319
stopped because of lack of funds for the drug. During the next 6 glucose control deteriorated despite increasing doses of insulin, and in January, 1990, the patient was admitted to Kimberley Hospital in diabetic ketoacidotic coma (pH 720, PO, was
weeks
11 3kPa, base excess -13, standard bicarbonate 11
mmol/1, blood
glucose 31-6 mmol/1). 24 h after therapy began he had a respiratory arrest and died 6 days after admission. The development of somatostatin analogues for therapeutic use in acromegalyZ is a major advance in the management of a disease that is associated with substantial morbidity and mortality.3.4 Although dopamine agonists reduce GH concentrations in about 75% of patientsS they are generally not as effective as somatostatin analogues. Diabetes mellitus
with increased prevalence in acromegaly, but ketoacidosis is rare.4 Among about 100 patients with acromegaly treated at Groote Schuur Hospital during the past 25 years, this is the second fatal case of ketoacidosis. occurs
days, respectively. The mean blood glucose concentration was 312 rrunol/1 (SE 0-8) in diabetic rats and 7-8 (0-2) mmol/l in non-diabetic rats when killed at the end of the study (150th day of age). These results, indicating that monoclonal antibodies to rat IFN-y reduce the incidence of diabetes in diabetes-prone rats, support a role for IFN-y in the pathogenesis of diabetes in these animals.
Institute of Internal Medicine, Infectious Diseases and Immunopathology, University of Milan,
Milan, Italy; Institute of Microbiology and Virology, University of Turin; and 2nd Department of Medical Pathology and Metabolic Diseases, University of Catania
FERDINANDO NICOLETTI PIER LUIGI MERONI SANTO LANDOLFO MARISA GARIGLIO SANDRA GUZZARDI WILMA BARCELLINI MICHELE LUNETTA LANFRANCO MUGHINI CARLO ZANUSSI
Endocrine
Endocrine Unit,
Department of Medicine, University of Cape Town Medical School and Groote Schuur Hospital, M. J. ABRAHAMSON Cape Town 9725, South Africa 1. Hams AG, Prestele H, Herold K, Boerlin V. Longterm efficacy of sandostatin (SMS 201-995, octreotide) in 178 acromegalic patients: results from the international multicentre acromegaly study group. In: Lamberts SWJ, ed. Sandostatin in the treatment of acromegaly. Berlin: Springer-Verlag, 1988: 117-25. 2. Ginsburg J. Consensus discussion and conclusions. In: Lamberts SWJ, ed. Sandostatin in the treatment of acromegaly. Berlin: Springer-Verlag, 1988: 163-71. 3. Bengtsson BA, Eden S, Ernest I, Oden A, Sjogren B. Epidemiology and longterm survival m acromegaly. Acta Med Scand 1988; 223: 327-35. 4. Nabarro JDN. Acromegaly. Clin Endocrinol 1987; 26: 481-512. 5. Besser GM, Wass JAH, Thorner MO. Bromocryptine in the medical management of acromegaly. Adv Biochem Psychopharmacol 1980; 23: 191-98.
AK, Farquharson MA, Hardman R. Aberrant expression of class II major histocompatibility complex molecules by B-cells and hyperexpression of class I major histocompatibility complex molecules by insulin containing islets in type-1 (insulin-dependent) diabetes mellitus. Diabetologia 1987; 30: 333-43. 2. Flyer DC, Burakoff SJ, Faller V. Retrovirus-induced changes in major histocompatibility complex antigen expression influence susceptibility to lysis by cytotoxic T lymphocytes. J Immunol 1985; 135: 2287-92. 3. Dean BM, Walker R, Bone AJ, Baird JD, Cooke A. Pre-diabetes in the spontaneously diabetic BB/E rat: lymphocyte subpopulations and expression of rat MHC class II molecules in endocrine cells. Diabetologia 1985; 28: 464-66. 4. Bottazzo GF. Beta cell damage in diabetic insulinitis: are we approaching a solution? Diabetologia 1984; 26: 241-49. 5. Pukel C, Baquerizo H, Rabinovitch A. Destruction of rat islet monolayers by cytokines: synergistic interactions of interferon gamma, tumour necrosis factor, lymphotoxin and interleukin 1. Diabetes 1988; 37: 133-36. 6. Campbell IL, Oxbrow L, Harrison LC. Interferon-gamma: pleiotropic effects on a rat pancreatic beta cell line. Moll Cell Endocrinol 1987; 52: 161-67. 1. Foulis
Prevention of diabetes in BB/Wor rats treated with monoclonal antibodies to
