1-Deoxynojirimycin containing Morus alba leaf-based food modulates the gut microbiome and expression of genes related to obesity.

BACKGROUND: Obesity is a serious disease with an alarmingly high incidence that can lead to other complications in both humans and dogs. Similar to humans, obesity can cause metabolic diseases such as diabetes in dogs. Natural products may be the preferred intervention for metabolic diseases such as obesity. The compound 1-deoxynojirimycin, present in Morus leaves and other sources has antiobesity effects. The possible antiobesity effect of 1-deoxynojirimycin containing Morus alba leaf-based food was studied in healthy companion dogs (n = 46) visiting the veterinary clinic without a history of diseases. Body weight, body condition score (BCS), blood-related parameters, and other vital parameters of the dogs were studied. Whole-transcriptome of blood and gut microbiome analysis was also carried out to investigate the possible mechanisms of action and role of changes in the gut microbiome due to treatment. RESULTS: After 90 days of treatment, a significant antiobesity effect of the treatment food was observed through the reduction of weight, BCS, and blood-related parameters. A whole-transcriptome study revealed differentially expressed target genes important in obesity and diabetes-related pathways such as MLXIPL, CREB3L1, EGR1, ACTA2, SERPINE1, NOTCH3, and CXCL8. Gut microbiome analysis also revealed a significant difference in alpha and beta-diversity parameters in the treatment group. Similarly, the microbiota known for their health-promoting effects such as Lactobacillus ruminis, and Weissella hellenica were abundant (increased) in the treatment group. The predicted functional pathways related to obesity were also differentially abundant between groups. CONCLUSIONS: 1-Deoxynojirimycin-containing treatment food have been shown to significantly improve obesity. The identified genes, pathways, and gut microbiome-related results may be pursued in further studies to develop 1-deoxynojirimycin-based products as candidates against obesity.

Effect of tetra-hydroxylated bile acid on size and insulin sensitivity of subcutaneous adipocytes in healthy lean cats.

Obesity leads to insulin resistance and is a major risk factor for the development of diabetes mellitus in cats. Prevention of obesity and obesity-induced insulin resistance is difficult, and reliable long-term strategies are currently lacking. Retinoid-related orphan receptor gamma (RORγ) was recently identified as an important transcription factor in the development of large insulin-resistant adipocytes in mice and humans. RORγ negatively affects adipocyte differentiation through expression of its target gene matrix metalloproteinase 3 (MMP3) and promotes the development of large insulin-resistant adipocytes. Preliminary studies in mice showed that RORγ can be inhibited by its ligand tetra-hydroxylated bile acid (THBA). In the present study, serum THBA levels were determined in healthy and diabetic cats. Moreover, potential side effects and the effects of THBA supplementation on adipocyte size, mRNA expression of RORγ, MMP3, interleukin 6, tumor necrosis factor α, adiponectin and leptin in feline subcutaneous adipocytes and insulin sensitivity were investigated in healthy normal weight cats. Thirteen healthy and 13 diabetic cats were used for determination of serum THBA level, and six healthy normal-weight cats were included in a feeding trial. Similar THBA levels were determined in serum of healthy and diabetic cats. Supplementation of 5 mg/kg THBA for 8 wk did not cause any negative effect on feeding behavior, general condition and blood parameters of tested cats. It significantly reduced adipocyte size and mRNA expression of MMP3, interleukin 6, and tumor necrosis factor α in adipocytes, while mRNA expression of adiponectin significantly increased and mRNA expression of RORγ and leptin remained unchanged. Administration of THBA did not influence fasting blood glucose levels or the response of cats to acute insulin administration. Based on these results, THBA is palatable and is considered safe for use in cats. It reduces expression of MMP3 and promotes the development of small adipocytes with increased expression of adiponectin and reduced expression of interleukin 6 and tumor necrosis factor α. Further studies are recommended to evaluate the effect of THBA on adipocyte size and insulin sensitivity in obese cats.

Pouteria ramiflora leaf extract on emulgel in wound healing activity in diabetic rats / Ação do extrato de folhas de Pouteria ramiflora em emulgel na atividade de cicatrização de feridas em ratos diabéticos

