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
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).
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.
Andersen DK, Elahi D, Brown JC, Tobin JD, Andres R 1978 Oral glucose augmentation of insulin secretion. Interactions of gastric inhibitory polypeptide with ambient glucose and insulin levels. J Clin Invest 62:152—161 Andres R 1971 Aging and diabetes. Med Clin North Am 55:835—846
Barbieri M, Rizzo MR, Manzella D, Paolisso G 2001 Age-related insulin resistance: is it and obligatory finding? The lesson from healthy centenarians. Diabetes Metab Res Rev 17:19—26 Bennett PH, Rushfroth NB, Miller M, Lecompte PM 1976 Epidemiologic studies of diabetes in the Pima Indians. Recent Prog Horm Res 32:333—376 Broughton DL, Taylor R 1991 Review: deterioration of glucose tolerance with age: the role of insulin resistance. Age Ageing 20:221—225 Chen M, Bergman R, Pacini G, Porte DJ 1985 Pathogenesis of age-related glucose intolerance in man: insulin resistance and decreased beta-cell function. J Clin Endocrinol Metab 60:13—20 Coon PJ, Bleecker ER, Drinkwater DT, Meyers DA, Goldberg AD 1989 Effects of body composition and exercise capacity on glucose tolerance, insulin, and lipoprotein lipids in healthy older men: a cross-sectional and longitudinal intervention study. Metabolism
Davidson MB 1979 The effect of aging on carbohydrate metabolism: a review of the English literature and a practical approach to the diagnosis of diabetes mellitus in the elderly. Metabolism 28:688—705 DeFronzo RA 1979 Glucose intolerance and aging: evidence for tissue insensitivity to insulin.
Diabetes 28:1095—1101 DeFronzo RA 1981 Glucose intolerance and aging. Diabetes Care 4:493—501 DeFronzo RA 1988 Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 37:667—687 DeFronzo R, Ferrannini E 1991 Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 14:173—194 DeFronzo R, Tobin JD, Andres R 1979 Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237:E214—E223 DeFronzo RA, Ferrannini E, Hendler R, Felig P, Wahren J 1983 Regulation of splanchnic and peripheral glucose uptake by insulin and hyperglycemia in man. Diabetes 32:35—45 Dowse G, Spark R, Mavo B et al 1994 Extraordinary prevalence of non-insulin-dependent diabetes mellitus and bimodal plasma glucose distribution in the Wanigela people of Papua New Guinea. Med J Aust 160:767—774 Egan J, Clocquet A, Elahi D 1999 Insulinotropic effect of exendin-4 in humans. Diabetologia 42:148A
Elahi D 1996 In praise of the hyperglycemic clamp. A method of assessment of beta-cell sensitivity and insulin resistance. Diabetes Care 19:278—286 Elahi D, Muller DC 2000 Carbohydrate metabolism in the elderly. Eur J Clin Nutr 54: S112— S120
Elahi D, Andersen DC, Brown J et al 1979 Pancreatic alpha- and beta-cell responses to GIP
infusion in normal man. Am J Physiol 237:E185—E191 Elahi D, Andersen DC, Muller DC, Tobin JD, Brown JC, Andres R 1984 The enteric enhancement of glucose-stimulated insulin release. The role of GIP in aging, obesity and non-insulin-dependent diabetes mellitus. Diabetes 33:950—957
Elahi D, Muller DC, McAloon-Dyke M, Tobin JD, Andres R 1993 The effect of age on insulin response and glucose utilization during four hyperglycemic plateaus. Exp Gerontol 28:393— 409
