Physiological Aspects of Nutrient Handling

6. Physiological Aspects of Nutrient Handling

Before discussing details of the pathophysiology of feline diabetes, a few aspects of the physiological role of the key hormonal players will be briefly summarized. In healthy animals, pancreatic insulin secretion is controlled mainly by nutrients (Figure 6 & Figure 7). Insulin action in target tissues is mediated by the insulin receptor. Binding of insulin to its receptor activates the receptor intrinsic tyrosine kinase which then triggers rapid effects (e.g., translocation of the insulin-sensitive glucose transporter GLUT4 and modification of the activity of metabolic enzymes) and delayed effects relying on influences on gene transcription. The latter are mediated by the transcription factor peroxisome proliferator-activated receptor γ (PPARγ). This transcription factor is targeted by the antidiabetic drugs thiazolidinediones which increase insulin sensitivity.

Figure 6. Regulation of insulin secretion by glucose in pancreatic beta-cells.

Figure 7. Regulation of insulin secretion by amino acids and fatty acids in pancreatic beta-cells.

Pancreatic Glucose Sensing in Cats

Cats given intravenous or peroral glucose loads exhibit a strong increase in insulin secretion. Similarly, intravenous administration of amino acids, such as arginine, increases insulin secretion in cats. Under natural feeding conditions, nutrient induced insulin release seems to be very efficient because postprandial hyperglycemia is absent in cats fed a high protein diet (Figure 4a & Figure 4b). However, the relative contribution of amino acids versus glucose in respect to the meal induced increase in circulating insulin levels is less clear. In recent years, the nutrient sensing machinery in the feline pancreas has been partly elucidated (Schermerhorn, 2006). Despite the low activity of hepatic glucokinase (GK), pancreatic GK is present in cats and its activity seems to be comparable to other species. GK is one of the main components of the glucose sensing mechanism (Schuit et al., 2001). Other essential components such as subunits of ATP-sensitive K+ channels (Figure 6 & Figure 7), Kir6.2 and SUR1, have also been characterized in cats (Schermerhorn, 2006).

Potentiation of Nutrient-stimulated Insulin Secretion by Incretins

Nutrient-stimulated insulin secretion is potentiated by incretin hormones, the most important being glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP; formerly known as gastric inhibitory polypeptide). Incretins are defined as hormones that are released in response to nutrients and that potentiate nutrient-induced pancreatic insulin secretion. Due to incretin action, a given glucose load triggers a more pronounced insulin response when administered orally than parenterally (for review: Drucker, 2001).

In humans and laboratory rodents, GLP-1 is secreted in response to meal ingestion with blood levels rising postprandially. Part of GLP-1 secretion is due to a direct effect of luminal glucose on the ileal L-cells through a glucose sensing mechanism. It is believed, however, that nutrients also indirectly trigger the release of ileal GLP-1 because plasma GLP-1 levels rise within minutes after meal onset, i.e. long before any ingested nutrient might reach the ileum (Drucker, 2001). GLP-1’s potent insulinotropic effect is glucose-dependent and disappears at plasma glucose levels below approximately 4.5 mmol/l (80 mg/dL). Therefore, GLP-1 usually does not induce hypoglycemia. GLP-1 acts via a potentiation of glucose-induced insulin release, most likely by an interaction at the ATP-dependent K+-channel (see above; Figure 6), but also through effects directly involving the secretion of insulin granula.

GLP-1 also seems to stimulate insulin biosynthesis and the synthesis of the glucose sensing machinery, mainly the GLUT2 glucose transporter and glucokinase. Finally, GLP-1 also exerts trophic effects on beta-cells and its precursors, thereby stimulating beta-cell differentiation and proliferation. This is accompanied by an inhibition of beta-cell apoptosis which seems to play a major role in the development of human 2DM (Donath et al., 2005) and most likely feline DM.

Similar to amylin, GLP-1 has been shown to diminish glucagon release. This effect is glucose-dependent in that GLP-1 inhibits glucagon release at euglycemic or hyperglycemic levels but not at hypoglycemic levels when glucagon’s effect to defeat hypoglycemia is necessary and important.

Pancreatic Amylin

Pancreatic beta-cells are also the major source for amylin which is co-synthesized and co-secreted with insulin in response to appropriate stimuli (Lutz & Rand, 1996). The lack of amylin and its metabolic effects may play a role in the development of human 2DM and feline DM. These effects are unrelated to the propensity of human and feline amylin to form amyloid deposits which is another important contributing factor to feline DM (see below; O’Brien, 2002).

At least three hormonal effects of amylin are of physiological relevance and contribute to the regulation of nutrient metabolism:

• Inhibition of food intake (Lutz, 2005)
• Modulation of pancreatic glucagon release by reducing excessive postprandial hyperglycemia (Edelman & Weyer, 2002)
• Regulation of gastric emptying (Edelman & Weyer, 2002).

It should be mentioned that none of these effects has so far been confirmed in cats but their physiological relevance has clearly been shown in both humans and rodents. However, a preliminary study in healthy cats has shown that amylin may reduce circulating glucagon levels in cats (Furrer et al., 2005) (see also below and Figure 16). In humans, the amylin analogue pramlintide (Symlin®) is now an approved adjunct treatment to insulin for diabetic patients for its effects to reduce glucagon secretion and to inhibit gastric emptying.