Reviews/Commentaries/ADA Statements PERSPECTIVES ON THE NEWS

Type 1 Diabetes and Hypoglycemia

ZACHARY T. BLOOMGARDEN, MD cause but substantially contribute” to the development of type 1 diabetes. Human is- lets can in this setting express MHC I and his is the first of a series of articles 3–4 years must be developed, perhaps interferons even without an inflammatory based on presentations at the Amer- by eliminating preexisting autoaggressive infiltrate in individuals genetically at risk. T ican Diabetes Association Scientific T-cells. Ongoing trials to prevent and Von Herrath described, however, an- Sessions held 6–10 June 2008 in San cure recent-onset type 1 diabetes with other phenomenon, where under certain Francisco, California. immune-based and combinatorial ther- circumstances viruses can prevent type 1 apies need to achieve durable immune diabetes, supporting the “hygiene hypothe- Type 1 Diabetes and the ␤-Cell suppression while at the same time preserv- sis” that type 1 diabetes occurs in developed Matthias von Herrath (La Jolla, CA) re- ing overall immunity to prevent malignancy countries where the immune system has a ceived the American Diabetes Association and infection ultimately, an approach must lesser opportunity to be appropriately (ADA) 2008 Outstanding Scientific be developed to strengthen the body’s own trained. He reviewed a study in which ac- Achievement Award for his research on ␤-cell immunoregulatory responses. celeration versus abrogation of diabetes in approaches to ␤-cell–specific immune in- Addressing the issue of the contribu- an animal model depended on the specific terventions for type 1 diabetes. He began tion of viral infections, von Herrath re- time of infection, with infection before or with a discussion of the evidence of a role viewed the hypothesis that viruses may after a specific time preventing rather than of viral infections in the development of trigger or enhance type 1 diabetes, noting causing diabetes in a type 1 diabetes–prone type 1 diabetes. In experimental models, that viruses can directly infect and lyse animal model. Regulatory T-cells reduce ␤ the immune response, augmenting produc- viral infection may either accelerate or re- -cells (1). Epidemiological evidence sug- ϩ tard the immunologic process leading to gests that such rapid cases of type 1 diabetes tion of CD4/CD25 T-cells leading to pro- type 1 diabetes. He pointed out that al- are uncommon. An alternate hypothesis, duction of interleukin (IL)-4 and IL-10. In though type 1 diabetes is clearly an auto- that viruses mimic ␤-cell antigens, appears diabetes-prone models, administration of immune disease, because a pancreas unlikely, as viral infections do not appear to systemic viral infection–induced regulatory transplanted from an unaffected to a type precipitate type 1 diabetes in otherwise in- T-cells to at-risk mice will transfer the pro- 1 diabetic identical twin is associated with tact animals (2). Rather, he suggested the tective effect, with suppression of CD8 T- an immune response and rejection, the “fertile field” hypothesis that, in the setting cell response to viral infections in part cause of autoreactivity is uncertain. Envi- of genetic predisposition to anti-islet auto- dependent on transforming growth factor ronmental factors are likely implicated: immunity, a viral infection can “push a pre- (TGF)-␤ production. Viral infection also in- viral and also nutritional. Furthermore, diabetic animal” into diabetes status. creases IL-10 and interferon-␥, which usu- the degree of islet inflammation in type 1 Upregulation of major histocompatibility ally play proinflammatory roles. Thus, diabetes is rather mild, which may shed complex (MHC) class I molecules and inter- TGF-␤ and other protective factors includ- light on how viral infections might con- feron-␣ may be found in human islets in the ing tumor necrosis factor (TNF)-␣ down- tribute to the disease process because only absence of immune infiltration, which is regulate the antiviral immune response, 3–4% of islets in pre-diabetic patients— possibly a signature of viral infection, von which normally occurs as a virus is being and not a great deal