Elahi D, McAloon-Dyke M, Fukagawa N et al 1994 The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7-37) in normal and diabetic subjects. Regul Pept 51:63—74 Engdahl J, Veldhuis J, Farrell P 1977 Altered pulsatile insulin secretion associated with endurance training. J Appl Physiol 79:1977—1985 Evans W, Farrell P 2001 The aging pancreas: effects of aging on insulin secretion action. In: Jefferson LS, Cherrington AD (eds) Handbook of Physiology. Section 7: The endocrine system. Vol 2: The endocrine pancreas and regulation of metabolism. Oxford University Press, Oxford, p 969—998 Ferrannini E, Vichi S, Beck-Nielsen H, Laakso M, Paolisso G, Smith U 1996 Insulin action and age. European group for the study of insulin resistance (EGIR). Diabetes 45:947—953 FinkRI, Kolterman OG, Griffin J, Olefsky JM 1983 Mechanisms of insulin resistance inaging. J
Clin Invest 71:1523—1535 Harris M, Flegal K, Cowie C et al 1998 Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in US adults. The third national health and nutrition examination survey, 1988—1994. Diabetes Care 21:518—524 Jackson RA, Blix PM, Matthews JA et al 1982 Influence of ageing on glucose homeostasis. J Clin
Endocrinol Metab 55:840—848 Kaplan NM 1989 The deadly quartet. Upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Arch Intern Med 149:1514—1520 Loo SG, Dowse GK, Finch C, Zimmet P 1993 Bimodality analysis of frequency distributions of 2-hour plasma glucose concentrations in the urban Micronesian population of Kiribati. J Diabetes Complicat 7:73—80 Maneatis T, Condie R, Reaven G 1982 Effect of age on plasma glucose and insulin responses to a test mixed meal. J Am Geriatr Soc 30:178—182 Meneilly G, Minaker K, Elahi D, Rowe J 1987 Insulin action in aging man: evidence for tissue-
specific differences at low physiologic insulin levels. J Gerontol 42:196—201 Meneilly GS, Ryan AS, Veldhuis JD, Elahi D 1997 Increased disorderliness of basal insulin release, attenuated insulin secretory burst mass, and reduced ultradian rhythmicity of insulin secretion in older individuals. J Clin Endocrinol Metab 82:4088—4093 Meneilly GS, Ryan AS, Minaker KL, Elahi D 1998 The effect of age and glycemic level on the response of the b-cell to glucose-dependent insulinotropic polypeptide and peripheral tissue sensitivity to endogenously released insulin. J Clin Endocrinol Metab 83:2925—2932 Meneilly G, Veldhuis J, Elahi D 1999 Disruption of the pulsatile and entropic modes of insulin release during an unvarying glucose stimulus in elderly individuals. J Clin Endocrinol Metab 84:1938—1943
Meneilly G, McIntosh CHS, Pederson R et al 2001a Glucagon-like peptide-1 (7-37) augments insulin release in elderly patients with diabetes. Diabetes Care 24:964—965 Meneilly GS, McIntosh CHS, Pederson RA et al 2001b Effect of glucagon-like peptide-1 on noninsulin-mediated glucose uptake in the elderly patient with diabetes. Diabetes Care, in press Meneilly G, Egan J, Greig N, Veldhuis J, Habener J, Elahi D 2001c Twelve Weeks of
Continuous Administration of GLP-1 in Elderly Diabetic Patients. Diabetologia 44:910A Mojsov S, Heinrich G, Wilson I, Ravazzola M, Orci L, Habener J 1986 Preproglucagon gene expression in pancreas and intestine diversifies at the level of post-translational processing.
