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CASE PRESENTATION

  1. Top of page
  2. CASE PRESENTATION
  3. CASE SUMMARY
  4. DIFFERENTIAL DIAGNOSIS
  5. DISCUSSION
  6. FINAL DIAGNOSIS
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Chief symptom

A 30-year-old woman with diabetes mellitus and recently diagnosed severe lupus nephritis and renal insufficiency was admitted for a renal biopsy and anticipated initiation of immunosuppressive therapy.

History of the present illness

The patient had been admitted to the hospital 2 months previously for evaluation of weight loss, diffuse myalgias, arthralgias, nausea, vomiting, facial rash, lower extremities, and facial edema. Evaluation revealed acute renal insufficiency, with a creatinine level of 5.2 mg/dl and an active urinary sediment with 4+ proteinuria, 2+ hematuria, and red blood cell casts. Tests for antinuclear antibodies (ANAs), antibodies to Sm antigen, and antibodies to RNP were positive. Tests for antibodies to double-stranded DNA, SSA, SSB, and glomerular basement membrane were negative, as was testing for antineutrophil cytoplasmic antibodies. Both C3 and C4 levels were low (Table 1). A kidney biopsy was scheduled and intravenous (IV) pulse therapy with methylprednisolone was started. However, on the second day of her admission, the patient signed out of the hospital against medical advice. Her creatinine at discharge was 4.8 mg/dl.

Table 1. Initial laboratory evaluation*
TestValueNormal value
  • *

    ALT = alanine aminotransferase; AST = aspartate aminotransferase; hpf = high-power field; anti-dsDNA = anti–double-stranded DNA; ANCA = antineutrophil cytoplasmic antibody; anti-GBM= antibodies against glomerular basement membrane.

White blood cell count, cells/mm32.84–11
 Neutrophils, %7745–85
 Bands, %60–7
 Lymphocytes, %1316–50
 Monocytes, %40–10
Hematocrit, %22.338–47
Platelet count, cells/mm3150150–400
Blood urea nitrogen, mg/dl606–22
Creatinine, mg/dl9.250.5–1.1
Sodium, mmoles/liter135135–145
Potassium, mmoles/liter63.5–5.1
Bicarbonate, mmoles/liter1623–29
Chloride, mmoles/liter10298–107
Albumin, gm/dl2.53.5–4.8
Total bilirubin, mg/dl0.30.3–1.2
ALT, units/liter75–31
AST, units/liter135–40
Blood glucose, mg/dl17970–110
Triglycerides, mg/dl10740–200
Urinalysis  
 Blood2+Negative
 Protein4+Negative
 Red blood cells/hpf>1000–5
 White blood cells/hpf50–5
24-hour urine protein, gm/24 hours130–0.15
Antinuclear antibodies1:1,280, speckledNegative
Anti-SSA/Ro antibodiesNegativeNegative
Anti-SSB/La antibodiesNegativeNegative
Anti-Sm antibodiesPositive<20
Anti-RNP antibodiesPositive<20
Anti-dsDNA, IU/ml4.4<5
ANCANegativeNegative
Anti-GBM, units/ml<3<3
C3, mg/dl4480–170
C4, mg/dl1216–40

Over the next 2 months, the patient developed progressively worsening body aches, nausea, vomiting, and edema in the lower extremities and face. The facial rash persisted and a new rash on her upper and mid-back appeared. She had been using ibuprofen 600 mg up to 4 times a day for 3–4 days prior to readmission.

Medical history

Her medical history was notable for diabetes mellitus, which was incidentally diagnosed a few months before this admission, when she presented to the hospital for evaluation of a genital infection and was found to have elevated blood glucose tests in the range of 400–700 mg/dl with glycosylated hemoglobin of 13.9 mg/dl. She had a brief hospital admission and insulin therapy was prescribed.

Family history

There was no family history of any rheumatic disorder.

Social history

The patient is African American. She was not sexually active.

Habits

The patient reported no alcohol, tobacco, or illegal drug use.

Medications on admission

She was taking ibuprofen 600 mg 4 times daily, a multivitamin daily, an iron supplement, and lispro insulin 3 times daily with meals.

