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4.3.0.0 Type 2 Di­a­betes

Type 2 di­a­betes, pre­vi­ous­ly re­ferred to as “nonin­sulin-‍de­pen­dent di­a­betes” or “adult-‍onset di­a­betes,” ac­counts for 90– 95% of all di­a­betes. This form en­com­pass­es in­di­vid­u­als who have rel­a­tive (rather than ab­so­lute) in­sulin deficien­cy and have pe­riph­er­al in­sulin re­sis­tance. At least ini­tially, and often through­out their life­time, these in­di­vid­u­als may not need in­sulin treat­ment to sur­vive.

There are var­i­ous caus­es of type 2 di­a­betes. Al­though the specific eti­olo­gies are not known, au­toim­mune de­struc­tion of β-‍cells does not occur and pa­tients do not have any of the other known caus­es of di­a­betes. Most but not all pa­tients with type 2 di­a­betes are over­weight or obese. Ex­cess weight it­self caus­es some de­gree of in­sulin re­sis­tance. Pa­tients who are not obese or over­weight by tra­di­tion­al weight cri­te­ria may have an in­creased per­cent­age of body fat dis­tribut­ed pre­dom­i­nant­ly in the ab­dom­i­nal region.

DKA sel­dom oc­curs spon­ta­neous­ly in type 2 di­a­betes; when seen, it usu­al­ly aris­es in as­so­ci­a­tion with the stress of an­oth­er ill­ness such as in­fec­tion or with the use of cer­tain drugs (e.g., cor­ti­cos­teroids, atyp­i­cal an­tipsy­chotics, and sodi­um–glu­cose co­trans­porter 2 in­hibitors) (45,46). Type 2 di­a­betes fre­quent­ly goes undi­ag­nosed for many years be­cause hy­per­glycemia de­vel­ops grad­u­al­ly and, at ear­li­er stages, is often not se­vere enough for the pa­tient to no­tice the clas­sic di­a­betes symp­toms. Nev­er­the­less, even undi­ag­nosed pa­tients are at in­creased risk of de­vel­op­ing macrovas­cu­lar and mi­crovas­cu­lar com­pli­ca­tions.

Whe­re­as pa­tients with type 2 di­a­betes may have in­sulin lev­els that ap­pear nor­mal or el­e­vat­ed, the high­er blood glu­cose lev­els in these pa­tients would be ex­pect­ed to re­sult in even high­er in­sulin val­ues had their β-cell func­tion been nor­mal. Thus, in­sulin se­cre­tion is de­fec­tive in these pa­tients and insufficient to com­pen­sate for in­sulin re­sis­tance.

In­sulin re­sis­tance may im­prove with weight re­duc­tion and/‍or phar­ma­co­log­ic treat­ment of hy­per­glycemia but is sel­dom re­stored to nor­mal.

The risk of de­vel­op­ing type 2 di­a­betes in­creas­es with age, obe­si­ty, and lack of phys­i­cal ac­tiv­i­ty. It oc­curs more fre­quent­ly in women with prior GDM, in those with hy­per­ten­sion or dys­lipi­demia, and in cer­tain racial/eth­nic sub­groups (African Amer­i­can, Amer­i­can In­di­an, His­pan­ic/‍Latino, and Asian Amer­i­can). It is often as­so­ci­at­ed with a strong ge­net­ic predispo­si­tion or fam­i­ly his­to­ry in first-‍de­gree rel­a­tives, more so than type 1 di­a­betes. How­ev­er, the ge­net­ics of type 2 di­a­betes is poor­ly un­der­stood. In adults with­out tra­di­tion­al risk fac­tors for type 2 di­a­betes and/‍or younger age, con­sid­er an­ti­body test­ing to ex­clude the di­ag­no­sis of type 1 di­a­betes (i.e., GAD).

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4.4.0.0 Screen­ing and Test­ing

4.4.1.0 Screen­ing and Test­ing for Predi­a­betes and Type 2 Di­a­betes in Asymp­tomat­ic Adults

Screen­ing for predi­a­betes and type 2 di­a­betes risk through an in­for­mal as­sess­ment of risk fac­tors (Table 2.3) or with an as­sess­ment tool, such as the ADA risk test (Fig. 2.1) (di­a­betes.org/‍socrisktest), is rec­om­mend­ed to guide pro­viders on whether per­form­ing a di­ag­nos­tic test (Table 2.2) is ap­pro­pri­ate. Predi­a­betes and type 2 di­a­betes meet cri­te­ria for con­di­tions in which early de­tec­tion is ap­pro­pri­ate. Both con­di­tions are com­mon and im­pose significant clin­i­cal and pub­lic health bur­dens. There is often a long presymp­tomat­ic phase be­fore the di­ag­no­sis of type 2 di­a­betes. Sim­ple tests to de­tect preclin­i­cal dis­ease are read­i­ly avail­able. The du­ra­tion of glycemic bur­den is a strong pre­dic­tor of ad­verse out­comes. There are ef­fec­tive in­ter­ven­tions that pre­vent pro­gres­sion from predi­a­betes to di­a­betes (see Sec­tion 3 “Pre­ven­tion or Delay of Type 2 Di­a­betes”) and re­duce the risk of di­a­betes com­pli­ca­tions (see Sec­tion 10 “Car­dio­vas­cu­lar Dis­ease and Risk Man­age­ment” and Sec­tion 11 “Mi­crovas­cu­lar Com­pli­ca­tions and Foot Care”).

Ap­prox­i­mate­ly one-‍quar­ter of peo­ple with di­a­betes in the U.S. and near­ly half of Asian and His­pan­ic Amer­i­cans with di­a­betes are undi­ag­nosed (38,39). Al­though screen­ing of asymp­tomat­ic in­di­vid­u­als to iden­tify those with predi­a­betes or di­a­betes might seem rea­son­able, rig­or­ous clin­i­cal tri­als to prove the ef­fec­tiveness of such screen­ing have not been con­duct­ed and are unlike­ly to occur.