more at the time of Herrath explained. The absence of inflam- cleared to reduce the systemic immune re- diagnosis—are affected by insulitis. Ap- matory infiltrate suggests that this is directly sponse. The contraction of the antiviral im- proaches to prevention might include caused by viral infection, which further mune response “pulls along with itself the modification of genes that predispose to supports the notion of the virus’ persistence cells that are attacking the islets.” The two diabetes and their gene products or mod- because these markers typically downregu- components for clinical treatment will be ification of environmental factors, but late rapidly after infections resolve. As a elimination of autoreactive T-cells and the emerging evidence suggests that type 1 consequence of virally induced, interferon- achievement of long-term tolerance diabetes is polygenic, with protective as dependent increased MHC class I expres- through induction of regulatory T cells. well as enhancing genes, not all of which sion by ␤-cells, autoaggressive CD8 Combination therapies will be needed to in- can suitably be altered. cytotoxic T-cells are seen in islets in a rodent crease efficacy while reducing adverse ef- Curing type 1 diabetes might be ac- model (3), along with ␤-cell destruction, fects of immunosuppression. von Herrath complished with an unlimited ␤-cell while ␤-cells not expressing MHC I “are in- reviewed the effect of anti-CD3 antibodies source, perhaps from stem cells, to make visible to the immune system.” Thus, viral and vaccination with ␤-cell antigens and islet transplantation more generally feasi- infection may lead to type 1 diabetes by found that they have limited effect but ap- ble. ␤-Cell augmentation may be an inter- making an underlying autoimmune state pear safe, suggesting that the combination mediate goal for which islet transplant manifest. von Herrath concluded that spe- of both approaches may be more effective. protocols not flawed by loss of islets after cific ␤-cell trophic viral infections “do not Noting that induction of effector T-cells ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● (Teffs) and regulatory T-cells (Tregs) occurs Zachary T. Bloomgarden, MD, is a practicing endocrinologist in New York, New York, and is affiliated with during infection, inflammation, and auto- the Division of Endocrinology, Mount Sinai School of Medicine, New York, New York. immunity, von Herrath addressed the un- DOI: 10.2337/dc09-zb01 © 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly derstanding of “switch factors” such as cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons. specific cytokines that will favor Tregs org/licenses/by-nc-nd/3.0/ for details. rather than Teff “to recruit your own im-

DIABETES CARE, VOLUME 32, NUMBER 1, JANUARY 2009 e1 Perspectives on the News mune system to do the job.” He showed a tion was combined with a short course of cells. The approach that Herold has taken is study of subcutaneous administration of anti-CD3. Other combinations of immuni- to use antibodies directed at the ε-portion of GAD leading to activation and proliferation zation with systemic immune modulators CD3, which lead to disease reversal with a of Tregs. Cytokines such as TGF-␤, IL-4, have been tested, and the combination of peri-islet regulatory lymphocyte infiltrate and IL-10 can modulate this process, gen- oral and intranasal insulin showed synergy seen histologicaly. The initially used anti- erating antigen-presenting cells that reduce as well. CD3 preparation, muromonab, is a mouse Teffs and augment generation of Tregs. One In silico simulation of optimal treat- antibody that causes toxicity from T-cell ac- does not need, then, to use the precise auto- ment regimens may allow optimization of tivation; currently used modified human- antigen driving the immune response to experimental and, later, treatment parame- ized molecules do not show Fc binding produce regulatory T-cells leading to long- ters. In two ongoing intranasal insulin trials, leading to far less T-cell proliferation and term tolerance while avoiding systemic side the one with daily administration appears interferon-␥ production, with higher levels effects. In animal models, it is possible to ineffective, while less frequent dosing may of IL-10 and only transient T-cell depletion. show complete and permanent protection be more effective—an outcome predicted In 21 new-onset type 1 diabetic patients with administration of oral insulin, with by such a simulation. Treatment of type 1 treated for 14 days, TNF-␣ and IL-5, -6, and peri-insulitis representing recruitment of diabetes will require greater availability of -10 levels rose, with a mild cytokine-release protective Tregs. Not all ␤-cell proteins are human pancreases and better in vivo imag- syndrome of headache, fever, and rash oc- suitable for inducing Tregs, so for human ing of pancreatic islets. von Herrath sug- curring and one patient developing throm- treatment, it may be necessary to develop gested the need to test combination bocytopenia. Insulin requirements were tools for determining which islet antigen therapies before single drugs have been ap- stable with treatment while progressively and what dosage are optimal for a given pa- proved, given his perception that single increasing in control patients. C-peptide tient, as well as to define the appropriate treatments for type 1 diabetes will be inef- levels fell by 50% at 1 year and by 75% at 2 time for administration. Dose appears to fective. The development of biomarkers to years in control subjects but were stable or play a crucial role, with administration of predict success of an intervention would be even increased at 1 year in 15 of the treated porcine and human insulin in animal mod- useful, with longitudinal T cell studies po- patients (5), though then decreasing 50% at els appearing protective only in a specific tentially such markers. “The ultimate goal,” 2 years, suggesting that a second course of dosage range. Intranasal insulin protects von Herrath concluded, “should be an early treatment at 1 year might be appropriate (an young mice but precipitates diabetes in childhood vaccine.” approach now being studied). older mice, suggesting the importance In a lecture at the Mount Sinai Diabetes Another set of studies will involve of timing, although it may be possible Conference on 23 October 2008, Kevin treatment of pre-diabetic relatives with with combination therapies or use of Herold (New Haven, CT) discussed anti- abnormal glucose tolerance and multiple suitable adjuvants to ensure that regu- CD3 treatment of type 1 diabetes. Recalling positive autoantibodies, and treatment of latory but not islet-attacking T-cells will the classic concept that type 1 diabetes rep- patients with type 1 diabetes present for be produced. resents the summation of many years of 4–12 months is also being explored. ϩ von Herrath again noted the potential progressive ␤-cell destruction, with the dis- CD8 T-cell levels increase with treat- synergy between anti-CD3 and antigen- ease becoming clinically manifest after loss ment, indicating the presence of regula- specific immunotherapy, suggesting that of almost all insulin production, he sug- tory T-cells that appear to reduce the such an approach may circumvent side ef- gested that now it appears that between 30 activity of cytotoxic T-cells. TNF-␣ may fects and enhance efficacy, with encourag- and 50% of ␤-cells remain present at the be responsible for this effect, which can ing results in animal studies showing onset of the disease—far more than thought be blocked in vitro by incubation with reversal of recent-onset diabetes—which is previously. This offers the possibility that anti–TNF-␣. Herold showed evidence much more difficult to attain than preven- immune treatment may markedly amelio- that as a result of anti-CD3 treatment, tion. Hyperglycemic mice are refractory to rate the subsequent course, given the close rather than elimination of diabetes- combination therapy, suggesting that opti- association between endogenous insulin se- specific T-cells reactive to islet autoanti- mal glycemic regulation characterizes indi- cretory capacity and glycemic control. CD3 gens, the number of such cells rise over viduals with potential benefit either as a is the principal T-cell antigen recognition