Recurrent Severe Hypoglycemia Research Articles

Validation of Islet Transport From a Geographically Distant Isolation Center Enabling Equitable Access and National Health Service Funding of a Clinical Islet Transplant Program for England.

Islet transplantation has become established as a successful treatment for type 1 diabetes complicated by recurrent severe hypoglycemia. In the UK access has been limited to a few centrally located units. Our goal was to validate a quality-assured system for safe/effective transport of human islets in the UK and to successfully undertake the first transplants with transported islets. Pancreases were retrieved from deceased donors in the north of England and transported to King's College London using two-layer method (TLM) or University of Wisconsin solution alone. Islets were isolated and transported back to Newcastle in standard blood transfusion or gas-permeable bags with detailed evaluation pre- and posttransport. In the preclinical phase, islets were isolated from 10 pancreases with mean yield of 258,000 islet equivalents. No significant differences were seen between TLM and University of Wisconsin solution organ preservation. A significant loss of integrity was demonstrated in islets shipped in gas-permeable bags, whereas sterility, number, purity, and viability were maintained in blood transfusion bags. Maintenance of secretory granules and glucose-stimulated insulin secretion was confirmed following transport. A Standard Operating Procedure enabling final pretransplant quality control from a simple side-arm sample was validated. Moreover, levels of insulin and cytokines in transport medium were low, enabling transplant without centrifugation/resuspension at the recipient site. Six clinical transplants of transported islets were undertaken in five recipients with 100% primary graft function and resolution of severe hypoglycemia. Safe and clinically effective islet transport has been established facilitating sustainable NHS funding of a clinical islet transplant program for the UK.

High serum ACE activity predicts severe hypoglycaemia over time in patients with type 1 diabetes

Aims/hypothesis. High serum angiotensin-converting enzyme (ACE) activity is associated with increased risk of severe hypoglycaemia (SH) within 1 year in type 1 diabetes. We wanted to find out whether ACE activity is stable over time and predicts SH beyond 1 year, and if gender differences exist in the association between ACE activity and risk of SH. Methods. A follow-up study of 128 adult patients with type 1 diabetes was conducted. At entry, ACE activity was measured. For 12 months, patients prospectively recorded events of severe hypoglycaemia (SH). At a median of 40 months, ACE activity was measured again and participants recalled the number of SH in the last year. Results. ACE activity is reproducible over 40 months (p < 0.00001). Patients with SH during the baseline study also had SH during follow-up (p < 0.00001). Serum ACE activity measured at baseline was positively associated with the rate of SH at follow-up (p = 0.0003) with a 3.2-fold increased rate of SH in subjects belonging to the upper ACE quartile compared to subjects in the three lowest quartiles (p < 0.00001). The association between high serum ACE activity and increased risk of SH did not differ significantly in women and men. Conclusion. In type 1 diabetes individual serum ACE activity is reproducible over time. High ACE activity predicts recurrent SH over at least 40 months with no differences between genders.

Is cognitive impairment the fourth diabetic microvascular complication?

Is cognitive impairment the fourth diabetic microvascular complication?

The Effect of Recurrent Severe Hypoglycemia on Cognitive Performance in Children With Type 1 Diabetes

The purpose of this study was to investigate the existence and extent of cognitive impairment in type 1 diabetic children with episodes of recurrent severe hypoglycemia, using meta-analysis to synthesize data across studies. The meta-analysis sample included: 441 children with diabetes and recurrent severe hypoglycemia, 560 children with diabetes and without recurrent severe hypoglycemia. Overall, children with type 1 diabetes and recurrent severe hypoglycemia had slightly lower performance than diabetic children without severe hypoglycemia, only in some cognitive domains: intelligence, memory, learning, and verbal fluency/language. Greater impairment was found in memory and learning. No impairment was found for motor speed. Our results seem to confirm the hypothesis that recurrent severe hypoglycemia has a selective negative effect on the children's cognitive functions. However, these results must be considered with caution taking into account factors such as small sample sizes, the different definitions of severe hypoglycemia, and the variety of neuropsychological tests used.