A large Eu­ro­pean ran­domized con­trolled trial com­pared the im­pact of screen­ing for di­a­betes and in­ten­sive mul­ti­fac­to­ri­al in­ter­ven­tion with that of screen­ing and rou­tine care (47). Gen­er­al prac­tice pa­tients be­tween the ages of 40 and 69 years were screened for di­a­betes and ran­domly as­signed by prac­tice to in­ten­sive treat­ment of mul­ti­ple risk fac­tors or rou­tine di­a­betes care. After 5.3 years of fol­low-‍up, CVD risk fac­tors were mod­estly but significant­ly im­proved with in­ten­sive treat­ment com­pared with rou­tine care, but the in­ci­dence of first CVD events or mor­tal­i­ty was not significant­ly dif­ferent be­tween the groups (40). The ex­cel­lent care pro­vided to pa­tients in the rou­tine care group and the lack of an un­screened con­trol arm lim­it­ed the au­thors’ abil­i­ty to de­ter­mine whether screen­ing and early treat­ment im­proved out­comes com­pared with no screen­ing and later treat­ment after clin­i­cal di­ag­noses. Com­put­er sim­u­la­tion mod­el­ing stud­ies sug­gest that major benefits are like­ly to ac­crue from the early di­ag­no­sis and treat­ment of hy­per­glycemia and car­dio­vas­cu­lar risk fac­tors in type 2 di­a­betes (48); more­over, screen­ing, be­gin­ning at age 30 or 45 years and inde­pen­dent of risk fac­tors, may be cost-‍ef­fec­tive (<$11,000 per qual­i­ty-adjusted life-‍year gained) (49). Ad­di­tion­al con­sid­er­a­tions re­gard­ing test­ing for type 2 di­a­betes and predi­a­betes in asymp­tomat­ic pa­tients in­clude the fol­low­ing.

Fig­ure 2.1 - ADA risk test (di­a­betes.org/‍socrisktest).

Age

Age is a major risk fac­tor for di­a­betes. Test­ing should begin at no later than age 45 years for all pa­tients. Screen­ing should be con­sid­ered in over­weight or obese adults of any age with one or more risk fac­tors for di­a­betes.

BMI and Eth­nic­i­ty

In gen­er­al, BMI ≥25 kg/m2 is a risk fac­tor for di­a­betes. How­ev­er, data sug­gest that the BMI cut point should be lower for the Asian Amer­i­can pop­u­la­tion (50,51). The BMI cut points fall con­sis­tent­ly be­tween 23 and 24 kg/m2 (sen­si­tiv­i­ty of 80%) for near­ly all Asian Amer­i­can sub­groups (with lev­els slight­ly lower for Japanese Amer­i­cans). This makes a round­ed cut point of 23 kg/m2 prac­ti­cal. An ar­gu­ment can be made to push the BMI cut point to lower than 23 kg/m2 in favor of in­creased sen­si­tiv­i­ty; how­ev­er, this would lead to an un­ac­cept­ably low specificity (13.1%). Data from the WHO also sug­gest that a BMI of ≥23 kg/m2 should be used to define in­creased risk in Asian Amer­i­cans (52). The finding that one-‍third to one­half of di­a­betes in Asian Amer­i­cans is undi­ag­nosed sug­gests that test­ing is not oc­cur­ring at lower BMI thresh­olds (53,54).

Ev­i­dence also sug­gests that other pop­u­la­tions may benefit from lower BMI cut points. For ex­am­ple, in a large multieth­nic co­hort study, for an equiv­a­lent in­ci­dence rate of di­a­betes, a BMI of 30 kg/m2 in non-‍His­pan­ic whites was equiv­a­lent to a BMI of 26 kg/m2 in African Amer­i­cans (55).

Med­i­ca­tions

Cer­tain med­i­ca­tions, such as glu­co­cor­ti­coids, thi­azide di­uret­ics, some HIV med­i­ca­tions, and atyp­i­cal an­tipsy­chotics (56), are known to in­crease the risk of di­a­betes and should be con­sid­ered when de­cid­ing whether to screen.

Test­ing In­ter­val

The ap­pro­pri­ate in­ter­val be­tween screen­ing tests is not known (57). The ra­tio­nale for the 3-year in­ter­val is that with this in­ter­val, the num­ber of false-‍pos­i­tive tests that re­quire confirma­to­ry test­ing will be re­duced and in­di­vid­u­als with false-‍neg­a­tive tests will be retest­ed be­fore sub­stan­tial time elaps­es and com­pli­ca­tions de­vel­op (57).

Com­mu­ni­ty Screen­ing

Ide­al­ly, test­ing should be car­ried out with­in a health care set­ting be­cause of the need for fol­low-‍up and treat­ment. Com­mu­ni­ty screen­ing out­side a health care set­ting is gen­er­ally not rec­om­mend­ed be­cause peo­ple with pos­i­tive tests may not seek, or have ac­cess to, ap­pro­pri­ate fol­low-‍up test­ing and care. How­ev­er, in specific sit­u­a­tions where an ad­e­quate re­fer­ral sys­tem is es­tab­lished be­forehand for pos­i­tive tests, com­mu­ni­ty screen­ing may be con­sid­ered. Com­mu­ni­ty test­ing may also be poor­ly tar­get­ed; i.e., it may fail to reach the groups most at risk and inap­pro­pri­ately test those at very low risk or even those who have al­ready been di­ag­nosed (58).

Screen­ing in Den­tal Prac­tices

Be­cause pe­ri­odontal dis­ease is as­so­ci­at­ed with di­a­betes, the util­i­ty of screen­ing in a den­tal set­ting and re­fer­ral to pri­ma­ry care as a means to im­prove the di­ag­no­sis of predi­a­betes and di­a­betes has been ex­plored (59-61), with one study es­ti­mat­ing that 30% of pa­tients ≥30 years of age seen in gen­er­al den­tal prac­tices had dys­g­lycemia (61). Fur­ther re­search is need­ed to demon­strate the fea­si­bil­i­ty, ef­fec­tiveness, and costef­fec­tiveness of screen­ing in this set­ting.

