The classification of diabetes mellitus and the tests used for its diagnosis were brought into order by the National Diabetes Data Group of the USA and the second World Health Organization Expert Committee on Diabetes Mellitus in 1979 and 1980. Apart from minor modifications by WHO in 1985, little has been changed since that time. There is however considerable new knowledge regarding the aetiology of different forms of diabetes as well as more information on the predictive value of different blood glucose values for the complications of diabetes. A WHO Consultation has therefore taken place in parallel with a report by an American Diabetes Association Expert Committee to re-examine diagnostic criteria and classification. The present document includes the conclusions of the former and is intended for wide distribution and discussion before final proposals are submitted to WHO for approval. The main changes proposed are as follows. The diagnostic fasting plasma (blood) glucose value has been lowered to > or =7.0 mmol l(-1) (6.1 mmol l(-1)). Impaired Glucose Tolerance (IGT) is changed to allow for the new fasting level. A new category of Impaired Fasting Glycaemia (IFG) is proposed to encompass values which are above normal but below the diagnostic cut-off for diabetes (plasma > or =6.1 to or =5.6 to <6.1 mmol l(-1)). Gestational Diabetes Mellitus (GDM) now includes gestational impaired glucose tolerance as well as the previous GDM. The classification defines both process and stage of the disease. The processes include Type 1, autoimmune and non-autoimmune, with beta-cell destruction; Type 2 with varying degrees of insulin resistance and insulin hyposecretion; Gestational Diabetes Mellitus; and Other Types where the cause is known (e.g. MODY, endocrinopathies). It is anticipated that this group will expand as causes of Type 2 become known. Stages range from normoglycaemia to insulin required for survival. It is hoped that the new classification will allow better classification of individuals and lead to fewer therapeutic misjudgements.

Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation.

the growth of knowledge regarding the etiology and pathogenesis of diabetes has led many individuals and groups in the diabetes community to express the need for a revision of the nomenclature, diagnostic criteria, and classification of diabetes. As a consequence, it was deemed essential to develop an appropriate, uniform terminology and a functional, working classification of diabetes that reflects the current knowledge about the disease. (1)

Report of the expert committee on the diagnosis and classification of diabetes mellitus

25. Multiple Imputation for Nonresponse in Surveys. By D. B. Rubin. ISBN 0 471 08705 X. Wiley, Chichester, 1987. 258 pp. £30.25.

Multiple Imputation for Nonresponse in Surveys

New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single-nucleotide polymorphisms (SNPs) in 1464 patients with T2D and 1467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D), we identified and confirmed three loci associated with T2D-in a noncoding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1-and replicated associations near HHEX and in SLC30A8 found by a recent whole-genome association study. We identified and confirmed association of a SNP in an intron of glucokinase regulatory protein (GCKR) with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases.

https://science.sciencemag.org/content/sci/316/5829/1331.full.pdf

Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.

/pdf/discovery-and-refinement-of-loci-associated-with-lipid-17wc78w8iu.pdf

Discovery and refinement of loci associated with lipid levels

Spontaneous hyperinsulinemic hypoglycemia in adults is most frequently caused by sporadic, solitary pancreatic beta-cell tumors, whereas hyperinsulinemic hypoglycemia in childhood is commonly caused by generalized beta-cell dysfunction.1 Mutations in the beta-cell sulfonylurea-receptor (SUR1) gene or inward-rectifying potassium-channel (Kir6.2) gene were found in some patients.2–7 A distinct syndrome of hyperinsulinism with hyperammonemia was recently described,8,9 apparently caused by mutations in the glutamate dehydrogenase gene.10 However, many sporadic and familial cases of hyperinsulinism remain unexplained. Some may be due to somatic mutations in other genes, as suggested by reports of autosomal dominant familial hyperinsulinism that was . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM199801223380404

