Behavioral manipulation of the diabetic phenotype in ob/ob mice

The genetically obese mouse (C57BL/6J ob/ob) is a commonly used model of non-insulin-dependent diabetes mellitus. However, our studies demonstrate that, while the animal is significantly hyperinsulinemic, it in fact does not show consistent hyperglycemia in the resting state. During stress, both obese animals and their lean littermates become hyperglycemic, but the magnitude of the hyperglycemia is exaggerated in the obese mice. Obese animals also show an exaggerated plasma glucose increase in response to epinephrine injection. This increase in plasma glucose is accompanied by a decrease in plasma insulin in response to both stress and epinephrine. Our findings suggest that environmental stimuli influence the expression of diabetes in the C57BL/6J obese mouse and therefore must be considered in studies of this animal model of diabetes.     

Effect of genetic background on the therapeutic effects of dehydroepiandrosterone (DHEA) in diabetes-obesity mutants and in aged normal mice

Dehydroepiandrosterone (DHEA) was fed at 0.1-0.4% in the diet to genetically diabetic (db/db) or obese (ob/ob) C57BL/KsJ (BL/Ks) or C57BL/6J (BL/6) mice. Treatment of BL/Ks-db/db or ob/ob mice with 0.4% DHEA prevented hyperglycemia, islet atrophy, and severe diabetes associated with this inbred background, but did not affect weight gain and food consumption. Homozygous obese (ob) or diabetes (db) mice on the BL/6 background were more sensitive to DHEA, and the mild, transient hyperglycemia associated with ob or db gene expression on the BL/6 inbred background could be prevented by 0.1% DHEA. Both body weight and food consumption were decreased in BL/6 mutants maintained on 0.1% DHEA whereas this effect was not seen in BL/Ks mutants fed up to 0.4% DHEA. Early therapy with 0.4% DHEA, initiated at 2 wk of age, prevented the development of most diabetes symptoms and decreased the rate of weight gain in pups of all genotypes. In addition to therapeutic effects on both obese mutants, DHEA effected significant changes in an aging study using normal BL/6 female mice. Four weeks of DHEA treatment initiated at 2 yr of age improved glucose tolerance and at the same time reduced plasma insulin to a "younger" level. This suggests that DHEA may act in insulin-resistant mutant mice and in aging normal mice to increase the sensitivity to insulin.     

Temporal relationship of tissue somatostatin-like immunoreactivity to metabolic changes in genetically obese and diabetic mice

Somatostatin-like immunoreactivity (SRIF-LI) content in 2 N acetic acid extracts of hypothalamus, gastric antrum, and pancreas was measured in genetically obese (C57BL/6J ob/ob and db/db) and diabetic (C57BL/KsJ db/db and ob/ob) mice and normal littermate controls from 5 to 24 wk to determine the relationship of previously reported changes to the development of metabolic abnormalities. Hypothalamic SRIF-L concentration was similar in control, diabetic, and obese mice at all ages and increased progressively with age in all groups. Gastric antrum SRIF-LI was similar in all groups of mice at all ages. Obese mice gained weight progressively and showed moderate hyperglycemia and marked hyperinsulinemia from 5 wk of age. Pancreatic SRIF-LI content in obese (C57BL/6J) animals was similar to that in lean littermate controls, but pancreatic SRIF-LI concentration (expressed by weight or protein content) was decreased until 8 (6J ob/ob) and 10 (6J db/db) wk. Diabetic (C57BL/KsJ) mice showed a similar metabolic pattern until 10 wk with no change in pancreatic SRIF-LI content or concentration. Thereafter a progressive fall in serum insulin and a marked rise in serum glucose was associated with increasing pancreatic SRIF-LI content and concentration. These studies suggest that the genetically hyperphagic syndromes are unassociated with any change in hypothalamic or gastric SRIF-LI; that pancreatic SRIF-LI increases occur in response to, rather than as the cause of, relative hypoinsulinemia; and that the genetic background of the mice (KsJ or 6J) rather than the mutant gene (db or ob) determines the defect in carbohydrate metabolism and the pancreatic SRIF-LI response.     

