Diabetes Mellitus and the Kidneys.

The pathomechanisms implicated in diabetic kidney disease in people are present in dogs and cats and, in theory, could lead to renal complications in companion animals with long-standing diabetes mellitus. However, these renal complications develop during a long period, and there is little to no clinical evidence that they could lead to chronic kidney disease in companion animals.

p-Coumaric acid attenuates high-fat diet-induced oxidative stress and nephropathy in diabetic rats.

The prevalence of persistent hyperglycaemia during diabetes, impair antioxidant defence system and generate reactive oxygen species, which majorly contribute to its progression and associated complications. Phytochemicals were suggested to scavenge-free radicals and exert antioxidant effects required to improve insulin sensitivity and reduce the occurrence of diabetes-associated complications. We hypothesise that a phenolic phytochemical p-coumaric can reduce diabetes-induced oxidative stress and improve diabetes-associated nephropathy in rats. The aim of this study is to analyse the protective effects of p-coumaric acid against diabetes-induced oxidative stress and nephropathy in high-fat diet-induced diabetic rats. The oral feeding of p-coumaric acid (20 mg/kg for 12 weeks) was found to significantly decrease the elevated levels of blood glucose in high-fat diet-induced type 2 diabetic rats. p-Coumaric acid treatment also decreases the kidney weight whilst increasing the total body weight of diabetic rats. Furthermore whilst evaluation of the different renal functioning tests, p-coumaric acid significantly improves histopathological changes and the levels of urea, creatinine and uric acid in serum of diabetic rats, which was otherwise elevated under diabetic conditions. Our results also highlight that p-coumaric acid is an efficient compound with antioxidant properties and improves the diabetes-induced change in lipid peroxidation and activities of antioxidant enzymes: catalase, glutathione-S-transferase and superoxide dismutase. p-Coumaric acid thus possesses the potential to prevent diabetic nephropathy by reducing oxidative stress and can thus serve as a potential drug target for pharmaceutical companies.

Long Non-Coding RNA CYP4B1-PS1-001 Inhibits Proliferation and Fibrosis in Diabetic Nephropathy by Interacting with Nucleolin.

BACKGROUND/AIMS: Our previous studies demonstrated that a novel long non-coding RNA, CYP4B1-PS1-001, was significantly downregulated in early diabetic nephropathy in vivo and in vitro, and CYP4B1-PS1-001 overexpression could inhibit the proliferation and fibrosis of mouse mesangial cells (MMCs). However, the underlying mechanism of the CYP4B1-PS1-001-mediated regulation of proliferation and fibrosis in diabetic nephropathy remains undetermined. METHODS: RNA-protein pull-down assay, RNA-binding protein immunoprecipitation, and mass spectrometry were used to investigate CYP4B1-PS1-001 interacted with the upregulated protein nucleolin (NCL). siRNA method was applied to knockdown NCL in MMCs, the interaction between CYP4B1-PS1-001 and NCL were determined by Western blot analysis and RT-qPCR. The effect of CYP4B1-PS1-001 in the regulation of NCL was detected by cycloheximide (CHX) and ubiquitination assays. RESULTS: We found that CYP4B1-PS1-001 interacts with NCL, and CYP4B1-PS1-001 inhibits the proliferation and fibrosis of MMCs depending on interaction with NCL. Furthermore, degradation of CYP4B1-PS1-001-associated NCL was mediated by a ubiquitin proteasome-dependent pathway. CONCLUSION: Our study provides evidence that CYP4B1-PS1-001 regulates the ubiquitination and degradation of NCL and thereby plays a critical role in the proliferation and fibrosis of MMCs, indicating that CYP4B1-PS1-001 and NCL may be promising prognostic biomarkers and molecular targets for the treatment of diabetic nephropathy.

NR4A1 Promotes Diabetic Nephropathy by Activating Mff-Mediated Mitochondrial Fission and Suppressing Parkin-Mediated Mitophagy.