interferon-&ggr; SIR,-.Laboratory evidence supports the view that interferon-y (IFN) plays a part in the pathogenesis of insulin-dependent diabetes mellitus (IDDM) in man and in animal models (NOD mice, BB/Wor rats). One possible mechanism by which IFN might contribute to beta cell destruction is by modulating the expression of class 1 and class II MHC antigens on the beta cell surface. Hyperexpression of class I antigens1 may render beta cells sensitive to the action of cytotoxic T lymphocytes,z while the "aberrant" expression of class II molecules on the insulin-producing cell, as in newly diagnosed IDDM and in the acutely diabetic BB/Wor rat,1,3 may induce diabetes by allowing the beta cell to acquire an antigen-presenting function.4 IFN-y may amplify beta cell destruction by activating effectors such as macrophages and natural killer cells and, alone or in combination with interleukin-1, tumour necrosis factor, and lymphotoxin, may affect the growth, function, and viability of the insulin-producing cells and (pro) insulin biosynthesis.6 These observations prompted us to study the effect of monoclonal antibodies to rat IFN-y in diabetes-prone rats. Fifty-four 30-day-old BB/Wor rats were randomised into three groups (A, B, and C). The prevalence of diabetes was estimated by the supplier (Mollegard, Lille Skensved, Denmark) to be 80-85% between the 60th and 120th day of age. The animals were maintained at 23°C with a 12 h light-dark cycle, and food and water ad libitum, and were tested for glycosuria (’Tes Tape’, Lilly) twice a week. They were considered to exhibit overt diabetes after 2 consecutive days of glycosuria followed by hyperglycaemia (glucose-oxidase method on samples from the tail vein). The monoclonal antibody to rat IFN-y was a mouse IgG1 (Holland Biotechnology, Leiden, Netherlands) with a neutralising activity confirmed in our laboratory as being 3900 U/mg. This was administered twice a week intraperitoneally at a concentration of 250 µg in 400 µl of sterile water to 14 rats (group A) from the 30th to the 150th day of age. Group B rats were treated with the same amounts of IgG1 monoclonal mouse anti-rat immunoglobulins. Group C constituted the untreated controls. The frequency of diabetes was 75% (15/20) in group B, 80% (16/20) in group C, and 14% (2/14) in group A (p
stopped because of lack of funds for the drug. During the next 6 glucose control deteriorated despite increasing doses of insulin, and in January, 1990, the patient was admitted to Kimberley Hospital in diabetic ketoacidotic coma (pH 720, PO, was
weeks
11 3kPa, base excess -13, standard bicarbonate 11
mmol/1, blood
glucose 31-6 mmol/1). 24 h after therapy began he had a respiratory arrest and died 6 days after admission. The development of somatostatin analogues for therapeutic use in acromegalyZ is a major advance in the management of a disease that is associated with substantial morbidity and mortality.3.4 Although dopamine agonists reduce GH concentrations in about 75% of patientsS they are generally not as effective as somatostatin analogues. Diabetes mellitus
with increased prevalence in acromegaly, but ketoacidosis is rare.4 Among about 100 patients with acromegaly treated at Groote Schuur Hospital during the past 25 years, this is the second fatal case of ketoacidosis. occurs
days, respectively. The mean blood glucose concentration was 312 rrunol/1 (SE 0-8) in diabetic rats and 7-8 (0-2) mmol/l in non-diabetic rats when killed at the end of the study (150th day of age). These results, indicating that monoclonal antibodies to rat IFN-y reduce the incidence of diabetes in diabetes-prone rats, support a role for IFN-y in the pathogenesis of diabetes in these animals.
Institute of Internal Medicine, Infectious Diseases and Immunopathology, University of Milan,
Milan, Italy; Institute of Microbiology and Virology, University of Turin; and 2nd Department of Medical Pathology and Metabolic Diseases, University of Catania
FERDINANDO NICOLETTI PIER LUIGI MERONI SANTO LANDOLFO MARISA GARIGLIO SANDRA GUZZARDI WILMA BARCELLINI MICHELE LUNETTA LANFRANCO MUGHINI CARLO ZANUSSI
Endocrine
Endocrine Unit,
Department of Medicine, University of Cape Town Medical School and Groote Schuur Hospital, M. J. ABRAHAMSON Cape Town 9725, South Africa 1. Hams AG, Prestele H, Herold K, Boerlin V. Longterm efficacy of sandostatin (SMS 201-995, octreotide) in 178 acromegalic patients: results from the international multicentre acromegaly study group. In: Lamberts SWJ, ed. Sandostatin in the treatment of acromegaly. Berlin: Springer-Verlag, 1988: 117-25. 2. Ginsburg J. Consensus discussion and conclusions. In: Lamberts SWJ, ed. Sandostatin in the treatment of acromegaly. Berlin: Springer-Verlag, 1988: 163-71. 3. Bengtsson BA, Eden S, Ernest I, Oden A, Sjogren B. Epidemiology and longterm survival m acromegaly. Acta Med Scand 1988; 223: 327-35. 4. Nabarro JDN. Acromegaly. Clin Endocrinol 1987; 26: 481-512. 5. Besser GM, Wass JAH, Thorner MO. Bromocryptine in the medical management of acromegaly. Adv Biochem Psychopharmacol 1980; 23: 191-98.
