Nocturnal Blood Glucose Control in Type I Diabetes Mellitus

Nocturnal Blood Glucose Control in Type I Diabetes Mellitus GEREMIA B. BOLLJ, MD GABRIELE PERRIELLO, MD

CARMINE G. FANELLI, MD PlERPAOLO D E FEO, MD

A major problem in replacing insulin in type I diabetes mellitus is that currently no depot preparation exists that is capable of mimicking the background insulin secretion of the healthy pancreas. Because all of the currently available intermediate- or long-acting insulin preparations have a peaked-action profile, excess insulin action at midnight and insulin waning at dawn occur whenever such an insulin preparation is given at supper time. If the target fasting plasma glucose is the ambitious near-normoglycemia of intensive insulin therapy, intermediate-acting insulin at suppertime easily results in hypoglycemia in the early evening hours and hyperglycemia in the fasting state. The problems of overnight glycemia in type I diabetes are further complicated by the dawn phenomenon and the Somogyi phenomenon. The dawn phenomenon is the combination of an initial decrease in insulin requirements between ~2400 and —0300, followed by an increase in the insulin needs between —0500 and —0800. The dawn phenomenon is the result of changes in hepatic (and extrahepatic) insulin sensitivity, which are best attributed to nocturnal growth hormone secretion. The dawn phenomenon is a day-to-day reproducible event that occurs in nearly all diabetic patients. Its contribution to fasting hyperglycemia correlates with diabetes duration (inversely) and the HbA lc percentage (directly). Overall, it is estimated that the specific contribution of the dawn phenomenon to fasting hyperglycemia is —2 mM (—35 mg/dl), but it may be much greater because of the waning of the depot-insulin preparation injected the previous evening. The Somogyi phenomenon, strictly speaking, refers to fasting hyperglycemia that occurs after inducement of nocturnal hypoglycemia by regular insulin. Because the present therapeutic regimens of NPH/Lente insulin given at suppertime cause overnight hyperinsulinemia, excessive fasting hyperglycemia rarely follows nocturnal hypoglycemia, except when excessive glucose is ingested to correct hypoglycemia. However, nocturnal hypoglycemia may easily deteriorate glycemic control later in the day, because it induces prolonged posthypoglycemic insulin resistance, which results in postbreakfast and late-morning hyperglycemia. With nocturnal insulin therapy, it is important to consider the problems of insulin pharmacokinetics, the dawn phenomenon, and the Somogyi phenomenon to prevent both nocturnal hypoglycemia and excessive fasting hyperglycemia. In programs of intensive insulin therapy aiming at a goal of near-normoglycemia in the fasting state, intermediate-acting insulin should be given at bedtime and should not be combined with regular insulin at suppertime. In programs of nonintensive insulin therapy, intermediateacting insulin can be injected with regular insulin at supper, but the fasting plasma glucose goal should be increased to 10-12 mM to prevent nocturnal hypoglycemia. In conclusion, insulin deficiency is the most important cause of fasting hyperglycemia in type I diabetes mellitus. However, insulin excess around midnight, which results from depot-insulin administration at suppertime, is the cause of frequent nocturnal hypoglycemia in type I diabetic patients. Correction of abnormal insulin pharmacokinetics by either splitting the evening insulin administration (intensive insulin therapy) or by increasing the targeted fasting plasma glucose (nonintensive insulin therapy) is the key to preventing nocturnal hypoglycemia and decreasing fasting hyperglycemia, thus improving overnight glycemic control in type I diabetes mellitus. From the Department of Internal Medicine and Endocrine and Metabolism and Sciences, University of Perugia, Perugia, Italy. Address correspondence and reprint requests to Geremia B. Bolli, MD, Dipartimento Medicina Intema e Scienze Endocrine e Metaboliche, Via E. Dal Pozzo, 06126 Perugia, Italy. Type I diabetes, insulin-dependent diabetes mellitus; type II diabetes, non-insulin-dependent diabetes mellitus; CSII, continuous subcutaneous insulin infusion; DCCT, Diabetes Control and Complications Trial; CV, coefficient of variation; ADA, American Diabetes Association; MDI, multiple daily injections of insulin; HPLC, high-performance liquid chromatography.

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octurnal hypoglycemia (conventionally defined as plasma glucose < 3 mM [—55 mg/dl]) is a frequent event in patients with type I diabetes mellitus (1-13). However, because nocturnal hypoglycemia is usually asymptomatic (3,4,6,8,14) and the responses of counterregulatory hormones occur at higher plasma glucose values compared with those required to generate symptoms during a progressive fall in glycemia (15-17), it is likely that the true prevalence of nocturnal hypoglycemia in the everyday life of patients with type 1 diabetes is underestimated. Nocturnal hypoglycemia is a fearful condition for three main reasons. First, during sleep, the autonomic symptoms may not be potent enough to awaken the patient (18). Thus, an initially mild hypoglycemic episode may easily progress into severe hypoglycemia at a time when external assistance may not be available to the patient. Second, excessive correction of hypoglycemia at night by spontaneous counterregulation and/or by food ingestion may cause subsequent hyperglycemia. Third, there is concern that frequent episodes of unrecognized nocturnal hypoglycemia may induce hypoglycemia unawareness, which, in turn, predisposes the patient to severe hypoglycemia at any time during the day (19). Thus, it is important that patients with type I diabetes take measures to prevent nocturnal hypoglycemia. In fact, prevention of nocturnal hypoglycemia should be a goal in both intensive and nonintensive insulin therapy. In this paper, the most recent concepts on nocturnal glucoregulation in normal, nondiabetic subjects, as well as the problems of exogenous insulin replacement in type I diabetic patients are reviewed. Finally, the strategies of a rational therapeutic approach to the control of overnight glycemia in intensive and nonintensive insulin therapy is discussed.

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non, which is commonly observed in patients with type I (27) as well as in those with type II diabetes (28,29). Endogenous insulin secretion decreases in the early part of the night but appears to increase transiently between 0600 and 0800. Because the liver is normally exquisitely sensitive to even modest increases in portal plasma insulin concentration (30), it is likely that the slightly augmented insulin secretion between 0600 and 0800 (the "dawn phenomenon" of normal, nondiabetic subjects) (20,21,23) plays a role in preventing an exaggerated increase in glucose output by the liver (21,25,31) and in maintaining normoglycemia at dawn.

