Emaciated Patient with Slowly Progressed Type 1 Diabetes Mellitus Who Had Hypoglycemia Despite Impaired Insulin Secretion

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Case Report

Emaciated Patient with Slowly Progressed Type 1 Diabetes Mellitus who had Hypoglycemia Despite Impaired Insulin Secretion

Takeshi Ito, MD, FACP, Nobuya Fujita, MD, PhD, Naoki Maeda, MD, Masayoshi Komura, MD, Hideto Tomioka, MD, Nobuki Ohnishi, MD, Kunihiko Arai, MD, Mizue Yokoyama, MD, Ryoji Yoshida, MD, PhD

Department of Internal Medicine, Saiseikai Utsunomiya Hospital, Tochigi, Japan

ABSTRACT：We describe a 38-year-old, severely emaciated female with slowly progressive type 1 diabetes mellitus （SPIDDM), who had hypoglycemia due to fasting and an extremely low energy intake. After being diagnosed with diabetes mellitus（DM), she took in only 300-500 kcal per day and her weight had decreased to 30 kg, with a body mass index（BMI）of 11.4 kg／m2. She was admitted with hypoglycemia, and SPIDDM was confirmed by nearly- completely ceased insulin secretion and seropositivity towards anti-GAD antibody. After appropriate dietary therapy and insulin administration, she recovered from a state of emaciation and her glucose metabolism was restored. With this patient it proved very effective for the general physician to coordinate treatment for both diabetes and an eating disorder.

KEY WORDS：slowly progressive type 1 diabetes mellitus, eating disorder, hypoglycemia, emaciation, insulin therapy

Gen Med：2009；10：23-27

disorder is serious in females, and is considered to cause INTRODUCTION obesity or emaciation, as well as impaired glucose lowly progressive type 1（insulin-dependent）dia- metabolism that leads to hyper- or hypoglycemia, and betes mellitus（SPIDDM）starts in the non-insulin- diabetes-related complications6. Therefore, further studies of Sdependent state and ultimately becomes insulin- the relationship between type 1 DM and eating disorders are dependent diabetes mellitus（IDDM）with exhausted intrin- required to improve patient mortality7. sic insulin secretion over several years. Positivity for Here, we describe a severely emaciated female with an pancreatic islet-related auto-antibodies characterizes eating disorder who had survived SPIDDM without insulin SPIDDM, which accounts for about 5% of all diabetes therapy despite nearly ceased endogenous insulin production, mellitus（DM）that is considered type 21,2. Eating disorders and whose emaciation and impaired glucose metabolism that are diagnosed according to the Diagnostic and Statistical were repaired by administering insulin. Manual for Mental Disorders Text Revision（DSM-Ⅳ-TR)3 are more prevalent in type 1 diabetic, rather than non- diabetic, females4,5. Type 1 diabetes with a concurrent eating

Author for correspondening：Takeshi Ito, MD, FACP Department of Internal Medicine, Saiseikai Utsunomiya Hospital, 911-1 Takebayashi, Utsunomiya, Tochigi, 321-0974, Japan, Phone：＋81-28-626-5500, Fax：＋81-28-626-5573, E-mail：[email protected] Received for publication 30 August 2008 and accepted in revised form 19 November 2009 24 General Medicine, Vol. 10, No. 1, 2009