AK, Farquharson MA, Hardman R. Aberrant expression of class II major histocompatibility complex molecules by B-cells and hyperexpression of class I major histocompatibility complex molecules by insulin containing islets in type-1 (insulin-dependent) diabetes mellitus. Diabetologia 1987; 30: 333-43. 2. Flyer DC, Burakoff SJ, Faller V. Retrovirus-induced changes in major histocompatibility complex antigen expression influence susceptibility to lysis by cytotoxic T lymphocytes. J Immunol 1985; 135: 2287-92. 3. Dean BM, Walker R, Bone AJ, Baird JD, Cooke A. Pre-diabetes in the spontaneously diabetic BB/E rat: lymphocyte subpopulations and expression of rat MHC class II molecules in endocrine cells. Diabetologia 1985; 28: 464-66. 4. Bottazzo GF. Beta cell damage in diabetic insulinitis: are we approaching a solution? Diabetologia 1984; 26: 241-49. 5. Pukel C, Baquerizo H, Rabinovitch A. Destruction of rat islet monolayers by cytokines: synergistic interactions of interferon gamma, tumour necrosis factor, lymphotoxin and interleukin 1. Diabetes 1988; 37: 133-36. 6. Campbell IL, Oxbrow L, Harrison LC. Interferon-gamma: pleiotropic effects on a rat pancreatic beta cell line. Moll Cell Endocrinol 1987; 52: 161-67. 1. Foulis
Prevention of diabetes in BB/Wor rats treated with monoclonal antibodies to
interferon-&ggr; SIR,-.Laboratory evidence supports the view that interferon-y (IFN) plays a part in the pathogenesis of insulin-dependent diabetes mellitus (IDDM) in man and in animal models (NOD mice, BB/Wor rats). One possible mechanism by which IFN might contribute to beta cell destruction is by modulating the expression of class 1 and class II MHC antigens on the beta cell surface. Hyperexpression of class I antigens1 may render beta cells sensitive to the action of cytotoxic T lymphocytes,z while the "aberrant" expression of class II molecules on the insulin-producing cell, as in newly diagnosed IDDM and in the acutely diabetic BB/Wor rat,1,3 may induce diabetes by allowing the beta cell to acquire an antigen-presenting function.4 IFN-y may amplify beta cell destruction by activating effectors such as macrophages and natural killer cells and, alone or in combination with interleukin-1, tumour necrosis factor, and lymphotoxin, may affect the growth, function, and viability of the insulin-producing cells and (pro) insulin biosynthesis.6 These observations prompted us to study the effect of monoclonal antibodies to rat IFN-y in diabetes-prone rats. Fifty-four 30-day-old BB/Wor rats were randomised into three groups (A, B, and C). The prevalence of diabetes was estimated by the supplier (Mollegard, Lille Skensved, Denmark) to be 80-85% between the 60th and 120th day of age. The animals were maintained at 23°C with a 12 h light-dark cycle, and food and water ad libitum, and were tested for glycosuria (’Tes Tape’, Lilly) twice a week. They were considered to exhibit overt diabetes after 2 consecutive days of glycosuria followed by hyperglycaemia (glucose-oxidase method on samples from the tail vein). The monoclonal antibody to rat IFN-y was a mouse IgG1 (Holland Biotechnology, Leiden, Netherlands) with a neutralising activity confirmed in our laboratory as being 3900 U/mg. This was administered twice a week intraperitoneally at a concentration of 250 µg in 400 µl of sterile water to 14 rats (group A) from the 30th to the 150th day of age. Group B rats were treated with the same amounts of IgG1 monoclonal mouse anti-rat immunoglobulins. Group C constituted the untreated controls. The frequency of diabetes was 75% (15/20) in group B, 80% (16/20) in group C, and 14% (2/14) in group A (p
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