Physical examination

Her weight was 85 kilograms, her height was 175 centimeters, her blood pressure was 159/98 mm Hg, and her heart rate was 114 beats per minute. She was afebrile. Oral mucosa was moist without ulcers. There was no lymphadenopathy in cervical, axillary, or femoral chains. There was 3+ symmetric pitting edema of the lower extremities. Multiple hyperpigmented infiltrated skin papules and plaques, some with white scale, were present on the chest, upper arms, and upper and mid-back. Hyperpigmentation of the anterior and lateral skin folds of the neck, axillae, and periocular and perioral areas was also noted. Cardiovascular, pulmonary, abdominal, joint, and neurologic examinations were unremarkable.

Diagnostic testing

Laboratory tests are summarized in Table 1 and included leukopenia with lymphopenia, anemia, normal platelet count, creatinine of 9.25 mg/dl, blood glucose of 179 mg/dl, and albumin of 2.5 gm/dl. Urinalysis by dipstick showed 2+ hematuria and 4+ protein; microscopic examination showed more than 100 red blood cells (RBCs) per high-power field, with many dysmorphic RBCs and multiple RBC casts. A 24-hour urine collection contained 13 gm of protein. A renal ultrasound revealed two normal-size echogenic kidneys with no evidence of obstruction.

Initial hospital course

A kidney biopsy was performed. Light microscopy showed proliferative endocapillary changes with focal distribution (<50% of glomeruli) (Figure 1A), moderate interstitial inflammatory infiltrates, mild interstitial fibrosis, and tubular atrophy (Figure 1B). Immunofluorescent testing demonstrated granular deposition of IgG, C3, and C1q along the peripheral capillary walls and mesangial areas (Figure 1C).

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Figure 1. Renal biopsy results. A, Glomerulus with endocapillary proliferation and expanded mesangium (arrow). B, Moderate interstitial inflammatory infiltrates, mild interstitial fibrosis (left arrow), and tubular atrophy (right arrow). C, Granular deposition of IgG, C3, and C1q along the peripheral capillary walls and mesangial areas.

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Following the renal biopsy, the patient received IV methylprednisolone 1,000 mg daily for 3 days, followed by oral prednisone 60 mg/day. Mycophenolate mofetil 500 mg twice a day was initiated with the plan to progressively increase the dose to 1,000 mg twice a day. Hemodialysis was started on the third hospital day. On day 4, while receiving 60 mg of prednisone daily, she was found to be hyperglycemic with blood glucose levels of >600 mg/dl. The doses of subcutaneous insulin were increased, but the patient continued to have persistent, severe hyperglycemia. She was transferred to the medical intensive care unit for initiation of continuous IV insulin infusion. The insulin dosage was increased up to 60 units/hour without improvement of hyperglycemia. The rheumatology service was asked for an opinion regarding the possibility of decreasing the glucocorticoid dose, given the concern for a component of glucocorticoid-induced insulin resistance.

CASE SUMMARY

  1. Top of page
  2. CASE PRESENTATION
  3. CASE SUMMARY
  4. DIFFERENTIAL DIAGNOSIS
  5. DISCUSSION
  6. FINAL DIAGNOSIS
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

The patient had systemic lupus erythematosus (SLE) with manifestations, including a discoid lupus rash, leucopenia, lymphopenia, positive serologies (ANA, anti-Sm antibodies), and class III lupus nephritis. Therapy was initiated with high-dose glucocorticoids and mycophenolate mofetil. She was critically ill, with renal insufficiency requiring hemodialysis and severe hyperglycemia refractory to high-dose insulin therapy. The etiology of hyperglycemia in this patient was unclear, particularly given that she had previously been responsive to insulin.

DIFFERENTIAL DIAGNOSIS

  1. Top of page
  2. CASE PRESENTATION
  3. CASE SUMMARY
  4. DIFFERENTIAL DIAGNOSIS
  5. DISCUSSION
  6. FINAL DIAGNOSIS
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

The differential diagnosis in this case of severe hyperglycemia consisted of an exacerbation of preexisting diabetes mellitus due to treatment with glucocorticoids versus another cause of secondary insulin resistance, including obesity, uremia, or immune-mediated insulin resistance.