Endoscopic Localization and Tattooing of a Proinsulinoma for Minimally Invasive Resection

Hypoglycemia can be common in patients using insulin injections or certain antidiabetes medications. In rare cases, hypoglycemia can be caused by a pancreatic insulinoma. We report a case of a 33-year-old woman found to have severe recurrent hypoglycemia. Diagnostic studies such as continuous glucose monitoring and a hospitalized fast provided biochemical evidence for a proinsulinoma. After abdominal multidetector contrast-enhanced computerized tomography failed to detect pancreatic abnormalities, endoscopic ultrasonography identified and localized a 9-mm pancreatic tail lesion. At the time of endoscopy, the lesion was tattooed with ultrasonographic guidance for subsequent laparoscopic visualization and curative resection.

Severe recurrent hypoglycaemia following discontinuation of olanzapine

Severe hypoglycaemia is a diagnostic challenge.1 It is often explained by mismatch between insulin doses, food ingestion and exercise. Recurrent hypoglycaemia can indicate underlying medical problems. Drug related events usually concern insulin or sulphonylureas. However, withdrawal of drugs which can cause insulin resistance can be causative if insulin or sulphonylureas continue.2We report the case of an insulin-treated patient who presented with severe recurrent hypoglycaemia. After exclusion of secondary causes of hypoglycaemia it was established that at the time of diagnosis of diabetes he had been taking olanzapine. This had subsequently been discontinued. Olanzapine is recognised to cause diabetes and diabetic ketoacidosis. Our patient was able to discontinue insulin therapy.

Morphologic analysis of focal and diffuse forms of congenital hyperinsulinism

Congenital hyperinsulinism is clinically characterized by an inappropriate insulin secretion resulting in recurrent severe hypoglycemia. Nesidioblastosis, the proliferation of islet cells budding off from ducts, has been considered for years as the histologic lesion responsible for the syndrome. In our morphologic studies, we demonstrate that nesidioblastosis is not specific of the disease, which is actually not a single entity. Indeed, we recognize the existence of 2 different forms-a diffuse form and a focal form-and demonstrate that they can be differentiated by morphologic criteria, even on frozen sections during surgery. This histologic distinction directs the therapeutic approach because the patients experiencing the focal form of the syndrome can be completely cured by a very limited pancreatectomy. Molecular findings confirmed the reliability of this histologic distinction, showing a specific background for each form.

Glucagon Treatment for Post‐Gastric Bypass Hypoglycemia

Hyperinsulinemic hypoglycemia is a recently described complication of Roux-en-Y gastric bypass (RYGB). We hypothesized that glucagon administration would help maintain normal postprandial plasma glucose concentrations by stimulating hepatic glucose output, and if so, represent a new therapeutic option for postbypass hypoglycemia. In this study, we compared the insulin and glycemic response to a mixed meal with and without concomitant glucagon infusion in a patient with severe recurrent hypoglycemia after RYGB. Although effective in transiently raising postprandial plasma glucose values, glucagon infusion was also associated with higher insulin concentrations, and failed to prevent symptomatic hypoglycemia. This case demonstrates that glucagon may have limited clinical utility in the treatment of post-RYGB hyperinsulinemic hypoglycemia.

“Dead in bed”: a tragic complication of type 1 diabetes mellitus

"Dead in bed" is a tragic description of a particular type of sudden death in type 1 diabetes mellitus (DM). Patients are typically found dead in the early morning, lying in an undisturbed bed, having been well the previous evening. The incidence of "dead in bed" syndrome is not known but studies suggest figures of between 4.7 and 27.3% of all unexplained deaths in type 1 DM. The pathogenesis is unclear but patients typically have a preceding history of recurrent severe hypoglycaemia. We describe two cases of "dead in bed" syndrome which occurred at our institution within a 12-month period.

Sustained Efficacy of Continuous Subcutaneous Insulin Infusion in Type 1 Diabetes Subjects with Recurrent Non-Severe and Severe Hypoglycemia and Hypoglycemia Unawareness: A Pilot Study