BACKGROUND/AIMS: Disrupted mitochondrial dynamics, including excessive mitochondrial fission and mitophagy arrest, has been identified as a pathogenic factor in diabetic nephropathy (DN), although the upstream regulatory signal for mitochondrial fission activation and mitophagy arrest in the setting of DN remains unknown. METHODS: Wild-type (WT) mice and NR4A1 knockout (NR4A1-KO) mice were used to establish a DN model. Mitochondrial fission and mitophagy were evaluated by western blotting and immunofluorescence. Mitochondrial function was assessed by JC-1 staining, the mPTP opening assay, immunofluorescence and western blotting. Renal histopathology and morphometric analyses were conducted via H&E, Masson and PASM staining. Kidney function was evaluated via ELISA, western blotting and qPCR. RESULTS: In the present study, we found that nuclear receptor subfamily 4 group A member 1 (NR4A1) was actually activated by a chronic hyperglycemic stimulus. Higher NR4A1 expression was associated with glucose metabolism disorder, renal dysfunction, kidney hypertrophy, renal fibrosis, and glomerular apoptosis. At the molecular level, increased NR4A1 expression activated p53, and the latter selectively stimulated mitochondrial fission and inhibited mitophagy by modulating Mff and Parkin transcription. Excessive Mff-related mitochondrial fission caused mitochondrial oxidative stress, promoted mPTP opening, exacerbated proapoptotic protein leakage into the cytoplasm, and finally initiated mitochondria-dependent cellular apoptosis in the setting of diabetes. In addition, defective Parkin-mediated mitophagy repressed cellular ATP production and failed to correct the uncontrolled mitochondrial fission. However, NR4A1 knockdown interrupted the Mff-related mitochondrial fission and recused Parkin-mediated mitophagy, reducing the hyperglycemia-mediated mitochondrial damage and thus improving renal function. CONCLUSION: Overall, we have shown that NR4A1 functions as a novel malefactor in diabetic renal damage and operates by synchronously enhancing Mff-related mitochondrial fission and repressing Parkin-mediated mitophagy. Thus, finding strategies to regulate the balance of the NR4A1-p53 signaling pathway and mitochondrial homeostasis may be a therapeutic option for treating diabetic nephropathy in clinical practice.

SIRT3 Facilitates Amniotic Fluid Stem Cells to Repair Diabetic Nephropathy Through Protecting Mitochondrial Homeostasis by Modulation of Mitophagy.

BACKGROUND/AIMS: Amniotic fluid stem cells (AFSCs) transplantation is a promising therapeutic strategy for diabetic nephropathy. Sirtuin3 (SIRT3) is a novel mitochondrial protective factor. In the present study, we aimed to investigate whether SIRT3 protects against hyperglycemia-induced AFSCs damage and enhances the therapeutic efficiency of AFSCs in diabetic nephropathy. METHODS: To establish the diabetic nephropathy model, db/ db mice were used. AFSCs were obtained and transplanted into the kidney tissue of db/ db mice. Gain-of-function assay with SIRT3 overexpression was performed in AFSCs via adenoviral transfections (Ad/SIRT3). Cellular viability and apoptosis were measured via MTT, TUNEL assay and western blotting. Mitochondrial function was assessed via JC1 staining, mPTP opening assay, mitochondrial respiratory function analysis, and immunofluorescence analysis of cyt-c. Mitophagy was assessed via western blotting and immunofluorescence analysis. Renal histopathology and morphometric analysis were conducted via H&E, Masson and PASM staining. Kidney function was detected via ELISA assay, western blotting and qPCR. RESULTS: SIRT3 was downregulated in AFSCs under high glucose stimulation, where its expression was positively correlated with AFSCs survival and proliferation. Regaining SIRT3 activated mitophagy protecting AFSCs against high glucose-induced apoptosis via preserving mitochondrial function. Transplanting SIRT3-overexpressing AFSCs in db/db mice improved the abnormalities in glucose metabolic parameters, including the levels of glucose, insulin, C-peptide, HbA1c and inflammatory markers. In addition, the engraftment of SIRT3-modified AFSCs also reversed renal function, decreased renal hypertrophy, and ameliorated renal histological changes in db/db mice. Functional studies confirmed that SIRT3-modified AFSCs promoted glomerulus survival and reduced renal fibrosis. CONCLUSION: Collectively, our results demonstrate that AFSCs may be a promising therapeutic treatment for ameliorating diabetes and the development of diabetic nephropathy and that the overexpression of SIRT3 in AFSCs may further increase the efficiency of stem cell-based therapy.

Yucca schidigera extract modulates the lead-induced oxidative damage, nephropathy and altered inflammatory response and glucose homeostasis in Japanese quails.