J Biol Chem 261:11880—11889 Natali A, Toschi E, Camastra S, Gastaldelli A, Groop L, Ferrannini E 2000 Determinants of postabsorptive endogenous glucose output in non-diabetic subjects. European group for the study of insulin resistance (EGIR). Diabetologia 43:1266—1272
Nathan D, Schreiber E, Fogel H, Mojsov S, Habener J 1992 Insulinotropic action of glucagonlike peptide-I (7-37) in diabetic and nondiabetic subjects. Diabetes Care 15: 270-276
National Diabetes Data Group 1979 Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 28:1039-1057 Pacini G, Valerio A, Beccaro F, Nosadini R, Cobelli C, Crepaldi G 1988 Insulin sensitivity and beta-cell responsivity are not decreased in elderly subjects with normal OGTT. J Am Geriatr Soc 36:317-323
Paolisso G, Gambardella A, Ammendola S et al 1996 Glucose tolerance and insulin action in healthy centenarians. Am J Physiol 33:E890-E894 Perley M, Kipnis D 1967 Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic subjects. J Clin Invest 46:1954-1962 Pimenta W, Korytkowski M, Mitrakou A et al 1995 Pancreatic beta-cell dysfunction as the primary genetic lesion in NIDDM. Evidence from studies in normal glucose tolerant individuals with a first-degree NIDDM relative. JAMA 273: 1855-1861 Porksen N, Munn S, Steer J, Vore S, Veldhuis J, Butler P 1995 Pulsatile insulin secretion accounts for 70% of total insulin secretion during fasting. Am J Physiol 269:E478-E488 Reaven G 1988 Banting Lecture 1988. Role of insulin resistance in human disease. Diabetes 37:1595-1607
Reaven G, Chen N, Hollenbeck C, Chen YD 1989 Effect of age on glucose tolerance and glucose uptake in healthy individuals. J Am Geriatr Soc 37:735-740 Rizza RA, Mandarino LJ, Gerich JE 1981 Dose-response characteristics for effects of insulin on production and utilization of glucose in man. Am J Physiol 240:E630-E639 Rosenthal M, McMahan CA, Stern MP et al 1985 Evidence of bimodality of two hour plasma glucose concentrations in Mexican Americans: results from the San Antonio Heart Study. J Chronic Dis 38:5-16
Rowe J, Minaker K, Pallota J, Flier J 1983 Characterization of the insulin resistance of aging. J
Clin Invest 71:1581-1587 Ryan A, Elahi D 1996 The effects of acute hyperglycemia and hyperinsulinemia on plasma leptin levels: its relationships with body fat, visceral adiposity, and age in women. J Clin Endocrinol Metab 81:4433-4438
Ryan AS, Egan JM, Habener JF, Elahi D 1998 Insulinotropic hormone glucagon-like peptide-1-(7-37) appears not to augment insulin-mediated glucose uptake in young men during euglycemia. J Clin Endocrinol Metab 83:2399-2404 Ryan A, Muller D, Elahi D 2001 Sequential hyperglycemic-euglycemic clamp to assess b-cell and peripheral tissue: studies in female athletes. J Appl Physiol 91:872-881 Shimokata H, Muller DC, Fleg JL, Sorkin J, Ziemba AW, Andres R1991 Age as an independent determinant of glucose tolerance. Diabetes 40:44-51 Stout RW 1990 Insulin and atheroma. Diabetes Care 13:631-654
The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus 1997 Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 20:1183-1197
Weir GC, Mojsov S, Hendrick GK, Habener JF 1989 Glucagonlike peptide I (7-37) actions on endocrine pancreas. Diabetes 38:338-342 WHO 1985 Diabetes mellitus. World Health Organization, Geneva (Technical Report Series
WHO 1999 Definition, diagnosis and classification of diabetes mellitus and its complications. Report of a WHO consultation, part 1: Diagnosis and classification of diabetes mellitus. World Health Organization, Geneva Zamboni M, Armellini F, Harris T et al 1997 Effects of age on body fat distribution and cardiovascular risk factors in women. Am J Clin Nutr 66:111-115
Zavaroni I, Dall'Aglio E, Bruschi F et al1986 Effect of age and environmental factors on glucose tolerance and insulin secretion in a worker population. J Am Geriatr Soc 34:271—275 Zimmet P, Whitehouse S 1978 Bimodality of fasting and two-hour glucose tolerance distributions in a Micronesian population. Diabetes 27:793—800
Was this article helpful?
I can't believe I'm actually writing the book that is going to help you achieve the level of health and fitness that you always dreamed of. Me, little scrawny sickly Darlene that was always last picked in gym class. There's power in a good story here so get this book now.