This study evaluated the effect of CSII on hypoglycemia awareness and on glucose profile in type 1 diabetes (T1D) subjects with repeated non-severe or severe hypoglycemia (NS or SH, respectively). We included subjects (1) older than 18 years, (2) with T1D duration of >5 years, (3) on multiple doses of insulin, and (4) without micro- or macrovascular complications and more than four NS events per week (in the last 8 weeks) and more than two SH events (in the last 2 years). NS/SH episodes and hypoglycemia awareness were evaluated. A 72-h continuous glucose monitoring (CGM) was performed before continuous subcutaneous insulin infusion (CSII). A hypoglycemia-induced test was used to evaluate each patient's symptoms in euglycemia/hypoglycemia. Quality of life (QoL) was also evaluated. After 6, 12, and 24 months, all the subjects were reevaluated. Twenty subjects were included (34.0 +/- 7.5 years old, 12 women, A1c 6.7 +/- 1.1%, 16.2 +/- 6.6 years of diabetes' duration). At baseline, 19 out of 20 subjects displayed hypoglycemia unawareness, which diminished significantly during the follow-up (3 out of 20). NH episodes per week diminished from 5.40 +/- 2.09 at baseline to 2.75 +/- 1.74 at the end of the follow-up (P < 0.001). SH episodes fell from 1.25 +/- 0.44 per subject-year to 0.05 +/- 0.22 after 24 months (P < 0.001). Hemoglobin A1c remained unaltered. With CGM, the percentage of values within 70-180 mg/dL increased (53.2 +/- 11.0% to 60.3 +/- 17.1%, P = 0.13), and the percentage of values <70 mg/dL decreased (13.7 +/- 9.4% to 9.1 +/- 5.2%, P = 0.07), after 24 months. Mean amplitude of glycemic excursions diminished after 24 months of CSII (136 +/- 28 mg/dL to 115 +/- 19 mg/dL; P < 0.02). An improvement in all the aspects of QoL was observed. The basal alteration in symptom response to an induced hypoglycemia improved after 24 months of initiating CSII leading to a response indistiguishable from that observed in a control group of subjects with T1D without repeated NH and SH. CSII prevents hypoglycemic episodes, improves hypoglycemia awareness, and ameliorates glycemic profile in T1D subjects with repeated NS/SH. Its use is also associated with an improvement in diabetes QoL.

Hypoglycemia with Intensive Insulin Therapy: A Systematic Review and Meta-Analyses of Randomized Trials of Continuous Subcutaneous Insulin Infusion Versus Multiple Daily Injections

Hypoglycemia limits the efficacy of intensive insulin therapy. The extent to which continuous insulin infusion (CSII) overcomes this limitation is unclear. The aim was to summarize evidence on the effect of CSII and multiple daily injections (MDIs) on glycemic control and hypoglycemia. We searched electronic databases between 2002 and March 2008. We selected published randomized trials of CSII vs. MDI. Reviewers working in duplicate and independently extracted study characteristics and quality and differences in glycosylated hemoglobin (HbA1c) and hypoglycemic events. We found 15 eligible randomized trials of moderate quality, with elevated baseline and end-of-study HbA1c levels. Patients with type 1 diabetes using CSII had slightly lower HbA1c [random-effects weighted mean difference, -0.2%; 95% confidence interval (CI), -0.3, -0.1, compared with MDI], with no significant difference in severe (pooled odds ratio, 0.48; 95% CI, 0.23, 1.00) or nocturnal hypoglycemia (pooled odds ratio 0.82, 95% CI 0.33, 2.03). Adolescents and adults with type 1 diabetes enrolled in crossover trials had nonsignificantly fewer minor hypoglycemia episodes per patient per week (-0.08; 95% CI, -0.21, 0.06) with CSII than MDI; children enrolled in parallel trials had significantly more episodes (0.68; 95% CI, 0.16, 1.20; P(interaction) = 0.03). Outcomes were not different in patients with type 2 diabetes. Contemporary evidence indicates that compared to MDI, CSII slightly reduced HbA1c in adults with type 1 diabetes, with unclear impact on hypoglycemia. In type 2 diabetes, CSII and MDI had similar outcomes. The effect in patients with hypoglycemia unawareness or recurrent severe hypoglycemia remains unclear because of lack of data.

Gastrointestinal stromal tumour and hypoglycemia in a Fjord pony: Case report

BackgroundNeoplasia may cause hypoglycemia in different species including the horse, but hypoglycemia has not previously been reported in the horse associated with gastrointestinal stromal tumours.Case presentationA case of a gastrointestinal stromal tumour in a Fjord pony with severe recurrent hypoglycemia is presented. The mechanism causing the hypoglycemia was not established.ConclusionThis case indicates that a gastrointestinal stromal tumour may cause hypoglycemia also in the horse.

