Case Report
Type B Insulin-resistance syndrome: a cause of reversible
Lancet 2014; 384: 1548
Assistance Publique-Hôpitaux
de Paris, Department of
Endocrinology, Nutrition, and
Diabetes (O Bourron PhD,
M Halbron MD, F Andreelli PhD,
A Hartemann PhD), Department
of Internal Medicine (M Hie MD,
G Leroux MD, Z Amoura MD),
and Department of
Biochemistry (M Fonfrede PhD),
Pitié-Salpêtrière Hospital,
Paris, France; Department of
Molecular Biology, Saint-
Antoine Hospital, Paris, France
(C Vigouroux PhD); Sorbonne
Universités, Paris, France
(O Bourron,
M Caron-Debarle PhD, M Hie,
F Andreelli, Z Amoura,
C Vigouroux, A Hartemann);
INSERM UMR_S 938
Saint-Antoine Research Centre,
Paris, France (M Caron-Debarle,
C Vigouroux); INSERM UMR_S
1138 Centre de recherche des
Cordeliers, Paris, France
(O Bourron, A Hartemann); and
Institute of Cardiometabolism
and Nutrition, Paris, France
(O Bourron, M Halbron,
M Caron-Debarle, F Andreelli,
C Vigouroux, A Hartemann)
Correspondence to:
Dr Olivier Bourron, Service de
Diabétologie, Hôpital de la
Pitié-Salpêtrière,
75013 Paris, France
olivier.bourron@psl.aphp.fr
See Online for appendix
A B
Figure: Acanthosis nigricans before and after rituximab therapy
Acanthosis nigricans of the neck (A) and axillary area (B). Regression of acanthosis nigricans was associated with
disappearance of anti-insulin receptor autoantibodies.
1548
autoimmune hypoglycaemia
Olivier Bourron, Martine Caron-Debarle, Miguel Hie, Zahir Amoura, Fabrizio Andreelli, Marine Halbron, Michelle Fonfrede, Gaëlle Leroux,
Corinne Vigouroux, Agnès Hartemann
A 44-year-old man was diagnosed with diabetes in our
department in 2010, and after a short period on insulin, he
was started on metformin. Autoantibodies consistent with
type 1 diabetes were negative. In 2011, the patient developed
hypoglycaemia, both while fasting and after physical
activity, despite stopping metformin. He also developed
widespread acanthosis nigricans (figure) and polyarthralgia,
and had 10 kg weight loss. Despite recurrent hypoglycaemia,
his HbA1c remained high (7·4% of total haemoglobin).
After a 72 h fast, his glucose was 2·3 mmol/L, with
inappropriately high serum insulin (26·3 pmol/L) and
C peptide (0·1 nmol/L) concentrations. Despite fasting
hypoglycaemia, 2 h after a 75 g oral glucose tolerance test
(OGTT) his glucose was 12·6 mmol/L with serum insulin
1659·8 pmol/L and C peptide 2·1 nmol/L.
A pancreatic endoscopic ultrasound, ¹¹¹In-octreotide
scintigraphy, and abdominal CT scan were normal. We
also ruled out self-administration of hypoglycaemic
drugs, adrenal or growth hormone deficiency,
hypothyroidism, and tumours secreting insulin-like
growth factor-1 (IGF-1), IGF-2, or its precursors (big
IGF-2). The patient had polyclonal hypergamma-
globulinaemia, antinuclear and antiribonucleoprotein
antibodies, antiextractable nuclear antigen, neutropenia,
and decreased serum complement concentrations,
suggestive of systemic lupus erythematosus.
Serum anti-insulin receptor antibodies (anti-IRAbs),
which inhibit the binding of insulin to its receptor and
exert insulin-like effects in vitro1 (appendix), led us to the
diagnosis of type B insulin-resistance syndrome associated
with systemic lupus erythematosus. Anti-insulin antibodies
were negative.
In August, 2012, we gave the patient two injections of
rituximab (anti-CD 20 monoclonal antibodies) 15 days
apart, with total disappearance of circulating B lymphocytes
(CD19+). 3 months after treatment, the frequency of
hypoglycaemia decreased and by June, 2013, his HbA1c
was 5·6% and fasting test was normal (lowest glucose
3·8 mmol/L with serum insulin 4·9 pmol/L and
C peptide 0·1 nmol/L). OGTT was normal, he had no
episodes of hypoglycaemia during 5 days of continuous
glucose monitoring, and anti-IRAbs were no longer
detectable. His acanthosis nigricans decreased and he
gained 4 kg of weight.
Type B insulin resistance syndrome, caused by
autoantibodies directed against the insulin receptor, is
frequently associated with autoimmune diseases, most
commonly systemic lupus erythematosus.2 Patients usually
present with weight loss, hyperandrogenism, and widespread
acanthosis nigricans, with insulin resistance, hypera-
diponectinaemia, and hypotriglyceridaemia. Patients rarely
develop initial or secondary hypoglycaemia, sometimes
with unsuppressed insulinaemia, which might be due to
defective degradation of insulin–insulin receptor complexes.2
Hypoglycaemia might be explained by variations in serum
anti-IRAb concentration, with high antibody titres causing
antagonist effects and low titres causing agonist effects.3
Alternatively, populations of both activating and blocking
antibodies might coexist.2 In our patient, systemic lupus
erythematosus associated anti-IRAbs were probably
responsible for both hypoglycaemia and initial diabetes. After
rituximab treatment, depletion of the anti-IRAbs-secreting
B-cell population was associated with resolution of
both hypoglycaemia and diabetes. Rituximab, which is an
efficient immunosuppressive treatment for hyperglycemia,4,5
might also be effective in hypoglycaemia linked to type B
insulin resistance.
Contributors
OB, MH, ZA, FA, and GL cared for the patient. MC-D and CV measured
anti-insulin receptor antibodies. MF measured insulin and C peptide.
OB, CV, and AH wrote the report. Consent to publication was obtained.
References
1 Auclair M, Vigouroux C, Desbois-Mouthon C, et al. Antiinsulin
receptor autoantibodies induce insulin receptors to constitutively
associate with insulin receptor substrate-1 and -2 and cause severe cell
resistance to both insulin and insulin-like growth factor I.
J Clin Endocrinol Metab 1999; 84: 3197–206.
2 Arioglu E, Andewelt A, Diabo C, Bell M, Taylor SI, Gorden P. Clinical
course of the syndrome of autoantibodies to the insulin receptor
(type B insulin resistance): a 28-year perspective. Medicine (Baltimore)
2002; 81: 87–100.
3 Dons RF, Havlik R, Taylor SI, Baird KL, Chernick SS, Gorden P.
Clinical disorders associated with autoantibodies to the insulin
receptor. Simulation by passive transfer of immunoglobulins to rats.
J Clin Invest 1983; 72: 1072–80.
4 Coll AP, Thomas S, Mufti GJ. Rituximab therapy for the type B
syndrome of severe insulin resistance. N Engl J Med 2004; 350: 310–11.
5 Malek R, Chong AY, Lupsa BC, et al. Treatment of type B insulin
resistance: a novel approach to reduce insulin receptor
autoantibodies. J Clin Endocrinol Metab 2010; 95: 3641–47.
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