The present study was conducted to explore the toxic effects of lead (Pb) on the physiological responses of Japanese quails and to investigate the potential modulatory role of Yucca schidigera extract (YSE) against these effects. 360 mature Japanese quails (at 2 months of age) were used and the experiment was lasted for 8 weeks. The birds were divided into six equal groups as follow: control (basal diet, BD), BD+Pb (100 mg/kg diet), BD+YSE (100 mg/kg diet), BD+YSE (200 mg/kg diet), BD+Pb (100 mg/kg diet) +YSE (100 mg/kg diet) and BD+ Pb (100 mg/kg diet) + YSE (200 mg/kg diet). Pb induced a significant reduction in superoxide dismutase (SOD) and catalase (CAT) activities and reduced glutathione (GSH) level. While, increased protein carbonyl (PC) and malondialdehyde (MDA) content in tissues of exposed birds. Pb increased level of 8-hydroxy-2-deoxyguanosine (8-OHdG) and lactate dehydrogenase (LDH) activity in serum. YSE significantly reduced the Pb -induced oxidative stress in co-treated groups especially at 200 mg/kg diet. YSE could modulate the Pb -induced decreased urea, creatinine and beta-2 microglobulin (B2M) levels. YSE200 was found to be better than the YSE100 in decreasing levels of inflammatory markers including tumor necrosis factor (TNF-α), nitric oxide (NO), transforming growth factor-ß1 (TGF-ß1) and vascular endothelial growth factor (VEGF). Furthermore, YSE significantly regulates glucose homeostasis in co-exposed quails. Pb residues were found to be significantly higher in kidney and pancreas tissues of Pb group compared to other groups. YES decreased the expression of metallothionein-1 in the renal and pancreatic tissues, while elevated insulin expression in the pancreatic cells by immunostaining in co-exposed groups. In conclusion, the present results conclusively demonstrate the potential modulatory effect of YSE against the Pb-induced toxic effects in different organs of Japanese quails.

MicroRNA­146a/NAPDH oxidase4 decreases reactive oxygen species generation and inflammation in a diabetic nephropathy model.

The present study investigated the role of microRNA (miR)­146a in a diabetic nephropathy (DN) model, and its molecular mechanism. DN mice were given intraperitoneal injections of streptozotocin (55 mg/kg/day) for 5 consecutive days as an in vivo DN model. The HK­2 human kidney cell line were exposed to 45% D­glucose as an in vitro DN model. Firstly, it was demonstrated that miR­146a expression was inhibited and NAPDH oxidase 4 (Nox4) was increased in DN mice. In HK­2 cells, overexpression of miR­146a inhibited Nox4 protein expression and decreased reactive oxygen species (ROS) generation, oxidative stress and inflammation, and suppressed vascular cell adhesion molecule­1 (VCAM­1) and intracellular adhesion molecule­1 (ICAM­1) protein expression. Nacetylcysteine, a Nox4 inhibitor, was demonstrated to inhibit ROS generation, suppress VCAM­1 and ICAM­1 protein expression, and decrease oxidative stress and inflammation in HK­2 cells following overexpression of miR­146a. In conclusion, these results indicated that miR­146a/Nox4 decreases ROS generation and inflammation and prevents DN. Therefore, miR­146a may represent a novel anti­inflammatory and ­oxidative modulator of DN.

PGC-1α ameliorates kidney fibrosis in mice with diabetic kidney disease through an antioxidative mechanism.

The production of reactive oxygen species (ROS) is a common phenomenon in podocyte impairment, which leads to the irreversible progression of chronic kidney diseases, such as diabetic kidney disease (DKD). Previous research has indicated that peroxisome proliferator­activated receptor γ (PPARγ) coactivator­1α (PGC­1α) participates in mitochondrial biogenesis and energy metabolism in certain mitochondria­enriched cells, including myocardial and skeletal muscle cells. Therefore, we hypothesized that PGC­1α may be a protective nuclear factor against energy and oxidative stress in DKD. To investigate this hypothesis, db/db diabetic mice were used to establish a DKD model and the PPARγ agonist rosiglitazone was employed to induce PGC­1α expression in vivo. Additionally, immortalized mouse podocytes and SV40 MES 13 renal mesangial cells were utilized for in vitro experiments. The expression levels of PGC­1α and genes associated with kidney and cell injury were determined by western blotting or reverse transcription-quantitative polymerase chain reaction and intracellular ROS levels were assessed by 2',7'-dichlorodihydrofluorescein diacetate. The results of the present study demonstrated that endogenous PGC­1α expression exhibited protective effects against oxidative stress, glomerulosclerosis and tubulointerstitial fibrosis in experimental DKD. These results indicated a potential role of PGC­1α in the amelioration of key pathophysiological features of DKD and provided evidence for PGC­1α as a potential therapeutic target in DKD.