The genus Pouteria has been studied because it presents various activities, among which is its anti-inflammatory potential. The effects of Pouteria ramiflora Carbopol gel on the healing of skin wounds in diabetic rats were evaluated by microscopic imaging. Streptozotocin was administered intraperitoneally in animals that had fasted for 12 hours, a situation confirmed by the glycemic index (> 240 mg dL-¹). An excision on the back of the animals was performed and three groups were formed: Control (Gel), Ethanolic extract (Ext) and Gel + extract 2% (Ext+gel); the histopathological evaluation occurred on the 7th, 14th, 21st and 30th days after the post-operative period. The results of the phytochemical prospecting of P. ramiflora extract demonstrated the major presence of phenolic compounds and flavonoids; the assessment of the inflammatory infiltrate on the 7th day was higher on group Ext and Ext+gel when compared to group Control; on the 14th day control and Ext (p<0.05). The quantification of fibroblasts was higher on the 7th day among the three treatments, control and Ext (p<0.05), on the 21st day. Angiogenesis showeda higher number of vessels in Ext+gel group (p<0.05) on the 7th day; in Control, Ext and Ext+gel (p<0.05) on the 14th day; and Control and Ext (p<0.05)on the 21st day. The histopathological results showed that the formulation Ext+gel was efficient in tissue reparation and decrease in inflammatory cells on the diabetic's animals.

O gênero Pouteria apresenta várias aplicações terapêuticas e, dentre elas, grande potencial antiflamatório. Os efeitos do gel de Pouteria ramiflora sobre a cicatrização de feridas na pele de ratos diabéticos foram avaliados pela histomorfometria. A estreptozotocina foi administrada por via intraperitoneal em animais após jejum de 12 horas, a confirmação de indução da diabetes foi confirmada pelo índice glicêmico (> 240 mg dL-1). Foi realizada uma incisão no dorso do animal e foram criados 3 grupos de tratamento: controle (gel carbopol), extrato etanólico (Ext) e Gel + extrato etanólico à 2% (Ext+gel); a avaliação histopatológica foi realizada no 7º, 14º, 21º e 30º dias após o período pós operatório. Os resultados da prospecção fitoquímica dos extratos de P. ramiflora demonstraram majoritariamente a presença de compostos fenólicos e flavonóides; o infiltrado inflamatório avaliado no 7º dia foi maior para animais do grupo controle em relação aos grupos Ext (p<0.05) e Ext+gel 2% (p<0.05); no 14º dia o controle e Exp (p<0.05) apresentaram aumento significativo dos infiltrados inflamatórios. A presença de fibroblastos foi elevada no 7º dia em todos os tratamentos. O processo da angiogênese mostrou um maior número de vasos sanguíneos entre os grupos Ext e Ext+gel (p<0.05) no 7º dia; no 14º dia o grupo controle, Ext (p<0.05), Control e Ext+gel (p<0.05) apresentaram aumento de vascularização, e no 21º dia apenas os grupos controle e Ext (p<0.05). Os resultados histopatológicos mostraram que a formulação gel carbopol + extrato etanólico a 2% foi eficiente na reparação de tecidos e na diminuição de células inflamatórias nos animais diabéticos.

Calcium homeostasis in diabetes mellitus.

Diabetes mellitus (DM) is becoming a lifestyle-related pandemic disease. Diabetic patients frequently develop electrolyte disorders, especially diabetic ketoacidosis or nonketotic hyperglycemic hyperosmolar syndrome. Such patients show characteristic potassium, magnesium, phosphate, and calcium depletion. In this review, we discuss a homeostatic mechanism that links calcium and DM. We also provide a synthesis of the evidence in favor or against this linking mechanism by presenting recent clinical indications, mainly from veterinary research. There are consistent results supporting the use of calcium and vitamin D supplementation to reduce the risk of DM. Clinical trials support a marginal reduction in circulating lipids, and some meta-analyses support an increase in insulin sensitivity, following vitamin D supplementation. This review provides an overview of the calcium and vitamin D disturbances occurring in DM and describes the underlying mechanisms. Such elucidation will help indicate potential pathophysiology-based precautionary and therapeutic approaches and contribute to lowering the incidence of DM.

Hypothyroidism associated with acromegaly and insulin-resistant diabetes mellitus in a Samoyed.

BACKGROUND: The aetiology of insulin resistance (IR) in naturally occurring canine hypothyroidism is poorly understood and likely multifactorial. Excess secretion of growth hormone (GH) by transdifferentiated pituitary cells may contribute to IR in some hypothyroid dogs, but although this has been demonstrated in experimental studies, it has not yet been documented in clinical cases. CASE REPORT: A 4-year-old male entire Samoyed presented with an 8-month history of pedal hyperkeratosis and shifting lameness, which had been unresponsive to zinc supplementation, antibiotics and glucocorticoid therapy. The dog also exhibited exercise intolerance and polydipsia of 12 and 2 months duration, respectively. On physical examination, obesity, poor coat condition, widened interdental spaces and mild respiratory stridor were noted. Initial laboratory test results revealed concurrent hypothyroidism and diabetes mellitus (DM). Further investigations showed IR, GH excess and a paradoxical increase of GH following stimulation with thyrotropin-releasing hormone. CONCLUSIONS: To the authors' knowledge, this is the first reported case that suggests that GH alterations may have clinical significance in naturally occurring hypothyroidism. Among other factors, hypothyroidism-induced GH excess should be considered as a possible cause of IR in patients suffering from hypothyroidism and concurrent DM. In such cases, DM may reverse with treatment of hypothyroidism, as was documented in this case.

