The authors conclude that nocturnal hypoglycemia is frequent, of long duration and associated with bedtime blood glucose concentrations of <100 mg/dl to 150 mg/dl.

Comment
These data confirm a large body of evidence, first reported nearly a quarter of a century ago, that hypoglycemia, particularly nocturnal hypoglycemia, occurs commonly in patients with insulin-treated diabetes [1–3]. The authors do not provide a critical discussion of the accuracy of the CGMS used at the time of their study (late 1999 and early 2000). The performance of the sensor has been questioned [4]. Thus, the present data may to some extent overestimate the absolute frequency of nocturnal hypoglycemia, its absolute duration, or both. Nonetheless, in the context of the available information, these data support the conclusion that nocturnal hypoglycemia is very common in type 1 diabetes.
The authors point out that none of their patients used regular (soluble) insulin. The intermediate-acting insulin used by the patients treated with a basal-bolus insulin regimen is not specified; presumably it was not one of the newer, long-acting insulin analogs, insulin glargine or detemir, which have been reported to produce somewhat less nocturnal hypoglycemia [5, 6].
It is interesting that there was no significant inverse relationship between HbA1c levels and the number of low CGMS glucose values, a finding seemingly at variance with previous data [7, 8]. The results underscore the fact that hypoglycemia occurs in patients with a broad range of glycemic control.
In practice, clinicians recognize that lower bedtime blood glucose concentrations are associated with higher rates of nocturnal hypoglycemia. Preventive strategies have been recommended based on the bedtime glucose value as discussed by the authors and others [9]. Nonetheless, the present data suggest that no bedtime blood glucose concentration is truly safe.
There is evidence that physiological and behavioral defenses against developing hypoglycemia, which are already compromised by absent glucagon and reduced sympathoadrenal (including adrenomedullary epinephrine) responses to a given level of hypoglycemia, are impaired further during sleep in patients with type 1 diabetes [10, 11]; and, presumably as a result of reduced sympathoadrenal-mediated arousal, patients with type 1 diabetes are much less likely to be awakened by hypoglycemia (and thus able to recognize and treat their hypoglycemia) than are non-diabetic individuals [11].
Hypoglycemia remains the limiting factor in the glycemic management of diabetes [12]. Current approaches to the prevention of nocturnal hypoglycemia [13] include insulin regimen adjustments ranging from changes in insulin dosage, timing, or both, through the use of rapid-acting insulin analogs (e.g. lispro or aspart) with meals during the day and of long-acting basal insulin analogs (e.g. glargine or detemir) in a basal-bolus regimen to the use of continuous subcutaneous insulin infusion during the night — and bedtime snacks. However, the efficacy of the latter is largely limited to the first half of the night. Experimental approaches include bedtime administration of the glucagon-stimulating amino acid alanine, the epinephrine-simulating b2-adrenergic agonist terbutaline or the slowly digested complex carbohydrate uncooked cornstarch and administration of an a-glucosidase inhibitor with the evening meal. Obviously, these are far from ideal. Clearly, people with diabetes need glucose-regulated insulin replacement or secretion [12, 13].

References
 1. Gale EAM, Tattersall RB. Unrecognized nocturnal hypoglycemia in insulin-treated diabetics. Lancet 1979; 19: 1049–52.
 2. Pramming S, Thorsteinsson B, Bendtson I et al. Nocturnal hypoglycaemia in patients receiving conventional treatment with insulin. Br Med J 1985; 291: 376–9.
 3. Bendtson I, Kverneland A, Pramming S, Binder C. Incidence of nocturnal hypoglycemia in insulin-dependent diabetic patients on intensive therapy. Acta Med Scand 1988; 223: 543–8.
 4. McGowan K, Thomas W, Moran A. Spurious reporting of nocturnal hypoglycemia by CGMS in patients with tightly controlled type 1 diabetes. Diabetes Care 2002; 25: 1499–503.
 5. Ratner RE, Hirsch IR, Neifring JL et al., for the US Study Group of Insulin Glargine in Type 1 Diabetes. Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes. Diabetes Care 2000; 23: 639–43.
 6. Hermansen K, Madsbad S, Perrild H et al. Comparison of the soluble basal insulin analog insulin detemir with NPH insulin. Diabetes Care 2001; 24: 296–301.
 7. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 977–86.
 8. Mühlhauser I, Overmann H, Bender R et al. Risk factors for severe hypoglycaemia in adult patients with type 1 diabetes — a prospective population based study. Diabetologia 1997; 41: 1274–82.
 9. Kalergis M, Schriffrin A, Gougeon R et al. Impact of bedtime snack composition on prevention of nocturnal hypoglycemia in adults with type 1 diabetes undergoing intensive insulin management using lispro before meals. Diabetes Care 2003; 26: 9–15.
10. Jones TW, Porter P, Sherwin RS et al. Decreased epinephrine responses to hypoglycemia during sleep. N Engl J Med 1998; 338: 1657–62.
11. Banarer S, Cryer PE. Sleep-related hypoglycemia-associated autonomic failure in type 1 diabetes: reduced awakening from sleep during hypoglycemia. Diabetes 2003; 52: 1195–203.
12. Cryer PE. Hypoglycemia: the limiting factor in the glycaemic management of type I and type II diabetes. Diabetologia 2002; 45: 937–48.
13. Cryer PE, Davis SN, Shamoon H. Hypoglycemia in diabetes. Diabetes Care. In press.

Summary and Comment:
Philip E. Cryer, St Louis, MO, USA