Gene expression profiles of nondiabetic and diabetic obese mice suggest a role of hepatic lipogenic capacity in diabetes susceptibility

Obesity is a strong risk factor for the development of type 2 diabetes. We have previously reported that in adipose tissue of obese (ob/ob) mice, the expression of adipogenic genes is decreased. When made genetically obese, the BTBR mouse strain is diabetes susceptible and the C57BL/6J (B6) strain is diabetes resistant. We used DNA microarrays and RT-PCR to compare the gene expression in BTBR-ob/ob versus B6-ob/ob mice in adipose tissue, liver, skeletal muscle, and pancreatic islets. Our results show: 1) there is an increased expression of genes involved in inflammation in adipose tissue of diabetic mice; 2) lipogenic gene expression was lower in adipose tissue of diabetes-susceptible mice, and it continued to decrease with the development of diabetes, compared with diabetes-resistant obese mice; 3) hepatic expression of lipogenic enzymes was increased and the hepatic triglyceride content was greatly elevated in diabetes-resistant obese mice; 4) hepatic expression of gluconeogenic genes was suppressed at the prediabetic stage but not at the onset of diabetes; and 5) genes normally not expressed in skeletal muscle and pancreatic islets were expressed in these tissues in the diabetic mice. We propose that increased hepatic lipogenic capacity protects the B6-ob/ob mice from the development of type 2 diabetes.     

Muscarinic stimulation and antagonism and glucoregulation in nondiabetic and obese hyperglycemic mice

Plasma glucose and insulin responses to a muscarinic agonist (bethanechol chloride) and a muscarinic antagonist (atropine) were evaluated in obese C57BL/6J ob/ob mice and in lean C57BL/6J + /? mice. In lean +/? mice, plasma glucose decreased in response to 1 and 2 micrograms/g bethanechol chloride, whereas insulin increased significantly. In ob/ob mice, insulin increased remarkably in response to bethanechol administration (saline, 632 +/- 80 microU/ml; 2 micrograms/g bethanechol chloride, 1794 +/- 97 microU/ml; n = 10), but surprisingly, plasma glucose also rose significantly (saline, 230 +/- 14 mg/dl; 2 micrograms/g bethanechol chloride, 363 +/- 18 mg/dl, n = 10). This exaggerated hyperglycemia in ob/ob mice was not associated with significant changes in plasma glucagon. Furthermore, administration of propranolol hydrochloride did not diminish bethanechol chloride-induced hyperglycemia in ob/ob mice. Administration of atropine (2.5, 5, and 10 mg/kg body wt) induced a significant decrease in plasma insulin without changes in plasma glucose in ob/ob mice, whereas neither plasma insulin nor plasma glucose changed in lean mice. Finally, conversion of [14C]alanine to glucose was increased in ob/ob mice after bethanechol chloride administration, indicating that muscarinic stimulation increases gluconeogenesis in an animal model of type II (non-insulin-dependent) diabetes.     

Alteration of islet cell populations in spontaneously diabetic mice.

Endocrine-cell populations in the islets of Langerhans of mutant mice with a severe hypoinsulinemic diabetes (ob/ob or db/db on the C57BL/KsJ background) or with a mild hyperinsulinemic diabetes (ob/ob or db/db on the C57BL/6J background) were studied quantitatively by immunofluorescence and morphometry. In severely diabetic mice, islets presented a reduced proportion of insulin containing cells but increased glucagon-, somatostatin-, and pancreatic polypeptide (PP)-containing cells, as compared with islets of control (+/+) mice. An inverse change was observed in islets of mildly diabetic mice: islets were hypertrophic and composed mostly of insulin-containing cells, with decreased proportions of glucagon-, somatostatin-, and PP-containing cells. In both types of diabetic syndromes, the changes in cell populations induced a qualitative alteration of cellular interrelationships in the affected islets.     

Wound collagen accumulation in obese hyperglycemic mice

We used C57-BL ob/ob mice as a model to study wound healing in type II (adult-onset) diabetes. Planimetry was used to assess rate of closure in standard open skin wounds. In agreement with previous subcutaneous wound collagen-accumulation studies, closure was slower in the ob/ob mice. Subcutaneous implants were used to evaluate wound collagen accumulation. Weanling mice have collagen accumulation similar to lean littermates (mean 3.43 micrograms/cm vs. 3.46 micrograms/cm), but the same ob/ob animals had decreased wound collagen (mean 2.39 micrograms/cm vs. 3.02 micrograms/cm, P less than 0.04) when mature. Other ob/ob animals fed a restricted diet (and thus not obese) had normal collagen accumulation at the same age. Neither insulin nor diet restriction restored wound collagen accumulation in phenotypically obese mice. Because collagen accumulation is not improved by measures that control hyperglycemia (insulin and diet restriction) and the defect was seen only in phenotypically obese ob/ob mice, the decreased wound collagen accumulation may be due in part to structural changes in adipose tissue.     