the first 3 months after treatment. These ϩ marker of the degree of severity of the dia- receptor, and CD4 and CD8 are additional may be markers of CD8 regulatory T- betes or because of intrinsic benefit of T-cell molecules involved in antigen recog- cells. Studies with otelixizumab, a related improved glycemia. Both arms of the nition. Histological examination of islets in anti-CD3 compound, have shown similar ϩ combined treatment increase Treg and human type 1 diabetes involves CD8 and effects, and anti-CD20 is being studied in ϩ result in loss of aggressive CD8 T-cells. In an CD3 T-cells and relatively few CD4 T-cells animal models. animal model, increased induction of CD4/ (4) in contrast to the findings in the non- A final question is whether ␤-cell re- CD25 Tregs and decreased CD8 Teff in obese diabetic (NOD) mouse (a commonly generation can be demonstrated after spleen and pancreatic lymph nodes were used animal model), implying that treat- anti-CD3 treatment. In NOD mice, it ap- seen after combined treatment. In a small ment approaches based on the model may pears that ϳ10% of ␤-cells are newly pro- clinical study, type 1 diabetic patients not readily be extrapolated to man. duced from precursor elements, with many with higher IL-10 and Tregs had better The finding of autoantibodies to multi- of the remaining new cells appearing to be subsequent glycemic control, suggesting ple islet antigens, including GAD, insulin, generated from previously dysfunctional that vaccines increasing Tregs might im- insulinoma-associated protein 2, and anti- ␤-cells expressing GLUT2 but not insulin. prove glycemia. In a study with intransal islet cell antibodies is typical at clinical dia- Herold noted that exenatide, rather than in- proinsulin, proinsulin-specific adaptive betes onset, although these antibodies are creasing ␤-cell regeneration, seems to in- Tregs were seen, with enhanced disease not required for ␤-cell destruction, for crease insulin content of the previously prevention when proinsulin immuniza- which the main effectors are reactive T- dysfunctional cells, thus appearing to be a e2 DIABETES CARE, VOLUME 32, NUMBER 1, JANUARY 2009 Bloomgarden promising approach to treatment of early ability to treat all forms of diabetes. Saisho month period and found those with im- type 1 diabetes. There may be an effect of et al. (abstract 1,588) studied pancreas at paired hypoglycemia awareness to have a modest levels of postprandial hyperglyce- autopsy within 12 h of death from 105 3.7-fold greater likelihood of severe hy- mia increasing ␤-cell regeneration; how- nondiabetic lean subjects aged 20–100 poglycemia than those without impaired ever, above a certain level of glycemia, years and found that despite marked at- awareness and to have 1.4 vs. 0.6 blood glucose toxicity effects predominate. rophy of the acinar pancreas from age 60 glucose levels Ͻ65 mg/dl per week on Several studies presented at the ADA years with a corresponding increase in home capillary glucose monitoring, re- meeting shed further light on causes and pancreatic fat, mean ␤-cell mass remained spectively; 5-day continuous glucose approaches to treatment of type 1 diabe- remarkably constant, implying the exis- monitoring at the end of the study, how- tes. Ferrannini et al. (abstract 150) ana- tence of regulatory factors preserving ever, failed to show significantly more ep- lyzed characteristics of type 1 diabetes ␤-cells and that the increased incidence of isodes of glucose Ͻ55 or Ͻ40 mg/dl. development in 325 islet cell autoanti- type 2 diabetes with aging is not due to Marrett et al. (abstract 586) analyzed self- body-positive, nondiabetic, first-degree loss of ␤-cell mass. From the same group, reported weight gain among 2,008 type 2 relatives from the Diabetes Prevention Minh et al. (abstract 4) obtained pancre- diabetic individuals who were not receiv- Trial-1 study, finding that among the 113 ata at autopsy from six nondiabetic preg- ing insulin and were participating in the who had developed diabetes, impaired nant women and nine nonpregnant U.S. National Health and Wellness Survey ␤-cell glucose sensitivity rather than a de- women, matched for