Longitudinal prevalence of hypertension, proteinuria, and retinopathy in dogs with spontaneous diabetes mellitus.

BACKGROUND: The prevalence and progression of vascular complications of spontaneous diabetes mellitus (DM) in dogs have not been described. OBJECTIVES: To investigate the effects of duration of disease, as estimated by time since DM diagnosis, and glycemic control on prevalence of systemic hypertension, proteinuria, and diabetic retinopathy in dogs with spontaneous DM. ANIMALS: Seventeen client-owned dogs with spontaneous DM. METHODS: Prospective, longitudinal observational study. Dogs with DM of less than 1 year's duration were recruited and evaluated once every 6 months for 24 months. Recorded measures included indirect BP, urine albumin, protein and creatinine concentrations, serial blood glucose and serum fructosamine concentrations, ophthalmic examination, and a standardized behavioral questionnaire. RESULTS: Eleven dogs completed the 2-year follow-up period, during which the highest recorded prevalence of systolic and diastolic hypertension was 55 and 64%, respectively. Prevalence of microalbuminuria and elevated urine protein:creatinine ratio (UPC) ranged up to 73 and 55%, respectively. Prevalence of retinopathy ranged up to 20%. No significant effect of time since DM diagnosis or glycemic control was detected for any of the measures examined. Additionally, no significant associations between BP, urine albumin concentration, UPC and retinopathy were detected. CONCLUSIONS AND CLINICAL RELEVANCE: With the exception of proteinuria, which was substantial in some cases, clinically deleterious diabetic vascular complications were not identified in dogs in this study.

Diabetes and the kidney in human and veterinary medicine.

Diabetic nephropathy is a well-recognized clinical consequence of both type 1 and type 2 diabetes mellitus in humans. Major risk factors include poor glycemic control, hypertension, and microalbuminuria, as well as genetic factors. In both type 1 and 2 diabetics with nephropathy, structural changes occur in the kidneys before overt clinical disease. Studies suggest that some of the risk factors and structural renal changes of human diabetes also exist in diabetic dogs and cats. This article assembles existing information on the presence of risk factors, laboratory and histologic findings, and consequences of human diabetic nephropathy as applied to cats.

Diabetes causes inhibition of glucose-6-phosphate dehydrogenase via activation of PKA, which contributes to oxidative stress in rat kidney cortex.

The incidence of diabetic nephropathy has been increasing. Studies have shown that oxidative stress (due to increased oxidant production and/or decreased antioxidant activity) is a critical underlying mechanism. The principal intracellular reductant is NADPH whose production is mainly dependent on glucose-6-phosphate dehydrogenase (G6PD) activity. Our work in cultured cells previously showed that high glucose caused activation of protein kinase A (PKA) and subsequent phosphorylation and inhibition of G6PD activity and hence decreased NADPH (Zhang Z, Apse K, Pang J, and Stanton RC. J Biol Chem 275:40042-40047, 2000). The purpose of this study was to determine whether these findings occur in diabetic rats (induced by streptozotocin) compared with control. G6PD activity and accordingly NADPH levels and glutathione levels were significantly decreased in diabetic kidneys compared with control kidneys. Lipid peroxidation was significantly increased, which correlated with decreased G6PD activity (r = 0.48). G6PD expression was significantly reduced, which correlated with decreased G6PD activity (r = 0.72). PKA activity and serine phosphorylation of G6PD were significantly increased and were closely correlated with decreased G6PD activity (r = 0.51 for PKA activity; r = 0.93 for serine phosphorylation of G6PD). Insulin treatment and/or correction of hyperglycemia ameliorated the changes caused by diabetes. In conclusion, chronic hyperglycemia caused inhibition of G6PD activity via decreased expression and increased phosphorylation of G6PD, which therefore led to increased oxidative stress.

17beta-Estradiol replacement improves renal function and pathology associated with diabetic nephropathy.