Figure 1—Plasma glucose concentration, rates of glucose production and utilization, plasma insulin and C-peptide concentrations, and calculated rates of endogenous insulin secretion in However, in several studies in normal nondiabetic subjects studied overnight normal, nondiabetic subjects, no eviduring sleep. From Bolli et al. (21). © by the dence has been found for early morning American Diabetes Association. increases in plasma insulin (22,32-39), C-peptide concentration (37-39), and hepatic glucose production in elderly subjects (22,31,40). In general, this sugOVERNIGHT BLOOD GLUCOSE gests that in normal, nondiabetic subHOMEOSTASIS IN NORMAL, NONDIABETIC SUBJECTS— In nor- jects, the dawn phenomenon is not a mal, nondiabetic individuals, plasma glu- universal finding, and, in particular, the cose concentration remains virtually the dawn phenomenon is less likely to occur same during the night and early morning in the elderly as compared with younger hours, despite changes in glucose, pan- subjects (31). However, even in studies creatic insulin, and counterregulatory in which plasma insulin and C-peptide hormone secretion (20-23). As shown have not been found to increase at dawn in Fig. 1, the rate of glucose production (25), lipolysis has been observed to be by the liver decreases in the early part of suppressed in the early evening hours the night, remains stable until 0600, and compared with the dawn hours in norfinally increases slightly until 0900. Be- mal, nondiabetic subjects. This suggests cause the rate of glucose utilization that insulin sensitivity is lower at dawn closely matches that of glucose produc- than during the early evening hours. Or, tion at any time, the cumulative glucose according to Blackard et al. (41), insulin balance remains virtually zero, i.e., sensitivity is greater soon after midnight plasma glucose concentration is remark- and, at dawn, it merely returns to preably stable overnight. The physiological midnight values. Taken together, the reasons for the decrease in the rate of studies demonstrating (20,21,23,31) and hepatic glucose production soon after those denying (35-40) the dawn phe2400 are not clear. Growth hormone nomenon in normal, nondiabetic subspikes secreted in the early part of the jects, indicate that a perfect nocturnal night that have insulin-like effects on he- blood glucose homeostasis is maintained patic glucose production (24) and/or a in the physiological situation as long as reduction in peripheral glucose utiliza- the continuous background secretion of tion by insulin-independent tissues (25) insulin by the pancreas restrains hepatic (most likely the brain during the sleep glucose production and prevents develhours [26]) may explain this phenome- opment of fasting hyperglycemia.

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OVERNIGHT INSULIN REQUIREMENTS IN SUBJECTS WITH TYPE I DIABETES— Over the last 15 years, several studies have shown that the rate of subcutaneous (14,22,42) or intravenous (43-50) insulin infusion necessary to maintain overnight plasma glucose concentration in the normal range (in subjects with type I diabetes increases between 0400 and 0800 compared with the 2400-0400 period. If the greater insulin requirements at dawn are not met, hyperglycemia develops (51). However, in most studies (44,45,47-49), with few exceptions (46,50,52), in which the so-called artificial pancreas (GCIIS, Biostator, Miles Laboratories, Elkhart, IN) was used, the insulin requirements at dawn were considerably overestimated because of a technical artifact of the Biostator (53,54). In fact, the peristaltic pump of the Biostator inactivates most of the insulin infused because, after running for 4 - 5 h, the temperature increases above 39°C, especially at the low rates needed to meet the insulin requirements at night (53,54). Because of such an artifact, the apparent increase in the insulin requirements in the 0600-0900 period, compared with that between 2400 and 0600, has been reported to be as great as 5 0 100%, with peak increases up to 300% (44,45,47-49). When insulin is infused overnight using a syringe pump, which does not inactivate the insulin contained in the solution (53,54), the nocturnal insulin requirements of subjects with type I diabetes (Fig. 2) (55) appear to be qualitatively and quantitatively similar to the estimated rates of endogenous insulin secretion of the normal, nondiabetic subjects of Fig. 1. Thus, when investigated under proper methodological conditions, the insulin requirements of patients with type I diabetes closely mimic the physiological patterns of endogenous insulin secretion of nondiabetic subjects, i.e., they decrease in the early part of the night and subsequently increase at dawn. The magnitude of such an increase (per-

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I.V. FEEDBACK INSULIN INFUSION (HARVARO PUMP)

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Figure 2—Overnight insulin requirements to maintain plasma glucose concentration in the normal range in 114 type 1 diabetic patients who infused insulin with a syringe pump. From Perriello et al. (55). © by Diabetologia.

centage increase in insulin requirements between 0500 and 0700, compared with the period between 0100-0300) is —20%, which is considerably lower than that reported by early Biostator studies (50-100%) (44,45,47-49) and is similar to that of normal, nondiabetic subjects (21). The increase in insulin requirements at dawn in the absence of preceding or concomitant insulin deficiency is defined as the dawn phenomenon. Because insulin requirements increase at dawn, fasting hyperglycemia may develop in patients with type I diabetes if the need for greater insulin bioavailability is not met at this time. In addition, because insulin requirements decrease after midnight, hypoglycemia may develop, especially if there is excessive insulin bioavailability at this time. Unfortunately, the usual evening injection of a depot-insulin preparation results in hyperinsulinemia in the early night hours and hypoinsulinemia at dawn. These nonphysiological pharmacokinetics of insulin favor the occurrence of nocturnal hypoglycemia and early morning hyperglycemia. In turn, nocturnal hypoglycemia either may be prolonged enough to result in fasting hypoglycemia or may contribute to fasting and postbreakfast hyperglycemia, depending on the prevailing plasma insulin


concentrations, state of counterregulation, and/or glucose ingestion to correct the preceding hypoglycemia. The contribution of the dawn phenomenon, that of nocturnal hypoglycemia (Somogyi phenomenon), and insulin deficiency to fasting and postbreakfast hyperglycemia, is discussed separately. THE DAWN PHENOMENON IN TYPE I DIABETES

Definition The term "dawn phenomenon" was introduced by Maria Ines Schmidt in 1981 to indicate the sudden development of hyperglycemia after 0500 in type I diabetes patients whose blood glucose concentrations were reasonably stable until that time of day (56). Since then, it has become common practice to refer to any kind of early morning hyperglycemia observed in insulin-treated diabetic patients in the absence of nocturnal hypoglycemia as the "dawn phenomenon." Such a definition of the dawn phenomenon, however, also includes a usual cause of early morning hyperglycemia in patients with type I diabetes, namely the insulin deficiency resulting from the waning of subcutaneous absorption of the intermediate- or long-acting insulin injected on the previous evening. Strictly speaking, the term "dawn phenomenon" should be limited to indicate specifically the increase in insulin requirements (or development of hyperglycemia if the greater need for insulin is not met) in the absence of declining insulin delivery, as well as in the absence of nocturnal hypoglycemia (57). Such a definition implies that the dawn phenomenon can only be accurately assessed as the cause of fasting hyperglycemia in diabetic subjects in whom insulin deficiency is prevented (for example, by CSII). Because in all insulin-treated diabetic patients, plasma insulin concentrations usually fall overnight after the evening injection of depot insulin (58-60), the contribution of insulin deficiency and that of the dawn phenomenon cannot be separated.


1993

In other words, the contribution of the dawn phenomenon to fasting hyperglycemia cannot be quantified merely on clinical grounds, but requires an experimental assessment.

