrepresentative of the general diabeticpopulation.71 Another problem is the largenumber of uncontrolled retrospective studies.To date there has been only one small prospec-tive randomized controlled trial comparingAGB versus medical treatment of T2DM, whichachieved 72% normoglycemia 2 years afterAGB vs 13% in the medical control arm.72 Asubsequent analysis73 also suggested that AGBhad a favorable health economic impact.However, diabetes relapse is also recognizedafter bariatric surgery.74,75 In addition to this, itis obvious that long-term treatments fordiabetes should be safe. Whilst the short-termsafety of bariatric surgery is well described76,77

more complex surgery leads to higher operativemortality and complication rates. Malabsorptivebariatric surgery also generates long-termmicro-nutrient deficiencies that require close moni-toring and replacement.78 There is currentlyincreasing interest in using bariatric surgery asa diabetes treatment for people with BMI below35 kg/m2, although the ADA has urged cautionand recommends further research.27

ECONOMIC IMPACT OF TYPE 2DIABETES

At the beginning of the 21st century, T2DM isone of the most serious economic challengesfacing the world. Reliable economic data aredifficult to obtain, and so the best cost estimatescome from more developed healthcare systems.In the US, for example, the total direct costs oftreating diabetes were estimated at $116 billionin 2007, with an additional $58 billion in lostproductivity,79 although these figures underesti-mated the full cost. Nevertheless, this still repre-sented a colossal 12.8% of US Gross DomesticProduct. Currently, T2DM poses the over-whelming economic burden, as a result of itsprevalence and the costs of its complications.

In the UK, most routine management of dia-betes is undertaken within primary caresettingsd91% of this is for T2DM. Between1997 and 2007, prescribing costs for T2DMincreased by 89%, with a 28% increase for dia-betes-specific prescribing. There was a 112%increase in primary care appointments, andthe overall costs of treating T2DM rose by59%.80 Recent analyses have found 12.6% ofacute hospital admissions to be diabetes-related,and that diabetes accounts for 10.8% of hospitaloutpatient attendances.81 The percentage ofacute hospital expenditure attributable to dia-betes rose from 8.7% to 12.3% between 1994and 2004.81 Thus we have seen substantial risesin both primary and secondary care costs attrib-utable to T2DM.

FUTURE DIRECTIONS

Diabetes researchers of the 19th and early 20th

centuries would be amazed at the advancesdescribed in this book, although some funda-mental controversies remain and new challengeshave arisen. The major new challenge is theworldwide explosion of T2DMrelated to obesity.Although clinical trials have demonstrated the

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feasibility of diabetes prevention,50,51,82 it hasbeen less clearhow toachieve this cost-effectively.Public health programs on this scale requirepolitical and economic cooperation. Weightloss is now commonly seen as a key treatmentpriority and yet many diabetes clinicsremain poorly equipped to offer good supportfor weight loss. The optimum drug treatmentregimens remain unclear with the use of oralagents, the newer incretin mimetics, andinsulins requiring longer-term studies. Basicresearch on the molecular geneticsand the endocrinology of T2DM andobesitydespecially the mechanisms of diabetesremission after bariatric surgerydmay lead tonew forms of treatment.

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