age and prepreg- 2007. Weight gain during the prior year ficiency in absolute insulin secretion rate nancy BMI, showing a tripling of ␤-cell of 10–20 pounds was reported by 47% was the main predictor of progression, mass from week 20 to 40 of gestation with and of Ͼ20 pounds by 25% and corre- with accelerated reduction in this param- significantly more small islets and in- lated with experience of more severe hy- eter shortly before onset of diabetes. creased numbers of cells positive for in- poglycemia, worry about hypoglycemia, Keenan et al. (abstract 173) found that sulin in pancreatic ducts without change and reduced satisfaction with treatment. 31% of 276 individuals with type 1 dia- in ␤-cell size. Horowitz et al. (abstract A number of approaches are being de- betes for Ͼ50 years had either GAD or 246) showed opposing effects of prolactin veloped to address issues related to hypo- insulinoma-associated protein 2 antibod- and glucocorticoids on ␤-cell genes in- glycemia. Page et al. (abstract 15) studied ies in association with higher C-peptide cluding FoxO1, PGC1␣, PPAR␣, and 10 type 1 diabetic patients during hypo- levels, suggesting residual insulin pro- CPT-1 and on ␤-cell GLUT2 expression, glycemia either with or without ingestion ducing cells. One of the C-peptide– insulin production, and fatty acid oxida- of medium chain triglycerides and found positive patients required treatment with tion, suggesting a role in the preservation that the supplement improved verbal an immunosuppressant (mycophenolate (and perhaps expansion) of ␤-cell mass memory during hypoglycemia without mofetil) for an intercurrent illness and and function during pregnancy. Clark differences in glucose or counterregula- had a 4.7-fold increase in peak C-peptide et al. (abstract 1,604) examined lipofus- tory hormone levels; plasma ketones and and a 50% reduction in daily insulin dos- cin body accumulation (a feature of aging free fatty acids were elevated during hy- age, raising the intriguing possibility of that occurs in long-lived, postmitotic cells poglycemia in those receiving the supple- benefit of immune modulation many such as neurons and cardiac myocytes) in ment. They (abstract 22) found that years after type 1 diabetes onset. Luo et al. islet ␤-cells obtained at surgery from bi- glucagon decreases in response to a mixed (abstract 1596) reported that coculture of opsy specimens of 42 nondiabetic and six meal or sulfonylurea in nondiabetic indi- human islets with allogenic bone marrow diabetic individuals and found a linear viduals but increases in type 1 diabetic cells stimulated islet growth, reduced increase in lipofuscin area with age in patients; Cooperberg and Cryer interpret IL-1␤ and ␤-cell apoptosis, and increased islets from both diabetic and nondia- this to show that intraislet insulin (per- PDX-1 expression, which suggests in- betic patients, suggesting reduction in haps among other ␤-cell secretory creased ␤-cell regeneration. Coad (ab- turnover and neogenesis of ␤-cells with products) normally suppresses ␣-cell stract 1618), noting that ␤-cells have been age. At age Ͻ20 years, 58% of cells did glucagon secretion, whereas in the ab- observed in the biliary system of normal not contain lipofuscin, while at age Ͼ40 sence of ␤-cell secretion the ␣-cell stim- mice and that there is similar embryolog- this was only seen in 15% of cells. The ulatory effects of nutrient and the ical origin of islets and biliary epithelium, authors commented that islets trans- sulfonylurea become manifest. Leu et al. cultured mouse adult gall bladder epithe- planted from older donors should be (abstract 20) found that, as expected, an lium with adenoviral infection to express studied to ascertain whether insulin se- episode of hypoglycemia reduced the the islet transcription factors showing in- cretory function decreases. counterregulatory response to a second sulin mRNA and protein with increase in episode the next day; this was pre- release in response to glucose. Brown Hypoglycemia vented by infusion of the opioid recep- et al. (abstract 227) showed progressive Smith et al. (abstract 577) compared 31 tor blocker naloxone during the initial increase in glucagon secretion during a and 19 insulin-treated diabetic patients episode, suggesting that treatments meal accompanying the reduction in C- who were aware and unaware of hypogly- blocking opioid signaling may have peptide secretion during the first year af- cemia and found 75 and 43% adherence benefit in individuals with hypoglyce- ter diagnosis in 23 type 1 diabetic patients to recommendations for changes in treat- mia unawareness. In contrast, Davis (abstract numbers refer to the ADA Scien- ment regimens, respectively, suggesting et al. (abstract 21) administered the tific Sessions, Diabetes 57 [Suppl. 