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The system that regulates insulin secretion from beta-cells in the islet of Langerhans has a capsaicin-sensitive inhibitory component. As calcitonin gene-related peptide (CGRP)-expressing primary sensory fibers innervate the islets, and a major proportion of the CGRP-containing primary sensory neurons is sensitive to capsaicin, the islet-innervating sensory fibers may represent the capsaicin-sensitive inhibitory component. Here, we examined the expression of the capsaicin receptor, vanilloid type 1 transient receptor potential receptor (TRPV1) in CGRP-expressing fibers in the pancreatic islets, and the effect of selective elimination of capsaicin-sensitive primary afferents on the decline of glucose homeostasis and insulin secretion in Zucker diabetic fatty (ZDF) rats, which are used to study various aspects of human type 2 diabetes mellitus. We found that CGRP-expressing fibers in the pancreatic islets also express TRPV1. Furthermore, we also found that systemic capsaicin application before the development of hyperglycemia prevents the increase of fasting, non-fasting, and mean 24-h plasma glucose levels, and the deterioration of glucose tolerance assessed on the fifth week following the injection. These effects were accompanied by enhanced insulin secretion and a virtually complete loss of CGRP- and TRPV1-coexpressing islet-innervating fibers. These data indicate that CGRP-containing fibers in the islets are capsaicin sensitive, and that elimination of these fibers contributes to the prevention of the deterioration of glucose homeostasis through increased insulin secretion in ZDF rats. Based on these data we propose that the activity of islet-innervating capsaicin-sensitive fibers may have a role in the development of reduced insulin secretion in human type 2 diabetes mellitus.

Intermediate NIA doses induced moderate changes of glucose tolerance [glucose area under the curve increased from 940 Ϯ 175 to 1,598 Ϯ 462 mM ⅐ min, P Ͻ 0.001 (100 mg/kg) and from 890 Ϯ 109 to 1,669 Ϯ 691 mM ⅐ min, P ϭ 0.003 (67 mg/kg)] with reduced insulin secretion [1,248 Ϯ 602 pM ⅐ min after 16 days and 1,566 Ϯ 190 pM ⅐ min after 60 days vs. 3,251 Ϯ 804 pM ⅐ min in normal animals (P Ͻ 0.001)] and ␤-cell mass [5.5 Ϯ 1.4 mg/kg after 27 days and 7.9 Ϯ 4.1 mg/kg after 60 days vs. 17.7 Ϯ 4.7 mg/kg in normal animals (P ϭ 0.009)]. The combination of NIA and STZ provided a model characterized by fasting and especially postprandial hyperglycemia and reduced, but maintained, insulin secretion and ␤-cell mass. This model holds promise as an important tool for studying the pathophysiology of diabetes and development of new pharmacological agents for treatment of the disease.in vivo pharmacology; large-animal model; glucose tolerance; ␤-cell reduction; glucose-stimulated insulin secretion.THE STUDY OF THE PATHOPHYSIOLOGY and treatment of diabetes requires well characterized animal models that resemble aspects of the disease in humans. Various forms of diabetes occur spontaneously or can be induced in several species of animals. Most of the available models are based on rodents; however, nonrodent models of diabetes are urgently needed as a valuable supplement to rodents for both practical and physiological reasons.The pig is useful as a model for human physiology and pathophysiology, because many organ systems resemble those of the human. Of special interest for the study of diabetes is the similarities to humans found in the clinical chemistry (7,10,12,14,24,26,55), nutrition and gastrointestinal tract (4,8,11,20,35,40,51), pancreas development and morphology (21,36,37,44,49,54), and metabolism (3, 35). These characteristics make swine an interesting species for studies of metabolic abnormalities in diabetes. The Göttingen minipig is especially suitable for long-term studies because of its small size and ease of handling, even at full maturity (6).Pancreatectomy has been investigated as a method of inducing diabetes in pigs (33,34,50,55). However, high rates of mortality have been observed postoperatively (50, 55), meaning that this technique should be used with great caution, and alternatives should be considered because of welfare considerations. Chemical induction of diabetes offers the advantage of preservation of both exocrine and endocrine cell populations other than ␤-cells, thus resembling the situation in human diabetes (55). Several stable models have been established for overt type 1 diabetes in the pig by the use of pharmacological induction of ␤-cell damage with streptozotocin (STZ), either as single or repeated injections (2, 15, 16, 27-29, 46, 55). Substantially increased fasting plasma glucose (FPG) levels and decreased insulin secretion in response to glucose stimuli have been obtained as well as increases in plasma triglycerides and total cholesterol (27,29). Late complications typical of diabetes, such...

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Objective: It has earlier been demonstrated that capsaicin-induced desensitization improves insulin sensitivity in normal rats. However, whether increased capsaicin-sensitive nerve activity precedes the onset of insulin resistance in diet-induced obesity -and therefore might be involved in the pathophysiology -is not known. Further, it is of relevance to investigate whether capsaicin desensitization improves glycaemic control even in obese individuals and we therefore chose the obese Zucker rats to test this. Design and methods: Plasma levels of calcitonin gene-related peptide (CGRP; a marker of sensory nerve activity) was assessed in 8-week-old Zucker rats. To investigate whether capsaicin desensitization (100 mg/kg at 9 weeks of age) would also ameliorate glycaemia in this non-diabetic model, we assessed oral glucose tolerance at 7 weeks after capsaicin. Results: It was found that plasma CGRP levels were elevated in obese Zucker rats prior to the onset of obesity (16.1^3.4 pmol/l in pre-obese Zucker rats vs 6.9^1.1 pmol/l in lean littermates; P ¼ 0.015) despite similar body weights. Furthermore, capsaicin desensitization reduced both fasting blood glucose (4.3^0.2 mmol/l vs 5.1^0.2 mmol/l in controls; P ¼ 0.050) as well as the mean blood glucose level during an oral glucose tolerance test (OGTT) (6.8^0.3 mmol/l vs 8.6^0.5 mmol/l in control obese rats; P ¼ 0.024) whereas the plasma insulin levels during the OGTT were unchanged. However this did not lead to an improvement in insulin resistance or to a reduction of tissue triglyceride accumulation in muscle or liver. Conclusion: We concluded that capsaicin-induced sensory nerve desensitization improves glucose tolerance in Zucker rats. Since, in this study, plasma CGRP levels, a marker of sensory nerve activity, were increased in the pre-obese rats, our data support the hypothesis that increased activity of sensory nerves precedes the development of obesity and insulin resistance in Zucker rats. European Journal of Endocrinology 153 963-969

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