Immunoreactive neurotensin in the pancreas of genetically obese and diabetic mice. A longitudinal study

Immunoreactive neurotensin (IR-NT) content in 2 N acetic acid extracts of pancreas was measured in genetically diabetic (C57BL/KsJ db/db and ob/ob) and obese (C57BL/6J ob/ob and db/db) mice and normal littermate controls from 5 to 24 wk of age to determine the relationship of any changes to the development of metabolic abnormalities. Pancreatic IR-NT in obese mice showed no consistent change compared with lean littermate controls. In contrast, diabetic mice demonstrated an increase in pancreatic IR-NT that occurred at 6-8 wk of age, and maximal about the time of islet B-cell failure (8-10 wk), and persisted over the study period. Pancreatic IR-NT eluted in two peaks on reverse phase high-pressure liquid chromatography, one of which exhibited a retention time similar to that of synthetic NT. These findings suggest that pancreatic IR-NT concentration is regulated by insulin, with elevated levels occurring in association with insulin deficiency and its metabolic consequences but not with insulin resistance. Taken together with the previous demonstration that NT influences pancreatic islet hormone secretion, the present findings support a possible role of endogenous NT in islet hormone regulation.     

Increased hemoglobin AIc in diabetic mice.

The minor hemoglobins AIa, AIb, and AIc were studied in mice with either genetic or chemically induced diabetes. Hemoglobin AIc was elevated approximately twofold in all the phenotypically diabetic mice studied (C57BL/KsJ-db/db, C57BL/KsJ-ob/ob, C57BL/6J-db/db, and alloxan- and streptozotocin-treated mice). Elevation of the hemoglobin AIc in C57BL/6J-db/db mice was of short duration, reflecting the transitory diabetes characteristic of these mice. The degree of increase of hemoglobin AIc levels was unrelated to severity of hyperglycemia, duration of diabetes, age of mouse, or body weight. It is not known what factor(s) dictates the steady-state concentration of hemoglobin AIc.     

Effects of hyperglycemia on function of isolated mouse pancreatic islets transplanted under kidney capsule

The insulin release from isolated pancreatic islets grafted under the kidney capsule was examined by means of a modified kidney-perfusion technique. The grafts, consisting of 150 C57BL/6 or 250 C57BL/Ks mouse islets, were implanted syngeneically under the left kidney capsule of normoglycemic or alloxan-induced diabetic recipients 4 wk before the perfusion. In both mouse strains, islets grafted to normoglycemic animals showed an immediate distinct peak of insulin release when challenged with high glucose, whereas no response was observed from islets grafted to hyperglycemic mice. In a similar way in C57BL/Ks mice, arginine stimulated insulin release from the islet grafts in normoglycemic but not in hyperglycemic recipients. Insulin treatment of the diabetic recipients, however, partially normalized the insulin response to glucose. Islet grafts were removed in toto and analyzed for contents of insulin, glucagon, somatostatin, and DNA or rates of glucose-stimulated (pro)insulin biosynthesis. In both mouse strains, islets implanted into hyperglycemic animals contained significantly less insulin, and their rates of (pro)insulin biosynthesis were markedly decreased. Insulin treatment only marginally affected these parameters. The glucagon content of the grafted islets was unaffected by the hyperglycemia in both strains of mice, whereas a significant decrease in the somatostatin content was observed in the C57BL/Ks mice. We concluded that grafted islets exposed to prolonged hyperglycemic stress become functionally impaired in mice of both strains. Our perfusion technique of islet-graft-bearing kidneys in combination with biochemical studies on the removed grafts provides a suitable model for studies of the effects of prolonged hyperglycemia on islet beta-cell function.     