Severe Recurrent Hypoglycemia after Gastric Bypass Surgery

Bariatric surgery is, at present, the most effective method to achieve major, long-term weight loss in severely obese patients. Recently, severe recurrent symptomatic hyperinsulinemic hypoglycemia was described as a consequence of gastric bypass surgery (GBS) in a small series of patients with severe obesity. Pancreatic nesidioblastosis, a hyperplasia of islet cells, was postulated to be the cause, and subtotal or total pancreatectomy was the suggested treatment. We observed that severe, disabling hypoglycemia after GBS occurred only in patients with loss of restriction. Whether restoration of gastric restriction might treat severe, recurrent hypoglycemia after GBS is unknown. Therefore, gastric restriction was restored by surgical placement of a silastic ring (n = 8, first two patients with additional distal pancreatectomy) or an adjustable gastric band (n = 4) around the pouch in 12 consecutive patients presenting with severe hypoglycemia (blood glucose below 2.2 mM). At follow-up after restoration of gastric restriction (median follow-up 7 months, range 5 to 19 months), 11 patients demonstrated no hypoglycemic episodes, while one had recurrence of hypoglycemia and underwent distal pancreatectomy. Procedural mortality was 0% and morbidity 8.3%. Patients suffering from severe recurrent hypoglycemia after GBS can be treated, in most cases, just by restoration of gastric restriction. Distal pancreatectomy should be considered a second-line treatment.

Genetic Variation and Activity of the Renin-Angiotensin System and Severe Hypoglycemia in Type 1 Diabetes

Background The deletion-allele of the angiotensin-converting enzyme (ACE) gene and elevated ACE activity are associated with increased risk of severe hypoglycemia in type 1 diabetes. We explored whether genetic and phenotypic variations in other components of the renin-angiotensin system are similarly associated. Methods Episodes of severe hypoglycemia were recorded in 171 consecutive type 1 diabetic outpatients during a 1-year follow-up. Participants were characterized at baseline by gene polymorphisms in angiotensinogen, ACE, angiotensin-II receptor types 1 (AT1R) and 2 (AT2R), and by plasma angiotensinogen concentration and serum ACE activity. Results Three risk factors for severe hypoglycemia were identified: plasma angiotensinogen concentration in the upper quartile (relative rate [RR] vs. lower quartile 3.1, 95% confidence interval [CI,] 1.4-6.8), serum ACE activity in the upper quartile (RR vs. lower quartile 2.9, 95% CI, 1.3-6.2), and homo- or hemizygosity for the A-allele of the X chromosome-located AT2R 1675G/A polymorphism (RR vs. noncarriers 2.5, 95% CI, 1.4-5.0). The three risk factors contributed independently to prediction of severe hypoglycemia. A backward multiple regression analysis identified a high number of renin-angiotensin system-related risk factors and reduced ability to perceive hypoglycemic warning symptoms (impaired hypoglycemia awareness) as predictors of severe hypoglycemia. Conclusions High renin-angiotensin system activity and the A-allele of the AT2R 1675G/A polymorphism associate with high risk of severe hypoglycemia in type 1 diabetes. A potential preventive effect of renin-angiotensin system blocking drugs in patients with recurrent severe hypoglycemia merits further investigation.

Association of malignant insulinoma and type 2 diabetes mellitus: A case report

We report a case of recurrent hypoglycemia due to malignant insulinoma in a type 2 diabetic patient correctly controlled for years with the same doses of oral antidiabetic agents.A 79-year-old woman was admitted for recurrent severe hypoglycemia. She had a history of type 2 diabetes since 2000. HbA1c was 7.8% when she reported mild hypoglycemia and 5.8% when recurrent hypoglycemia appeared despite progressive diminution of glicazide. Severe hypoglycemia continued despite interrupting diabetes medications. At admission, results showed inappropriately elevated insulin, C-peptide and proinsulin levels despite significant hypoglycemia. CT scan showed “cystic” nodes in the pancreas and in the liver. Liver biopsy found a well-differentiated neuroendocrine carcinoma with positive staining for chromogranin A and negative staining for insulin. Hypoglycemia improved with diazoxide, lanreotide and dextrose infusion. Liver chemoembolization was planned. Severe edema, dyspnea, hyponatremia, and hypo-osmolarity occurred. The patient's clinical status deteriorated rapidly with severe cardiac, renal and hepatic failure. She died in a few days. Association of diabetes mellitus and insulinoma is extremely rare. Malignant insulinoma survival is less than two years, shorter when hepatic localizations are present at diagnosis. Association of diabetes with insulinoma delays the diagnosis, but does not alter prognosis or favor carcinoma frequency. Lanreotide was inefficient in our patient despite good responses described in the literature. Heart, respiratory and renal failures have been described with diazoxide independently of the doses; this may in part explain the rapid death. Insulinoma should be considered as a cause of unusual and recurrent hypoglycemia in a diabetic patient especially if it persists after interrupting antidiabetic agents.