Table 1. Laboratory data upon admission. CASE REPORT Urinalysis Blood chemistry A38-year-female was transferred to our hospital for a Protein ― TP 5.3 g／dl detailed examination of weight loss and hypoglycemia Glucose ― Alb 3.5 g／dl despite her diabetes mellitus. Her personality was inflexible Blood ― BUN 9.4 mg／dl and methodical and she exhibited compulsive neurosis-like Ketone ― UA 3.7 mg／dl symptoms, but showed no anxiety or depression. Diabetes Cr 0.4 mg／dl and psychological illness was unknown in her family history. Blood cell count T-chol 117 mg／dl Four years before admission she had chronic thyroiditis, WBC 2600／ml TG 65 mg／dl 4 but fasting plasma glucose（FPG）of 130 mg／dl, HbA1c of RBC 362×10 ／ml T-Bil 1.0 mg／dl 7.5%, and sugars detected in her urine led to a diagnosis of Hb 11.0 g／dl ALP 1440 U／l diabetes mellitus（DM）at the hospital to which she was Ht 32.8% ChE 74 U／l Plt 22.3×104／ml AST 221 U／l previously admitted. At that time a physician specializing in ALT 371 U／l diabetes care took charge of her, and a 1,400 kcal dietary HBs Ag ― g-GTP 322 U／l restriction was advised. However, she became pathologically HCV Ab ― LDH 461 U／l fixated on the notion of zero calories and thus consumed FPG＊ 53 mg／dl only boiled vegetables. We estimated that she had taken in HbA1c 5.9% 300-1, 000 kcal／day during prior to hospitalization. Two Na 135 mEq／l years and 8 months before admission, glimepiride（1mg） K 3.6 mEq／l and supplemental thyroid hormone treatment（levothyroxine Cl 95 mEq／l sodium）were prescribed, but she visited her previous CRP ＜0.3 mg／dl hospital irregularly. During the next 4 years, her weight ＊FPG, fasting plasma glucose gradually declined from 54 to 40 kg. One year and 6 months before admission menstruation ceased. Two weeks before admission the patient weighed approximately 40 kg, and she became intractable and the patient was transferred to our was an active mother. Due to family problems, she ate hospital. nothing for 5 days before admission to her previous hospital. At transfer to our facility, a physical examination revealed On the day of admission to the hospital, she lost the following：height 162 cm, body weight 30 kg and BMI consciousness while driving and had a traffic accident. 11. 4 kg／m2, with distinct skeletal emaciation. The ocular Though no injuries or epilepsy were apparent, she was conjunctivas were free of anemia and jaundice, the thyroid admitted to the previous hospital for detailed testing due to was not palpable, the chest and abdomen were free of severe emaciation（37 kg）and hypoglycemia［plasma glu- abnormalities, and fine hair was absent. Table 1 shows the cose of（PG）20 mg／dl, measured using a portable blood blood and urinary findings at admission to our hospital, glucose meter during transport to the Emergency Room]. which indicate leukocytopenia, hypoproteinemia, and liver Upon admission, because her level of consciousness on the damage. Fasting plasma glucose（FPG）was low（53 mg／dl） Glasgow Coma Scale was 13（E4 V4 M5), glucose was and HbA1c was within the normal range（5.8%）without infused intravenously and she became alert immediately. ketosis［urinary ketone（−）］or acidosis（pH 7.49, pCO2 8 − Based on conditions that matched Whippleʼs triad , hospital 45. 3 mmHg, HCO3 33. 9 mmol／／／L, BE 9. 5 mmol／L).To staff determined that she was likely to have suffered a treat the diabetes and emaciation, we, along with a hypoglycemia attack. Although neither insulin nor an oral psychiatrist, initially counseled the patient and made antidiabetic agent was administered, the low trend in plasma substantial effort to change her harmful perception that glucose levels continued. Despite 1 month of hospitalization, skipping meals would prevent an increase in blood glucose her weight declined to 30 kg［（body mass index（BMI）11. and the use of insulin and to help her understand that her 4kg／m2, degree of obesity −48. 0%）]. At the hospital, progressive emaciation was life-threatening. Physicians although a physician specializing in diabetes care took charge specializing in diabetes care, members of a nutrition support of her and encouraged her to keep up an appropriate energy team, nursing staff, and psychiatrists all offered suggestions intake, she only ate vegetables（300-500 kcal／day）and during the case conference. However, some of the advice refused blood tests, drip infusions, and psychiatric consulta- given was conflicting. For patients greatly obsessive about tion, insisting that it was much better to skip meals than to eating disorders and blood glucose levels, it is not wise to receive insulin infusions. The patient-doctor relationship consult without coordination；therefore, the attending doctor, Ito T, et al. Emaciated patient with slowly progressed type 1 diabetes mellitus 25

Table 2. Endocrinological data before treatment IRI ＜1.00 mU／ml TSH 0.487 mIU／ml S-CPR＊ ＜0.05 ng／ml freeT4 1.83 ng／dl U-CPR＊＊ 7.8 mg／day freeT3 1.55 pg／ml anti-GAD Ab 99.0 U／ml Anti-Tg Ab 16.5 U／ml anti-IA-2Ab 11 U／ml Anti-TPO Ab ＜0.3 U／ml anti-insulin Ab 3.6% ACTH 58.2 pg／ml Cortisol 47.4 mg／dl Adrenaline 94 pg／ml Noradrenaline 421 pg／ml Glucagon 131 pg／ml GH 36.8 ng／ml ＊S-CPR, serum-C-peptide immunoreactivity；＊＊U-CPR, urinary-C-peptide immunoreactivity 75g-oral glucose tolerant test（OGTT) Time（min) PG†（mg／dl) IRI （mU／ml) S-CPR（ng／ml) Cortisol（mg／dl) 0 59 ＜1.00 0.08 47.7 30 101 ＜1.00 0.35 46 60 69 ＜1.00 0.15 39.9 90 163 ＜1.00 0.53 36.4 120 193 ＜1.00 0.67 36.2 180 2031.14 0.87 29.8 †PG, plasma glucose HLA DNA typing DRB1＊04051-080302／DQB1＊0401-060101

