The Natural History of Diabetes H. ST. GEORGE TUCKER, JR. Department of Medicine, Medical College of Virginia, Richmond The familial tendency of dia­ ST AGES OF DIABETES diabetic parents. Such children betes has been recognized for cen­ should all be genetically predia­ turies. The genetic studies of Pincus The life history of a diabetic pa­ betic, although all need not develop and White (1933) , Steinberg and tient may be regarded as consisting diabetes. These authors have mar­ Wilder (1952), Post (1962), and of three stages: (I) prediabetes, shalled impressive evidence both of others seem to indicate that dia­ (II) asymptomatic or chemical dia­ beginning vascular disease of the betes is transmitted as a simple betes, and (III) overt or sympto­ diabetic type, and of certain bio­ autosomal recessive trait. If this is matic diabetes. Asymptomatic or chemical abnormalities preceding so, it is obvious that the tendency chemical diabetes is sometimes the development of chemically de­ to diabetes must be established at further divided into diabetes pres­ tectable diabetes. the moment of conception. What ent only with stress, and diabetes Vascular abnormalities found in does this tendency to diabetes con­ present without stress (Table 1). prediabetes include: (a) abnormal sist of, and what determines when In general, the di abetic patient finger pulse waves (Camerini­ the disease we have called "dia­ appears to progress through one Diivalos, 1965a), (b) venular dila­ betes" will appear? What is the stage to the next, although in some tation in the bulbar conjunctiva status of the predisposed individual patients, stage II is either very brief with increased venule : arteriole di­ prior to the onset of overt dia­ or unrecognized, and many dia­ ameter ratio (Camerini-Diivalos et betes? betics may remain asymptomatic al., 1964), (c) thickened basement It has long been known that and never reach stage III. Diabetes membrane of capillaries on gingival large babies are often born to appearing early in life is more biopsy (Camerini-Diivalos, 1965b), mothers later destined to become likely to be severe, and diabetes de­ (d) on ear lobe biopsy (Camerini­ diabetic. This and the observation veloping late in life generally is Diivalos et al., 1964), and (e) in that transient diabetes during preg­ mild and often asymptomatic. Some the glomerular capillaries on renal nancy or other stress is often the factors that can alter the natural biopsy ( Camerini-Diivalos, 1965a). forerunner of later overt diabetes course of diabetes are illustrated in In addition it seems likely that led Jackson (1960), Conn and Figures 1 and 2. some fetal abnormalities in babies Fajans (1961), and others to re­ of prediabetic mothers may result gard this period before the develop­ VASCULAR DISEASE AND from vascular disturbances in the ment of obvious diabetes as an im­ BIOCHEMICAL CHANGES IN placenta. portant one, a period of active PREDIABETIC STATE Chemical changes reported in dynamic changes which culminate prediabetes include the following : in the appearance of clinical dia­ It would appear that the key to (a) Although the glucose tolerance betes. Jackson, and Conn and Fa­ better understanding of the patho­ test of the prediabetic is within nor­ jans have called this period "pre­ physiology of diabetes might be mal limits, the mean blood sugar of diabetes." Others prefer the term, found in the events occurring in the all prediabetics is significantly "diabetes premellitus." prediabetic period. The first prob­ higher than that of non-prediabetic We might define diabetes as a lem lies in knowing how to recog­ controls at 1, 1 V2, 2 and 3 hours genetically determined metabolic nize the prediabetic patient, since, after glucose. (b) In prediabetics disease, the predisposition to which by definition, all tests of carbohy­ the fasting serum free fatty acids is established at conception. It may drate metabolism are normal in this are increased, and their fall after ultimately progress to the stage of state. Camerini-Diivalos ( 1965a and glucose is delayed. ( c) Serum sialic clinical diabetes with insulin insuf­ b), Rees and their colleagues (1964) acid is increased in prediabetes. ficiency and the accompanying .have attacked the problem by study­ ( d) Serum insulin-like-activity manifestations of hyperglycemia, ing a group of children who were (ILA) is increased fasting and after glycosuria, and abnormal metabo­ either the identical twins of dia­ glucose (Camerini-Diivalos, 1965a). lism of protein and fat. betic patients or the children of two ( e) Synalbumin insulin antagonist 2 MCV QUARTERLY 2(1): 2-5, 1966 H. ST. GEORGE TUCKER, JR. of Vallance-Owen is increased (Vallance-Owen and Ashton, 1963). (f) "Bound" insulin of Antoniades TABLE 1 Stages in Life History of a Diabetic is increased (Camerini-Davalos, 1965a). (g) Prediabetics show an From conception to first evidence of increased rise in blood growth hor­ I. Prediabetes impaired insulin reserve. No demon- mone three hours after glucose, fol­ strabl e abnormality in carbohydrate lowing the