Hyperglycemia associated with glucocorticoid therapy

Therapy with glucocorticoids is associated with the risk of hyperglycemia in patients without known diabetes mellitus (induction of diabetes mellitus), and with worsening glycemic control in patients with established diabetes mellitus (aggravation of diabetes mellitus). Glucocorticoid excess causes decreased beta cell insulin production and insulin resistance through stimulation of hepatic gluconeogenesis, inhibition of glucose uptake in adipose tissue, and alteration of receptor and postreceptor functions (1, 2). In patients with severe manifestations of systemic lupus (e.g., rapidly progressing glomerulonephritis or central nervous system disease), high doses of IV methylprednisolone followed by daily oral prednisone are generally prescribed in an effort to induce a rapid remission. In such cases, the high cumulative prednisone dose has been found to strongly correlate with the risk of developing glucocorticoid-induced diabetes mellitus (odds ratio 6.35) (3). These patients can usually be effectively treated using antidiabetic noninsulin agents and/or insulin therapy. A variety of glucocorticoid tapering protocols have been employed in patients with severe lupus nephritis, but in general the initial dose is maintained for at least 2–4 weeks before it can be tapered down (4, 5). Glucocorticoid withdrawal is usually associated with an improvement in glycemic control and a reduced need for oral glucose-lowering agents and insulin therapy.

Our patient had started high doses of glucocorticoids for treatment of her severe lupus nephritis. It is possible that her glycemic control had become increasingly difficult in this setting. However, most exacerbations of insulin resistance respond to IV insulin therapy (6), and 60 units/hour was considered an excessive insulin dosage without effect.

Insulin resistance syndromes

The insulin resistance syndromes are characterized by a less than expected cellular and metabolic response to insulin, associated with elevated circulating insulin levels (7). Insulin resistance due to the development of antibodies against exogenous insulin derived from nonhuman species was once a common occurrence but has become extremely rare with the use of recombinant human insulin. A new spectrum of insulin resistance has now become increasingly recognized. The roles of obesity, inflammation associated with uremia, metabolic syndrome, insulin resistance associated with polycystic ovary syndrome, and inherited causes of insulin resistance have been extensively studied.

Our patient was overweight and had severe renal insufficiency due to her lupus nephritis. It was possible that she could have developed insulin resistance due to the effects of loss of kidney metabolic function in addition to insulin resistance from critical illness (8). However, prior to this episode, she had a normal response to administration of insulin and it was unexpected that she had developed this degree of insulin resistance solely due to uremia. Nevertheless, her clinical status was concerning because insulin resistance has been associated with adverse outcomes, including high mortality in critically ill patients with acute renal failure (7).

In the setting of connective tissue disease, type B insulin resistance caused by polyclonal IgG antibodies against the insulin receptor needs to be considered. This rare entity was first described more than 30 years ago among 6 African American women (9), but has subsequently also been reported to occur in males and younger patients (10). The syndrome has been described in association with SLE, systemic sclerosis, Sjögren's syndrome, primary biliary cirrhosis, autoimmune thrombocytopenia, and Hashimoto thyroiditis (9). Most patients with type B insulin resistance present with severe hyperglycemia that requires high daily doses of insulin and have profound glucosuria, polyuria, and weight loss. Features of systemic autoimmune disease are frequently associated with, and usually precede the recognition of, the insulin receptor antibody syndrome (11). The pathogenesis of type B insulin resistance has not been conclusively demonstrated, but it is believed that the antibodies against insulin receptor lead to insulin resistance by sterically interfering with insulin binding (12).

Arioglu et al (11) described the general features and the natural history of type B insulin resistance based on data from a cohort of 24 patients followed at the National Institutes of Health (NIH) for up to 28 years. The most consistent underlying syndrome was SLE (46% met the American College of Rheumatology criteria for SLE [≥4 criteria] and an additional 25% had 3 criteria) (13). More than 50% of the patients had lupus nephritis. In addition to hyperglycemia requiring high daily insulin doses (mean insulin dosage 5,100 IU/day), other clinical features of the syndrome seen in this cohort included acanthosis nigricans (88%) with involvement of the periocular and perioral areas resulting in typical facies, hyperandrogenism, and ovarian enlargement in women. The patients had high circulating insulin levels and unusually low fasting triglyceride levels (in contrast to other types of insulin resistance that are usually associated with significant hypertriglyceridemia). Detection of the insulin receptor antibodies is considered definitive for the diagnosis of type B insulin resistance.

