Measures of insulin action and b-cell function in the same test

Original article:
Importance of obtaining independent measures of insulin secretion and insulin sensitivity during the same test: results with the Botnia clamp. Tripathy D, Wessman Y, Gullström M, Tuomi T, Groop L. Diabetes Care 2003; 26(5): 1395–401.

Summary and Comment:
Isaac Sinay, Buenos Aires, Argentina

Summary

In order to validate and apply a method to provide reliable and independent measures of first-phase insulin response (FPIR) and insulin sensitivity (M-value) in the same test, Tripathy et al. combined two tests to measure simultaneously insulin secretion and insulin sensitivity.
A regular intravenous glucose tolerance test (0.3 g/kg glucose i.v.) was followed 60 min later by a euglycemic-hyperinsulinemic clamp (45 mU/m2) for a further 120 min (the Botnia clamp). The Botnia clamp also took account of insulin sensitivity in relation to b-cell function (disposition index).
The study was performed in subjects with normal glucose tolerance (NGT) and impaired glucose tolerance (IGT) or type 2 diabetes and was then applied to subjects with and without a first-degree family history of diabetes. The results were compared with those obtained in the same subjects using a euglycemic clamp performed without a prior glucose bolus. Reproducibility was examined in 13 subjects (five NGT and eight IGT/type 2 diabetes) using two Botnia clamps with a 1-week interval.
The results showed a good degree of reproducibility. The mean coefficient of variation for repeat M-values was 9% (r = 0.983; p < 0.00001), with uniform variability across the range from NGT to diabetes.
The mean coefficient of variation for FPIRs was 27% in NGT and 12% in IGT (combined NGT/IGT = 23%).
The values obtained between the Botnia and euglycemic-hyperinsulinemic clamps, performed in random order with a 1-week interval, were studied in nine subjects (four NGT and five IGT/diabetes). The M-values were similar and correlated strongly (7.23 ± 1.14 and 7.79 ± 1.14 mg fat-free mass kg-1 min-1, respectively; ns).
Application of the Botnia clamp in subjects with (n = 25) and without (n = 16) a first-degree family history of diabetes showed that those with a family history had lower insulin sensitivity in comparison with those without a family history (5.6 ± 0.4 vs. 7.5 ± 0.6 mg kg-1 min-1, respectively; p = 0.02). The FPIRs between both groups were similar. But when b-cell function was expressed as a disposition index, subjects with a family history showed a significant reduction in b-cell function (1284 ± 181 vs. 1985 ± 288 mIU mg-1 kg-1 min-1; p = 0.04).

Comment

From a methodological point of view it is interesting that the glucose bolus given at the start of the study did not affect insulin sensitivity, with a low coefficient of variation across a wide range of glucose tolerance.
The Botnia clamp appears to be a simpler tool to assess b-cell function and insulin action than the frequently sampled intravenous glucose tolerance (FSIGT) test. The number of plasma samples can be reduced to six. Insulin sensitivity is not derived from insulin values obtained during the test, therefore measurements of insulin sensitivity are not affected in conditions of impaired b-cell function or insulin treatment, as happens with the FSIGT test [1].
One of the limitations of the proposed test is the considerable variation observed in glucose-stimulated insulin secretion (FPIR). Also, the test is not suitable for insulin-treated patients on account of the absence of FPIR in these subjects.
The results observed in subjects with and without a family history of diabetes showed that those with a first-degree family history were insulin-resistant; when FPIR was adjusted to the degree of insulin sensitivity they also demonstrated defective b-cell function (Fig. 1). These data have been previously reported [2].

Fig. 1: FPIR, disposition index (DI) and insulin sensitivity (M-value) in non-diabetic subjects with and without a first-degree family history of diabetes.

The authors’ observations open up a new area of application with links to clinical diabetes practice in populations where reliable and independent measures of b-cell function and insulin action assessed during the same test could be a valuable tool in predicting the risk of metabolic and cardiovascular disorders. For instance, although obese individuals tend to be insulin-resistant, not all those who are overweight or obese exhibit decreased b-cell action [3]. There is evidence that the increased risk of cardiovascular disease is seen primarily in obese individuals who are also insulin-resistant [4]. Detection of the FPIR and disposition index might identify an additional risk marker to enable intervention strategies to be focused on a smaller group of individuals who could benefit among the large existing population suffering from obesity [5].
Most women with polycystic ovary syndrome (PCOS), characterized by chronic anovulation and hyperandrogenism, are insulin-resistant. PCOS affects 6–10% of women of reproductive age [6]. Impaired glucose tolerance and diabetes affect 40% of these women [6] and they also show a higher risk of myocardial infarction [7]. Therefore, in women afflicted by this chronic endocrinological disorder, the Botnia clamp could be a valuable tool to predict which individuals are likely to convert to type 2 diabetes and develop a higher risk of coronary heart disease.
Hypertension is another clinical entity that is strongly associated with insulin levels and insulin resistance [8]. However, insulin sensitivity in hypertension is heterogeneous. For example, Shew et al. [9] found that hypertensive subjects with abnormal electrocardiograms were insulin-resistant compared with those with normal electrocardiograms. It is important to assess whether both insulin sensitivity and insulin secretion are impaired in hypertensive subjects, because this would suggest some degree of impaired glucose tolerance and an additive impact on the risk of cardiovascular disease.
The Botnia clamp would enable investigators to study, in the same test, the interaction between b-cell function and insulin action in insulin-resistant subjects with a high risk of type 2 diabetes and cardiovascular disease.

References