Pathogenesis Theoretically, the need for more insulin at dawn may be attributable to either an increase in plasma insulin clearance, a decrease in insulin sensitivity, or a combination of both factors. Although some studies have suggested that insulin clearance may increase at dawn in patients with type I diabetes (47,50, 61-63), these results have not been confirmed by other investigators (22,54, 64-66). Thus, the increased insulin requirements at dawn must be solely attributable to a decrease in insulin sensitivity at this time of the day (57). In fact, insulin sensitivity has been found to be greater in the 2400-0200 period, compared with the 0600-0800 period, both at the level of the liver, as well as the peripheral, insulin-dependent tissues in conditions of euglycemia (66). This is not in contrast to the observation of Widmer et al. (65) who found no apparent change in insulin sensitivity between the 0100-0200 and 0700-0800 periods in a group of type I diabetic patients. In fact, the studies of Widmer et al. (65) were performed in hyperglycemic conditions (plasma glucose ~ 7 mM), and it is well known that hyperglycemia can compensate for impaired insulin action by a massaction effect (67). It is interesting to note that the overnight changes in insulin sensitivity are short lived. In the studies of Perriello et al. (66), the difference in insulin action in the interval of 2400-0200, compared with 0600-0800, tended to disappear during the second hour of the clamp experiments. Thus, the overnight changes in insulin action are transient. Theoretically, both overproduction of glucose by the liver and underutilization of glucose by peripheral insulin-sensitive tissues, primarily the muscle (68), may contribute to development of hyperglycemia attributable to the dawn phenomenon. However, in the postab-

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Overnight glycemia

sorptive state the plasma insulin concentrations are usually < 100-150 pM (—15-20 |xU/ml), whereas after the breakfast insulin injection, plasma insulin concentration may increase up to 180-250 pM ( - 2 5 - 3 5 |iU/ml) (14,58, 59,69). According to a dose-response curve model of analysis of insulin action (30,70), the low plasma insulin concentrations of the fasting state suppress only the rate of hepatic glucose production, without stimulating the glucose utilization, whereas the greater postmeal plasma insulin concentration also stimulates glucose uptake by peripheral insulin-sensitive tissues. Thus, the insulin resistance of the dawn phenomenon (55) contributes to fasting hyperglycemia primarily, if not exclusively, by accelerating glucose production from the liver. Underutilization of glucose by the muscle, in addition to overproduction of glucose, also becomes a factor after the breakfast meal, contributing to postprandial hyperglycemia (14). Nonhormonal and hormonal factors might account for the decreased insulin sensitivity at dawn, compared with the early night hours or, as suggested by Blackard et al. (41), for the greater insulin sensitivity after midnight compared with the dawn period. Among the counterregulatory hormones (Fig. 3) (51), plasma glucagon does not change overnight, whereas plasma catecholamines at dawn do not reach a threshold concentration necessary to exert appreciable metabolic effects (71). In addition, pharmacological blockade of a-, (3-adrenergic receptors does not prevent the increase in insulin requirements at dawn (27). With regard to cortisol, the time interval between its increase at —0500 and the subsequent development of insulin resistance at —0600-0700 appears to be too short for this hormone to play a role (72,73). In fact, suppression of cortisol secretion using metyrapone (45) or dexamethasone (47) does not reduce insulin requirements at dawn. At present, consistent evidence indicates that nocturnal surges of growth

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phenomenon may explain several clinical features of this condition. For example, spikes of growth hormone secretion in the early part of the night might well impair hepatic and extrahepatic insulin action at dawn, with a lag phase of 3 - 5 h, which is typical of growth hormoneinduced insulin resistance (24,81,82). In addition, nocturnal growth hormone secretion is exaggerated in diabetic patients under suboptimal glycemic control (83 86) and may contribute to the greater dawn phenomenon observed in these patients compared with patients with better glycemic control (55). On the other hand, bringing growth hormone secretion to normal by optimization of glycemic control may contribute to attenuation of 2400 0200 0400 0600 0600 TIME OF DAY ( H o u r s ) early morning insulin requirements (and hyperglycemia) in patients receiving Figure 3—Plasma counterregulatory hormone long-term intensive insulin therapy (55). INSULIN

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concentrations in patients with type I diabetes studied overnight during physiological sleep. Frequency From Campbell et al. (51). © by Metabolism. Based on studies in which insulin defi-

hormone are implicated in the development of increased hepatic glucose production and hyperglycemia at dawn in type I diabetes mellitus. First, the integrated responses of nocturnal growth hormone secretion correlates with insulin requirements and/or hyperglycemia at dawn in several (51,66,74) but not all studies (35,75). Second, suppression of nocturnal growth hormone secretion by anticholinergic agents (74,76-78) orsomatostatin (27,79,80) has resulted in a virtual disappearance of the dawn phenomenon. The findings of the latter study were obtained under conditions of progressive insulin deficiency overnight, which resulted from use of the Biostator (53,54) and have been confirmed by experiments in which insulin deficiency was avoided with intravenous infusion of insulin using a syringe pump (66). Third, growth hormone-deficient patients with type I diabetes do not exhibit a dawn phenomenon (63). The major role of growth hormone in the pathogenesis of the dawn

ciency in the early morning hours was prevented, and excluding the Biostator studies, it can be estimated that the dawn phenomenon, defined as an increase in plasma glucose and/or insulin requirements at dawn, occurs in 80-100% of patients with type I diabetes (14,22,42, 43,54,55,64,74,75). Therefore, it appears that virtually all type I diabetic patients exhibit a dawn phenomenon. Reproducibility Based on the long-standing clinical observation of the great day-to-day variability of overnight and fasting blood glucose concentration of patients with type I diabetes, as well as nocturnal insulin requirements as assessed by the artificial pancreas (48), it has been concluded that the dawn phenomenon varies significantly from day to day in patients with type I diabetes (48). However, it is likely that the large day-to-day variability in the subcutaneous absorption of the depot-insulin preparations injected in the evening (87), as well as the daily variability in the loss of biologically active insulin infused by the artificial



pancreas (53, 54), make important contributions to the remarkable changes in fasting plasma glucose observed on different days in patients with type I diabetes as well as to the reported day-to-day variability in the insulin requirements at dawn (48). When the variability in overnight delivery of biologically active insulin is prevented by infusing insulin, either by using a syringe pump or by adding human albumin to the insulin infusate (53,54), the overnight insulin requirements and the dawn phenomenon in patients with type I diabetes are very reproducible from day to day, with a CV < 6% (46,55). These results suggest that nocturnal insulin requirements and the dawn phenomenon are remarkably reproducible from day to day in patients with type I diabetes. Thus, the clinical observation of large daily fluctuations of nocturnal and fasting glycemia of patients with type I diabetes should be explained by the daily variability of subcutaneous absorption of the evening depotinsulin preparations, rather than by intrinsic variability in overnight insulin requirements. Contribution to fasting hyperglycemia The extent to which the dawn phenomenon contributes to early morning glycemia remains controversial. By measuring the 2400-0700 increase in plasma glucose concentrations during overnight insulin delivery at a fixed rate, it was found in the initial Biostator studies that the dawn phenomenon accounted for quite a large increase in plasma glucose concentration; i.e., —5-7 mM (—90-125 mg/ dl) (51). However, in studies in which the artifact of waning insulin was prevented by infusing insulin with a syringe pump, plasma glucose concentration increased only—1.5-2 mM (—25-35 mg/ dl) in the period from 2400-0700 (14,22,43,50,54,63,75,88). Thus, it is likely that the specific contribution of the dawn phenomenon to fasting hyperglycemia is quite modest and definitively


smaller than originally proposed (51). However, because in the everyday life of patients with type I diabetes, the dawn phenomenon is invariably associated with some waning of insulin injected subcutaneously the evening before, in clinical conditions, the midnight-dawn increase in plasma glucose concentration largely exceeds that indicated by experimental studies (54,63,75,88).