High frequency of missense mutations in glycogen storage disease type VI

Deficiency of liver glycogen phosphorylase in glycogen storage disease (GSD) type VI results in a reduced ability to mobilize glucose from glycogen. Six mutations of the PYGL gene, which encodes the liver isoform of the enzyme, have been identified in the literature. We have characterized eight patients from seven families with GSD type VI and identified 11 novel PYGL gene defects. The majority of the mutations were missense, resulting in the substitution of highly conserved residues. These could be grouped into those that were predicted to affect substrate binding (p.V456M, p.E673K, p.S675L, p.S675T), pyridoxal phosphate binding (p.R491C, p.K681T), or activation of glycogen phosphorylase (p.Q13P) or that had an unknown effect (p.N632I and p.D634H). Two mutations were predicted to result in null alleles, p.R399X and [c.1964_1969inv6;c.1969+1_+4delGTAC]. Only 7 of the 23 (30%) reported PYGL alleles carry nonsense, splice site or frameshift mutations compared to 68-80% of affected alleles of the highly homologous muscle glycogen phosphorylase gene, PYGM, that underlie McArdle disease. There was heterogeneity in the clinical symptoms observed in affected individuals. These varied from hepatomegaly and subclinical hypoglycaemia, to severe hepatomegaly with recurrent severe hypoglycaemia and postprandial lactic acidosis. We conclude that deficiency of liver glycogen phosphorylase is predominantly the result of missense mutations affecting enzyme activity. There are no common mutations and the severity of clinical symptoms varies significantly.

A randomized pilot study in Type 1 diabetes complicated by severe hypoglycaemia, comparing rigorous hypoglycaemia avoidance with insulin analogue therapy, CSII or education alone

To determine potential for amelioration of recurrent severe hypoglycaemia without worsening in overall control in individuals with long-standing Type 1 diabetes (T1DM). Twenty-one people with T1DM characterized by altered hypoglycaemia awareness and debilitating severe hypoglycaemia were randomized in a pilot 24-week prospective study to optimized analogue therapy (ANALOGUE; lispro/glargine); continuous subcutaneous insulin infusion therapy (CSII; lispro); or re-education with relaxation of blood glucose targets on existing conventional insulin regimen (EDUCATION). Glycaemic profiles and duration of biochemical hypoglycaemia were measured by continuous subcutaneous glucose monitoring and self-monitored blood glucose. Further severe hypoglycaemia was prevented in five participants (71%) in each group (P = 0.06). Incidence of severe hypoglycaemia was: 0.6 (ANALOGUE), 0.9 (CSII), and 3.7 (EDUCATION) episodes per patient year. Restoration of hypoglycaemia awareness was confirmed by validated questionnaire in three (43%) ANALOGUE, four (57%) CSII and five (71%) EDUCATION patients. Glycated haemoglobin (HbA1c) was significantly improved in the ANALOGUE group between weeks 0 and 24 (8.6 +/- 1.1 vs. 7.6 +/- 0.8%; P = 0.04 for change). Non-significant improvement was seen in the CSII group (8.5 +/- 1.9 vs. 7.4 +/- 1.0%; P = 0.06). No change in HbA1c was seen in the EDUCATION group (8.5 +/- 1.1 vs. 8.3 +/- 1.0%; P = 0.54). There were no episodes of diabetic ketoacidosis or any other adverse events in any group. In this pilot randomized trial comparing optimized ANALOGUE, CSII or EDUCATION alone in unselected individuals with recurrent severe hypoglycaemia, we show potential for restoring hypoglycaemia awareness and preventing further severe hypoglycaemia with concomitant improvement in glycaemic control in ANALOGUE and CSII groups.