Adeno-associated virus transduction of islets with interleukin-4 results in impaired metabolic function in syngeneic marginal islet mass transplantation

Previous studies suggest that therapeutic expression of interleukin (IL)-4 by islet cells improves their efficacy in transplantation models directed at reversing type 1 diabetes. We investigated the effects of introducing IL-4 into islets with recombinant adeno-associated virus (rAAV) on the reversal of hyperglycemia in a syngeneic marginal islet mass transplantation model. C57BL/6 islets were mock-transduced or transduced with rAAV expressing murine IL-4 (rAAV-IL-4) or rAAV expressing green fluorescent protein (rAAV-GFP) before transplantation of a marginal mass into diabetic mice. Normoglycemia was achieved in only 1/7 mice receiving rAAV-IL-4 transduced islets in comparison to 6/6 mock-transduced and 4/6 rAAV-GFP transduced animals. The failure of IL-4 expressing islets was not associated with cellular toxicity of rAAV or impairment of glucose-stimulated insulin release in vitro. Islet expression of IL-4 led to impaired metabolic function in mice receiving a marginal mass of syngeneic islets.     

Analysis of differential survival of syngeneic islets transplanted into hyperglycemic C57BL/6J versus C57BL/KsJ mice

C57BL/KsJ (BKs) male mice were more sensitive to diabetes induction by administration of multiple low-doses of streptozotocin (Sz) than were C57BL/6J (B6) male mice. Analysis of islet size and insulin content of the two parental strains did not indicate that differences in drug sensitivity could be attributed to an effect of genetic background on islet size or insulin content. 50 BKs islets implanted into the spleens of BKs male mice made diabetic by Sz were eliminated within 12 days posttransplantation, whereas an equal number of B6 islets implanted into the spleens of diabetic B6 recipients were retained, even though the numbers of islets implanted were insufficient to effect remission from hyperglycemia. In contrast to the rapid loss of islets implanted into spleens of hyperglycemic BKs recipients, BKs islets implanted into spleens of normoglycemic recipients were not eliminated, thus suggesting that the basis for the differential survival between the B6 and BKs strains reflected their ability to survive hyperglycemic stress rather than a differential ability to replicate. Since BKs beta cells have been shown to respond to hyperglycemia by expression of an endogenous retroviral gene that cannot be expressed by B6 beta cells, the possibility that this differential survival represents a strain difference in autoreactivity against islet cells is raised.     

Altered beta-endorphin, Met- and Leu-enkephalins, and enkephalin-containing peptides in pancreas and pituitary of genetically obese diabetic (db/db) mice during development of diabetic syndrome

We have recently shown that in addition to beta-endorphin the opioid peptides Met- and Leu-enkephalin and their apparent precursors are localized in islet endocrine cells of the rat pancreas. To begin evaluating a possible role for these pancreatic opiates in the pathophysiology of genetic diabetes in rodents, immunoreactive beta-endorphin and Met- and Leu-enkephalins were measured in acetic acid extracts of pancreas and pituitary of C57BL/KsJ db/db mice and their lean littermates. Groups of animals were studied during three phases of development of the diabetic syndrome in the mutant mice: at 4 (hyperinsulinemic and prediabetic); 6, 9, and 12 (frankly obese and diabetic); and 30 (hypoinsulinemic) wk of age. Elevations or decreases (P less than .05) were found in db/db mice (vs. lean littermates) as follows: pituitary content of Met-enkephalin was twofold higher at all ages studied; pituitary free Leu-enkephalin was lower at 4 wk and reversed to higher at 6-30 wk; pancreatic beta-endorphin was 30% lower at 4 wk and reversed to threefold higher at 6-12 wk; Met- and Leu-enkephalin-containing larger peptides were elevated at one or more points between 6 and 12 wk in both the pancreas and the pituitary. Thus, the onset of overt obesity between 4 and 6 wk of age was accompanied by a marked rise in both pancreatic beta-endorphin and pituitary Leu-enkephalin; similar elevations in these parameters have been reported previously in C57BL/6J ob/ob mice at approximately 12 wk of age.(ABSTRACT TRUNCATED AT 250 WORDS)     

Transmission of porcine encephalomyocarditis virus (EMCV) to mice by transplanting EMCV-infected pig tissues

