Antibodies to glutamic acid decarboxylase as predictors of insulin-dependent diabetes mellitus before clinical onset of disease.

DURING the past decade a wealth of information concerning the pathogenesis of Type I diabetes has become available. Two spontaneous animal models of the disease have been discovered and characteriz...

Type I diabetes mellitus. A chronic autoimmune disease.

Background: Multiple laboratory tests are used in the diagnosis and management of patients with diabetes mellitus The quality of the scientific evidence supporting the use of these assays varies substantially

Approach: An expert committee drafted evidence-based recommendations for the use of laboratory analysis in patients with diabetes An external panel of experts reviewed a draft of the guidelines, which were modified in response to the reviewers’ suggestions A revised draft was posted on the Internet and was presented at the AACC Annual Meeting in July, 2000 The recommendations were modified again in response to oral and written comments The guidelines were reviewed by the Professional Practice Committee of the American Diabetes Association

Content: Measurement of plasma glucose remains the sole diagnostic criterion for diabetes Monitoring of glycemic control is performed by the patients, who measure their own plasma or blood glucose with meters, and by laboratory analysis of glycated hemoglobin The potential roles of noninvasive glucose monitoring, genetic testing, autoantibodies, microalbumin, proinsulin, C-peptide, and other analytes are addressed

Summary: The guidelines provide specific recommendations based on published data or derived from expert consensus Several analytes are of minimal clinical value at the present time, and measurement of them is not recommended

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Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus

The 1921 discovery of insulin was a Big Bang from which a vast and expanding universe of research into insulin action and resistance has issued. In the intervening century, some discoveries have ma...

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Mechanisms of Insulin Action and Insulin Resistance

Insulin-dependent diabetes mellitus (IDDM) is a chronic disorder that results from autoimmune destruction of the insulin-producing pancreatic beta cells. Much has been learned during the past decade about the underlying genetics, natural history, and pathogenesis of IDDM. In this review, we shall describe some of this new information and discuss how it might be used to prevent the disease. Epidemiology IDDM occurs most frequently in persons of northern European descent. Among other racial groups, such as blacks, Native Americans, and Asians, the disease is less common1. The incidence ranges from a low of 1 to 2 per 100,000 per . . .

The Pathogenesis of Insulin-Dependent Diabetes Mellitus

A sensitive assay was used to measure the binding of iodine-125-labeled insulin in serum obtained from 112 newly diagnosed insulin-dependent diabetics before insulin treatment was initiated. Two groups of nondiabetics served as controls: children with a variety of diseases other than diabetes and nondiabetic siblings of insulin-dependent diabetics. Eighteen of the diabetics were found to have elevated binding and 36 were above the 95th percentile of control values. The insulin-binding protein is precipitated by antibody to human immunoglobulin G, has a displacement curve that is parallel and over the same concentration range as serum from long-standing insulin-dependent diabetics, and elutes from a Sephacryl S-300 column at the position of gamma globulin. These insulin antibodies are present in a large percentage of newly diagnosed, untreated diabetics and may be an immune marker of B-cell damage.

