Mild streptozotocin diabetes in the Göttingen minipig. A novel model of moderate insulin deficiency and diabetes

Abstract

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...

Reduction of beta cell mass: partial insulin secretory compensation from the residual beta cell population in the nicotinamide?streptozotocin G�ttingen minipig after oral glucose in vivo and in the perfused pancreas

“…Male Göttingen minipigs (aged 11-14 months, weight 26±3 kg [range [21][22][23][24][25][26][27][28][29][30], n=12) were obtained from the barrier unit at Ellegaard Göttingen minipigs (Dalmose, Denmark) and housed in single pens under controlled conditions as described previously [19]. Pigs were allowed at least 2 weeks recovery after surgery and were trained carefully in all experimental procedures prior to the start of the experiments.…”

“…Two central venous catheters (Certo 455, B. Braun Melsungen, Melsungen, Germany) were inserted surgically under general anaesthesia, and post-surgical analgesia was maintained as previously described [19]. At the start of the study period, all animals had recovered fully from the surgical procedure as evaluated by normal behaviour and eating patterns.…”

“…Beta cell mass was reduced in six animals using a combination of 67 mg/kg NIA (Sigma N-3376; Sigma-Aldrich, Steinheim, Germany) and 125 mg/kg STZ (Sigma S-0130; Sigma-Aldrich) as described previously [19], and six animals were kept as untreated controls.…”

“…The MMTT, consisting of 25 g SDS minipig fodder and 2 g/kg glucose (500 g/l; SAD, Copenhagen, Denmark), was performed in non-restrained animals as described previously [19]. The MMTT was performed in the beta-cell-reduced animals (NIA+STZ group) 1 week after treatment.…”

“…However, it is at present unclear how the changes observed in vitro relate to the defects in insulin secretion seen in individual beta-cell-reduced animals in vivo, and what their role in the development of diabetes might be. The nicotinamide (NIA)-streptozotocin (STZ) Göttingen minipig is a model of moderate insulin deficiency and hyperglycaemia due to a primary reduction in beta cell mass [19]. In this model, beta cell function in vivo has previously been demonstrated to be closely related to beta cell mass [20].…”