initial supression of metabolism. growth hormone levels by the glu­ cose (Unger, 1965). Many of these biochemical (a) With stress only: changes are slight and many need Blood sugar (BS) elevated only with confirmation. The significance of stress, such as i.nfection or pregnancy. increases in ILA or in "bound" in­ II. Asymptomatic or Glucose tolerance test (GTT) normal. Chemical Diabetes Cortisone GTT abnormal. sulin is in dispute. Nevertheless it does appear that there are biochem­ (b) Present without stress: ical abnormalities during predia­ Postprandial BS elevated. Fasting betes. Among these observations BS normal or slightly elevated. Little the most significant would seem to or no g lycosuria. GTT abnormal. be the finding of increased amounts of insulin in the blood, even by im­ munoassay when measured 1 hour Ill. Symptomatic or Persistent hyperglycemia and glycosuria. after glucose, not only in predia­ Overt Diabetes Po lyuria, thirst, etc. G TT not necessary. betics, but early in the course of juvenile diabetes, and in most maturity-onset diabetics. The find­ ing of a high insulin level at a time when blood sugar is high challenges our earlier concept of diabetes as a manifestation of simple insulin in­ sufficiency. There must be a reason tory process is able to maintain VASCULAR COMPLICATIONS for the apparent ineffectiveness of normal or nearly normal carbohy­ OF DIABETES insulin. This question is at the heart drate metabolism. If the antagonism of much of the investigation in dia­ to insulin continues, the pancreas The vascular disease of diabetes betes today. Some of the possible may be driven to the point of fail­ is chiefly a microangiopathy, i.e., a causes for insulin ineffectiveness ure. Such islet cell failure may be degenerative change in capillaries, that have been proposed are listed first manifest by inability to release venules, and arterioles throughout in Table 2. insulin promptly in response to a the body that eventually produces rise in blood glucose. The process such pathologic lesions as retinop­ may be at first reversible to some athy, glomerulosclerosis, and possi­ THE PRIMARY METABOLIC extent, but later becomes irreversi­ bly neuropathy. These complica­ DEFECT IN DIABETES ble with more or less complete fail­ tions were formerly thought to ure of insulin secretion. This seems result from years of deranged me­ Whatever mechanism is ulti­ to be the case with many juvenile tabolism. The discovery of incipient mately found to be responsible for diabetics where early remission oc­ microangiopathy in various sites in insulin antagonism, current think­ curs after institution of treatment, prediabetes and in the early stages ing strongly favors the concept that only to be followed in a few months of chemical diabetes casts doubt on the primary event in diabetes is not by total and permanent pancreatic the view that these changes result pancreatic failure, but extrapancre­ failure. In the maturity-onset dia­ solely from the metabolic abnor­ atic antagonism to insulin or inacti­ betic, the antagonism to insulin is mality produced by insulin defi­ vation of insulin of some sort. As less severe; pancreatic failure de­ ciency and supports the view that available active insulin diminishes, velops only late in life and seldom the metabolic disturbance and the some form of feedback mechanism, becomes complete. In many such vascular disease may be independ­ possibly a transitory rise in blood patients the use of sulfonylurea ent facets of the fundamental glucose, causes the pancreas to re­ drugs improves the release of insu­ genetic disease. On the other hand, lease more insulin until a new lin by the ft-cells to a degree ade­ there is a sizeable body of clinical equilibrium is reached. During the quate to maintain carbohydrate opinion that the progression of vas­ stage of prediabetes, this compensa- homeostasis. cular disease is more severe in 3 NATURAL HISTORY OF DIABETES those patients with the greatest OVERT OR metabolic abnormality, although SYMPTOMATIC Knowles ( 1964), reviewing all the DIABETES literature, did not believe the ques­ tion could be answered on the pres­ ent evidence. The appearance of CHEMICAL OR retinitis and glomerulosclerosis in ASYMPTOMATIC DIABETES patients with diabetes resulting from hemochromatosis (Becker and Mil­ ler, 1960) or pancreatitis, and the observation that similar lesions de­ velop in dogs made diabetic by al­ loxan or growth hormone (Blood­ PREDIABETES worth, 1965), bring us back to the role of insulin deficiency and al­ 10 20 30 40 50 60 70 80 tered metabolism in the genesis of the vascular lesion. The fact that AGE the glucose tolerance tests of pre­ diabetics, while normal, show sig­ Fig. 1-The course of diabetes with age is indicated as a line sloping upward as nificantly higher blood sugar levels the disease becomes more severe. Prediabetes is indicated as a clear zone, and after glucose than in non-predia­ diabetes is indicated by stippling, which is heavier toward the top as the disease betics suggests that there may al­ becomes more severe.