tolerated to prevent nocturnal hypoglycemia. THE SOMOGYI PHENOMENON

Historical background The frequent development of marked hyperglycemia after an episode of insulininduced hypoglycemia was first recognized in patients with type I diabetes shortly after the introduction of insulin therapy more than 60 years ago (90). In 1938, Somogyi postulated that "hypoglyDawn phenomenon: is it an cemia activates the glycogenolytic mechobstacle to intensive insulin anism which breaks down glycogen in therapy? Although recent studies (63,75,88) indi- the liver and sends it into the blood cate that the magnitude of the dawn phe- stream. By its own momentum, this pronomenon is smaller than originally pro- cess also overshoots and, as a conseposed (51), the dawn phenomenon quence, produces hyperglycemia" (91). continues to represent a limit to the sucSomogyi observed that in some cess of intensive insulin therapy because patients treated with injections of regular overnight insulin requirements of type 1 insulin before each main meal (which diabetic patients are variable, i.e., they was then the only available therapy), glydecrease soon after midnight and in- cosuria, which was absent in the early crease later at dawn. The combination of night hours, became relevant in the early such a pattern of nocturnal insulin re- morning. Although Somogyi could not quirements (Fig. 2) and the pharmaco- measure glucose in blood or (of course) kinetics of the depot-insulin prepara- counterregulatory hormones, he hypothtions given in the evening, which result esized that the excess of the evening dose in a peak plasma insulin bioavailability of insulin in these patients activated soon after midnight, are responsible for counterregulation in response to unrecthe high frequency of hypoglycemia re- ognized nocturnal hypoglycemia, which, ported in type I diabetic patients soon in turn, would result in rebound hyperafter midnight. Thus, the evening insulin glycemia. This hypothesis was supported dose should be titrated on the basis of by his observation that a decrease in the the 0200 blood glucose to prevent noc- evening insulin dose resulted in a reducturnal hypoglycemia. With such a strat- tion of glycosuria in the early morning in egy, it is understandable that blood glu- 5 type I diabetes patients (92). cose will increase after 0200 because Interestingly, although Somogyi's insulin requirements increase at dawn, a theory was not experimentally tested or time at which the depot insulin given the critically discussed for more than 40 evening before begins to wane. Any at- years, the concept that "hypoglycemia tempt of intensive insulin therapy to de- begets hyperglycemia" quickly gained crease fasting plasma glucose in the wide popularity among physicians in the morning by merely increasing the basal late 1950s. Even today, despite the fact rate of CSI1 or the dose of evening depot- that numerous experimental and clinical insulin results in an unacceptably high studies have finally clarified the mechafrequency of nocturnal hypoglycemia nisms and defined the clinical relevance (8,10,89). Thus, unless insulin is given at of the Somogyi phenomenon, the classic variable rates overnight (22), because of textbook Harrison's Principles of Internal the dawn phenomenon, some degree of Medicine describes this phenomenon and modest fasting hyperglycemia must be simply ignores the insulin pharmacoki-


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Overnight glycemia

netics (93). Interestingly, as originally proposed by Somogyi (91), reduction of the evening insulin dose to decrease fasting hyperglycemia is still recommended (93). Studies showing that decreases in insulin doses reduced both hypoglycemic episodes and hyperglycemic excursions in patients with type I diabetes (92,94,95); that posthypoglycemic hyperglycemia in such patients was produced by increases in circulating counterregulatory hormones (58,96-99); that posthypoglycemic glucose intolerance did not occur in nondiabetic individuals with hypopituitarism (100,101); and that posthypoglycemic hyperglycemia could be attenuated by p adrenergic blockade (99) seemed to support the Somogyi concept of posthypoglycemic hyperglycemia as a phenomenon secondary to excessive counterregulation. In 1980, however, Gale et al. (58) demonstrated that fasting hyperglycemia after nocturnal hypoglycemia in type I diabetes is usually associated with an important waning of the insulin effect initially responsible for the onset of hypoglycemia. After these authors proposed that a waning of insulin, rather than hormonal counterregulation, was the primary mechanism of posthypoglycemic hyperglycemia (58), a long-standing controversy began on the actual existence, mechanisms, and clinical implications of the Somogyi phenomenon (102-104).

Mechanisms of posthypoglycemic glucose intolerance Acute, insulin-induced hypoglycemia is followed by glucose intolerance for several hours (95,100,101,105-110). In normal, nondiabetic subjects, this is the result of both impaired insulin secretion (95,100,101,105-110)—most likely attributable to stimulation of a-adrenergic receptors of pancreatic (3-cells by catecholamines (111,112)—as well as insulin resistance following hypoglycemia (95,100,101,105-110). The primacy of the latter as compared with the former

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mechanism is indicated by the fact that posthypoglycemic glucose intolerance occurs in patients with type I diabetes in the absence of endogenous insulin secretion (99,110,113). Posthypoglycemic insulin resistance is induced by the same counterregulatory factors that normally prevent severe hypoglycemia during continuous hyperinsulinemia (114). As reviewed elsewhere (115), these factors include suppression of endogenous insulin secretion, which limits portal hyperinsulinemia (114) and secretion of the counterregulatory hormones, glucagon (116), catecholamines (112), growth hormone (117), and cortisol (118). Notably, the counterregulatory effects of catecholamines and, most likely, those of growth hormone and cortisol, are partly directed and partly mediated by enhanced release of free fatty acids and glycerol from adipose tissue (119,120). The posthypoglycemic insulin resistance is typically prolonged over at least 7-12 h (14,109,110,113,121); it is located both in the liver and peripheral insulin-sensitive tissues, primarily the muscle, with a resultant excess rate of glucose production and suppression of glucose utilization (14,108,110) for the prevailing plasma glucose and insulin concentrations (67). In theory, all the counterregulatory hormones (glucagon, catecholamines, growth hormone, and cortisol) may contribute to the pathogenesis of posthypoglycemic insulin resistance. In normal, nondiabetic subjects, it is likely that the response of glucagon to hypoglycemia plays an important role in the early phase of posthypoglycemic insulin resistance at the level of the liver. In fact, it has been shown that in response to insulin hypoglycemia, glucagon, which does not affect glucose utilization (116), sustains hepatic glucose production long-term (116), most likely because its effects on gluconeogenesis are prolonged not evanescent (122). Thus, glucagon has the potential characteristics for inducing protracted hepatic insulin resistance. However, patients with type I diabetes often lack appropriate responses

of glucagon to insulin-induced hypoglycemia (123), especially a few years after the onset of diabetes (124). In these patients, catecholamines, the rapid-acting counterregulatory hormones (115), in an early phase, 2 - 4 h (109,113), and growth hormone and cortisol, the slowacting counterregulatory hormones (115) in a late phase, 5-12 h (100, 101,110,125,126), account for the posthypoglycemic insulin resistance. Therefore, there is no doubt that in any subject undergoing insulin hypoglycemia, diabetic or not, hypoglycemia begets glucose intolerance, primarily by inducing a prolonged state of insulin resistance.

