The effect of age on pancreatic b cell sensitivity

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A major component of glucose homeostasis is the balance between insulin secretion and tissue sensitivity to insulin. Again there are many reports that either support or refute a decline in pancreatic b cell response to glucose as a function of age. However, very few investigators have examined b cell secretion in a dose—response manner. We have performed 230 hyperglycaemic clamps for 2 h at four doses (3.0, 5.4, 7.9 and 12.8mmol/l above basal glucose levels) in healthy young, middle-aged and old volunteers (Elahi et al 1993). Deconvolution analysis, which provides an analysis of insulin secretion from the plasma insulin concentration curves, showed that insulin secretion is characterized by (1) a spike lasting about one minute (first phase), (2) cessation of secretion from 0—15 min, (3) a step increase at 15 min to a level above basal, and (4) a gradual increase in secretion from 15—120 min. In these dose—response studies, as the hyperglycaemic level increased, there was a gradual increase in insulin response within each age group. Furthermore, with each group, comparisons of insulin responses between doses were statistically significant both for the early phase insulin response and for each of the succeeding 30 min periods (30—60, 60—90 and 90—120 min) of the late-phase insulin response. However, in neither the early phase, nor the later-phase insulin responses were there any statistically significant differences among the age groups (Fig. 5). These results are consistent with the observation of DeFronzo (1979) where hyperglycaemic clamps were performed at 6.9 mmol/l above basal in young, middle-aged and old. Using the Min Mod technique, two studies (Chen et al 1985, Pacini et al 1988) have also shown that neither first phase nor second phase insulin response differs significantly between young and old. Thus, the redundant, unnecessary consensus is that insulin secretion does not differ in ageing.

As previously discussed, comparisons between groups (e.g. young vs. old) have inherent difficulties due to the differences between them other than age. In our own studies, we have tried to 'match' for differences using several approaches. In the clamp studies reported above (Elahi et al 1993), we allowed a higher BMI entry criterion in the young than the old in order to match for loss of LBM and increased adiposity in the older group. In a study of insulin secretion of women master athletes across the age span, we carefully restricted entry criteria for both VO2 max and percentage in order to examine the effect of ageing in very active individuals who maintained their LBM. We found, again, that insulin secretion does not differ in ageing (Ryan et al 2001). However, despite our strict entry criteria for similarity for percentage fat, older female athletes had higher amount of visceral fat than younger female athletes (*30cm2) (Ryan & Elahi 1996). An elegant cross sectional study (Pimenta et al 1995) enrolled 100 volunteers of European ancestry with normal OGTT according to the 1985 WHO criteria. There were two groups (n = 50 in each), one of which had at least one first-degree

FIG. 5. Bimodal time course of the plasma insulin response to fixed hyperglycaemia. There is a graded increase in insulin as hyperglycaemia increases, and a delay in the fall of plasma insulin in response to the instantaneous fall in glucose at the end of the clamp.

type 2 relative. The two groups were matched for gender, age, weight, height, waist hip ratio, HbA1C , and fasting glucose and insulin levels. None were being treated for hypertension and none were engaged in habitual exercise. A hyperglycaemic clamp at a plasma glucose level 180mg/dl (10mmol/l) was performed for three hours. In 62 individuals (26 from the type 2 group and 36 from the normal group) an additional hyperinsulinaemic—euglycaemic clamp (240 m' Um—2' min—1) was also performed. Again, the two groups were carefully matched for all the confounding variables listed above. The group with a first-degree type 2 relative had reduced first and second phase insulin response (cf. Fig. 2 of Pimenta et al 1995). However, their peripheral tissue sensitivity to insulin (from both clamps) was not significantly different. This study demonstrates that middle-aged (* 40 2 years) individuals of European ancestry with normal OGTT but with a first-degree type 2 diabetic relative have impaired b cell function without a significant reduction in peripheral tissue sensitivity to insulin as compared with normal individuals without a type 2 diabetic relative. Furthermore, b cell defects were not uniform. These results support the hypothesis that a defect in insulin secretion precedes a defect in insulin sensitivity in the development of type 2 diabetes.

During a hyperglycaemic clamp in normal and type 2 diabetic individuals, second phase insulin response is seen to progressively increase throughout the 180 or 240 min duration of the clamp. Does the second phase response ever plateau? We have performed a 10 h hyperglycaemic clamp at *190mg/dl (10.6 mmol/l) in young (age = 23 1 years, BMI = 23 0.6, WHR = 0.8, VO2 max = 44 ml'kg71'min71, 5 males and 5 females) and old (age = 80 2, BMI = 24 0.5, WHR = 0.89, VO2 = max 21ml'kg71'min71, 5 males and 5 females) with normal OGTTs (Meneilly et al 1999). First phase insulin responses were not different between the two groups (Fig. 6). Second phase insulin responses increased progressively until *120 to 150 min in the old after which it reached a plateau. In the young a plateau was not reached until * 300 min. The second phase insulin responses were significantly different after 120 min. Glucose infusion rates necessary to maintain the stable hyperglycaemia reached a plateau at * 180—240 min in both groups, but at significantly different rates. We also obtained one-minute samples for determination of plasma insulin levels for 150 min during both the basal period and after 1 h of achievement of a plateau in the rate of glucose infusion. Insulin release was evaluated by cluster analysis (Porksen et al 1995, Engdahl et al 1977). Disorderly insulin release, a reduction in the amplitude and mass of rapid insulin pulses and decreased frequency of ultradian pulses is characteristic of normal ageing in the basal state (Meneilly et al 1997). In the stimulated state, a reduction in mass and amplitude of rapid pulses, decrease in frequency and regularity of ultradian pulses occurs with ageing (Meneilly et al 1999).

FIG. 6. Plasma insulin response during a 10 h hyperglycaemic clamp at *11 mmol/l. The insert on the bottom shows the first phase insulin response with an adjusted scale.

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