Effects of Duration of Type 2 Diabetes Mellitus on Insulin Secretion

Farhad Zangeneh, MD; Puneet S. Arora, MD; Peter J. Dyck, MD; Lynn Bekris; Ake Lernmark, PhD; Sara J. Achenbach; Ann L. Oberg, PhD; Robert A. Rizza, MD


Endocr Pract. 2006;12(4):388-393. 

In This Article

Abstract and Introduction

Objective: To gain insight into the effects of duration of type 2 diabetes on insulin secretion in patients with type 2 diabetes mellitus.
Methods: C-peptide concentrations were measured every 2 years before and after intravenous injection of 1 mg of glucagon in 89 patients with type 2 diabetes (51 men and 38 women) as part of the Rochester Diabetic Neuropathy Study in those subjects who participated in follow-up (median, 12 years; range, 6 to 14).
Results: Although insulin secretion decreased over time (P<0.001) in the group as a whole, both the pattern and the rate of decline in C-peptide concentration differed considerably among the study subjects. Insulin secretion, whether measured as fasting C-peptide, 6-minute C-peptide, or postglucagon increment in C-peptide concentrations, declined with increasing duration of diabetes in approximately half of the patients but either increased or remained essentially constant over time in the other half. The decrease in insulin secretion was not associated with a deterioration in glycemic control because hemoglobin A1c also declined (P<0.005) during the same interval.
Conclusion: We conclude that insulin secretion decreases over time in many patients with type 2 diabetes. Because the rate of decline is variable, the predictive value of any single measurement is limited. These data indicate that although a decrease in insulin secretion over time is characteristic of type 2 diabetes mellitus, it is not inevitable.

Diabetes develops when the secretion of insulin is insufficient to maintain plasma glucose concentrations within the normal range.[1] Type 1 diabetes results from immune destruction of pancreatic beta cells.[2,3] The cause of beta cell loss in patients with type 2 diabetes is less well defined and is likely to be multifactorial. Although it is generally accepted that type 2 diabetes is associated with a progressive loss of insulin secretion over time,[4,5,6,7,8,9] no published studies have documented the rate of loss of insulin secretion in patients who have had type 2 diabetes longer than 10 years.

Many studies have examined the pattern of insulin secretion within the first 5 to 10 years after diagnosis of diabetes. For example, the United Kingdom Prospective Diabetes Study (UKPDS)[5] and the Belfast Diet Study[4] used homeostasis model assessment of beta cell function to analyze insulin secretion in patients with newly diagnosed type 2 diabetes. Both studies showed that beta cell function (an index of insulin secretion) decreased during the 5 to 10 years after diagnosis of diabetes and that this decrease was associated with a deterioration in glycemic control.[4,5] Saad et al[6] also reported that fasting and 2-hour postglucose challenge insulin concentrations in Pima Indians decreased during the first 5 to 7 years after diagnosis of diabetes. Similarly, Niskanen et al[8] reported that the cumulative incidence of insulin deficiency, defined as a plasma C-peptide concentration of less than 0.7 nmol/L after intravenous injection of 1 mg of glucagon, increased from 3% at 5 years after diagnosis of diabetes to 7% at 10 years after diagnosis. Furthermore, Mauvais-Jarvis et al[9] reported that the postglucagon increment in C-peptide level decreased by 35% in patients of sub-Saharan African origin during the first 10 years after diagnosis of type 2 diabetes. In contrast, Borg et al[7] noted that when antibody-positive subjects (that is, patients who presumably had type 1 diabetes) were carefully excluded, the fasting C-peptide concentration either did not change or even increased slightly during the first 12 years after diagnosis of type 2 diabetes. Thus, the rate and the consistency of deterioration of insulin secretion in patients with long-term diabetes (that is, more than 10 years) have not been well defined.

In an attempt to document a better characterization of the effects of the duration of type 2 diabetes on insulin secretion, plasma C-peptide concentrations (in the fasting state and at 6 minutes after intravenous administration of glucagon) were measured every 2 years as part of the prospective population-based Rochester Diabetic Neuropathy Study.[10] Patients who still had endogenous insulin secretion[11] at the time of entry into the study (defined as a fasting C-peptide concentration or a 6-minute postglucagon increment in C-peptide concentration greater than 0.17 nmol/L), who had no evidence of autoimmunity (anti-GADA65 or IA-2 antibody negative), and who had at least 6 years of follow-up were included in the analysis. We report that although insulin secretion declined over time in the diabetic population as a whole, the temporal pattern of change was variable, with insulin secretion in many patients either remaining essentially constant or actually increasing. Of interest, the decrease in insulin secretion in the population as a whole was associated with a decline (rather than an increase) in hemoglobin A1c (A1C), an indication that loss of beta cell function is not inevitably associated with deterioration in glycemic control.


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