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4.4.2.0 Screen­ing and Test­ing for Predi­a­betes and Type 2 Di­a­betes in Chil­dren and Ado­les­cents

In the last decade, the in­ci­dence and preva­lence of type 2 di­a­betes in ado­les­cents has in­creased dra­mat­i­cal­ly, es­pe­cial­ly in racial and eth­nic mi­nor­i­ty pop­u­la­tions (33). See Table 2.4 for rec­om­men­da­tions on risk-‍based screen­ing for type 2 di­a­betes or predi­a­betes in asymp­tomat­ic chil­dren and ado­les­cents in a clin­i­cal set­ting (13). See Ta­bles 2.2 and 2.5 for the cri­te­ria for the di­ag­no­sis of di­a­betes and predi­a­betes, re­spec­tive­ly, which apply to chil­dren, ado­les­cents, and adults. See Sec­tion 13 “Chil­dren and Ado­les­cents” for ad­di­tion­al in­for­ma­tion on type 2 di­a­betes in chil­dren and ado­les­cents.

Some stud­ies ques­tion the va­lid­i­ty of A1C in the pe­di­atric pop­u­la­tion, es­pe­cial­ly among cer­tain eth­nicities, and sug­gest OGTT or FPG as more suit­able di­ag­nos­tic tests (62). How­ev­er, many of these stud­ies do not rec­og­nize that di­a­betes di­ag­nos­tic cri­te­ria are based on long-‍term health out­comes, and val­i­da­tions are not cur­rently avail­able in the pe­di­atric pop­u­la­tion (63). The ADA ac­knowl­edges the lim­it­ed data sup­port­ing A1C for di­ag­nos­ing type 2 di­a­betes in chil­dren and ado­les­cents. Al­though A1C is not rec­om­mend­ed for di­ag­no­sis of di­a­betes in chil­dren with cys­tic fibro­sis or symp­toms sug­gestive of acute onset of type 1 di­a­betes and only A1C as­says with­out in­ter­fer­ence are ap­pro­pri­ate for chil­dren with hemoglobinopathies, the ADA con­tin­ues to rec­om­mend A1C for di­ag­no­sis of type 2 di­a­betes in this co­hort (64,65).

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5.0.0.0 GES­TA­TION­AL DI­A­BETES MEL­LI­TUS

5.1.0.0 Rec­om­men­da­tions

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5.2.0.0 Defini­tion

For many years, GDM was defined as any de­gree of glu­cose intol­er­ance that was first rec­og­nized dur­ing preg­nan­cy (40), re­gard­less of whether the con­di­tion may have pre­dat­ed the preg­nan­cy or per­sist­ed after the preg­nan­cy. This defini­tion fa­cil­i­tat­ed a uni­form strat­e­gy for de­tec­tion and clas­sification of GDM, but it was lim­it­ed by im­pre­ci­sion.

The on­go­ing epi­dem­ic of obe­si­ty and di­a­betes has led to more type 2 di­a­betes in women of child­bear­ing age, with an in­crease in the num­ber of preg­nant women with undi­ag­nosed type 2 di­a­betes (66). Be­cause of the num­ber of preg­nant women with undi­ag­nosed type 2 di­a­betes, it is rea­son­able to test women with risk fac­tors for type 2 di­a­betes (67) (Table 2.3) at their ini­tial pre­na­tal visit, using stan­dard di­ag­nos­tic cri­te­ria (Table 2.2). Women di­ag­nosed with di­a­betes by stan­dard di­ag­nos­tic cri­te­ria in the first trimester should be clas­sified as hav­ing pre­ex­ist­ing preges­ta­tional di­a­betes (type 2 di­a­betes or, very rarely, type 1 di­a­betes or mono­genic di­a­betes). Women found to have predi­a­betes in the first trimester may be en­cour­aged to make lifestyle changes to re­duce their risk of de­vel­op­ing type 2 di­a­betes, and per­haps GDM, though more study is need­ed (68). GDM is di­a­betes that is first di­ag­nosed in the sec­ond or third trimester of preg­nan­cy that is not clear­ly ei­ther pre­ex­ist­ing type 1 or type 2 di­a­betes (see Sec­tion 14 “Man­age­ment of Di­a­betes in Preg­nan­cy”). The In­ter­na­tion­al As­so­ci­a­tion of the Di­a­betes and Preg­nan­cy Study Groups (IADPSG) GDM di­ag­nos­tic cri­te­ria for the 75-g OGTT as well as the GDM screen­ing and di­ag­nos­tic cri­te­ria used in the two-‍step ap­proach were not de­rived from data in the first half of preg­nan­cy, so the di­ag­no­sis of GDM in early preg­nan­cy by ei­ther FPG or OGTT val­ues is not ev­i­dence based (69).

Be­cause GDM con­fers in­creased risk for the de­vel­op­ment of type 2 di­a­betes after de­liv­ery (70,71) and be­cause ef­fec­tive pre­ven­tion in­ter­ven­tions are avail­able (72,73), women di­ag­nosed with GDM should re­ceive life­long screen­ing for predi­a­betes and type 2 di­a­betes.

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5.3.0.0 Di­ag­no­sis

5.3.1.0 Overview

GDM car­ries risks for the moth­er, fetus, and neonate. Not all ad­verse out­comes are of equal clin­i­cal im­por­tance. The Hy­per­glycemia and Ad­verse Preg­nan­cy Out­come (HAPO) study (74), a large-‍scale multi­na­tion­al co­hort study com­plet­ed by more than 23,000 preg­nant women, demon­strat­ed that risk of ad­verse ma­ter­nal, fetal, and neona­tal out­comes con­tin­u­ously in­creased as a func­tion of ma­ter­nal glycemia at 24–28 weeks of ges­ta­tion, even with­in ranges pre­vi­ous­ly con­sid­ered nor­mal for preg­nan­cy. For most com­pli­ca­tions, there was no thresh­old for risk. These re­sults have led to care­ful recon­sid­er­a­tion of the di­ag­nos­tic cri­te­ria for GDM. GDM di­ag­no­sis (Table 2.6) can be ac­com­plished with ei­ther of two strate­gies:

1. “One-‍step” 75-g OGTT or
2. “Two-‍step” ap­proach with a 50-g (nonfast­ing) screen fol­lowed by a 100-g OGTT for those who screen pos­i­tive

Dif­fer­ent di­ag­nos­tic cri­te­ria will iden­tify dif­ferent de­grees of ma­ter­nal hy­per­glycemia and ma­ter­nal/fetal risk, lead­ing some ex­perts to de­bate, and dis­agree on, op­ti­mal strate­gies for the di­ag­no­sis of GDM.

