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Richard W Nelson and Claudia E Reusch

Diabetes mellitus is a common disease in dogs and cats. The most common form of diabetes in dogs resembles type 1 diabetes in humans. Studies suggest that genetics, an immune-mediated component, and environmental factors are involved in the development of diabetes in dogs. A variant of gestational diabetes also occurs in dogs. The most common form of diabetes in cats resembles type 2 diabetes in humans. A major risk factor in cats is obesity. Obese cats have altered expression of several insulin signaling genes and glucose transporters and are leptin resistant. Cats also form amyloid deposits within the islets of the pancreas and develop glucotoxicity when exposed to prolonged hyperglycemia. This review will briefly summarize our current knowledge about the etiology of diabetes in dogs and cats and illustrate the similarities among dogs, cats, and humans.

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ST Dheen, K Rajkumar, and LJ Murphy

Transgenic mice which overexpress insulin-like growth factor binding protein-1 (IGFPB-1) demonstrate fasting hyperglycemia, hyperinsulinemia and glucose intolerance in adult life. Here we have examined the ontogeny of pancreatic endocrine dysfunction and investigated islet cell proliferation and apoptosis in this mouse model. In addition we have examined pancreatic insulin content in transgenic mice derived from blastocyst transfer into non-transgenic mice. Transgenic mice were normoglycemic at birth but had markedly elevated plasma insulin levels, 56.2 +/- 4.5 versus 25.4 +/- 1.5 pmol/l, p < 0.001, and pancreatic insulin concentration, 60.5 +/- 2.5 versus 49.0 +/- 2.6 ng/mg of tissue, P < 0.01, compared with wild-type mice. Transgenic mice derived from blastocyst transfer to wild-type foster mothers had an elevated pancreatic insulin content similar to that seen in pups from transgenic mice. There was an age-related decline in pancreatic insulin content and plasma insulin levels and an increase in fasting blood glucose concentrations, such that adult transgenic mice had significantly less pancreatic insulin than wild-type mice. Pancreatic islet number and the size of mature islets were increased in transgenic animals at birth compared with wild-type mice. Both islet cell proliferation, measured by 5-bromo-2'-deoxyuridine labeling, and apoptosis, assessed by the in situ terminal deoxynucleotidyl transferase and nick translation assay, were increased in islets of newborn transgenic mice compared with wild-type mice. In adult mice both islet cell proliferation and apoptosis were low and similar in transgenic and wild-type mice. Islets remained significantly larger and more numerous in adult transgenic mice despite a reduction in pancreatic insulin content. These data suggest that overexpression of IGFBP-1, either directly or indirectly via local or systemic mechanisms, has a positive trophic effect on islet development.

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Olena A Fedorenko, Pawitra Pulbutr, Elin Banke, Nneoma E Akaniro-Ejim, Donna C Bentley, Charlotta S Olofsson, Sue Chan, and Paul A Smith

L-type channel antagonists are of therapeutic benefit in the treatment of hyperlipidaemia and insulin resistance. Our aim was to identify L-type voltage-gated Ca2+ channels in white fat adipocytes, and determine if they affect intracellular Ca2+, lipolysis and lipogenesis. We used a multidisciplinary approach of molecular biology, confocal microscopy, Ca2+ imaging and metabolic assays to explore this problem using adipocytes isolated from adult rat epididymal fat pads. CaV1.2, CaV1.3 and CaV1.1 alpha1, beta and alpha2delta subunits were detected at the gene expression level. The CaV1.2 and CaV1.3 alpha1 subunits were identified in the plasma membrane at the protein level. Confocal microscopy with fluorescent antibodies labelled CaV1.2 in the plasma membrane. Ca2+ imaging revealed that the intracellular Ca2+ concentration, [Ca2 +]i was reversibly decreased by removal of extracellular Ca2+, an effect mimicked by verapamil, nifedipine and Co2+, all blockers of L-type channels, whereas the Ca2+ channel agonist BAY-K8644 increased [Ca2+]i. The finding that the magnitude of these effects correlated with basal [Ca2+]i suggests that adipocyte [Ca2+]i is controlled by L-type Ca2+ channels that are constitutively active at the adipocyte depolarized membrane potential. Pharmacological manipulation of L-type channel activity modulated both basal and catecholamine-stimulated lipolysis but not insulin-induced glucose uptake or lipogenesis. We conclude that white adipocytes have constitutively active L-type Ca2+ channels which explains their sensitivity of lipolysis to Ca2+ channel modulators. Our data suggest CaV1.2 as a potential novel therapeutic target in the treatment of obesity.