From posthypoglycemic glucose intolerance to clinically overt posthypoglycemic hyperglycemia Posthypoglycemic insulin resistance is a finding common to nondiabetic (107, 110) and diabetic (108) subjects. In contrast, posthypoglycemic hyperglycemia does not occur in nondiabetic subjects (111) nor in subjects with type II diabetes (127) because in all these subjects, increased endogenous insulin secretion (in response to plasma glucose recovery from hypoglycemia) compensates for the posthypoglycemic insulin resistance. Posthypoglycemic hyperglycemia may occur, however, in patients with type I diabetes who have totally lost endogenous insulin secretion, depending on the balance between the response of counterregulatory hormones and prevailing plasma insulin concentrations (Fig. 4) (128). In fact, when hypoglycemia is induced in diabetic patients by a subcutaneous insulin injection, posthypoglycemic hyperglycemia is observed only in the patients with plasma insulin concentrations that fall below baseline values (group B, Fig. 4). On the contrary, patients with plasma insulin concentrations that remain above baseline for 12 h (group A, Fig. 4) have prolonged hypoglycemia and posthypoglycemic hyperglycemia does not occur. These results reinforce the concept that plasma insulin concentrations during hypoglycemia are

DIABETES CARE, VOLUME 16, SUPPLEMENT 3, DECEMBER

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critical not only to postnadir plasma glucose recovery (114), but also to the development of posthypoglycemic hyperglycemia as reported previously (128). However, the fact that excesses or deficiency of insulin prevent or allow the occurrence of posthypoglycemic hyperglycemia, respectively, does not necessarily contradict Somogyi's hypothesis that activation of counterregulation plays a role in the development of posthypoglycemic hyperglycemia. 2 4 6 8 10 12 In fact, compared with a control HOURS experiment (in which glucose infusion prevents hypoglycemia after a subcutaFigure 4—Glucose counterregulation to hypo- neous insulin injection), when hypoglygfycemia induced by a subcutaneous injection of cemia is allowed to occur, the counterinsulin is followed by hyperglycemic rebound inregulatory hormones not only restore type I diabetic patients who become insulin defi-euglycemia but cause greater hyperglycecient (group B) but not in those who remain mia than that of the control experiment hyperinsulinemic (group A) 6-7 h after insulinas a result of insulin deficiency (Fig. 5).

Thus, hypoglycemic activation of counterregulation exaggerates the hyperglycemia attributable to a mere waning of insulin (121). In addition, activation of counterregulation causes hyperglycemia, even when insulin waning is prevented (121). As shown in Fig. 6 (compared with a control experiment where hypoglycemia is prevented by glucose infusion after a subcutaneous insulin injection and later insulin deficiency is prevented by insulin infusion), when hypoglycemia is allowed to occur, the activation of counterregulation leads to hyperglycemia despite portal plasma insulin levels identical to those of the control study (14). Thus, for a given plasma insulin concentration, hypoglycemia may generate subsequent hyperglycemia. This corresponds to the principle that Somogyi postulated in 1938.

administration. From Bolli et al. (128). © by the

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Figure 6—Activation of hypogfycemic hormonal counterregulation by a subcutaneous insulin injection in subjects with type 1 diabetes results in hypergfycemic rebound, even when the late insulin deficiency of the experiments of Fig. 5 is prevented by an intravenous insulin infusion between 6 and 12 h after the subcutaneous insulin injection. From Bolli et al. (121). © by the New England Journal of Medicine.

Diurnal blood glucose control after nocturnal hypoglycemia in type I diabetes If Somogyi's hypotheses were true not only in the above strictly controlled experimental conditions (121), but also in the everyday life of insulin-treated diabetic subjects, and if asymptomatic nocturnal hypoglycemia occurred as often as indicated (1-13), then the Somogyi phenomenon could represent a frequent cause of morning hyperglycemia and could be why diabetic patients on intensive insulin therapy fail to maintain nearnormoglycemia. This, however, is not the case. In fact, several studies (6,811,13,129) that have monitored plasma glucose concentrations overnight have indicated that as a rule, nocturnal hypoglycemia is usually followed by low fasting blood glucose, whereas elevated fast-

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ing blood glucose after nocturnal hypoglycemia is instead the exception. Apparent experimental support for this view derives from clinical studies in which induction of hypoglycemia, either in late (130) or early evening (131), fails to result in exaggerated fasting or postprandial hyperglycemia. However, in these studies (130,131), in addition to their usual therapeutic evening insulin doses, the patients were infused with — 16 U of regular insulin over a 4-h period to induce nocturnal hypoglycemia. Thus, it is no surprise that in those studies (130,131) in which pharmacological, not therapeutic, doses of insulin were infused, nocturnal hypoglycemia was not followed by hyperglycemia, as previously reported (128). In addition, it should be noted that in all these clinical (6,8-11,13,129) and experimental stud-

ies (130,131), the patients received the usual therapeutic regimen, which consisted of an injection of depot insulin in the evening. These studies ( 6 , 8 11,13,129-131) really suggest that insulin resistance after nocturnal hypoglycemia is not potent enough to result in fasting hyperglycemia in the usual clinical condition in which a depot insulin preparation is injected on the evening for the overnight control. If hypoglycemia occurs in the early part of the night, posthypoglycemic insulin resistance may result in morning hyperglycemia if the diabetic patients are treated with therapeutic regimens that result in low insulin depots, such as CSII or multiple daily injections of regular insulin (87). This concept is illustrated in Fig. 7 (14). Interestingly, the posthypoglycemic hyperglycemia that occurs