Table 2.6 - Screen­ing for and di­ag­no­sis of GDM

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5.3.2.0 One-‍Step Strat­e­gy

The IADPSG defined di­ag­nos­tic cut points for GDM as the av­er­age fast­ing, 1-h, and 2-h PG val­ues dur­ing a 75-g OGTT in women at 24–28 weeks of ges­ta­tion who par­tic­i­pat­ed in the HAPO study at which odds for ad­verse out­comes reached 1.75 times the es­ti­mat­ed odds of these out­comes at the mean fast­ing, 1-h, and 2-h PG lev­els of the study pop­u­la­tion. This one-‍step strat­e­gy was an­tic­i­pat­ed to significant­ly in­crease the in­ci­dence of GDM (from 5–6% to 15–20%), pri­mar­i­ly be­cause only one abnor­mal value, not two, be­came sufficient to make the di­ag­no­sis (75). The an­tic­i­pat­ed in­crease in the in­ci­dence of GDM could have a sub­stan­tial im­pact on costs and med­i­cal in­fras­truc­ture needs and has the po­ten­tial to “med­i­calize” preg­nan­cies pre­vi­ous­ly cat­e­go­rized as nor­mal. A re­cent fol­low-‍up study of women par­tic­i­pat­ing in a blind­ed study of preg­nan­cy OGTTs found that 11 years after their preg­nan­cies, women who would have been di­ag­nosed with GDM by the one-‍step ap­proach, as com­pared with those with­out, were at 3.4-fold high­er risk of de­vel­op­ing predi­a­betes and type 2 di­a­betes and had chil­dren with a high­er risk of obe­si­ty and in­creased body fat, sug­gest­ing that the larg­er group of women iden­tified by the one-‍step ap­proach would benefit from in­creased screen­ing for di­a­betes and predi­a­betes that would ac­com­pa­ny a his­to­ry of GDM (76). Nev­er­the­less, the ADA rec­om­mends these di­ag­nos­tic cri­te­ria with the in­tent of op­ti­miz­ing ges­ta­tional out­comes be­cause these cri­te­ria were the only ones based on preg­nan­cy out­comes rather than end points such as pre­diction of sub­se­quent ma­ter­nal di­a­betes.

The ex­pect­ed benefits to the off­spring are in­ferred from in­ter­ven­tion tri­als that fo­cused on women with lower lev­els of hy­per­glycemia than iden­tified using older GDM di­ag­nos­tic cri­te­ria. Those tri­als found mod­est benefits in­clud­ing re­duced rates of large-for-ges­ta­tional-age births and preeclamp­sia (77,78). It is im­por­tant to note that 80–90% of women being treat­ed for mild GDM in these two ran­domized con­trolled tri­als could be man­aged with lifestyle ther­a­py alone. The OGTT glu­cose cut­offs in these two tri­als over­lapped with the thresh­olds rec­om­mend­ed by the IADPSG, and in one trial (78), the 2-h PG thresh­old (140 mg/dL [7.8 mmol/‍L]) was lower than the cut­off rec­om­mend­ed by the IADPSG (153 mg/dL [8.5 mmol/‍L]). No ran­domized con­trolled tri­als of iden­tifying and treat­ing GDM using the IADPSG cri­te­ria ver­sus older cri­te­ria have been pub­lished to date. Data are also lack­ing on how the treat­ment of lower lev­els of hy­per­glycemia af­fects a moth­er’s fu­ture risk for the de­vel­op­ment of type 2 di­a­betes and her off­spring’s risk for obe­si­ty, di­a­betes, and other metabol­ic dis­or­ders. Ad­di­tion­al well-‍de­signed clin­i­cal stud­ies are need­ed to de­ter­mine the op­ti­mal in­ten­si­ty of mon­i­tor­ing and treat­ment of women with GDM di­ag­nosed by the one-‍step strat­e­gy (79,80).

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5.3.3.0 Two-‍Step Strat­e­gy

In 2013, the Na­tion­al In­sti­tutes of Health (NIH) con­vened a con­sen­sus de­vel­op­ment con­fer­ence to con­sid­er di­ag­nos­tic cri­te­ria for di­ag­nos­ing GDM (81). The 15-‍mem­ber panel had repre­sentatives from obstetrics/‍gynecology, ma­ter­nal-‍fetal medicine, pe­di­atrics, di­a­betes re­search, bio­statis­tics, and other re­lat­ed fields. The panel rec­om­mend­ed a two-‍step ap­proach to screen­ing that used a 1-h 50-g glu­cose load test (GLT) fol­lowed by a 3-h 100-g OGTT for those who screened pos­i­tive. The Amer­i­can Col­lege of Ob­ste­tri­cians and Gy­ne­col­o­gists (ACOG) rec­om­mends any of the com­monly used thresh­olds of 130, 135, or 140 mg/dL for the 1-h 50-g GLT (82). A sys­tematic re­view for the U.S. Pre­ven­tive Ser­vices Task Force com­pared GLT cut-‍offs of 130 mg/dL (7.2 mmol/‍L) and 140 mg/dL (7.8 mmol/‍L) (83). The high­er cut­off yield­ed sen­si­tiv­i­ty of 70–88% and specificity of 69–89%, while the lower cut­off was 88–99% sen­si­tive and 66– 77% specific. Data re­gard­ing a cut­off of 135 mg/dL are lim­it­ed. As for other screen­ing tests, choice of a cut­off is based upon the trade-‍off be­tween sen­si­tiv­i­ty and specificity. The use of A1C at 24–28 weeks of ges­ta­tion as a screen­ing test for GDM does not func­tion as well as the GLT (84).