The protective factor of female gender appears to be lost in diabetes; the incidence of diabetes and its complications, including diabetic nephropathy, are equal in women and men. This study examined the effects of estrogen deficiency by ovariectomy (OVX) and replacement with 17beta-estradiol (OVX+E2) on renal function and pathology in the nondiabetic (ND) and streptozotocin (STZ)-induced diabetic (D) rat kidneys for 12 wk. Diabetes was associated with an increase in urine albumin excretion (UAE; ND, 0.39 +/- 0.03; D, 5.9 +/- 0.8 mg/day; P < 0.001), decrease in creatinine clearance (CrCl; ND, 0.69 +/- 0.03; D, 0.43 +/- 0.09 mg x min(-1) x 100 g body wt(-1); P < 0.05), increase in the index of glomerulosclerosis [GSI; ND, 0.01 +/- 0.01; D, 0.15 +/- 0.04 arbitrary units (AU); P < 0.01], tubulointerstitial fibrosis (TIFI; ND, 0.04 +/- 0.04; D, 0.68 +/- 0.2 AU; P < 0.01), and transforming growth factor-beta (TGF-beta) protein expression (ND, 0.61 +/- 0.02; D, 1.25 +/- 0.07 AU; P < 0.01). In the D group, the severity of these changes was augmented with OVX (UAE, 8.1 +/- 0.6 mg/day; CrCl, 0.40 +/- 0.04 mg x min(-1) x 100 g body wt(-1); GSI, 0.29 +/- 0.04 AU; TIFI, 0.90 +/- 0.06 AU; TGF-beta, 1.26 +/- 0.10 AU), whereas E2 replacement attenuated these changes (UAE, 6.3 +/- 0.8 mg/day; CrCl, 0.66 +/- 0.03 mg x min(-1) x 100 g body wt(-1); GSI, 0.06 +/- 0.02 AU; TIFI, 0.36 +/- 0.08 AU; TGF-beta, 0.57 +/- 0.08 AU). We conclude that E2 deficiency increases the severity of renal disease in a diabetic animal model and that E2 replacement is renoprotective by attenuating the decline in renal function and pathology associated with diabetes.

Corneal sensitivity in dogs with diabetes mellitus.

OBJECTIVE: To compare aesthesiometer-determined corneal sensitivity between diabetic and nondiabetic dogs and to investigate the correlation between corneal sensitivity and duration of diabetes or status of glycemic control, as estimated by use of glycated blood protein concentrations. ANIMALS: 23 diabetic and 29 nondiabetic normoglycemic dogs. PROCEDURE: A Cochet-Bonnet aesthesiometer was used to measure corneal touch threshold (CTT) in 5 corneal regions of each dog. At the time of ocular examination, duration of diabetes mellitus was estimated from the history, and blood was drawn for assessment of blood glycosylated hemoglobin and serum fructosamine concentrations. RESULTS: Median CTT for central, nasal, dorsal, temporal, and ventral corneal regions in nondiabetic dogs (1.6, 2.3, 2.8, 2.8, and 5.1 g/mm2, respectively) was significantly lower than in diabetic dogs (2.8, 4.0, 5.1, 5.1, and 6.6 g/mm2, respectively). Median regional CTT in diabetic dogs was not significantly correlated with estimated duration of diabetes mellitus or blood glycated protein concentrations. No significant difference was found in regional CTT between eyes of normoglycemic dogs with unilateral cataracts. CONCLUSIONS AND CLINICAL RELEVANCE: Diabetic dogs have significantly reduced corneal sensitivity in all regions, compared with nondiabetic normoglycemic dogs. Regional variation in corneal sensitivity is similar in diabetic and normoglycemic dogs. Neither glycemic control nor duration of diabetes, as estimated, is significantly correlated with corneal hyposensitivity. Corneal nerve dysfunction may be associated with recurrent or nonhealing ulcers in diabetic dogs for which no other underlying cause can be found.

Microvasculature of hydronephrotic kidneys in KK-A(Y) mice.

Spontaneous hydronephrosis in KK-A(Y) mice was studied using light and electron microscopy and scanning electron microscopy of resin casts to evaluate micro vascular changes in the kidney. The renal parenchyma was extremely thin as a result of tubular atrophy. Histologically, varying degrees of glomerulosclerosis were observed. Ultrastructurally, marked thickenings of the glomerular basal lamina, an increase in mesangial cells and matrix, and marked effacement of foot processes were observed. In resin casts, a marked reduction in number of glomeruli was evident. The capillaries were thin, strangulated and tom-off to varying degrees in severely affected glomeruli. In the medulla, the three-dimensional capillary network running along the tubules was lost and changed to a two-dimensional vascular bed. Despite severe hydronephrosis, the glomerular capillary network was relatively well preserved, being either slightly or moderately injured in approximately 60% of surviving glomeruli.

