The concept that idiopathic diabetes mellitus is a genetically heterogeneous group of disorders has been established by twin and HLA studied that have permitted the separation of juvenile-onset and maturity-onset diabetes. The extent of the heterogeneity within the juvenile-onset and maturity-onset types is still in question. On the basis of recent immunologic and metabolic studies we believe that further heterogeneity can be demonstrated within the juvenile-onset diabetic group. We wish to hypothesize that there are at least two distinct forms of juvenile-onset diabetes, one associated with HLA B8 and the other with BW15. The B8 type is characterized by autoimmunity, microangiopathy, and a stronger association with the HLA D locus. The BW15 type is characterized by antibody response to exogenous insulin and a stronger association with the HLA C locus. Greater understanding of the pathogenesis, natural history, and genetics of diabetes mellitus will result as the full extent of genetic heterogeneity is elucidated.

Improvement in the sensitivity and specificity of the C-peptide immunoassay and studies of larger groups of patients have increased our knowledge of the importance of residual beta-cell function and its metabolic consequences in insulin-treated diabetic patients. During the first five to 10 years after the onset of diabetes mellitus residual beta-cell function is demonstrable in the majority of insulin-treated patients irrespective of the severity of the initial symptoms and only partly dependent on the patient's age at diagnosis. Residual beta-cell function facilitates good control. Stable patients have a higher C-peptide concentration in plasma than unstable ones, but unmeasurable C-peptide is not always associated with poor control. More data are needed before the full significance of an even minimal reserve of beta-cell function is elucidated. It also remains to be shown whether the reductive in beta-cell function in diabetic patients has a qualitative as well as quantitative component.

Diabetic ketoacidosis is characterized by an excess secretion of counterregulatory hormones (glucagon, catecholamines, cortisol, and growth hormone). Experimental evidence obtained in both diabetic man and animals suggests that elevation of the plasma concentration of these hormones is necessary to initiate excess hepatic production of ketone bodies. This increase in hepatic ketogenesis in concert with inability of peripheral tissues to completely utilize ketone bodies results in clinical ketoacidosis. This hypothesis would suggest that pharmacologic control of excess counterregulatory hormone secretion would be a rational therapeutic modality to prevent diabetic ketoacidosis.

The chief purposes of this report are (a) to focus attention on various metabolic and pathophysiologic parameters relating prostaglandins (PGs) and thromboxanes to the slow but inexorable progression of vascular and blood cell dysfunction in diabetes mellitus and (b) to suggest areas of investigation that may be of fundamental importance for expanded areas of diabetes research. The prime thrust of these investigations would be to correlate these metabolic and pathophysiologic parameters with the vasculopathy of diabetes mellitus.

Much indirect evidence suggests, but does not prove, that insulin secretion depends on contractile proteins similar to those of skeletal muscle and cilia. Such proteins constitute a molecular basis for the emiocytotic extrusion of insulin granules. It is likely that the secretory machinery is complex, requiring over eight proteins. The available evidence is consistent with a model of saltatory granule movement oriented by microtubules and powered by actomyosin contraction in response to elevations in cytosol calcium. Because most diabetics secrete some insulin and because relatively little of the stored B-cell insulin is released in response to hyperglycemia, further research into the molecular mechanism of insulin granule release is needed.

It is well established that specific binding sites for insulin are present on the plasma membranes of target tissues. In order to explain how insulin regulates a wide variety of biologic functions both on the surface of the cell as well as in its interior, it has been postulated that insulin generates a second messenger at the cell surface. To date, however, no second messenger for insulin has been identified that can carry out all of insulin's known actions. Recent studies have demonstrated that, in addition to the plasma membrane, other subcellular organelles, such as the nucleus, have specific binding sites for insulin. There is also evidence indicating that large serum proteins such as albumin, large protein hormones such as prolactin, and small protein hormones such as insulin can enter intact cells. It is hypothesized, therefore, that insulin has at least two mechanisms of action on target tissues. One mechanism entails the direct binding of insulin to the plasma membrane, which in turn leads to its well-known effects on membrane transport. The other mechanism requires the entry of insulin itself into the interior of the cell and its subsequent direct binding to subcellular organelles. This latter process then serves to mediate many of the known intracellular functions of insulin.