Key fac­tors cited by the NIH panel in their de­ci­sion-‍mak­ing pro­cess were the lack of clin­i­cal trial data demon­strat­ing the benefits of the one-‍step strat­e­gy and the po­ten­tial neg­a­tive conse­quences of iden­tifying a large group of women with GDM, in­clud­ing med­i­calization of preg­nan­cy with in­creased health care uti­liza­tion and costs. More­over, screen­ing with a 50-g GLT does not re­quire fast­ing and is there­fore eas­i­er to ac­com­plish for many women. Treat­ment of high­er-‍thresh­old ma­ter­nal hy­per­glycemia, as iden­tified by the two-‍step ap­proach, re­duces rates of neona­tal macro­so­mia, large-for-ges­ta­tional-age births (85), and shoul­der dys­to­cia, with­out in­creas­ing small-for-ges­ta­tional-age births. ACOG cur­rently sup­ports the two-‍step ap­proach but notes that one el­e­vat­ed value, as op­posed to two, may be used for the di­ag­no­sis of GDM (82). If this ap­proach is im­ple­ment­ed, the in­ci­dence of GDM by the two-‍step strat­e­gy will like­ly in­crease marked­ly. ACOG rec­om­mends ei­ther of two sets of di­ag­nos­tic thresh­olds for the 3-h 100-g OGTT (86,87). Each is based on dif­ferent math­e­mat­i­cal con­ver­sions of the orig­i­nal rec­om­mend­ed thresh­olds, which used whole blood and nonen­zy­mat­ic meth­ods for glu­cose de­ter­mi­na­tion. A sec­ondary anal­y­sis of data from a ran­domized clin­i­cal trial of iden­tification and treat­ment of mild GDM (88) demon­strat­ed that treat­ment was sim­i­larly beneficial in pa­tients meet­ing only the lower thresh­olds (86) and in those meet­ing only the high­er thresh­olds (87). If the two-‍step ap­proach is used, it would ap­pear ad­van­ta­geous to use the lower di­ag­nos­tic thresh­olds as shown in step 2 in Table 2.6.

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5.3.4.0 Fu­ture Con­sid­er­a­tions

The conflict­ing rec­om­men­da­tions from ex­pert groups un­der­score the fact that there are data to sup­port each strat­e­gy. A cost-‍benefit es­ti­ma­tion com­par­ing the two strate­gies con­clud­ed that the one-‍step ap­proach is cost-‍ef­fec­tive only if pa­tients with GDM re­ceive postde­liv­ery coun­sel­ing and care to pre­vent type 2 di­a­betes (89). The de­ci­sion of which strat­e­gy to im­ple­ment must there­fore be made based on the rel­a­tive val­ues placed on fac­tors that have yet to be mea­sured (e.g., will­ing­ness to change prac­tice based on cor­re­la­tion stud­ies rather than in­ter­ven­tion trial re­sults, avail­able in­fras­truc­ture, and im­por­tance of cost con­sid­er­a­tions).

As the IADPSG cri­te­ria (“one-‍step strat­e­gy”) have been adopt­ed in­ter­na­tion­al­ly, fur­ther ev­i­dence has emerged to sup­port im­proved preg­nan­cy out­comes with cost sav­ings (90) and may be the pre­ferred ap­proach. Data com­par­ing pop­u­la­tion-‍wide out­comes with one-‍step ver­sus two-‍step ap­proaches have been in­con­sis­tent to date (91,92). In ad­di­tion, preg­nan­cies com­pli­cat­ed by GDM per the IADPSG cri­te­ria, but not rec­og­nized as such, have com­pa­ra­ble out­comes to preg­nan­cies di­ag­nosed as GDM by the more strin­gent two-‍step cri­te­ria (93,94). There re­mains strong con­sen­sus that es­tab­lish­ing a uni­form ap­proach to di­ag­nos­ing GDM will benefit pa­tients, care­givers, and pol­i­cy mak­ers. Longer-‍term out­come stud­ies are cur­rently un­der­way.

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6.0.0.0 CYS­TIC FI­BRO­SIS–RE­LAT­ED DI­A­BETES

Cys­tic fibro­sis–re­lat­ed di­a­betes (CFRD) is the most com­mon co­mor­bid­i­ty in peo­ple with cys­tic fibro­sis, oc­cur­ring in about 20% of ado­les­cents and 40–50% of adults (95). Di­a­betes in this pop­u­la­tion, com­pared with in­di­vid­u­als with type 1 or type 2 di­a­betes, is as­so­ci­at­ed with worse nu­tri­tion­al sta­tus, more se­vere inflam­ma­to­ry lung dis­ease, and greater mor­tal­i­ty. In­sulin insufficien­cy is the pri­ma­ry de­fect in CFRD. Ge­net­i­cal­ly de­ter­mined β-cell func­tion and in­sulin re­sis­tance as­so­ci­at­ed with in­fec­tion and inflam­ma­tion may also con­tribute to the de­vel­op­ment of CFRD. Milder abnor­malities of glu­cose tol­er­ance are even more com­mon and occur at ear­li­er ages than CFRD. Whether in­di­vid­u­als with IGT should be treat­ed with in­sulin re­place­ment has not cur­rently been de­ter­mined. Al­though screen­ing for di­a­betes be­fore the age of 10 years can iden­tify risk for pro­gres­sion to CFRD in those with abnor­mal glu­cose tol­er­ance, no benefit has been es­tab­lished with re­spect to weight, height, BMI, or lung func­tion. Con­tin­u­ous glu­cose mon­i­tor­ing or HOMA of β-cell func­tion (96) may be more sen­si­tive than OGTT to de­tect risk for pro­gres­sion to CFRD; how­ev­er, ev­i­dence link­ing these re­sults to long-‍term out­comes is lack­ing, and these tests are not rec­om­mend­ed for screen­ing (97).