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Critique of the Somogyi phenomenon Why is it that insulin resistance after nocturnal hypoglycemia does not result in morning hyperglycemia in the clinical condition of therapeutic administration of a depot insulin preparation on the evening? In other words, why is Somogyi's hypothesis demonstrable in strictly controlled experimental studies (14, 121,132) but not in the clinical situation Figure 7—Fasting and posibreakfast plasma of the everyday life of diabetic patients glucose concentration in patients with type I di- (6,8-11,13,129)? abetes treated with continuous subcutaneous inThe answer is an easy one. Prosulin infusion (monitoring only) and after induc-longed overnight therapeutic hyperintion or prevention of nocturnal hypoglycemia. sulinemia, which initiates nocturnal Perriello et al. (14). © by the New England hypoglycemia, prevents rebound hyperJournal of Medicine. glycemia in the morning, as shown in Fig. 4 (group A) (128) and as initially described by Gale et al. (58). In fact, to achieve a reasonably good fasting plasma under such conditions is only marginal glucose concentration in the morning, in the fasting state (plasma glucose con- the current therapeutic regimens (based centration at 0730 h ~ 1 mM, —18 mg/ on an evening injection of a depotdl, above that of the control night) but insulin preparation) overinsulinize the becomes important after breakfast, with diabetic patients overnight. Thus, the an increment of ~ 4 mM (—70 mg/dl) greater hepatic insulin resistance after (14). Similar findings have been reported hypoglycemia is easily blunted by the by Fowelin et al. (132) in an experimen- therapeutic hyperinsulinemia, which tal design in which diabetic patients were characterizes peripheral insulin delivery managed with multiple daily doses of in type I diabetes mellitus (69). Because regular insulin. After hypoglycemia was in the postabsorptive state insulin govinduced in the early morning, these au- erns plasma glucose concentration by thors observed no posthypoglycemic hy- merely restraining the rate of hepatic gluperglycemia in the fasting preprandial cose production without virtually instate but found prolonged hyperglycemia creasing the rate of utilization of glucose occurred after lunch (132). Taken to- by peripheral insulin-sensitive tissues gether, the studies of Perriello et al. (14) (muscle) (133), and because hepatic gluand Fowelin et al. (132) indicate that cose production by insulin is so easily suppressed by a few jiU/ml increments posthypoglycemic insulin resistance may in plasma insulin concentrations (30,70), result in prolonged glucose intolerance it is clear that posthypoglycemic hyperup to 10 h after hypoglycemia and that glycemia does not occur in the fasting meal ingestion within this time frame state if hyperinsulinemia coexists. Howcauses exaggerated hyperglycemia de- ever, therapeutic hyperinsulinemia of spite continued therapeutic insulin ad- type I diabetes mellitus is not great ministration. Note that these observa- enough to overcome the posthypoglycetions (14,132) were made in diabetic mic insulin resistance located in the patients treated with insulin regimens muscle. Thus, whenever glucose utilizathat result in low subcutaneous insulin tion by muscle comes into play in gludepot, such as CSI1 or multiple daily cose homeostasis, such as in the postinsulin injections (87). prandial period (134,135), subnormal ••• M O N I T O R I N G ONLY o-o INSULIN.HYPOGLYCEMIA PREVENTED • - • INSULIN.HY

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glucose uptake by the muscle (because of posthypoglycemic insulin resistance) causes hyperglycemia. This is the mechanism of posthypoglycemic abnormal glucose homeostasis in the studies of Perriello et al. (14) and Fowelin et al. (132), in which posthypoglycemic hyperglycemia did not occur in the postabsorptive state, but did after a meal. In view of these considerations, the clinical observation (6,8-11,13,129) that nocturnal hypoglycemia usually associates with low not high fasting plasma glucose concentrations is not surprising. This does not contradict the Somogyi theory. In fact, at the time of Somogyi, diabetic patients were treated with regular insulin at each meal. Clearly, at that time, the evening injection of regular insulin easily resulted in a progressive insulin deficiency overnight. Posthypoglycemic hyperglycemia occurs under this condition (Fig. 4, group B). With the advent of the era of NPH and Lente insulins in the 1950s, diabetic patients were switched from the previous condition of nocturnal underinsulination to the present one of overinsulination. Hence the rarity of rebound hyperglycemia in the modern era of insulin therapy. The lesson of the controversies of the Somogyi phenomenon What remains today of the Somogyi's hypothesis? First, Somogyi's original demonstration (105) that hypoglycemia produces insulin resistance has subsequently been confirmed by several investigators (14,95,100,101,106-110,132). It is now well established that nocturnal hypoglycemia results in rebound hyperglycemia in only a minority of circumstances (6,8-11,13,129), whereas the most common finding is that nocturnal hypoglycemia associates with low morning fasting plasma glucose as a result of overnight overinsulination by depotinsulin preparations. In clinical practice, this is the most common event because diabetic patients are usually given NPH insulin in the evening or at night to meet the nocturnal insulin requirements.

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However, when the subcutaneous insulin depot is low, such as in the therapeutic model of CSII or multiple daily injections (87), nocturnal hypoglycemia results in morning hyperglycemia (14,132). This occurs primarily after meals but not in the fasting state (14,132) because therapeutic hyperinsulinemia can largely compensate for hepatic but not muscular posthypoglycemic insulin resistance (14). It is likely that such a posthypoglycemic hyperglycemia would be even greater than reported (14,132) if the diabetic patients ingested excessive amounts of glucose during the hypoglycemic reaction, as often occurs in practice (136). Thus, it is now clear that with the rational regimens of intensive insulin therapy (137), posthypoglycemic insulin resistance may result in rebound hyperglycemia. This is primarily because these regimens are based on use of regular rather than depot-insulin preparations (138), resulting in a consistent reduction in the size of the subcutaneous insulin depot (87). A tentative speculation is that as regimens of intensive insulin therapy become more popular among type I diabetic patients, posthypoglycemic hyperglycemia will occur more frequently. In this regard, it is likely that future use of the "superfast" insulin analogues (139), the so-called monomeric insulins, will result in more frequent bouts of rebound hyperglycemia after hypoglycemia than is found with the current human insulin. This is because the subcutaneous insulin depot is much smaller with the superfast analogues than with the human insulin formulations, unless appropriate amounts of depot insulin are injected at the same time. Second, one should keep in mind that after any hypoglycemic episode there is a period of insulin resistance that lasts for several hours (14,109,110,113, 121). The fact that posthypoglycemic hyperglycemia does not occur in most clinical studies (6,8-11,13,129) should be interpreted as therapeutic hyperinsulinemia prevented hyperglycemia. If these