Systemic hypertension and proteinuria in dogs with diabetes mellitus.

OBJECTIVE: To determine prevalence and severity of systemic arterial hypertension and proteinuria in dogs with naturally developing diabetes mellitus (DM) and to determine whether these abnormalities were related to age, sex, duration of DM, or degree of control of glycemia. DESIGN: Case series and cohort study. ANIMALS: Fifty dogs with naturally developing DM. PROCEDURES: Blood pressure was measured in all 50 dogs. Thirty-eight dogs were evaluated once, and 12 were evaluated sequentially. Thirty-five were evaluated for proteinuria by determining protein-to-creatinine ratio in urine (n = 35) or by electrophoresis of urine (33). RESULTS: Hypertension was detected in 23 on the basis of a systolic pressure > 160 mm HG (12 dogs), a diastolic pressure > 100 mm HG (21), or a mean pressure > 120 mm HG (23). All dogs with systolic hypertension had concurrent diastolic and mean hypertension, and 19 of 21 dogs with diastolic hypertension had concurrent high mean pressure. Ten of 12 dogs reevaluated at subsequent visits had no change in blood pressure. Blood pressure remained consistent in 3 dogs tested at different times during the day on a single visit. Duration of DM and presence of proteinuria were significant predictors of hypertension. Seven of 35 (20%) dogs had an increased protein-to-creatinine ratio in their urine. Albumin concentration and albumin-to-creatinine ratio were significantly higher in urine from diabetic dogs, compared with healthy, nondiabetic dogs. Hypertension was associated with an increased albumin-to-creatinine ratio. CLINICAL IMPLICATIONS: Systemic hypertension and proteinuria may be common in diabetic dogs, but the clinical importance of these findings are, as yet, unknown.

Long-term complications of diabetes mellitus, Part I: Retinopathy, nephropathy, neuropathy.

Diabetic retinopathy, nephropathy, and neuropathy occur infrequently in small animals, but are capable of causing significant disease. The clinical and histopathologic findings seen with these late complications of diabetes are discussed. The pathogenesis of these disorders is most likely multifactorial; metabolic alterations secondary to the hyperglycemic state, and microvascular changes seen with diabetes have both been implicated. Current treatment consists of aggressive control of the hyperglycemia, as research continues into the pathology of the late complications in attempts to find a definitive therapy.

[Urine characteristics in dogs with diabetes mellitus. Is there a diabetic nephropathy in the dog?]. / Urinbefunde bei Hunden mit Diabetes mellitus. Gibt es eine diabetische Nephropathie beim Hund?

Dogs with spontaneous Diabetes mellitus were checked at regular intervals for protein excretion in the urine. A large number of dogs developed a proteinuria, very marked in some cases, with excretion of primarily macroproteins.

Glomerular lesions in spontaneously occurring diabetic WBN/Kob rats.

Glomerular lesions in WBN/Kob male rats with spontaneous diabetes were examined histopathologically. The glomerulopathy caused by diabetes was compared with lesions in chronic progressive nephropathy of non-diabetic SD and F344 male aged rats. Diffuse and global thickening of the mesangial area was observed only in WBN/Kob rats and showed a statistically significant correlation with serum glucose concentrations. Therefore, it suggested that the mesangial thickening was a result of hyperglycaemia. Fibrin cap-like lesions were seen in both WBN/Kob and non-diabetic SD or F344 male rats. The severity of these lesions was closely related to that of chronic progressive nephropathy and, therefore, the fibrin cap-like lesions were considered to be due to the chronic progressive nephropathy.

The association between spontaneous pyelonephritis and maturity-onset diabetes mellitus in male MM mice.

Blood glucose and glucose tolerance tests demonstrated that many male MM mice are diabetic. Serial urine sampling showed that the diabetes occurred only in mature MM males and consisted of a single self-limiting episode. Histological examination of the pancreas, together with measurements of body weight, glycosylated haemoglobin and plasma insulin, revealed that the diabetes was of the maturity-onset insulin-resistant type. Bacteriological examination of the urine samples showed that urinary tract infection, a known feature of male MM mice, occurred in the diabetics but only after the onset of hyperglucosuria. It was concluded that the high urinary glucose levels of diabetic MM males are of prime importance in the aetiology of the renal infection which occurs rarely in non-diabetic MM males or in other strains in the colony. An infectious aetiology for the diabetes per se was excluded by the existence of diabetes in germfree MM males.