Hypoglycemia Unawareness in Noninsulin-Dependent Diabetes Mellitus

Thiemo F. Veneman and Dirk W. Erkelens

Department of Internal Medicine, University Hospital Utrecht, Utrecht, The Netherlands

Address all correspondence and requests for reprints to: T. F. Veneman, M.D., Ph.D., University Hospital Utrecht, Department of Internal Medicine, P.O. Box 85500, 3508 GA Utrecht, The Netherlands.


    Introduction
 Top
 Introduction
 Review of the literature
 Conclusion
 References
 
THE PHENOMENON of hypoglycemia unawareness in patients with insulin-dependent diabetes mellitus (IDDM) has in recent years been subject to intensive research (1, 2). This has partly been stimulated by the findings of the Diabetes Control and Complications Trial, showing that intensive insulin therapy leads to decreased and delayed development of the long term complications of diabetes, but, on the other hand, also to a 3-fold increase in the incidence of severe hypoglycemia (3). Presently, the incidence and the major risk factors for the development of hypoglycemia unawareness have been delineated (4). The major risk factors are duration of the disease and improved metabolic control.

Surprisingly, little attention has been paid to the phenomenon in patients with noninsulin-dependent diabetes mellitus (NIDDM). This is remarkable, because they represent the majority of all patients with diabetes (>80%) (5), and more patients with NIDDM are being treated with some form of intensive therapy. Moreover, the use of metformin as a therapeutic agent is likely to increase the frequency of hypoglycemia (6).

It is well known that patients with NIDDM frequently have severe hypoglycemic episodes (7). Six percent have hypoglycemia each month and almost 15% less frequently. Seltzer reported that sulfonylurea derivatives are involved in 70% of all cases (8). From studies in normal subjects and IDDM patients we know that hypoglycemia can induce unawareness during a subsequent episode, thus inducing a vicious cycle (9). It is not known whether this also accounts for patients with NIDDM. Relatively little information is available regarding counterregulatory mechanisms in NIDDM. In this article we review the literature on the hypoglycemia unawareness phenomenon in patients with NIDDM.


    Review of the literature
 Top
 Introduction
 Review of the literature
 Conclusion
 References
 
Hormonal counterregulation.

There have been only a few studies that describe the hormonal responses to hypoglycemia in patients with NIDDM (10, 11, 12, 13, 14, 15, 16, 17).

In 1977, Nonaka et al. reported decreased glucagon responses to hypoglycemia in patients with NIDDM compared to normal controls (10). In this study, however, hypoglycemia was not standardized. In contrast, Levitt et al., in 1979, studied 10 nonobese patients with NIDDM and reported no difference in glucagon response to hypoglycemia compared to that in normal subjects (11). Boden et al. showed similar responses of epinephrine and glucagon secretion in 10 patients with NIDDM compared to normal controls (12). The basal glucagon concentrations, however, were higher in the diabetic patients. Bolli et al. reported impaired glucagon, GH, and cortisol responses during hypoglycemia in 13 patients with NIDDM, with no clinical evidence of autonomic neuropathy (13). In contrast, epinephrine release was normal, and norepinephrine release was increased compared to those in normal control subjects. In this study hypoglycemia was induced with sc administered insulin and was, therefore, prolonged and less severe (nadir, 3.4 mmol/L). Polonsky showed normal responses of epinephrine and glucagon in patients with NIDDM to standardized hypoglycemia (14). Heller et al., in 1987, reported similar responses of epinephrine, glucagon, cortisol, and GH to a similar degree of hypoglycemia (15).

Most recently, in 1994, Meneilly et al. studied counterregulatory hormone responses to hypoglycemia in elderly patients with NIDDM (16). Increased catecholamine responses, but decreased glucagon responses, were reported. GH and cortisol responses were normal. It has to be emphasized that the latter study was performed in elderly patients. Shamoon et al. reported reduced glucagon, increased epinephrine, and normal GH and cortisol responses (17).

These studies all have major drawbacks, which makes interpretation of the data difficult. In most studies patients with autonomic neuropathy were not excluded, and this influences the secretion of catecholamines. In some studies the hypoglycemic stimulus was not standardized. Obesity is known to influence counterregulatory hormone re-sponses, and subjects were not matched for body weight or body mass index (18). Other confounding factors not taken into account were age, glycemic control, and gender, all factors suggested to influence counterregulation (1).

Metabolic counterregulation.