We recently demonstrated that pigs infected with porcine encephalomyocarditis virus (EMCV) develop a persistent infection (up to 90 days post-infection (PI)) in the heart and brain that is accompanied by virus-induced pathologic changes, and that EMCV productively infects human cardiomyocytes in vitro, suggesting that EMCV may pose a risk to humans following transplantation of pig tissues to humans (Brewer et al. J Virol 2001; 75: 11621-11629). In this report, we demonstrate that intra-abdominal of myocardial or pancreatic sections from acutely-EMCV infected pigs (2 days PI) in either non-mutant C57BL/6 or C57BL/6-RAG-1-/- mice that lack B or T lymphocytes, resulted in transmission of the virus and acute fatal disease in all mice. In recipient RAG-1-/- mice, fatal EMCV disease occurred within 2 days post-transplantation, and it was accompanied by high virus titers in brain, heart, liver, spleen, kidneys and skeletal muscle, whereas in non-mutant C57BL/6 mice, disease occurred 5 to 6 days post-transplantation and was accompanied by lower virus titers. Transplantation of myocardial or pancreatic tissues from chronically EMCV-infected pigs (21 and 50 days PI) did not induce clinical disease, but resulted in detection of EMCV RNA in the brain of recipient RAG-1-/- mice, no viral RNA was detected in non-mutant C57BL/6 mice. Intra-abdominal transplantation of uninfected porcine myocardial tissues into RAG-1-/- mice followed by intramuscular inoculation with EMCV induced acute clinical disease but did not result in transmission of virus to the xenograft. These results show that EMCV can be efficiently transmitted from pig myocardial and pancreatic tissues to mice, providing a model of pig-to-human viral xenozoonosis that can be used to develop and test prophylactic and therapeutic measures against such infection.     

Reduced sensitivity of inducible nitric oxide synthase-deficient mice to multiple low-dose streptozotocin-induced diabetes

Nitric oxide (NO), synthesized by the inducible isoform of nitric oxide synthase (iNOS), has been proposed as a mediator of immune-induced beta-cell destruction in type 1 diabetes. To evaluate the role of iNOS for beta-cell dysfunction and death, we investigated the sensitivity of beta-cells from mice genetically deficient in this enzyme (iNOS-/-, background C57BL/6x129SvEv, H-2b) both to interleukin (IL)-1beta-induced beta-cell dysfunction in vitro and to multiple low-dose streptozotocin (MLDS)-induced diabetes in vivo. Exposure of islets isolated from C57BL/6 mice to IL-1beta for 24 h in vitro resulted in an induction of iNOS mRNA expression, an increase in nitrite formation, and a decrease in insulin release and proinsulin biosynthesis as compared with untreated C57BL/6 islets. IL-1beta failed to induce iNOS mRNA expression and increase nitrite formation by islets isolated from iNOS knockout mice (iNOS-/-), and no impairment in islet function was observed. The iNOS-/- mice showed a reduced incidence of hyperglycemia after treatment with MLDS as compared with wild-type C57BL/6 (H-2b) and 129 SvEv (H-2b) mice. On day 21 after the first streptozotocin (STZ) injection, 75% of the C57BL/6 mice and 100% of the 129SvEv mice had blood glucose levels >11 mmol/l, whereas the corresponding number for iNOS-/- mice was only 23%. This protection was not due to a delay in the onset of hyperglycemia, since no increase in number of hyperglycemic iNOS-/- mice was observed when the animals were followed up to 42 days. Moreover, islets isolated from iNOS-/- mice were susceptible to the in vitro deleterious effects of STZ. In conclusion, the present study provides evidence that iNOS may contribute to beta-cell damage after exposure to IL-1beta in vitro and treatment with MLDS in vivo.     

Genetic obesity unmasks nonlinear interactions between murine type 2 diabetes susceptibility loci

Nonlinear interactions between obesity and genetic risk factors are thought to determine susceptibility to type 2 diabetes. We used genetic obesity as a tool to uncover latent differences in diabetes susceptibility between two mouse strains, C57BL/6J (B6) and BTBR. Although both BTBR and B6 lean mice are euglycemic and glucose tolerant, lean BTBR x B6 F1 male mice are profoundly insulin resistant. We hypothesized that the genetic determinants of the insulin resistance syndrome might also predispose genetically obese mice to severe diabetes. Introgressing the ob allele into BTBR revealed large differences in diabetes susceptibility between the strain backgrounds. In a population of F2-ob/ob mice segregating for BTBR and B6 alleles, we observed large variation in pancreatic compensation for the underlying insulin resistance. We also detected two loci that substantially modify diabetes severity, and a third locus that strongly links to fasting plasma insulin levels. Amplification of the genetic signal from these latent diabetes susceptibility alleles in F2-ob/ob mice permitted discovery of an interaction between the two loci that substantially increased the risk of severe type 2 diabetes.     