2], that purely educational efforts may be in- ␥-aminobutyric acid-A receptor agonist 2008). sufficient to reduce behavioral and treat- alprazolam to 31 normal individuals Understanding of the normal ␤-cell ment patterns leading to such episodes. and showed blunting of epinephrine, and of the ␤-cell in type 2 diabetes will Choudhary et al. (abstract 580) studied norepinephrine, muscle sympathetic ultimately lead to improvement in the 87 type 1 diabetic patients over a 9–12 nerve activity, pancreatic polypeptide,

DIABETES CARE, VOLUME 32, NUMBER 1, JANUARY 2009 e3 Perspectives on the News glucagon, and growth hormone coun- ported a meta-analysis of nine trials of whose mean age and diabetes duration terregulatory responses during insulin- more than 1,600 type 2 diabetic individ- were 28 and 19 years, respectively, at ini- induced hypoglycemia the next day, uals receiving biphasic insulin aspart ver- tial observation. During follow-up, how- with worsening of the blunting induced sus biphasic human insulin, showing a ever, underweight patients (BMI Ͻ20 kg/ by hypoglycemia on the prior day. 55% reduction in major hypoglycemia m2) had greater mortality, overweight Henry et al. (abstract 19) measured oc- and 50% reduction in nocturnal hypogly- (25 Յ BMI Ͻ 30 kg/m2) was protective, cipital cortical glucose uptake and cemia with the former, although fasting and obesity (BMI Ն30 kg/m2) was neu- showed increased levels in a small glucose was reduced 37% more with the tral. The authors wondered whether the group of type 1 diabetic patients with latter agent. A1C and body weight apparent protection from weight gain hypoglycemia unawareness, suggesting changed similarly. Similarly, Hutchinson during follow-up reflected more insulin this to be due to increased transport. et al. (abstract 582) analyzed 1,005 seri- use, with 7% of patients initially and 84% Puente et al. (abstract 16) subjected rats ous hypoglycemia occurrences among at 18 years receiving Ն3 insulin doses/ to three consecutive days of moderate 11,813 type 2 diabetic individuals start- day. hypoglycemia or control infusion and ing insulin treatment and found a 28% found that 1 week after subsequent se- reduction in the risk of these events in vere hypoglycemia, neuronal damage users of analog insulin compared with Acknowledgments— Z.T.B. has served on was greater in the control group. Bree et users of human insulin who attained sim- speaker’s bureaus of Merck, NovoNordisk, Lilly, Amylin, Daichi Sankyo, and Glaxo- al. (abstract 17; from the same group) ilar mean A1C levels of 8.6–8.9%. SmithKline; has served on advisory panels for found, moreover, that severe hypergly- Medtronics, Takeda, Merck, AtherGenics, CV cemia caused by streptozotocin 14 days Type 1 diabetes epidemiology Therapeutics, Daichi Sankyo, BMS, and Astra previously increased neuronal damage Kahn et al. (abstract 317) analyzed Zeneca; holds stock in Abbott, Bard, from severe hypoglycemia. monthly distribution of birth dates of Medtronic, Merck, Millipore, Novartis, and The importance of in-hospital hypo- 9,146 diabetic patients in the U.S. who Roche; and has served as a consultant for No- glycemia is increasingly being addressed. were diagnosed at age Ͻ20 years and vartis, Dainippon Sumitomo Pharma America, Siram et al. (abstract 18) reported that were participating in the SEARCH for Di- Forest Laboratories, and Nastech. No other among 1,641 patients admitted to an in- abetes in Youth Study. Kahn et al. found a potential conflicts of interest relevant to this tensive care unit, glucose levels of Ͻ40 4% excess diabetes incidence in May and article were reported. mg/dl and, to a lesser extent, 40–69 a 5% deficit in November, suggestive of mg/dl were associated with increased early-life environmental exposures that References likelihood of acute renal injury and mor- contribute to childhood diabetes. 