There are other various aspects of the type B insulin resistance syndrome that permit a fairly confident diagnosis. Hyperinsulinemia is a consistent finding (7) that results from increased insulin secretion to compensate for the peripheral insulin resistance and, in many cases, from reduced insulin clearance. A paradoxical elevation of adiponectin in type B insulin resistance has been reported and is presumed to be due to direct effects on adipocytes of the loss in the insulin receptor function, or to loss of insulin action in mature adipose tissue (14). Adiponectin is a protein produced in adipose tissue and its levels are usually low in insulin resistance. Among patients in which a high suspicion of type B insulin resistance exists, adiponectin levels were found to be quite helpful in the diagnosis of insulin receptor dysfunction (levels >7 mg/liter had a 97% positive predictive value and <5 mg/liter had a 97% negative predictive value) (15). Significantly elevated levels of insulin-regulated hepatic proteins, sex hormone binding globulin, and insulin-like growth factor binding protein 1 (IGFBP-1) can also be found in these patients (11).

In our patient, the clinical picture was compatible with type B insulin resistance. She had demographic features and clinical manifestations (African American woman with lupus nephritis and periocular and perioral acanthosis nigricans) consistent with this diagnosis, and presented with severe hyperinsulinemic hyperglycemia not responsive to high doses of insulin.

Hospital course

The patient was maintained on 60 mg of prednisone daily for treatment of class III SLE nephritis. She continued to have markedly increased levels of blood glucose for several days despite progressive increases of IV insulin (up to 2,400 units/day). Further diagnostic tests were performed (Table 2). She had a strongly positive test for anti-insulin receptor antibodies (Figure 2). A diagnosis of type B insulin resistance syndrome was made based on multiple diagnostic criteria, including hyperglycemia despite massive doses of insulin, acanthosis nigricans with characteristic periocular and perioral lesions, African American race, and the association with SLE and lupus nephritis, high insulin levels, low triglyceride levels, high adiponectin and IGFBP-1 levels, and strongly positive anti-insulin receptor antibodies. The prognosis of this disease and further treatment strategies were discussed with the patient.

Table 2. Additional endocrinologic testing of the patient
TestNegativeNormal value
  • *

    Mean ± SD.

Fasting insulin, μU/ml1,900<17
Fasting C peptide, ng/ml27.50.8–3.1
Adiponectin, μg/ml>2516.6 ± 5.0*
Anti-insulin antibodiesNegativeNegative
Anti-insulin receptor antibodiesPositiveNegative
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Figure 2. Anti-insulin receptor antibodies of the patient (left panel) measured by immunoprecipitation of recombinant human insulin receptors, with positive and negative controls (right panel). Data indicate that the patient tested strongly positive for the anti-insulin receptor antibodies. Anti-insulin receptor antibodies measured courtesy of Dr. Robert K. Semple of the Cambridge University Metabolic Research Laboratories, Cambridge, UK.

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Type B insulin resistance has a heterogeneous clinical course. Remarkably, spontaneous remission of type B insulin resistance syndrome has been described. In the NIH case series, 6 (33%) of 18 patients had spontaneous improvement of the hyperglycemia and disappearance of the antibodies from the circulation over a period of 11 to 48 months (9). Interestingly, regression of acanthosis nigricans has been reported in temporal association with the disappearance of circulating anti-insulin receptor autoantibodies and achievement of euglycemia type B insulin resistance (16). Insulin is often administered in extremely high doses but usually fails to provide adequate glycemic control. There are numerous case reports of remission of the autoantibody syndrome using glucocorticoids and various other immunomodulatory agents that are usually administered for treatment of the associated autoimmune disease. In a case series including 7 patients with type B insulin resistance treated at the NIH, a standardized treatment protocol associating rituximab 750 mg/m2 of body surface area in two consecutive doses 2 weeks apart, cyclophosphamide 100 mg daily orally, and IV pulses of high-dose glucocorticoids was used (17). All 7 patients treated with this regimen achieved remission, with amelioration of hyperglycemia, discontinuation of insulin therapy, and resolution of hyperandrogenism. Occasionally, an incidental favorable response has been reported with plasma exchange and IV immunoglobulins (18, 19). The interpretation of the efficacy of different therapeutic regimens is difficult due to the rarity of this syndrome, the use of multiple agents, the lack of controlled data, and the possibility of spontaneous remission.