Free access

K Fosgerau, P Galle, T Hansen, A Albrechtsen, C de Lemos Rieper, B Klarlund Pedersen, L Kongskov Larsen, A Randrup Thomsen, O Pedersen, M Bagge Hansen, and A Steensberg

Abstract

Interleukin-6 (IL6) is critically involved in inflammation and metabolism. About 1% of people produce IL6 autoantibodies (aAb-IL6) that impair IL6 signaling in vivo. We tested the hypothesis that the prevalence of such aAb-IL6 is increased in type 2 diabetic patients and that aAb-IL6 plays a direct role in causing hyperglycemia. In humans, the prevalence of circulating high-affinity neutralizing aAb-IL6 was 2.5% in the type 2 diabetic patients and 1% in the controls (odds ratio 2.5, 95% confidence interval 1.2–4.9, P=0.01). To test for the role of aAb-IL6 in causing hyperglycemia, such aAb-IL6 were induced in mice by a validated vaccination procedure. Mice with plasma levels of aAb-IL6 similar to the 2.5% type 2 diabetic patients developed obesity and impaired glucose tolerance (area under the curve (AUC) glucose, 2056±62 vs 1793±62, P=0.05) as compared with sham-vaccinated mice, when challenged with a high-fat diet. Mice with very high plasma levels of aAb-IL6 developed elevated fasting plasma glucose (mM, 4.8±0.4 vs 3.3±0.1, P<0.001) and impaired glucose tolerance (AUC glucose, 1340±38 vs 916±25, P<0.001) as compared with sham-control mice on normal chow. In conclusion, the prevalence of plasma aAb-IL6 at levels known to impair IL6 signaling in vivo is increased 2.5-fold in people with type 2 diabetes. In mice, matching levels of aAb-IL6 cause obesity and hyperglycemia. These data suggest that a small subset of type 2 diabetes may in part evolve from an autoimmune attack against IL6.

Free access

Yoko Yagishita, Akira Uruno, Dionysios V Chartoumpekis, Thomas W Kensler, and Masayuki Yamamoto

The transcription factor Nrf2 (NF-E2-related factor 2) plays a critical role in oxidative stress responses. Although activation of Nrf2 signaling is known to exert anti-inflammatory effects, the function of Nrf2 in inflammation-mediated autoimmune disorders, such as type 1 diabetes, is not well established. To address the roles of Nrf2 in protection against autoreactive T-cell-induced type 1 diabetes, we used non-obese diabetic (NOD) mice, which are a polygenic model of human type 1 diabetes, to generate a genetic model for assessment of the contribution of Nrf2 activation to prevention and/or treatment of type 1 diabetes. Because Keap1 (Kelch-like ECH-associated protein 1) negatively regulates Nrf2, we used Keap1 gene knockdown driven by either hypomorphic or knockout Keap1 alleles, which enhanced Nrf2 signaling to moderate or excess levels, respectively. Nrf2 activation in the NOD::Keap1 FA/ mice inhibited T-cell infiltration within or near the islets, ameliorated impairment of insulin secretion and prevented the development of diabetes mellitus. Notably, Nrf2 activation decreased both the plasma interferon-γ (IFN-γ) levels and the IFN-γ-positive cell numbers in the pancreatic islets. The amelioration of diabetes was also observed in the NOD mice with two hypomorphic Keap1 alleles (Keap1 FA/FA) by intermediate activation of Nrf2. Both NOD::Keap1 FA/ and NOD::Keap1 FA/FA mice had a decreased incidence of diabetes mellitus, demonstrating that activation of Nrf2 signaling prevented the onset of type 1 diabetes mellitus in NOD mice. Thus, Nrf2 appears to be a potential target for the prevention and treatment of type 1 diabetes.