https://science.sciencemag.org/content/sci/222/4630/1337.full.pdf

Insulin antibodies in insulin-dependent diabetics before insulin treatment

The close anatomical relationships betaeen pancreatic alpha and beta cells makes possible their interaction at a local (paracrine) level. To demonstrate this in vivo, we have compared the acute glucagon response to intravenous arginine in the basal state and after beta cell suppression by infusions of insulin. The plasma glucose concentration was maintained by the glucose clamp technique. In six normal weight nondiabetics, infusion of insulin at 0.2 mU/kg per min (rate 1) raised the mean +/- SEM plasma insulin levels from 10 +/- 3 to 32 +/- 4 mU/liter and at 1 mU/kg per min (rate 2) raised plasma insulin to 84 +/- 8 mU/liter. This resulted in beta cell suppression, as shown by a diminution in the acute insulin response (incremental area under the insulin response curve, 0-10 min): basal = 283 +/- 61, 199 +/- 66 (rate 1) and 143 +/- 48 mU/liter per 10 min (rate 2) and a fall in prestimulus C-peptide from 1.05 +/- 0.17 to 0.66 +/- 0.15 and to 0.44 +/- 0.15 mM/liter (all P less than 0.01). This beta cell suppression was associated with increased glucagon responses to arginine: 573 +/- 75 (basal), 829 +/- 114 (rate 1), and 994 +/- 136 ng/liter per 10 min (rate 2) and increased peak glucagon responses 181 +/- 11 (basal), 214 +/- 16 (rate 1), and 259 +/- 29 ng/liter (rate 2) (all P less than 0.01). In all subjects, there was a proportional change between the rise in he acute glucagon response to arginine and the fall in the prearginine C-peptide level. To demonstrate that augmented glucagon response was due to betw cell suppression, and not to the metabolic effect of infused insulin, similar studies were performed in C-peptide-negative-diabetics. Their acute glucagon response to arginine was inhibited by the insulin infusion: 701 +/- 112 (basal), 427 +/- 33 (rate 1), and 293 +/- 67 ng/liter per 10 min (rate 2) as was their peak glucagon response: 268 +/- 69, 170 +/- 36, and 115 +/- 33 ng/liter (all P less than 0.01). Thus, hyperinsulinemia, within the physiological range achieved by insulin infusion, inhibits beta cell secretion which, via a paracrine mechanism, potentiates glucagon secretion.

https://dm5migu4zj3pb.cloudfront.net/manuscripts/110000/110251/JCI81110251.pdf

In vivo inhibition of glucagon secretion by paracrine beta cell activity in man.

The structure of the canine prepropancreatic polypeptide (preproPP) cDNA was determined. The nucleotide sequence conservation between human and canine preproPP is very high for the signal peptide (82%) and the region coding for the 36 amino acid pancreatic polypeptide (PP) (92%). The overall sequence homology for the C-terminal portion of proPP containing the icosapeptide and a C-terminal extension peptide is only 63% whereas the 3′-untranslated regions of human and canine PP mRNA share 73% homology after alignment for maximal homology. The only sequence conservation in icosapeptide is the region coding for the last 10 amino acids of the icosapeptide. Comparison of PP immunoactivity and PP mRNA concentrations in extracts of the developmentally distinct uncinate process and splenic lobes of the canine pancreas revealed the same ratio of mRNA concentrations (16 ± 6.5) and PP peptide concentrations (18 ± 7.0) in the uncinate process compared to the splenic lobe (n = 6). However, a similar comparison of insul...

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Canine Pancreatic Polypeptide Complementary Deoxyribonucleic Acid Sequence: Pancreatic Polypeptide and Insulin Messenger Ribonucleic Acid Distribution in the Lobes of the Pancreas

High molecular weight forms of ACTH have been detected in extracts of pituitary glands and pituitary tumor cells by Yalow and Berson (1971), Orth et al. (1973), Scott and Lowry (1974) and Eipper and Mains (1975). Fractionation of extracts of mouse pituitary cells (AtT-20/D-16v cell line) by SDS polyacrylamide gel electrophoresis has revealed the presence of four size classes of ACTH with apparent molecular weights of 31 000 (31K), 20–26 000 (20–26K), 12–15 000 (12–15K) and 4500 (4.5K) (Mains and Eipper, 1976). The 31K, 20–26K and 13–14K classes of ACTH are all glycosylated (Eipper et al., 1976; Roberts et al., 1978).

Thomas L. Paquette

Papers

Insulin antibodies in insulin-dependent diabetics before insulin treatment

In vivo inhibition of glucagon secretion by paracrine beta cell activity in man.

Canine Pancreatic Polypeptide Complementary Deoxyribonucleic Acid Sequence: Pancreatic Polypeptide and Insulin Messenger Ribonucleic Acid Distribution in the Lobes of the Pancreas

Biosynthesis and processing of a common precursor to adrenocorticotropin and β- LPH in mouse pituitary cells