CFRD mor­tal­i­ty has significant­ly de­creased over time, and the gap in mor­tal­i­ty be­tween cys­tic fibro­sis pa­tients with and with­out di­a­betes has con­sid­er­ably nar­rowed (98). There are lim­it­ed clin­i­cal trial dataon ther­a­py for CFRD. The largest study com­pared three reg­i­mens: pre­meal in­sulin as­part, repaglin­ide, or oral place­bo in cys­tic fibro­sis pa­tients with di­a­betes or abnor­mal glu­cose tol­er­ance. Par­tic­i­pants all had weight loss in the year pre­ced­ing treat­ment; how­ev­er, in the in­sulin-‍treat­ed group, this pat­tern was re­versed, and pa­tients gained 0.39 (± 0.21) BMI units (P = 0.02). The repaglin­ide-‍treat­ed group had ini­tial weight gain, but this was not sus­tained by 6 months. The place­bo group con­tin­ued to lose weight (99). In­sulin re­mains the most wide­ly used ther­a­py for CFRD (100).

Ad­di­tion­al re­sources for the clin­i­cal man­age­ment of CFRD can be found in the po­si­tion state­ment “Clin­i­cal Care Guide­lines for Cys­tic Fibro­sis2Re­lat­ed Di­a­betes: A Po­si­tion State­ment of the Amer­i­can Di­a­betes As­so­ci­a­tion and a Clin­i­cal Prac­tice Guide­line of the Cys­tic Fibro­sis Foun­da­tion, En­dorsed by the Pe­di­atric En­docrine So­ci­ety” (101) and in the In­ter­na­tion­al So­ci­ety for Pe­di­atric and Ado­les­cent Di­a­betes’s 2014 clin­i­cal prac­tice con­sen­sus guide­lines (102).

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7.0.0.0 POST­TRANS­PLAN­TA­TION DI­A­BETES MEL­LI­TUS

Sev­er­al terms are used in the lit­er­a­ture to de­scribe the pres­ence of di­a­betes fol­low­ing organ trans­plan­ta­tion. “New-‍onset di­a­betes after trans­plan­ta­tion” (NODAT) is one such des­ig­na­tion that de­scribes in­di­vid­u­als who de­vel­op new-‍onset di­a­betes fol­low­ing trans­plant. NODAT ex­cludes pa­tients with pretrans­plant di­a­betes that was undi­ag­nosed as well as posttrans­plant hy­per­glycemia that re­solves by the time of dis­charge (103). An­oth­er term, “posttrans­plan­ta­tion di­a­betes mel­li­tus” (PTDM) (103,104), de­scribes the pres­ence of di­a­betes in the posttrans­plant set­ting irre­spective of the tim­ing of di­a­betes onset.

Hy­per­glycemia is very com­mon dur­ing the early posttrans­plant pe­ri­od, with ˜90% of kid­ney al­lo­graft re­cip­i­ents ex­hib­iting hy­per­glycemia in the first few weeks fol­low­ing trans­plant (103-106). In most cases, such stress-‍ or steroidin­duced hy­per­glycemia re­solves by the time of dis­charge (106,107). Al­though the use of im­muno­sup­pres­sive ther­a­pies is a major con­trib­u­tor to the de­vel­op­ment of PTDM, the risks of trans­plant re­jec­tion out­weigh the risks of PTDM and the role of the di­a­betes care pro­vider is to treat hy­per­glycemia ap­pro­pri­ately re­gard­less of the type of im­muno­sup­pres­sion (103). Risk fac­tors for PTDM in­clude both gen­er­al di­a­betes risks (such as age, fam­i­ly his­to­ry of di­a­betes, etc.) as well as trans­plant-‍specific fac­tors, such as use of im­muno­sup­pres­sant agents (108). Whe­re­as posttrans­plan­ta­tion hy­per­glycemia is an im­por­tant risk fac­tor for sub­se­quent PTDM, a for­mal di­ag­no­sis of PTDM is op­ti­mally made once the pa­tient is sta­ble on main­te­nance im­muno­sup­pres­sion and in the ab­sence of acute in­fec­tion (106-108). The OGTT is con­sid­ered the gold stan­dard test for the di­ag­no­sis of PTDM (103,104,109, 110). How­ev­er, screen­ing pa­tients using fast­ing glu­cose and/‍or A1C can iden­tify high-‍risk pa­tients re­quir­ing fur­ther as­sess­ment and may re­duce the num­ber of over­all OGTTs re­quired.

Few ran­domized con­trolled stud­ies have re­port­ed on the short-‍ and long-‍term use of antihy­per­glycemic agents in the set­ting of PTDM (108,111,112). Most stud­ies have re­port­ed that trans­plant pa­tients with hy­per­glycemia and PTDM after trans­plan­ta­tion have high­er rates of re­jec­tion, in­fec­tion, and re­hos­pi­tal­iza­tion (106,108,113).

In­sulin ther­a­py is the agent of choice for the man­age­ment of hy­per­glycemia and di­a­betes in the hos­pi­tal set­ting. After dis­charge, pa­tients with pre­ex­ist­ing di­a­betes could go back on their pretrans­plant reg­i­men if they were in good con­trol be­fore trans­plan­ta­tion. Those with pre­vi­ous­ly poor con­trol or with per­sis­tent hy­per­glycemia should con­tin­ue in­sulin with fre­quent home self-‍mon­i­tor­ing of blood glu­cose to de­ter­mine when in­sulin dose re­duc­tions may be need­ed and when it may be ap­pro­pri­ate to switch to nonin­sulin agents.