Additional clinical course

Four weeks after her initial admission, the patient had persistent, severe hyperglycemia. She underwent 3 sessions of plasma exchange with 2 liters of exchange during each session. Thirty-six hours after the third plasma exchange session, her blood glucose measurements were much improved, her insulin requirements decreased significantly, and insulin therapy was completely withdrawn 4 days after her third plasma exchange session. The patient's renal function also improved significantly and she no longer required hemodialysis. She developed leukopenia and mycophenolate mofetil was discontinued. Four weeks after her admission, she was discharged home on 40 mg of prednisone daily, with a plan to initiate rituximab therapy as an outpatient. The serum creatinine level at discharge was 2.5 mg/dl.

One week after discharge, the patient had episodes of hypoglycemia daily. The day prior to her scheduled rituximab treatment, the patient was found unresponsive at home by her mother. Her capillary glucose was 19 mg/dl. The patient had not received any insulin since she was discharged from the hospital and she had not taken any oral hypoglycemic agents. She was given IV dextrose, regained consciousness, was brought to the hospital, and was admitted to the intensive care unit. Her physical examination was notable for a striking improvement of the acanthosis nigricans lesions compared to her examination during her prior admission, and laboratory tests were significant for persistent hypoglycemia and undetectable insulin levels. Dexamethasone was added, and the patient received a first dose of rituximab 700 mg intravenously and a second after one week. A few days later, she developed diarrhea, abdominal pain, and distension, and was diagnosed with Clostridium difficile colitis. Despite appropriate antibiotic therapy, she developed toxic megacolon with subsequent bowel perforation and sepsis, and underwent emergent total colectomy. The patient remained mechanically ventilated for 4 weeks after surgery, during which time she had continued episodes of severe hypoglycemia with intermittent glucose values of 30–40 mg/dl. This life-threatening hypoglycemia persisted despite intensive treatment with combinations of high-dose IV glucocorticoids, continuous IV dextrose infusion (up to 150 ml/hour of 10% dextrose solution), continuous enteral nutrition, and total parenteral nutrition with maximal lipid to induce postreceptor insulin resistance. She also received a 3-day trial of ritonavir, a human immunodeficiency virus (HIV) protease inhibitor used as antiretroviral therapy in patients infected with HIV, which has been shown to directly inhibit the glucose transporter 4 insulin-regulated transporter, leading to decrease glucose uptake in adipocytes (20). However, there was no significant change in the blood glucose after this treatment.

IV immunoglobulin therapy was administered twice during episodes of acute critical illness, with transient (24–72 hours) elevation of blood glucose. Additional plasma exchange was considered but postponed because of recurrent fevers, pneumonia, and bacteremia.

With intensive measures, the patient's status improved slowly and she became afebrile, and was weaned off vasopressors and antibiotics. She underwent a tracheostomy with plans to wean off of mechanical ventilation. She received a third dose of rituximab 700 mg intravenously, and a fourth dose 1 week later. Measurements of B lymphocytes (measured as CD19+ cells) were 14% prior to the second dose, 0% six weeks after the first dose, and remained undetectable 4 months after the treatment. She continued on hydrocortisone 25 mg every 8 hours, remained off of mycophenolate, and refused additional immunosuppressive therapy with cyclophosphamide. Her kidney function stabilized (creatinine 2 mg/dl), although she remained nephrotic. Blood glucose improved approximately 8 weeks after initiation of rituximab therapy, and the IV dextrose infusion was discontinued. However, she continued to require continuous enteral nutrition in addition to daily oral glucose supplements. The clinical course of the patient is shown in Figure 3.

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Figure 3. Clinical course of altered glycemic control and immunosuppressive therapy for the patient with type B insulin resistance in the setting of systemic lupus erythematosus with glomerulonephritis. Changes in glycosylated hemoglobin (HbA1c; left x-axis) and creatinine levels (right x-axis) over time (y-axis) are shown. HD = hemodialysis; IVIG = intravenous immunoglobulins; PLEX = plasma exchange; RTX = rituximab; MMF = mycophenolate mofetil; GC = glucocorticoids.