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episodes tend to recur often over time, one may wonder about the risks of longterm insulin resistance and chronic hyperinsulinemia (140,141). 5.0 r Third, the real message that Somogyi leaves us with is the importance of preventing hypoglycemia, especially at night. This should not be accomplished by simply reducing the dose of an evening insulin mixture, which consists of large doses of depot insulin. Instead, insulin should be administered accord- Figure 8—Action profile of Lente insulin ining to a physiological model, such as jected subcutaneousty in patients with type I injection of regular insulin at each meal diabetes, as assessed by the euglycemic clamp and intermediate-acting insulin at bed- technique (Perriello et at, unpublished observatime (138). There is no doubt that a tions). careful prevention strategy of hypoglycemia smooths the problems of blood glucose control and improves the quality of insulin sensitivity of diabetic patients is life of diabetic patients (18). increased. A few hours later, hyperglycemia develops because insulin bioavailability wanes at a time when insulin rePHARMACOKINETICS OF quirements increase because of the dawn INSULIN, NOCTURNAL phenomenon (Fig. 9) (142). Any attempt HYPOGLYCEMIA, AND FASTING HYPERGLYCEMIA— A major prob- to counteract fasting hyperglycemia by lem exists in the replacement of insulin simply increasing the evening dose of in patients with type I diabetes who have intermediate-acting insulin is likely to lost nearly all of their pancreatic p-cell result in greater hypoglycemia between mass, a satisfactory depot-insulin prepa- 2400 and 0300. In addition, the great ration capable of mimicking the constant day-to-day variability of subcutaneous background secretion of insulin by the absorption of both NPH and Lente-class pancreas of normal, nondiabetic subjects insulin preparations (87) contributes to (Fig. 1) is not available. The currently the day-to-day variability of nocturnal available intermediate- or long-acting in- blood glucose control and unpredictable sulin preparations, both NPH and Lente- risk for hypoglycemia. This makes it difclass insulins, all have a peaked action ficult to achieve safe and reproducible profile, with excessively high blood in- nocturnal blood glucose targets in diasulin levels 3 - 5 h after injection fol- betic patients. Clearly, then, even after lowed by rapidly worsening insulin defi- several decades of the era of NPH/Lente c i e n c y after 6 - 8 h (Fig. 8 ) . insulins, we still lack a depot-insulin Understandably, this time course poses preparation with a "square-wave" action particular difficulties during the night profile and reasonably good day-to-day and contributes in an important way to reproducibility of subcutaneous absorpthe high frequency of nocturnal hypogly- tion. cemia and fasting hyperglycemia of insuIn contrast to the problems of the lin-treated diabetic patients. For exam- depot-insulin preparations, the techple, any time a depot-insulin preparation nique of CSII offers the advantage of a is given before supper there is a risk of square-wave action profile and good rehypoglycemia in the early evening hours producibility of absorption because of because the peak insulin bioavailability the low subcutaneous insulin depot occurs 4 - 5 h after the injection (Fig. 8); (87). In fact, CSII results in a remarkably i.e., between 2400 and —0300, when the smooth blood glucose regulation overLENTE MC(NOVO) + VARIABLE OLUCOSE INFUSION

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phenomenon, must play the major role in the pathogenesis of excessive fasting hyperglycemia in patients with type 1 diabetes. With regard to the Somogyi phenomenon, with the present therapeutic 1800 2400 0500 regimens of injection of depot-insulin 0800 preparations in the evening resulting in Insulin resistance overnight hyperinsulinemia, should hy£ max-i Figure 10—Plasma glucose concentration poglycemia occur at night, fasting hyper• Somogyi 'Dawn overnight in normal, nondiabetic control subjects glycemia rarely develops, unless there is phenomenon' patients with type I diabetes treated with contin- an excessive glucose ingestion at the time uous subcutaneous insulin infusion at fixed rate of the hypoglycemic reaction. However, or stepped-up rate from 0300 to 0800. From nocturnal hypoglycemia may contribute 1800 2400 • 0500 0800 Koivisto et al. (22). © by the American Diabetes to important postbreakfast and lateAssociation. morning hyperglycemia. Action profile of depot insulin In conclusion, fasting hyperglycemia in type I diabetes is attributable to Injection trol in diabetes do not derive from in- the combination of waning of the depottrinsic brittleness of the diabetic patients, insulin preparations injected the evening but rather from the present inadequacy before and increased insulin require1800 2400 0800 0500 and/or irrational use of depot-insulin ments at dawn, the former mechanism preparations to meet the physiological being more important than the latter. Blood glucose concentrations E lO.On nocturnal insulin requirements. Thus, the key approach for reducing fastE ing hyperglycemia in type I diabetes is not to treat the dawn phenomenon, but PATHOGENESIS OF FASTING rather to deliver insulin overnight acHYPERGLYCEMIA IN TYPE I o> 3.0 TJ cording to models that mimic the physDIABETES — Theoretically, fasting hyO O m iological overnight insulin requirements perglycemia in type I diabetes has three 0800 1800 2400 0500 as closely as possible. different causes: insulin deficiency, the Clock time (h) dawn phenomenon, and the Somogyi Figure 9—Interaction offactors causing fast- phenomenon. RATIONAL APPROACH TO ing hyperglycemia in insulin-treated patients Except for a few diabetic patients NOCTURNAL INSULIN THERAPY with type I diabetes. Exaggerated growth- who are treated with CS1I, which main- IN TYPE I DIABETES— The above hormone spikes early in the night increase insulintains steady-state plasma insulin levels considerations on the nocturnal insulin resistance between 0500 and 0800. This dawn (22), the vast majority of patients are requirements in type I diabetes and the phenomenon is exaggerated by the waning of injected with intermediate-acting insulin pharmacokinetics of insulin should serve insulin levels from depot insulin given early thein the evening and become progressively as a basis for a rational approach to nocprevious evening and possibly by hypoglycemiainsulin deficient after 0200-0300 h. turnal insulin therapy. In general, the in the early night, which increases insulin resis-This occurs because the biological activstrategy of insulin administration at night tance further through counterregulatory hority of depot-insulin preparations de- may be part of a program of intensive or mone release (the Somogyi effect). This last creases rapidly 6 to 8 h after the subcu- nonintensive insulin therapy. However, mechanism is more potent in inducing postbreaktaneous injection (Fig. 8). Thus, insulin regardless of whether it is intensive or fast rather than fasting hyperglycemia. From deficiency is the rule in the early mom- nonintensive, insulin therapy at night Bolli et al. (142). © by Blackwell. ing hours in insulin-treated patients with should always be rational. "Rational" type I diabetes. means that insulin should be delivered As stated earlier, the dawn phe- according to a precise therapeutic model, night, despite the increase in blood glu- nomenon contributes to fasting hyper- which aims at defined nocturnal and cose in the early morning hours resulting glycemia by, at most, ~ 2 mM (—35 mg/ fasting blood glucose targets. Both intenfrom the dawn phenomenon (Fig. 10) dl) ( 1 4 , 2 2 , 4 3 , 5 0 , 5 4 , 6 3 , 7 5 , 8 8 ) . sive and nonintensive insulin therapy (22). This supports the concept that Therefore, in the conditions of daily life, share the common goal of prevention of most of the problems of overnight con- insulin deficiency, and not the dawn nocturnal hypoglycemia. In intensive inmmol/l T

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Table 1—Plasma glucose targets of intensive insulin therapy in type I diabetes