Relevance of hyperglycemia on the timing of functional loss of allogeneic islet transplants: implication for mouse model

BACKGROUND: The role of recipient hyperglycemia on timing of allograft survival is unknown. In this study, we investigated if and how variation in recipient glycemia affects the ability to achieve and maintain normoglycemia after transplant of C57BL/6 islets into diabetic BALB/c mice. METHODS AND RESULTS: 85 diabetic BALB/c mice with non-fasting glycaemia ranging between 275 and 600 mg/dL were transplanted with 400 C57BL/6 islets. The time of rejection inversely correlated with the pre-transplant blood glucose concentration (P=0.004). All the 13 mice with normoglycemia beyond 50 days had pretransplant glycemia <450 mg/dL and the presence of autologous beta cell function was demonstrated in 8 (>100 days function) by the persistence of normoglycemia after allograft removal. The presence of immunosuppression (rapamycin plus FK506 plus anti-IL-2Ra chain mAbs, n=31; rapamycin plus IL-10; n=29) removed the influence of pretransplant hyperglycemia but after treatment withdrawn the timing and the probability of graft loss correlate with the pretransplant hyperglycemia. Pretransplant glycemia was inversely correlated with HOMA-B and serum insulin showing that a significant residual beta cell mass was present in mice with glycemia <450 mg/dL. CONCLUSION: This study demonstrates that the timing of functional loss of islets allotransplantation depends on the degree of recipient hyperglycemia. This potential bias should be kept in count in experimental results and a threshold that excludes moderate diabetes should be used in defining recipient's eligibility.     

Antidiabetic effects of Panax ginseng berry extract and the identification of an effective component

We evaluated antihyperglycemic and anti-obese effects of Panax ginseng berry extract and its major constituent, ginsenoside Re, in obese diabetic C57BL/6J ob/ ob mice and their lean littermates. Animals received daily intraperitoneal injections of Panax ginseng berry extract for 12 days. On day 12, 150 mg/kg extract-treated ob/ob mice became normoglycemic (137 +/- 6.7 mg/dl) and had significantly improved glucose tolerance. The overall glucose excursion during the 2-h intraperitoneal glucose tolerance test decreased by 46% (P < 0.01) compared with vehicle-treated ob/ob mice. The improvement in blood glucose levels in the extract-treated ob/ ob mice was associated with a significant reduction in serum insulin levels in fed and fasting mice. A hyperinsulinemic-euglycemic clamp study revealed a more than twofold increase in the rate of insulin-stimulated glucose disposal in treated ob/ ob mice (112 +/- 19.1 vs. 52 +/- 11.8 micromol x kg(-1) x min(-1) for the vehicle group, P < 0.01). In addition, the extract-treated ob/ob mice lost a significant amount of weight (from 51.7 +/- 1.9 g on day 0 to 45.7 +/- 1.2 on day 12, P < 0.01 vs. vehicle-treated ob/ob mice), associated with a significant reduction in food intake (P < 0.05) and a very significant increase in energy expenditure (P < 0.01) and body temperature (P < 0.01). Treatment with the extract also significantly reduced plasma cholesterol levels in ob/ob mice. Additional studies demonstrated that ginsenoside Re plays a significant role in antihyperglycemic action. This antidiabetic effect of ginsenoside Re was not associated with body weight changes, suggesting that other constituents in the extract have distinct pharmacological mechanisms on energy metabolism.     

Genetic influences on the immunologic pathogenesis of encephalomyocarditis (EMC) virus-induced diabetes mellitus

DBA/2 and Balb/cBY mice were infected with approximately 30 plaque-forming units of the M-variant of encephalomyocarditis (EMC-M) virus. Seven days after inoculation the majority of the animals of both strains were hyperglycemic. A significant correlation between increased concentrations of virus in the pancreas and hyperglycemia was found among individual DBA/2 animals, but not among Balb/cBY mice. T-lymphocyte depletion of DBA/2 mice before infection failed to alter the incidence or severity of hyperglycemia in comparison to intact animals. Conversely, hyperglycemia in T-lymphocyte-depleted Balb/cBY mice was reduced substantially in comparison to infected immunocompetent animals. There appears to be at least two genetically influenced pathogenic mechanisms of diabetes in EMC-M virus-infected mice. In some strains of animals, hyperglycemia results exclusively from viral infection and the consequent injury to the beta cells, whereas in other animals, viral damage to the islets is compounded by immunologic events.