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DISCUSSION

  1. Top of page
  2. CASE PRESENTATION
  3. CASE SUMMARY
  4. DIFFERENTIAL DIAGNOSIS
  5. DISCUSSION
  6. FINAL DIAGNOSIS
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Paradoxically, one-third of patients with type B insulin resistance due to anti-insulin receptor antibodies may present with hypoglycemia or, as in this case, hypoglycemia may only occur after a prolonged period of hyperglycemia and extreme insulin resistance (9). In the NIH case series, 6 (25%) of 24 patients manifested some form of hypoglycemia during the course of their disease. A recent review reported on 22 additional cases with hypoglycemia caused by anti-insulin receptor antibodies (21). The exact mechanism of hypoglycemia in this syndrome is not known. Interestingly, a significant fall in the antibody titer appears to precede the occurrence of hypoglycemia in some patients that present initially with hyperglycemia (9, 22). The hypothesis is that at high titers, anti-insulin receptor antibodies may sterically inhibit insulin binding, inhibiting both glucose transport and normal receptor cycling, with the end result of a lack of available receptors. This leads to inhibition of insulin clearance and high levels of plasma insulin that are ineffective or insufficient to maintain normal blood glucose levels (Figure 4A). When the antibody titer falls either spontaneously or secondary to therapeutic measures such as plasma exchange or immunosuppressive drugs, the antibodies become able to stimulate the receptor (as they universally do in vitro) (23) and thus act as agonists, mimicking an unregulated insulin effect that inevitably leads to hypoglycemia (Figure 4B). Additionally, the anti-insulin receptor antibodies could possibly induce a conformational perturbation (24) or enhance the production of the receptor protein (25), inducing hypoglycemia in some patients.

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Figure 4. Proposed pathophysiology of hyper- and hypoglycemia type B insulin resistance syndrome. A, At high titers, anti-insulin receptor antibodies can lead to insulin resistance and hyperglycemia by sterically interfering with insulin binding at the level of the cell membrane (myocyte, adipocyte, or hepatocyte). Immunosuppressive medications (glucocorticoids, mycophenolate mofetil, or rituximab) and/or plasma exchange (PLEX) contribute to the decrease in the antibody (Ab) titer. B, At low titers, the Abs become able to stimulate the receptor (act as agonists), mimicking an unregulated insulin effect and allowing glucose transporter 4 (GLUT-4)–mediated glucose transport. This results in persistent hypoglycemia, independent of insulin. GC = glucocorticoids; MMF = mycophenolate mofetil; R = insulin receptor; RTX = rituximab.

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High doses of glucocorticoids are usually used in an attempt to reverse the hypoglycemia (15, 26, 27). Current therapeutic strategies include various immunosuppressive agents, IV immunoglobulins, or plasma exchange; however, optimal regimens or combinations of regimens have not been established.

The prognosis of type B insulin resistance is poor. In the NIH case series, the mortality rate was 54% (13 of 24 patients), and the deaths were related to cardiovascular, infectious, and autoimmune (SLE) complications, or end-stage renal disease (10). Eight of the 13 deaths in the NIH cohort occurred in patients who went into remission of the insulin receptor antibody syndrome. The occurrence of hypoglycemia in type B insulin resistance seems to be associated with a particularly poor prognosis: 3 of the patients who had presented with hyperglycemia and then developed hypoglycemia died of complications of hypoglycemia.

FINAL DIAGNOSIS

  1. Top of page
  2. CASE PRESENTATION
  3. CASE SUMMARY
  4. DIFFERENTIAL DIAGNOSIS
  5. DISCUSSION
  6. FINAL DIAGNOSIS
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

SLE with class III (focal proliferative) lupus nephritis and superimposed collapsing glomerulopathy, and type B insulin resistance due to antibodies against the insulin receptor resulting initially in severe hyperglycemia and subsequently in life-threatening hypoglycemia.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. CASE PRESENTATION
  3. CASE SUMMARY
  4. DIFFERENTIAL DIAGNOSIS
  5. DISCUSSION
  6. FINAL DIAGNOSIS
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Merkel had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Buhaescu, Rhee, McDonnell, Merkel.

Acquisition of data. Buhaescu, Rhee, York, McDonnell, Merkel.

Analysis and interpretation of data. Buhaescu, Rhee, York, McDonnell, Merkel.

REFERENCES

  1. Top of page
  2. CASE PRESENTATION
  3. CASE SUMMARY
  4. DIFFERENTIAL DIAGNOSIS
  5. DISCUSSION
  6. FINAL DIAGNOSIS
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
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