No stud­ies to date have es­tab­lished which nonin­sulin agents are safest or most effica­cious in PTDM. The choice of agent is usu­al­ly made based on the side ef­fect profile of the med­i­ca­tion and pos­si­ble in­ter­ac­tions with the pa­tient’s im­muno­sup­pres­sion reg­i­men (108). Drug dose ad­just­ments may be re­quired be­cause of de­creases in the glomeru­lar filtra­tion rate, a rel­a­tively com­mon com­pli­ca­tion in trans­plant pa­tients. A small short-‍term pilot study re­port­ed that met­formin was safe to use in renal trans­plant re­cip­i­ents (114), but its safe­ty has not been de­ter­mined in other types of organ trans­plant. Thi­a­zo­lidine­diones have been used suc­cess­ful­ly in pa­tients with liver and kid­ney trans­plants, but side ef­fects in­clude fluid re­ten­tion, heart fail­ure, and os­teope­nia (115,116). Dipep­tidyl pep­ti­dase 4 in­hibitors do not in­ter­act with im­muno­sup­pres­sant drugs and have demon­strat­ed safe­ty in small clin­i­cal tri­als (117,118). Well-‍de­signed in­ter­ven­tion tri­als ex­am­in­ing the efficacy and safe­ty of these and other antihy­per­glycemic agents in pa­tients with PTDM are need­ed.

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8.0.0.0 MONO­GENIC DI­A­BETES SYN­DROMES

8.1.0.0 Rec­om­men­da­tions

Mono­genic de­fects that cause β-cell dysfunc­tion, such as neona­tal di­a­betes and MODY, repre­sent a small frac­tion of pa­tients with di­a­betes (<5%). Table 2.7 de­scribes the most com­mon caus­es of mono­genic di­a­betes. For a com­pre­hen­sive list of caus­es, see Ge­net­ic Di­ag­no­sis of En­docrine Dis­or­ders (119).

Table 2.7 - Most com­mon caus­es of mono­genic di­a­betes (119)

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8.2.0.0 Neona­tal Di­a­betes

Di­a­betes oc­cur­ring under 6 months of age is termed “neona­tal” or “con­gen­i­tal” di­a­betes, and about 80–85% of cases can be found to have an un­der­ly­ing mono­genic cause (120). Neona­tal di­a­betes oc­curs much less often after 6 months of age, where­as au­toim­mune type 1 di­a­betes rarely oc­curs be­fore 6 months of age. Neona­tal di­a­betes can ei­ther be tran­sient or per­ma­nent. Tran­sient di­a­betes is most often due to over­ex­pres­sion of genes on chro­mo­some 6q24, is recur­rent in about half of cases, and may be treat­able with med­i­ca­tions other than in­sulin. Per­ma­nent neona­tal di­a­betes is most com­monly due to au­to­so­mal dom­i­nant mu­ta­tions in the genes en­cod­ing the Kir6.2 sub­unit (KCNJ11) and SUR1 sub­unit (ABCC8) of the β-cell KATP chan­nel. Cor­rect di­ag­no­sis has crit­i­cal im­pli­ca­tions be­cause most pa­tients with KATP-‍re­lat­ed neona­tal di­a­betes will ex­hib­it im­proved glycemic con­trol when treat­ed with high-‍dose oral sul­fony­lureas in­stead of in­sulin. In­sulin gene (INS) mu­ta­tions are the sec­ond most com­mon cause of per­ma­nent neona­tal di­a­betes, and, while in­ten­sive in­sulin man­age­ment is cur­rently the pre­ferred treat­ment strat­e­gy, there are im­por­tant ge­net­ic con­sid­er­a­tions, as most of the mu­ta­tions that cause di­a­betes are dom­i­nantly in­her­it­ed.

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8.3.0.0 Maturity-‍Onset Di­a­betes of the Young

MODY is fre­quent­ly char­ac­ter­ized by onset of hy­per­glycemia at an early age (clas­sically be­fore age 25 years, al­though di­ag­no­sis may occur at older ages). MODY is char­ac­ter­ized by im­paired in­sulin se­cre­tion with min­i­mal or no de­fects in in­sulin ac­tion (in the ab­sence of co­ex­is­tent obe­si­ty). It is in­her­it­ed in an au­to­so­mal dom­i­nant pat­tern with abnor­malities in at least 13 genes on dif­ferent chro­mo­somes iden­tified to date. The most com­monly re­port­ed forms are GCK-‍MODY (MODY2), HNF1A-‍MODY (MODY3), and HNF4A-‍MODY (MODY1).

Clin­i­cally, pa­tients with GCK-‍MODY ex­hib­it mild, sta­ble, fast­ing hy­per­glycemia and do not re­quire antihy­per­glycemic ther­a­py ex­cept some­times dur­ing preg­nan­cy. Pa­tients with HNF1A- or HNF4A-‍MODY usu­al­ly re­spond well to low doses of sul­fony­lureas, which are con­sid­ered first-‍line ther­a­py. Mu­ta­tions or dele­tions in HNF1B are as­so­ci­at­ed with renal cysts and uter­ine mal­for­ma­tions (renal cysts and di­a­betes [RCAD] syn­drome). Other ex­treme­ly rare forms of MODY have been re­port­ed to in­volve other tran­scrip­tion fac­tor genes in­clud­ing PDX1 (IPF1) and NEU­ROD1.

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8.4.0.0 Di­ag­no­sis of Mono­genic Di­a­betes

A di­ag­no­sis of one of the three most com­mon forms of MODY, in­clud­ing GCK-‍MODY, HNF1A-‍MODY, and HNF4A-‍MODY, al­lows for more cost-‍ef­fec­tive ther­a­py (no ther­a­py for GCK-‍MODY; sul­fony­lureas as first-‍line ther­a­py for HNF1A-‍MODY and HNF4A-‍MODY). Ad­di­tion­ally, di­ag­no­sis can lead to iden­tification of other af­fect­ed fam­i­ly mem­bers.