a general physician, coordinated advice and medical care to counteracting a tendency to hypoglycemia（Table 2).In with various professionals playing their own roles in one the 75 g-oral glucose tolerance test（OGTT）（Table 2), team. plasma glucose increased in a bimodal manner, indicating Thereafter, she changed her attitude to eating dramatically, impaired glucose tolerance. Plasma glucose again increased and 2 or 3 days after her admission to our hospital she started in delayed phases, accompanied by a slight increase in taking in 1, 200 kcal／day or more. She no longer needed insulin secretion. These findings suggested an imbalance in intravenous drips and did not experience further severe glucose metabolism and insulin secretion. S-CPR levels 6 hypoglycemia resulting in a loss of consciousness. Her minutes after 1 mg glucagon injection was 0. 68 ng／ml, endocrine data measured on Days 6-7 of our hospitalization consistent with S-CPR and U-CPR depletion. Human are shown in Table 2. Insulin, serum C-peptide immunor- leukocyte antigen（HLA）-DNA typing（Table 2）revealed eactivity（S-CPR), and urinary C-peptide immunoreactivi- that the patient had DRB1＊ 040501, DQB1＊0401（type 1 ty（U-CPR）were severely low. Based on a more than 4- diabetes susceptibility）and DQB1＊0601（type 1 diabetes year history of diabetes free of insulin therapy, nearly ceased protective）alleles9, confirming a diagnosis of SPIDDM. endogenous insulin secretion, and seropositivity towards Within two weeks after admission, she was able to take in anti-glutamic acid decarboxylase（GAD）antibody and anti- 1, 600 kcal／day constantly, however, because her body insulinoma-associated tyrosine phosphatase-like protein-2 weight did not increase from 30 kg, we administered insulin （IA-2）antibody, she was diagnosed with slowly progres- （2 U of lispro at meal times；total, 6 U／day）to raise her sive type 1 diabetes（SPIDDM). Despite the administration weight（FPG 66 mg／／／dl, postprandial PG 180 mg／dl. This of levothyroxine sodium, which had rendered her euthyroid strategy caused her to gain weight rapidly and improved the （Table 2), hypothyroidism with seropositivity towards anti- liver damage. She was discharged from our hospital on a Tg antibody indicated a diagnosis of chronic thyroiditis. regimen of thrice-daily insulin（4 U of lispro at meal times； Levels of counter-insulin hormones such as cortisol, growth total, 12 U／day). Thereafter, when she visited us one month hormone（GH), and catecholamines were high, perhaps due later, she had steadily gained weight and reached 44 kg（BMI 26 General Medicine, Vol. 10, No. 1, 2009

Figure 1. Clinical Course （BW：Body weight HbA1c：HemoglobinA1c FPG：Fasting plasma glucose)

