The incretin effect in ageing and in type 2 diabetes

Incretin is the umbrella term to cover the multiple gut factors (now known to be hormones) which augment insulin response above that which can be attributed to glucose alone. This insulinotropic effect has been demonstrated by matching the time course of the plasma glucose excursion following an OGTT with both an i.v. infusion of glucose (Perley & Kipnis 1967) and during a hyperglycaemic clamp. In the hyperglycaemic clamp, plasma glucose was increased to * 11 mmol/l for 2 h on two different occasions. In one, only glucose was infused, while in the second, an OGTT was administered at 60 min and the exogenous glucose infusion rate was adjusted during the second hour as the ingested glucose was being absorbed; in this manner the plasma glucose level remained at the same plateau level in the second hour as in the first hour (Andersen et al 1978). During the second hour in the study, despite the constancy of the plasma glucose concentration, a marked potentiation of insulin secretion was observed. The increase in insulin level is preceded by an increase in plasma concentration of a measured gut hormone, glucose-dependent insulinotropic polypeptide (GIP) by 5 min, with a subsequent time course very similar to the potentiation of insulin response. It was logical to attribute the increase in insulin to this hormone. To test this further, we subsequently infused GIP during the second hour of a hyperglycaemic clamp and we showed that GIP can indeed potentiate insulin response in normal individuals in a similar fashion to that observed following ingestion of glucose (Elahi et al 1979). We then examined b cell sensitivity to endogenously released GIP as a function of age (Elahi et al 1984) and b cell sensitivity to exogenously administered GIP as a function of age and hyperglycaemia (Meneilly et al 1998) during hyperglycaemic clamps. b cell sensitivity to endogenously released GIP was analysed from the association of the ratio of insulin response after OGTT to that which would occur had OGTT not been administered, divided by the ratio of GIP response after administration of OGTT to GIP levels before administration of OGTT:

[IRI (90-120 min+GIP) / IRI (90-120 min - GIP)] / [GIP (90-120 min) / (GIP (0-60 min)]

There was a significant negative age relationship, indicating that b cell sensitivity to GIP is reduced with advancing age (Elahi et al 1984). In studies with exogenous infusion of GIP, two hyperglycaemic clamps were performed at a level of * 11 mmol/l and at * 18 mmol/l in young (19-26 years) and old (67-79 years) volunteers (Meneilly et al 1998). A total of 93 clamps were performed. During each clamp, GIP was infused for 60min at a dose of 2pmol'kg71'min71 and 4pmol'kg71'min71. A clamp was also performed, at each glycaemic level, without GIP administration. The GIP levels during the basal state, before the infusion of GIP at hyperglycaemia and after infusion, were similar between groups and between hyperglycaemic plateaus during the 2 and 4pmol'kg71'min71 infusions (60-120min levels = *350 and 580pmol/l, respectively). In response to GIP infusions, significant increases in insulin occurred in young and old at both glucose levels. The potentiation of the insulin response caused by GIP was greater in the young subjects than the old in the 11 mmol/l glucose hyperglycaemic study. However, the insulin response to GIP was similar in both young and old during the 18 mmol/l glucose hyperglycaemic clamps. The insulinotropic effect of this incretin was greater in both the young and the old in the 18 mmol/l clamps than in the 11 mmol/l clamps. We concluded that normal ageing is characterized by a decrease in b cell sensitivity to GIP during modest hyperglycaemia. The age-related impairment in response to GIP may be an important cause of the glucose intolerance of ageing, a precursor for diabetes in this age group. The insulinotropic effect of GIP is increased with increasing levels of glycaemia, and the defect in b cell response to GIP disappears when plasma glucose is increased to higher levels.

While we were examining the effect of GIP on insulin secretion, Habener and colleagues (Mojsov et al 1986) reported the identification of another gut hormone, glucagon-like peptide 1 (GLP1), and subsequently showed it to have a potent insulinotropic effect in rats (Weir et al 1989). Infusions of GLP1 were also subsequently shown to lower fasting plasma glucose levels in type 2 diabetic patients (Nathan et al 1992). We examined the insulinotropic effect of GLP1 in normal glucose-tolerant and in type 2 diabetic volunteers during hyperglycaemic clamp (* 11 mol/l) and compared its effect to that of GIP (Elahi et al 1994). We demonstrated that GLP1 is indeed a more potent insulinotropic hormone than GIP. Furthermore, there was an additive effect of GIP and GLP1 on b cell stimulation. Most importantly, we showed that while GLP1 has a potent insulinotropic effect in type 2 individuals, albeit less than in normal glucose tolerant individuals, the GIP insulinotropic effect is totally absent. Thus GLP1 is being investigated as a potential therapeutic agent for the normalization of glucose homeostasis in type 2 diabetes.