Only two studies (13, 17) have addressed the metabolic responses to hypoglycemia in NIDDM. Bolli et al. reported that patients with NIDDM have a reduced compensatory increase in glucose production, and that the restoration of euglycemia was primarily the result of enhanced suppression of glucose utilization (13). He suggested that the increased catecholamine response and the greater increase in plasma free fatty acids might be involved. Shamoon et al. confirmed that patients with NIDDM had greater catecholamine and free fatty acid responses to hypoglycemia, but, in contrast to previous observations, also reported that glucose production was greater than that in normal volunteers, and whole body glucose utilization was lower (17).

Hypoglycemia unawareness.

Surprisingly, only a few reports are available on the occurrence of hypoglycemia unawareness in NIDDM (16, 19). Mitrakou et al. reported that NIDDM patients maintained intact responses to hypoglycemia (19). However, approximately 20% of all patients reported neuroglycopenic symptoms as the first to appear during hypoglycemia. Moreover, unawareness of hypoglycemia appeared to be related to the duration of the disease, as in IDDM, and not to metabolic control. A disadvantage of this study is that determination of hypoglycemia unawareness is only based upon questionnaires.

One other report regarding symptoms during hypoglycemia is that of Meneilly et al., who studied counterregulation and symptom awareness in elderly NIDDM patients (16). NIDDM patients had similar symptom awareness as age-matched controls, whereas epinephrine responses were increased. In another study of the same group, decreased awareness of autonomic, but not neuroglycopenic, symptoms in healthy elderly subjects was reported (20). Thus, the decreased awareness of autonomic symptoms seen in elderly NIDDM patients is also seen in healthy elderly subjects despite increased epinephrine responses in the former group. This suggests decreased ß-adrenergic sensitivity, which has been reported to occur during aging (21).

Studies in healthy subjects and IDDM patients have shown that an antecedent episode of hypoglycemia reduces counterregulatory and symptomatic responses during a following episode (9). This has been suggested to be a pathogenetic factor of hypoglycemia unawareness. Recently, Peacey et al. reported that antecedent hypoglycemia does not alter hormonal responses and even increases symptom scores in NIDDM during a subsequent hypoglycemic episode (22). This is a remarkable result that is in direct contrast to findings in IDDM. In another recent preliminary report from the same group, the neurophysiological responses to hypoglycemia in patients with NIDDM treated with insulin were compared to those of patients treated with sulfonylurea (23). Counterregulatory hormone responses were not different, but, in contrast, the adrenergic symptoms of tremor and sweating occurred to a lesser extent in the insulin-treated group. Nevertheless, in their conclusion these researchers state that no differences were detected in symptom response.


    Conclusion
 Top
 Introduction
 Review of the literature
 Conclusion
 References
 
Despite the relatively few studies regarding hormonal counterregulation in NIDDM during hypoglycemia, a consistent pattern has emerged. Overall, glucagon responses are reduced (10, 11, 13, 14, 16, 17), although not usually to the same extent as in IDDM. Plasma catecholamine responses are increased (13, 14, 16, 17), and GH and cortisol responses are generally normal (12, 15, 16, 17). Thus, the counterregulatory hormone responses in NIDDM differ markedly from those found in IDDM, in which both glucagon and catecholamine responses are reduced and, at least in those patients with hypoglycemia unawareness, GH and cortisol responses are also reduced (1, 4). No single explanation for this discrepancy is available, but the difference could be related to the strong increase in plasma FFA concentrations in NIDDM during hypoglycemia (13). This could suppress glucagon responses and subsequently increase catecholamine release as a compensatory response.

Very few data are available regarding awareness of hypoglycemia in NIDDM, showing that autonomic symptoms are decreased with age, but not necessarily due to diabetes, although 20% of a large group of NIDDM patients reported a neuroglycopenic symptom as the first to appear during hypoglycemia (19).

Obviously from the presently available data it appears that there are substantial differences in the reactions to hypoglycemia between IDDM and NIDDM. With the increasing efforts to tighten glycemic control in NIDDM, it can be anticipated that hypoglycemia will occur more frequently in the future. Therefore, it is of the utmost importance to clearly delineate the counterregulatory, symptomatic, and cognitive consequences of hypoglycemia in NIDDM.\.

Received December 6, 1996.

Revised February 13, 1997.

Accepted February 19, 1997.


    References
 Top
 Introduction
 Review of the literature
 Conclusion
 References
 

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