16.7), but her FPG and HbA1c were high（188 mg／dl and 7. seemed to develop the eating disorder through misunder- 9%, respectively), which indicated unsuccessful diabetic standing the dietary therapy for DM. Past case reports of control. Because of these findings, the dose of insulin was anorexia nervosa11 suggest that the causes of abnormal increased（6 U of lispro at meal times；total, 18 U per day） glucose metabolism and hepatic dysfunction seen in （Figure 1). She was later prescribed with intermediate- conditions of extremely low energy intake include hypogly- acting, neutral protamine Hagedorn（NPH）insulin at night cemia caused by malnutrition and lack of substrate of to control the diabetes, in addition to thrice-daily doses of gluconeogenesis. Similar factors were found in our patient as insulin lispro. At a follow-up visit after 6 months, good well. control of her eating disorder, emaciation, and SPIDDM were Loss of consciousness due to low blood glucose and liver shown by the examinations［54 kg（BMI 19.1), postpran- dysfunction can develop when an eating disorder is dial PG 188 mg／dl, HbA1c 7.1%]. accompanied by advanced emaciation. In our patient, both low blood glucose and liver dysfunction improved as her eating habits improved and her weight increased. We also DISCUSSION found that timely insulin administration was important in To recognize the slowly progressive type 1 DM in this terms of physical treatment and psychogenic stability, and patient was important. Had the progression been faster, the maintaining a balance between favorable diabetic control and probability of developing ketoacidosis might have increased. an eating disorder in such a patient is challenging. We considered that the pathological condition of this patient Low values of blood and urinary C-peptide and a low had remained in a delicate balance without ketoacidosis or reaction of serum C-peptide in the glucagon test indicated hypoglycemia because of the rate at which both the type 1 that her endogenous insulin production was extremely low DM and the eating disorder had progressed. due to 5 days of near-fasting prior to admission to our The patient apparently misunderstood the diet strategy hospital, although the production had not ceased completely during the early phase of DM and this led to an eating in the long term. Nonetheless, ketosis was not evident and the disorder, which resulted in advanced emaciation. Although reaction of plasma glucose in the OGTT was bimodal and her illness did not meet the diagnostic criteria of anorexia borderline. These phenomena with severe emaciation thus nervosa defined in the DSM-Ⅳ-TR, eating disorder was seemed to be caused by an extremely low energy intake and diagnosed. She had an aversion to hyperglycemia and DM, other impairments in mechanisms such as gluconeogenesis, which must have resulted from her eating disorder. Similar to ketogenesis due to depletion of adipose tissue, or glycogen our patient, a 31-year-old female developed an eating metabolism due to extremely lowered endogenous insulin disorder while undergoing insulin therapy to treat type 1 secretion. DM10. That patient also had an aversion to obesity and Ito T, et al. Emaciated patient with slowly progressed type 1 diabetes mellitus 27

manual of mental disorders, 4th edition（DSM-Ⅳ-TR), CONCLUSION American Psychiatric Association, Washington DC, 1994. For the treatment of this patient, we needed mental and 4．Jones JM, Lawson ML, Daneman D et al. Eating disorders in psychological interventions along with good communication adolescent females with and without type 1 diabetes：cross from a physician versed in nutrition and glucose metabolism. sectional study. BMJ 320：1563-6, 2000. 5．Colton P, Olmsted M, Daneman D et al. Disturbed eating In this case, the role of the general physician―who behavior and eating disorders in preteen and early teenage coordinated treatment as a primary doctor while communi- girls with type 1 diabetes：a case-controlled study. Diabetes cating with a psychiatrist, a physician specializing in diabetes Care 27：1654-9, 2004. care, nursing staff and the Nutrition Support Team―was 6．Peveler RC, Bryden KS, Neil HA et al. The relationship of very effective. disordered eating habits and attitudes to clinical outcomes in In conclusion, insulin therapy repaired emaciation and young adult females with type 1 diabetes. Diabetes Care restored glucose metabolism in a severely emaciated patient 28：84-8, 2005. with SPIDDM. The pathology of the relationship between 7．Nielsen S, Emborg C, Molbak AG. Mortality in concurrent severe emaciation and glucose metabolism, as well as the type 1 diabetes and anorexia nervosa. Diabetes Care 25： efficacy of insulin therapy should be of interest to any 309-12, 2002. clinician working with diabetic, hypoglycemic or emaciated 8．Whipple AO：The surgical therapy of hyperinsulinismus. J patients. Int Chir 3：237-76, 1938. 9．Awata T, Kuzuya T, Matsuda A, et al：Genetic analysis of HLA class Ⅱ alleles and susceptibility to type 1（insulin- References dependent）diabetes mellitus in Japanese subjects. Diabetologia 35：419-24, 1992. 1．Kobayashi T, Itoh T, Kosaka K et al. Time course of islet cell 10．Nishitani Y, Kanauchi M, Yamaji K et al. A case of insulin- antibodies and beta-cell function in non-insulin-dependent dependent diabetes mellitus complicated with anorexia stage of type Ⅰ diabetes. Diabetes 36：510-7, 1987. nervosa. J Nara Med Assoc 49：194-8, 1998（in Japanese). 2．Kobayashi T, Takemoto K, Nakanishi K et al. 11．Furuta S, Ozawa Y, Maejima K et al. Anorexia nervosa with Immunogenetic and clinical characterization of slowly severe liver dysfunction and subsequent critical complica- progressive IDDM. Diabetes Care 16：780-8, 1993. tions. Internal Medicine 38：575-9, 1999. 3．American Psychiatric Association. Diagnostic and statistical