Clinical studies of glucose variability and hypoglycemia in adult patients with type 1 diabetes

Diabetes mellitus type 1 is a condition characterized by elevated blood glucose values due to impaired insulin production. This condition is associated with increased morbidity from micro- and macrovascular complications. Studies have shown that lowering blood glucose reduces the incidence of these complications. However, the question of whether glycemic variability is an independent risk factor for the development of microvascular complications remains.

Studies I and II were retrospective observational studies performed on the same cohort of patients; it consisted of 100 patients who were randomly selected from 442 consecutive type 1 diabetic patients who attended our out-patient clinic. Standard deviation of blood glucose (SDBG) was calculated from 70 measurements over a period of 4 weeks. The onset and progression of micro- and macrovascular complications were recorded from 1990 to 2001. HbA1c values were recorded from 1985 to 2001. HbA1c variability was measured as the SD of collected HbA1c values. The prevalence of complications increased over time from 1990 to 2001. The prevalence of neuropathy increased from 29% to 47%. Statistical analysis showed that HbA1c was an independent predictor of the incidence (p = 0.004) and the prevalence (p = 0.01) of nephropathy. SDBG was found to be a predictor of the prevalence of peripheral neuropathy (p = 0.03) and showed borderline significance for the incidence of peripheral neuropathy (p = 0.07). The variability of HbA1c was found to be an independent factor that contributes to the development of microvascular complications. (p=0.019). We conclude that the short-term variability of blood glucose may be of importance for the development of peripheral neuropathy and that nerve tissue might be particularly vulnerable and we also conclude that the variability of HbA1c may be of importance for the development of microvascular complications.

Study III was an open, randomized, cross-over trial in 15 type 1 diabetes patients to compare glucose control assessed by a continuous glucose monitoring system (CGMS) Gold during basal insulin substitution with either a continuous subcutaneous insulin infusion (CSII) or glargine. Comparing CSII with glargine revealed that the mean blood glucose was lower with CSII, 9.11 vs. 10.31 (p=0.002). There was an average of 1.3 more episodes of values below 3.5 mmol/l with CSII (p=0.053). There were no significant differences in glucose variability measured as SDPG or the mean amplitude of glucose excursions (MAGE), although significantly longer periods of glucose values were spent within the target of 4.5-10.0 mmol/l with CSII (p=0.034). CSII provided superior glucose control compared with glargine, with lower mean blood glucose at longer periods of glucose values within target and a lower HbA1c with a somewhat smaller insulin dose (n.s). However, there was no significant difference with respect to glucose variability.

Study IV was an observational study of the prevalence of severe hypoglycemia (SH) in relation to risk factors in type 1 diabetic patients over a period of 14 years, 1984 to 1998. To investigate the problem of SH, we performed a cross-sectional survey of a cohort of 178 patients registered at our out-patient clinic in 1984 to be repeated in 1998. An identical questionnaire was sent to the patients at the beginning of 1985 and 1999 respectively, regarding the problem of SH in the preceding year. The use of multiple insulin injection therapy had increased from 71% to 98% (p<0.001) and the daily self-monitoring of blood glucose (SMBG) from 17% to 48% (p<0.001), between 1984 and 1998. An increasing number of patients reported unawareness of hypoglycemia, 54% vs. 40% (p<0.01), and nocturnal events were more frequent, 83% vs. 76% (p<0.05). The prevalence of SH had increased from 17% to 27% (p<0.05) and there was a slight decrease in HbA1c, 7.6% to 7.4% (p<0.05). In spite of the more frequent use of multiple injection therapy and more frequent SMBG, the prevalence of SH increased by more than 50% over 14 years, 1984 to 1998.

List of scientific papers

I. Can glycaemic variability, as calculated from blood glucose self-monitoring, predict the development of complications in type 1 diabetes over a decade? Bragd J, Adamson U, Bäcklund LB, Lins PE, Moberg E, Oskarsson, P. Diabetes Metab. 2008 Dec; 34(6 Pt1):612-6.
https://doi.org/10.1016/j.diabet.2008.04.005

II. Can HbA1c variability contribute to the development of microvascular complications in type 1 diabetes? Bragd J, Adamson U, Lins PE, and Oskarsson P. [Manuscript]

III. Basal insulin substitution with glargine or continuous subcutaneous insulin infusion in adult type 1 diabetes patients-a randomized controlled trial. Bragd J, von Döbeln A, Lins PE, Adamson U, Bergström J, Oskarsson P. Diabetes Technol Ther. 2010 Sep; 12(9):689-93.
https://doi.org/10.1089/dia.2010.0062

IV. A repeated cross-sectional survey of severe hypoglycaemia in 178 Type 1 diabetes mellitus patients performed in 1984 and 1998. Bragd J, Adamson U, Lins PE, Wredling R, Oskarsson P. Diabet Med. 2003 Mar; 20(3):216-9.
https://pubmed.ncbi.nlm.nih.gov/12675666