Familial Hyperinsulinism Caused by an Activating Glucokinase Mutation

Adenosine triphosphate (ATP)-sensitive potassium (K ATP ) channels couple the cellular metabolic state to electrical activity and are a critical link between blood glucose concentration and pancreatic insulin secretion. A mutation in the second nucleotide-binding fold (NBF2) of the sulfonylurea receptor (SUR) of an individual diagnosed with persistent hyperinsulinemic hypoglycemia of infancy generated K ATP channels that could be opened by diazoxide but not in response to metabolic inhibition. The hamster SUR, containing the analogous mutation, had normal ATP sensitivity, but unlike wild-type channels, inhibition by ATP was not antagonized by adenosine diphosphate (ADP). Additional mutations in NBF2 resulted in the same phenotype, whereas an equivalent mutation in NBF1 showed normal sensitivity to MgADP. Thus, by binding to SUR NBF2 and antagonizing ATP inhibition of K ATP channels, intracellular MgADP may regulate insulin secretion.

Adenosine diphosphate as an intracellular regulator of insulin secretion

The relationships among fiber type, glucose transporter (GLUT-4) protein content, and glucose transport activity stimulated maximally with insulin and/or contractile activity were studied by use of the rat epitrochlearis (15% type I-20% type II2a-65% type IIb), soleus (84-16-0%), extensor digitorum longus (EDL, 3-57-40%), and flexor digitorum brevis (FDB, 7-92-1%) muscles. Insulin-stimulated 2-deoxy-D-glucose (2-DG) uptake was greatest in the soleus, followed (in order) by the FDB, EDL, and epitrochlearis. On the other hand, contractile activity induced the greatest increase in 2-DG uptake in the FDB, followed by the EDL, soleus, and epitrochlearis. The effects of insulin and contractile activity on 2-DG uptake were additive in all the muscle preparations, with the relative rates being FDB greater than soleus greater than EDL greater than epitrochlearis. Quantitation of the GLUT-4 protein content with the antiserum R820 showed the following pattern: FDB greater than soleus greater than EDL greater than epitrochlearis. Linear regression analysis showed that whereas a relatively low and nonsignificant correlation existed between GLUT-4 protein content and 2-DG uptake stimulated by insulin alone, significant correlations existed between GLUT-4 protein content and 2-DG uptake stimulated either by contractions alone (r = 0.950) or by insulin and contractions in combination (r = 0.992). These results suggest that the differences in maximally stimulated glucose transport activity among the three fiber types may be related to differences in their content of GLUT-4 protein.

Glucose transporter protein content and glucose transport capacity in rat skeletal muscles

Nature 356, 162-164 (1992) THE following was omitted from the Acknowledgements section of this Letter: \"This work was supported in part by a NIH grant to M.A.P. Y.T. was a recipient of a mentor based fellowship award of the American Diabetes Association.\

/pdf/erratum-close-linkage-of-glucokinase-locus-on-chromosome-7p-2pred98oza.pdf

Erratum: Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus (Nature (1992) 356 (162-164))

Franz Matschinsky, * Yin Liang, * Prabakaran Kesavan, * Liqun Wang, * Philippe Froguel,t Gilberto Velho,t Daniel Cohen,t M. Alan Permutt,I Yukio Tanizawa,1 Thomas L. Jetton,11 Kevin Niswender,11 and Mark A. Magnuson,, *Department of Biochemistry and Biophysics, and the Diabetes Research Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104; tCentre d'Etude du Polymorphisme Humain, 75010 Paris, France; Metabolism Division, Washington University School of Medicine, St. Louis, Missouri 63110; and IlDepartment of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee 37232

/pdf/glucokinase-as-pancreatic-beta-cell-glucose-sensor-and-29cgkg7bsl.pdf

M. A. Permutt

Papers

Familial Hyperinsulinism Caused by an Activating Glucokinase Mutation

Adenosine diphosphate as an intracellular regulator of insulin secretion

Glucose transporter protein content and glucose transport capacity in rat skeletal muscles

Erratum: Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus (Nature (1992) 356 (162-164))

Glucokinase as pancreatic beta cell glucose sensor and diabetes gene.