Free access

Ronald Gonzalez, Benjamin K Reingold, Xiaodong Gao, Mandeep P Gaidhu, Robert G Tsushima, and Suraj Unniappan

Nesfatin-1 is a recently discovered multifunctional metabolic hormone abundantly expressed in the pancreatic islets. The main objective of this study is to characterize the direct effects of nesfatin-1 on insulin secretion in vitro using MIN6 cells and islets isolated from C57BL/6 mice. We also examined the expression of the nesfatin-1 precursor protein, nucleobindin 2 (NUCB2) mRNA, and nesfatin-1 immunoreactivity (ir) in the islets of normal mice and in the islets from mice with streptozotocin-induced type 1 diabetes and diet-induced obese (DIO) mice with type 2 diabetes. Nesfatin-1 stimulated glucose-induced insulin release in vitro from mouse islets and MIN6 cells in a dose-dependent manner. No such stimulation in insulin secretion was found when MIN6 cells/islets were incubated with nesfatin-1 in low glucose. In addition, a fourfold increase in nesfatin-1 release from MIN6 cells was observed following incubation in high glucose (16.7 mM) compared to low glucose (2 mM). Furthermore, we observed a significant reduction in both NUCB2 mRNA expression and nesfatin-1-ir in the pancreatic islets of mice with type 1 diabetes, while a significant increase was observed in the islets of DIO mice. Together, our findings indicate that nesfatin-1 is a novel insulinotropic peptide and that the endogenous pancreatic islet NUCB2/nesfatin is altered in diabetes and diet-induced obesity.

Free access

J Han and Y Q Liu

Pyruvate carboxylase (PC) activity is enhanced in the islets of obese rats, but it is reduced in the islets of type 2 diabetic rats, suggesting the importance of PC in β-cell adaptation to insulin resistance as well as the possibility that PC reduction might lead to hyperglycemia. However, the causality is currently unknown. We used obese Agouti mice (AyL) as a model to show enhanced β-cell adaptation, and type 2 diabetic db/db mice as a model to show severe β-cell failure. After comparison of the two models, a less severe type 2 diabetic Agouti-K (AyK) mouse model was used to show the changes in islet PC activity during the development of type 2 diabetes mellitus (T2DM). AyK mice were separated into two groups: mildly (AyK-M, blood glucose <250 mg/dl) and severely (AyK-S, blood glucose >250 mg/dl) hyperglycemic. Islet PC activity, but not protein level, was increased 1.7-fold in AyK-M mice; in AyK-S mice, islet PC activity and protein level were reduced. All other changes including insulin secretion and islet morphology in AyK-M mice were similar to those observed in AyL mice, but they were worse in AyK-S mice where these parameters closely matched those in db/db mice. In 2-day treated islets, PC activity was inhibited by high glucose but not by palmitate. Our findings suggest that islet PC might play a role in the development of T2DM where reduction of PC activity might be a consequence of mild hyperglycemia and a cause for severe hyperglycemia.

Free access

A Shirakami, T Toyonaga, K Tsuruzoe, T Shirotani, K Matsumoto, K Yoshizato, J Kawashima, Y Hirashima, N Miyamura, CR Kahn, and E Araki

Insulin receptor substrate 1 (IRS-1) gene polymorphisms have been identified in type 2 diabetic patients; however, it is unclear how such polymorphisms contribute to the development of diabetes. Here we introduced obesity in heterozygous IRS-1 knockout (IRS-1(+/-)) mice by gold-thioglucose (GTG) injection and studied the impact of reduced IRS-1 expression on obesity-linked insulin resistance. GTG injection resulted in approximately 30% weight gain in IRS-1(+/-) and wild type (WT) mice, compared with saline-injected controls. There was no difference in insulin sensitivity between lean IRS-1(+/-) and lean WT. Elevated fasting insulin levels but no change in fasting glucose were noted in obese IRS-1(+/-) and WT compared with the respective lean controls. Importantly, fasting insulin in obese IRS-1(+/-) was 1.5-fold higher (P<0.05) than in obese WT, and an insulin tolerance test showed a profound insulin resistance in obese IRS-1(+/-) compared with obese WT. The islets of obese IRS-1(+/-) were 1.4-fold larger than those of obese WT. The expression of insulin receptor and IRS-1 and IRS-2 was decreased in obese IRS-1(+/-), which could in part explain the profound insulin resistance in these mice. Our results suggest that IRS-1 is the suspected gene for type 2 diabetes and its polymorphisms could worsen insulin resistance in the presence of other additional factors, such as obesity.

