The
Carnivore Connection and Predisposition to Diabetes Mellitus
While the level of insulin resistance is certainly greater in cats with glucose intolerance or diabetes mellitus than it is in normal cats, it has been suggested that as a strict carnivore, the cat is inherently more insensitive to insulin and less able to cope with carbohydrate loads than other more omnivorous species. It has been proposed that during its evolutionary development the cat's natural diet of food of animal origin only has resulted in it becoming markedly adapted to a diet high in protein (approximately 54% of dry matter) and low in carbohydrates (approximately 8% of dry matter). This adaptation is reflected by the cat's unique metabolism of various nutrients, making it a true and strict carnivore. When comparing carbohydrate metabolism of the cat with those of other, more omnivorous species, there are a number of specific adaptations evident. These include altered levels of enzymes responsible for digestion and uptake of both starches and sugars in the intestine, an altered capacity to handle glucose loads including both a slower incorporation rate of glucose to glycogen and elongation of glucose elimination times with standard glucose tolerance tests, the effective absence of hepatic fructokinase and, perhaps most tellingly, the minimal hepatic glucokinase activity present in the cat. This low level of glucokinase activity limits the cat's ability to metabolise large glucose loads, as glucokinase has a far lower Km than hepatic hexokinase and hence is more readily able to respond to changes in blood glucose. According to the carnivore connection theory propagated by Brand Miller and Colagiuri, chronic ingestion of a low carbohydrate-high protein diet results in selection pressure favouring animals with a tendency for increased hepatic glucose production and decreased peripheral glucose utilisation, i.e., insulin resistance. Both the ability of insulin to inhibit hepatic glucose production and to augment tissue glucose disposal are therefore impaired. The increased hepatic glucose production is the result of the high protein intake and is mediated through an increased carbon flux through the gluconeogenic pathways. This increased carbon flux may be mediated by a number of different mechanisms including a mass action affect of increased concentrations of gluconeogenic substrates, an increase in glucagon levels that stimulate gluconeogenesis and/or the activation of a number of key enzymes in the gluconeogenic pathway. The decreased insulin stimulated glucose disposal by peripheral tissues is largely due to the decrease in carbohydrate intake and the consequent hypoinsulinaemia and/or reduced insulin efficacy peripherally, i.e., peripheral insulin resistance. In other words a predominantly carnivorous diet (or expressed another way a high protein-low carbohydrate diet) may produce metabolic adaptation which is effectively expressed as insulin resistance, both in the liver and peripheral tissues. As previously mentioned, insulin resistance in man is now recognised as the earliest metabolic defect in those destined to develop non-insulin dependent diabetes mellitus and enhanced insulin resistance is a feature of many diabetic cats. It has been proposed by the devotees of the carnivore connection theory that insulin resistance was the normal phenotype for an obligate or strict carnivore and this very insulin resistance increases the likelihood of the development of diabetes in strict carnivores fed a diet high in carbohydrate for any protracted period of time. Such diets, through evoking higher post prandial insulin responses, might lead to over stimulation of the pancreatic beta cells and ultimately result in their 'exhaustion' as well as of course reducing their functional capacity through such processes as glucose toxicity. When allowed to graze ad libitum, cats do not exhibit a post-prandial rise in blood glucose and hepatic glucokinase activity does not increase in response to increased carbohydrate feeding. Additional support for the cat's adaptation to a carnivorous diet is found with the levels of gluconeogenic enzymes present in feline hepatocytes. When a diet contains low amounts of glucose, hepatic gluconeogenesis is predicted to be the major pathway for maintaining blood glucose. Consistent with this latter expectation, the activities of key gluconeogenic enzymes, (glucose-6- phosphatase, fructose-1,6 bisphosphatase and pyruvate carboxylase) are increased in the liver of normal cats. Additionally, unlike the situation in rodents and man, the gluconeogenic capacity of the feline liver is not inhibited by glucose. The recently reported finding that in cats, stress hyperglycaemia is caused by enhanced hepatic glucose output rather than, as previously postulated, insulin resistance underscores the gluconeogenic potential of the feline liver and suggests its possible role in the genesis of pathological hyperglycaemia such as is observed in diabetes mellitus. Interestingly the low carbohydrate of the carnivore's diet may not be the only important factor in the development of impaired insulin secreting capacity. A recent study evaluating the effect of a high fat diet on glucose tolerance in intact male cats demonstrated a reduction in the acute insulin response to a glucose tolerance test suggesting diminished pancreatic insulin secretion and/or beta cell responsiveness to glucose as a result of high fat diets. Consequently the very adaptive processes that have favoured selection for the obligate carnivore also favour the development of hyperinsulinaemia and a chronic state of increased demand for insulin production being placed upon the beta cells of the pancreatic islets. While in its most overt form this may manifest itself as progressive islet destruction, in the cat, beta cell dysfunction appears to precede any obvious evidence for structural islet changes that can be correlated with this impaired function. Speaker Information |