A di­ag­no­sis of MODY should be con­sid­ered in in­di­vid­u­als who have atyp­i­cal di­a­betes and mul­ti­ple fam­i­ly mem­bers with di­a­betes not char­ac­ter­is­tic of type 1 or type 2 di­a­betes, al­though ad­mit­ted­ly “atyp­i­cal di­a­betes” is be­com­ing in­creas­ingly difficult to pre­cise­ly define in the ab­sence of a defini­tive set of tests for ei­ther type of di­a­betes. In most cases, the pres­ence of au­toan­ti­bod­ies for type 1 di­a­betes pre­cludes fur­ther test­ing for mono­genic di­a­betes, but the pres­ence of au­toan­ti­bod­ies in pa­tients with mono­genic di­a­betes has been re­port­ed (121). In­di­vid­u­als in whom mono­genic di­a­betes is sus­pect­ed should be re­ferred to a spe­cial­ist for fur­ther eval­u­a­tion if avail­able, and con­sul­ta­tion is avail­able from sev­er­al cen­ters. Read­i­ly avail­able com­mer­cial ge­net­ic test­ing fol­low­ing the cri­te­ria list­ed below now en­ables a cost-‍ef­fec­tive (122), often cost-‍sav­ing, ge­net­ic di­ag­no­sis that is in­creas­ingly sup­ported by health in­sur­ance. A biomark­er screen­ing path­way such as the com­bi­na­tion of uri­nary C-‍pep­tide/ cre­a­ti­nine ratio and an­ti­body screen­ing may aid in de­ter­min­ing who should get ge­net­ic test­ing for MODY (123). It is crit­i­cal to cor­rect­ly di­ag­nose one of the mono­genic forms of di­a­betes be­cause these pa­tients may be incor­rect­ly di­ag­nosed with type 1 or type 2 di­a­betes, lead­ing to subop­ti­mal, even po­ten­tially harm­ful, treat­ment reg­i­mens and de­lays in di­ag­nos­ing other fam­i­ly mem­bers (124). The cor­rect di­ag­no­sis is es­pe­cial­ly crit­i­cal for those with GCK-‍MODY mu­ta­tions where mul­ti­ple stud­ies have shown that no com­pli­ca­tions ensue in the ab­sence of glu­cose-‍lowering ther­a­py (125). Ge­net­ic coun­sel­ing is rec­om­mend­ed to en­sure that af­fect­ed in­di­vid­u­als un­der­stand the pat­terns of in­her­i­tance and the im­por­tance of a cor­rect di­ag­no­sis.

The di­ag­no­sis of mono­genic di­a­betes should be con­sid­ered in chil­dren and adults di­ag­nosed with di­a­betes in early adult­hood with the fol­low­ing find­ings:

Di­a­betes di­ag­nosed with­in the first 6 months of life (with oc­ca­sion­al cases pre­senting later, most­ly INS and ABCC8 mu­ta­tions) (120,126)

Di­a­betes with­out typ­i­cal fea­tures of type 1 or type 2 di­a­betes (neg­a­tive di­a­betes-‍as­so­ci­at­ed au­toan­ti­bod­ies, nonobese, lack­ing other metabol­ic fea­tures es­pe­cial­ly with strong fam­i­ly his­to­ry of di­a­betes)

Sta­ble, mild fast­ing hy­per­glycemia (100–150 mg/dL [5.5–8.5 mmol/‍L]), sta­ble A1C be­tween 5.6 and 7.6% (be­tween 38 and 60 mmol/‍mol), es­pe­cial­ly if nonobese

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9.0.0.0 Ref­er­ences

1. Amer­i­can Di­a­betes As­so­ci­a­tion. Di­ag­no­sis and clas­sification of di­a­betes mel­li­tus. Di­a­betes Care 2014;37(Suppl. 1):S81–S90
2. Dabe­lea D, Rew­ers A, Staf­ford JM, et al.; SEARCH for Di­a­betes in Youth Study Group. Trends in the preva­lence of ke­toaci­do­sis at di­a­betes di­ag­no­sis: the SEARCH for Di­a­betes in Youth Study. Pe­di­atrics 2014;133:e938–e945
3. New­ton CA, Raskin P. Di­a­bet­ic ke­toaci­do­sis in type 1 and type 2 di­a­betes mel­li­tus: clin­i­cal and bio­chem­i­cal dif­ferences. Arch In­tern Med 2004; 164:1925–1931
4. Skyler JS, Bakris GL, Boni­fa­cio E, et al. Dif­fer­entiationof di­a­betes by patho­phys­i­ol­o­gy, nat­u­ral his­to­ry, and prog­no­sis. Di­a­betes 2017;66:241– 255
5. Insel RA, Dunne JL, Atkin­son MA, et al. Stag­ing presymp­tomat­ic type 1 di­a­betes: a sci­en­tific state­ment of JDRF, the En­docrine So­ci­ety, and the Amer­i­can Di­a­betes As­so­ci­a­tion. Di­a­betes Care 2015;38:1964–1974
6. In­ter­na­tion­al Ex­pert Com­mit­tee. In­ter­na­tion­al Ex­pert Com­mit­tee re­port on the role of the A1C assay in the di­ag­no­sis of di­a­betes. Di­a­betes Care 2009;32:1327–1334
7. Knowl­er WC, Bar­rett-‍Con­nor E, Fowler SE, et al.; Di­a­betes Pre­ven­tion Pro­gram Re­search Group. Re­duc­tion in the in­ci­dence of type 2 di­a­betes with lifestyle in­ter­ven­tion or met­formin. N Engl J Med 2002;346:393–403
8. Tuomile­hto J, Lind­stro¨m J, Eriks­son JG, et al.; Finnish Di­a­betes Pre­ven­tion Study Group. Pre­ven­tion of type 2 di­a­betes mel­li­tus by changes in lifestyle among sub­jects with im­paired glu­cose tol­er­ance. N Engl J Med 2001;344: 1343–1350
9. Mei­jnikman AS, De Block CEM, Dirinck E, et al. Not per­form­ing an OGTT re­sults in significant underdi­ag­no­sis of (pre)di­a­betes in a high risk adult Cau­casian pop­u­la­tion. Int J Obes 2017;41: 1615–1620
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