Free access

Xue Jiang, Jia Xiao, Mulan He, Ani Ma, and Anderson O L Wong

Type II suppressor of cytokine signaling (SOCS) serve as feedback repressors for cytokines and are known to inhibit growth hormone (GH) actions. However, direct evidence for SOCS modulation of GH-induced insulin-like growth factor 1 (Igf1) expression is lacking, and the post-receptor signaling for SOCS expression at the hepatic level is still unclear. To shed light on the comparative aspects of SOCS in GH functions, grass carp was used as a model to study the role of type II SOCS in GH-induced Igf1 expression. Structural identity of type II SOCS, Socs1–3 and cytokine-inducible SH2-containing protein (Cish), was established in grass carp by 5’/3’-RACE, and their expression at both transcript and protein levels were confirmed in the liver by RT-PCR and LC/MS/MS respectively. In carp hepatocytes, GH treatment induced rapid phosphorylation of JAK2, STATs, MAPK, PI3K, and protein kinase B (Akt) with parallel rises in socs13 and cish mRNA levels, and these stimulatory effects on type II SOCS were shown to occur before the gradual loss of igf1 gene expression caused by prolonged exposure of GH. Furthermore, GH-induced type II SOCS gene expression could be negated by inhibiting JAK2, STATs, MEK1/2, P38 MAPK, PI3K, and/or Akt respectively. In CHO cells transfected with carp GH receptor, over-expression of these newly cloned type II SOCS not only suppressed JAK2/STAT5 signaling with GH treatment but also inhibited GH-induced grass carp Igf1 promoter activity. These results, taken together, suggest that type II SOCS could be induced by GH in the carp liver via JAK2/STATs, MAPK, and PI3K/Akt cascades and serve as feedback repressors for GH signaling and induction of igf1 gene expression.

Free access

Kanta Kon, Hiroshi Tsuneki, Hisakatsu Ito, Yoshinori Takemura, Kiyofumi Sato, Mitsuaki Yamazaki, Yoko Ishii, Masakiyo Sasahara, Assaf Rudich, Takahiro Maeda, Tsutomu Wada, and Toshiyasu Sasaoka

Disrupted sleep is associated with increased risk of type 2 diabetes. Central actions of orexin, mediated by orexin-1 and orexin-2 receptors, play a crucial role in the maintenance of wakefulness; accordingly, excessive activation of the orexin system causes insomnia. Resting-phase administration of dual orexin receptor antagonist (DORA) has been shown to improve sleep abnormalities and glucose intolerance in type 2 diabetic db/db mice, although the mechanism remains unknown. In the present study, to investigate the presence of functional link between sleep and glucose metabolism, the influences of orexin antagonists with or without sleep-promoting effects were compared on glucose metabolism in diabetic mice. In db/db mice, 2-SORA-MK1064 (an orexin-2 receptor antagonist) and DORA-12 (a DORA) acutely improved non-rapid eye movement sleep, whereas 1-SORA-1 (an orexin-1 receptor antagonist) had no effect. Chronic resting-phase administration of these drugs improved glucose intolerance, without affecting body weight, food intake, locomotor activity and energy expenditure calculated from O2 consumption and CO2 production. The expression levels of proinflammatory factors in the liver were reduced by 2-SORA-MK1064 and DORA-12, but not 1-SORA-1, whereas those in the white adipose tissue were reduced by 1-SORA-1 and DORA-12 more efficiently than 2-SORA-MK1064. When administered chronically at awake phase, these drugs caused no effect. In streptozotocin-induced type 1-like diabetic mice, neither abnormality in sleep–wake behavior nor improvement of glucose intolerance by these drugs were observed. These results suggest that both 1-SORA-type (sleep-independent) and 2-SORA-type (possibly sleep-dependent) mechanisms can provide chronotherapeutic effects against type 2 diabetes associated with sleep disturbances in db/db mice.