1. Yoon JW, Austin M, Onodera T, Notkins tality; insulin administration reduced the Tuomilehto et al. (abstract 23) de- AL: Isolation of a virus from the pancreas likelihood of both renal insufficiency and scribed another temporal trend in type 1 of a child with diabetic ketoacidosis. mortality regardless of hypoglycemia, al- diabetes. Incidence in Finnish children N Engl J Med 300:1173–1179, 1979 though subcutaneous appeared less likely aged Ͻ15 years increased from 32.2 to 2. Christen U, Edelmann KH, McGavern than intravenous insulin treatment to be 64.7 cases per 100,000 people in the gen- DB, Wolfe T, Coon B, Teague MK, Miller associated with improved outcome. Dhir eral population per year in 1980 and SD, Oldstone MB, von Herrath MG: A vi- ral epitope that mimics a self antigen can et al. (abstract 579) described 182 in- 2005, respectively; the rate of increase ap- accelerate but not initiate autoimmune di- hospital hypoglycemia episodes typically pears to have accelerated in the 1990s. abetes. J Clin Invest 114:1290–1298, occurring after 3 days in the hospital, with Johnson et al. (abstract 24) reported a 2004 risk factors including reduced nutritional 47% increase in prevalence of diabetes in 3. Filippi CM, Juedes AE, Oldham JE, Ling intake, major organ dysfunction, resolv- the province of Alberta, Canada, during E, Togher L, Peng Y, Flavell RA, von Herrath MG: Transforming growth fac- ing infection, increasing insulin dose, and the past decade, with a particularly dra- ϩ decreasing steroid dose in 60, 31, 22, 12, matic 93% increase among those age 1–4 tor-␤ suppresses the activation of CD8 and 4% of cases, respectively. Natoli et al. years—suggestive of type 1 rather than T-cells when naive but promotes their (abstract 578) analyzed a hospitalization type 2 diabetes. survival and function once antigen expe- database of 103,813 diabetic patients Obesity in type 1 diabetes and its rienced: a two-faced impact on autoim- munity. Diabetes 57:2684–2692, 2008 from 2000–2006 and found that those overlap with type 2 diabetes and insulin Ͻ 4. Itoh N, Hanafusa T, Miyazaki A, Miya- experiencing glucose 70 mg/dl had a resistance are gaining interest. Shay et al. gawa J, Yamagata K, Yamamoto K, Waguri 58% greater likelihood of discharge to a (abstract 900) found, as expected, that M, Imagawa A, Tamura S, Inada M: nursing facility, a 7% greater inpatient euglycemic clamp insulin sensitivity was Mononuclear cell infiltration and its rela- mortality, and, on average, three addi- approximately twice as great in 15 type 1 tion to the expression of major histocom- tional hospital days with 39% higher cost. diabetic patients compared with that in patibility complex antigens and adhesion Pittas et al. (abstract 500) reported on a 42 type 2 diabetic patients. Insulin sensi- molecules in pancreas biopsy specimens meta-analysis of 15 randomized trials of tivity more strongly correlated with BMI, from newly diagnosed insulin-dependent intensive insulin therapy in 8,472 criti- waist size, percent body fat, and triglycer- diabetes mellitus patients. J Clin Invest 92: cally ill, hospitalized, nonpregnant adult ide level in the type 1 than in the type 2 2313–2322, 1993 5. Herold KC, Hagopian W, Auger JA, patients, with glycemic goal 103–186 vs. diabetic group, while it was less strongly Poumian-Ruiz E, Taylor L, Donaldson D, 139–260 mg/dl, and showed no differ- associated with diastolic blood pressure. Gitelman SE, Harlan DM, Xu D, Zivin RA, ence in mortality but a 4.3-fold greater Conway et al. (abstract 29) found that Bluestone JA: Anti-CD3 monoclonal anti- likelihood of hypoglycemia. baseline BMI was associated with 18-year body in new-onset type 1 diabetes melli- Davidson et al. (abstract 576) re- mortality in 655 type 1 diabetic patients tus. N Engl J Med 346:1692–1698, 2002

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