Recently, it has been shown during a hyperglycaemic clamp (* 11 mmol/l) GLP1 significantly potentiates insulin release in elderly type 2 diabetic volunteers (age 570 years). The potentiation is clinically relevant and at least threefold greater than insulin release with glucose alone (Fig. 7) (Meneilly et al 2001a). The same volunteers were also examined with a hyperinsulinaemic—euglycaemic clamp during infusion of somatostatin in the presence and absence of GLP1 (Meneilly et al 2001b). The plasma glucose was allowed to fall to a normal level in both euglycaemic clamps (* 5.3 mmol/l). During these two clamp studies both plasma insulin and glucose levels were similar. We showed that peripheral tissue sensitivity to insulin was significantly greater when GLP1 was infused. This study demonstrates that in states of glucose intolerance, such as type 2 diabetes, GLP1 has insulinomimetic, or at least insulin-augmenting, properties in peripheral tissues which can not be attributed to the well known delayed gastric emptying properties of GLP1. It was previously reported that while there was a small tendency for GLP1 to augment peripheral tissue sensitivity to insulin in young normal glucose tolerant men, the increase was not statistically significant (Ryan et al 1998).

We are currently examining the role of continuous subcutaneously administered GLP1 for 12 weeks in type 2 diabetic volunteers. These volunteers were previously

FIG. 7. Plasma glucose, insulin and C-peptide levels during the hyperglycaemic clamp studies.

being treated with oral hypoglycaemic agents and none had received insulin for control of blood glucose. Hyperglycaemic clamps (5.4mmol/l above basal glucose level) were performed before and at 12 weeks of GLP1 treatment. Our preliminary data have shown that GLP1 is at least as good as the usual hypoglycaemic agents in the control of glucose homeostasis, as demonstrated by the amount of insulin released during the clamp and by a lowering of HbA1C (Meneilly et al 2001c). More importantly, we obtained 2min samples before and

6 weeks after treatment with GLP1 during a hyperglycaemic clamp in two volunteers. Insulin release was evaluated by cluster analysis (Porksen et al 1995, Engdahl et al 1977). The results show that GLP1 restores insulin burst amplitude in the diabetic patients from a low level (* 8 pmol/l) to those normally observed in elderly individuals with a normal glucose tolerance (* 30 pmol/l) (Meneilly et al 2001c). Thus, this hormone appears to be an excellent candidate for the treatment of type 2 diabetes and studies from multiple research centres are currently evaluating the long-term efficacy of this hormone.

It should be noted that GLP1 has a relatively short half-life (*2min). Therefore, continuous infusion will most likely be necessary for its use as a monotherapeutic agent. This will probably not be well tolerated by the patient. However, its use will probably be most efficacious as a secondary agent and this use has several advantages which will become obvious as clinical trials continue. We also note that several investigators/pharmaceutical companies are making substitutions in the amino acid sequence of GLP1, which increase its half-life substantially. However, human clinical trials with these agents have not been reported other than for very acute administrations. Finally, there is a naturally occurring analogue of GLP1, exendin 4, which is found in the salivary gland of the Gila monster. This peptide has at least 10 times the potency of GLP1 and at least 150-fold longer half-life. Acute administration of this peptide augments insulin release markedly (Egan et al 1999). Additionally, limited experience in type 2 diabetic patients receiving twice daily administration of this peptide for a month has shown excellent control of glucose levels (J. M. Egan, G. S. Meneilly & D. Elahi, unpublished results 2001). There are no data from humans on the efficacy of this peptide as a function of age, to our knowledge.

We re-affirm that ageing is associated with a deterioration of glucose tolerance. The deterioration in large part can be attributed to insulin resistance and not insulin secretion. The cause of this deterioration is mainly attributable to lifestyle changes (increased adiposity, loss of LBM, reduced activity, changes in diet) or to genetic factors. That insulin resistance is not an obligatory result of ageing is best exemplified by the demonstration of maintained insulin secretion and action across the age-span in women athletes (Ryan et al 2001) and by preserved insulin action in healthy centenarians (102 0.8 years) compared to octogenarians (78 0.7 years) and middle-aged volunteers (44 1.8 years) (Barbieri et al 2001, Paolisso et al1996).

Acknowledgements

We express our appreciation to all the volunteers who participated in our studies. We also thank the staff of the clinical research centre at our various medical centres and the excellent technical support of our staff. We thank Restoragen, Inc. and Amylin Pharmaceutical, Inc. for the generous donation of drugs and their support. The studies were also supported in part by NIH

grant AG-00599, the intramural research program of the NIA, a grant from the Canadian Diabetes Association, and the Medical Research Council of Canada.

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