Implantable insulin pumps. A position statement about their clinical use

Aim To review clinical use of implantable insulin pumps and to suggest indications for this therapy. Methods The EVADIAC group performed a review of published reports on implantable insulin pumps for the last 15 years and analyzed its own centralized database. From this update, a position statement on indications of this therapy is drawn. Results Published papers mostly report safety and effectiveness data from observational cumulated experiences of 15–350 patient-years. While HbA 1c reduction does not reach statistical significance in all reported studies, improvement of blood glucose stability and reduction of severe hypoglycaemia appear as constant characteristics of this therapy. When compared to subcutaneous insulin therapy in randomized controlled studies, implantable pumps allow significantly reduced blood glucose fluctuations and improved quality of life in both type 1 and type 2 diabetic patients, and a significant weight decrease in type 2 diabetic patients. While the EVADIAC registry shows the reduced occurrence of pump-pocket complications thanks to preventive measures and a lower incidence of catheter obstructions following improvements of catheter design, underdelivery due to insulin aggregation in pumps remains a recurrent although reversible issue. Determinants of increased anti-insulin antibody production in some patients remain elusive but impact on blood glucose control is limited in most cases. Conclusion From analyzed data, the EVADIAC group states that implantable pumps can be safely indicated and provide metabolic improvements in type 1 diabetic patients who remain far from targeted HbA 1c below 7% and/or experience large fluctuations of blood glucose including recurrent severe hypoglycaemia, in spite of intensive follow-up and education when treated by subcutaneous insulin.

Case Study: Cognitive Impairment, Depression, and Severe Hypoglycemia

The following case study illustrates the clinical role of mental health professionals who specialize in the treatment of people with diabetes. This case describes the diagnostic dilemma presented by a patient with diabetes and a history of severe hypoglycemia complicated by other medical, psychiatric, social, and functional problems. Cognitive impairment (e.g., memory loss, increased distractibility, and confusion) can present a difficult diagnostic problem for clinicians because it can be symptomatic of many underlying and undetected clinical conditions. Careful diagnosis is crucial because some causes may be progressive and irreversible, whereas other causes may be reversible with medical or psychiatric treatment. Some of the more noteworthy causes are related to medication, alcohol, aging, depression, and, as in this case study, the possible consequences of recurrent severe hypoglycemia related to diabetes.1 Diabetes, of course, may cause an increase in cognitive decline over the course of time because of vascular risk factors.2 Some evidence suggests that acute hyperglycemia may have a negative impact on cognitive performance.3 Depression is the most common of the reversible causes of memory impairment, and people with diabetes are twice as likely to suffer from depression as those without diabetes.4 Recent evidence suggests that diabetes may create alterations in regions of the brain that are associated with affect regulation and increase the risk for developing a depressive disorder.5 Fortunately, problematic medications can be modified, and alcohol misuse or depression can be treated. Unfortunately, despite its relevance to the course of diabetes, depression is recognized and treated in fewer than one-third of people with diabetes.4 The relationship between recurrent severe hypoglycemia and cognitive impairment remains unclear. Both prospective and longitudinal studies of cognitive function have been so plagued by methodological problems that it is difficult to unequivocally determine whether patients who experience repeated episodes …

Glucose-Lowering Effects of Sulfasalazine in Type 2 Diabetes

Salicylates are therapeutic agents clinically useful in treating inflammatory bowel diseases and arthropathies. These drugs have also demonstrated glucose-lowering effects in type 2 diabetes (1–2). Sulfasalazine (SSZ) is a compound that is cleaved in vivo to 5-aminosalicylic acid (a salicylate) and sulfapyridine (a sulfonamide antibiotic). We report a case of a patient with systemic lupus erythematosus (SLE) and type 2 diabetes on high-dose insulin therapy, who after initiating SSZ experienced recurrent severe hypoglycemia and eventually achieved normoglycemia without the need for diabetes medications. After caring for the index patient, and then two others manifesting similar metabolic responses to SSZ, we conducted a systematic chart review to evaluate glycemic effects of SSZ in a cohort of diabetic patients. A 37-year-old woman with SLE, iron-deficiency anemia, metamphetamine usage, and a 1-year history of type 2 diabetes was referred to the Santa Clara Valley Medical Center (SCVMC) diabetes clinic for treatment of severe hyperglycemia. She took 100 units of insulin daily (NPH 35 units b.i.d., regular 10 units t.i.d.), yet her self-monitored blood glucose (SMBG) values consistently exceeded 16.7 mmol/l, and she experienced polyuria/dipsia and blurry vision. Other medications were prednisone 7.5 mg/day and hydroxychloroquine. On examination, the patient was cachexic, weighing 44 kg. Laboratory evaluation revealed normal …