(-125-145 mg/dl). Until such a bedtime glucose target is achieved, it is unIdeal Realistic wise to increase the basal rate of CSII overnight because of the risk of hypoglyPlasma glucose (fasting and 5-6 mM 7-8 mM before meals) (-90-110 mg/dl) (-125-145 mg/dl) cemia soon after midnight. Understandably, with such an approach, no snack HbAlc (%)* 5-6 6-7 should be given at bedtime. Note that •Determined by HPLC; the range for nondiabetic subjects is 3.8-5.5%. CSII at night can be easily combined with multiple-daily injections of regular sulin therapy, a secondary goal is the approach to intensive insulin therapy be- insulin throughout the day (145). This is long-term maintenance of near-normo- cause it relies exclusively on delivery of probably a good therapeutic comproglycemia using physiological models of regular insulin, which possesses more mise; it combines the advantages of inphysiological pharmacokinetics com- sulin pharmacokinetics of CSII at night insulin delivery (137). pared with depot-insulin preparations with the convenience of MDI during the (87), i.e., lower day-to-day variability of day. Intensive insulin therapy Unfortunately, the current popuThe ideal candidate for intensive therapy subcutaneous absorption. CSII is the is a young patient with new- or recent- only approach that results in a square- larity of CSII is rather low among type I onset type I diabetes. The hypothesis be- wave insulin profile at night (22), thus diabetic patients, primarily because the hind a program of intensive insulin ther- avoiding the peak insulin effect between MDI regimen results in mean glycemic apy (137) is that long-term maintenance 2400 and 0200 and the insulin waning at control and %HbAlc values as good as of mean blood glucose below the hyper- dawn observed after injection with de- those obtained with CSII (143). Howglycemic threshold resulting in long- pot-insulin (Fig. 8). As a result, plasma ever, there is no doubt that glycemic term vascular complications will prevent glucose concentration is remarkably sta- control at night is more difficult with or postpone the appearance of the late ble overnight (Fig. 9). CSII may be used MDI than with CSII because MDI relies micro- and/or macroangiopathy (prima- at a variable rate overnight, i.e., a lower on depot insulins, whereas CSII uses ry prevention hypothesis) or delay pro- rate may be given between 1100 and only regular insulin. To limit the probgression of initial complications (second- 0300 and a higher rate between 0300- lems of nocturnal hypo/hyperglycemia ary intervention hypothesis). The DCCT 0700 (22). However, this sophisticated related to the use of depot-insulin prep(143) has proven both these hypotheses. approach is seldom required. Usually, arations, the following considerations The glycemic targets of intensive CSII is maintained at a fixed rate, which should be taken into account. First, the therapeutic model of insulin therapy are given in Table 1. The allows easy prevention of hypoglycemia reason for considering the realistic in- in the early evening hours and avoids Fig. 11 should be considered where the stead of the ideal blood glucose targets is excessive hyperglycemia in the fasting patient is given a presupper injection of that strict, long-term normoglycemia state. However, to safely use CSII at a regular insulin and a bedtime injection of cannot be realized without a possible risk fixed rate, it is important to keep in mind depot insulin (NPH/Lente). As with CSII, of severe hypoglycemia (143) because of that the rate of insulin infusion should be it is important to achieve a bedtime the present limitations of insulin therapy, titrated for the blood glucose goal of blood glucose of - 7 - 8 mM (-125-145 such as erratic absorption of subcutane- - 6 - 7 mM (-110-130 mg/dl) at 0300, mg/dl) before any attempt is made to ously injected insulin and empirical esti- not at 0700 because the insulin require- titrate the night dose of depot insulin. No mates of the patient's insulin needs. ments in early night are lower than those snack should be given after supper with (138). Recently, the realistic blood glu- of late night (Fig. 9). This is an important this therapeutic regimen. Depot insulin cose targets of Table 1 have been proven rule for preventing nocturnal hypoglyce- should be given in a dose that results in to successfully prevent frequent hypogly- mia with CSII. Because of the dawn phe- a fasting blood glucose similar to that of cemia during intensive insulin therapy in nomenon, the CSII at a fixed rate is ex- bedtime ( - 7 - 8 mM [-125-145 mg/ IDDM while maintaining optimal long- pected to result in a 0400-0700 blood dl]). Because of the low insulin absorpterm blood glucose control as indicated glucose increase, usually 55-60 yr insulin therapy, which aims to achieve a fasting and/or with advanced microvascuplasma glucose of —7-8 mM (—125-145 mg/ lar complications. This form of insulin dl), hypoglycemia between 2400 and 0300 inev- therapy aims to prevent the metabolic catastrophes of diabetes (ketoacidosis, itably would occur.

reduced by ingestion of a bedtime snack, clearly the most rational measure is not to buffer excessive nocturnal hyperinsulinemia with an extra carbohydrate intake, but rather to rationalize insulin delivery. Thus, the split injection of regular insulin at supper and depot insulin at bedtime is a necessary therapeutic measure to prevent nocturnal hypoglycemia in intensive insulin therapy and its possible tragic consequences, such as the "dead in bed syndrome" (146). Finally, could a long- acting insulin preparation such as Ultralente, have any advantage over intermediate-acting insulin (NPH/Lente) in the control of nocturnal postabsorptive blood glucose?

hyperosmolarity, and severe hypoglycemia) but does not target near-normoglycemia. It is important to prevent hypoglycemia in aged diabetic patients with advanced vascular complications. Therefore, the glycemic goals of nonintensive insulin therapy are considerably higher than those of intensive insulin therapy (Table 2). The model in Fig. 11 illustrates the use of nonintensive insulin therapy to prevent hypoglycemia at night. Compared with intensive insulin therapy, insulin doses should be reduced to achieve the glycemic goals given in Table 2. In very old, disabled patients, premixed insulin preparation (20-30% regular, 80-70% NPH) can be injected before supper, but the dose should be sufficient to prevent plasma glucose con-

Table 2—Plasma glucose targets of nonintensive insulin therapy in type I diabetes Plasma glucose (fasting and before meals) HbAlc(%)*

8-11 mM (-145-200 mg/dl) 7.5-8.5

'Determined by HPLC; the range for nondiabetic subjects is 3.8-5.5%.


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centration < 8 mM (—145 mg/dl) at 0300 h (Fig. 12). Clearly, the greater insulin requirements at dawn will lead to increases in fasting plasma glucose at 0700 h (up to 10-12 mM, - 1 8 0 - 2 1 5 mg/dl) with nonintensive insulin therapy. Such a relatively high fasting blood glucose should not alarm the patient; rather, it should be assurance that nocturnal hypoglycemia has not occurred. It should be stressed that patients on nonintensive insulin therapy, which has glycemic goals deliberately above normal, by no means receive a lower standard of care, less attention, or less interest than those on intensive insulin therapy. On the contrary, because nonintensive therapy is relevant to the majority of type I diabetic patients, physicians and paramedical personnel should devote the necessary time and skills to assisting and educating these patients so that they may achieve the goal of a good quality of life without the acute complications of diabetes or its therapy, i.e., hypoglycemia. The careful prevention of nocturnal hypoglycemia using the therapeutic models of Figs. 11 and 12 is an important part of this therapeutic plan.

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Acknowledgments—This work was supported by the Consiglio Nazionale delle Ricerche (CNR Grant 93.00220.CT04; and finalized project "aging" grant 93:00352. PF40) and by the Juvenile Diabetes Foundation (grant 193 108). The editorial help of Patricia Boyce and the technical assistance of Gionipero Cipicioni are gratefully acknowledged.

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References

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