Oxidative stress and innate immunity in feline patients with diabetes mellitus: the role of nutrition.

This study was undertaken to test the hypothesis that oxidative stress is increased and neutrophil function is decreased in cats with diabetes mellitus (DM). Measures of oxidative stress and neutrophil function were evaluated in 20 control and 15 diabetic cats. Cats were then fed a diet designed specifically for feline diabetics (Purina DM Dietetic Management Feline Formula) for 8 weeks, after which all assays were repeated. Cats with DM had significantly less plasma superoxide dismutase (SOD) than control cats, consistent with a greater degree of oxidative stress in the DM group. Following 8 weeks of consuming a diabetes-specific diet glutathione peroxidase, an antioxidant enzyme increased significantly in both groups. Other parameters of oxidative stress, as well as neutrophil function, were similar between groups and did not change following dietary intervention. The DM cats were significantly older and heavier than the control cats, which may have contributed to differences in parameters of oxidative stress and levels of antioxidant enzymes between these groups, but the decreased level of SOD enzyme in the diabetic group would appear to support the continued development of targeted antioxidant supplementation for this cats with this disease.

Outcome of dogs with diabetic ketoacidosis: 127 dogs (1993-2003).

The aim of this study was to retrospectively describe the outcome of 127 dogs with naturally occurring diabetic ketoacidosis (DKA) and to examine the association between outcome of canine DKA and clinical and clinicopathologic findings. Eighty-two (65%) dogs were diagnosed with DKA at the time of initial diagnosis of diabetes mellitus (DM). Eighty-seven dogs (69%) had one or more concurrent disorders diagnosed at the time of hospitalization. Commonly identified concurrent conditions included acute pancreatitis (52, 41%), urinary tract infection (21, 20%), and hyperadrenocorticism (19, 15%). Dogs with coexisting hyperadrenocorticism were less likely to be discharged from the hospital (P = .029). Of 121 treated dogs, 89 dogs (70%) survived to be discharged from the hospital, with a median hospitalization of 6 days. Nonsurvivors had lower ionized calcium concentration (P < .001), lower hematocrit (P = .036), lower venous pH (P = .0058), and larger base deficit (P = .0066) than did survivors. Time from admission to initiation of subcutaneous insulin therapy was correlated with lower serum potassium concentration (P = .0056), lower serum phosphorus concentration (P = .0043), abnormally high white blood cell count (P = .0060), large base deficit (P = .0015), and low venous pH (P < .001). Multivariate analysis showed that base deficit was associated with outcome (P = .021). For each unit increase in the base deficit, there was a 9%) greater likelihood of discharge from the hospital. In conclusion, the majority of dogs with DKA were not previously diagnosed with DM. Concurrent conditions and electrolyte abnormalities are common in DKA and are associated with length of hospitalization. Survival was correlated to degree of anemia, hypocalcemia, and acidosis.

Antihyperglycaemic and antioxidant effect of hyponidd, an ayurvedic herbomineral formulation in streptozotocin-induced diabetic rats.

Hyponidd is a herbomineral formulation composed of the extracts of ten medicinal plants ( Momordica charantia, Melia azadirachta, Pterocarpus marsupium, Tinospora cordifolia , Gymnema sylvestre, Enicostemma littorale, Emblica officinalis, Eugenia jambolana, Cassia auriculata and Curcuma longa). We have investigated hyponidd for its possible antihyperglycaemic and antioxidant effect in diabetic rats. Rats were rendered diabetic by streptozotocin (STZ) (45 mg kg(-1) body weight). Oral administration of hyponidd (100 mg kg(-1) and 200 mg kg(-1)) for 45 days resulted in significant lowered levels of blood glucose and significant increased levels of hepatic glycogen and total haemoglobin. An oral glucose tolerance test was also performed in experimental diabetic rats in which there was a significant improvement in blood glucose tolerance in the rats treated with hyponidd. Hyponidd administration also decreased levels of glycosylated haemoglobin, plasma thiobarbituric acid reactive substances, hydroperoxides, ceruloplasmin and alpha-tocopherol in diabetic rats. Plasma reduced glutathione and vitamin C were significantly elevated by oral administration of hyponidd. The effect of hyponidd at a dose of 200 mg kg(-1) was more effective than glibenclamide (600 microg kg(-1)) in restoring the values to near normal. The results showed that hyponidd exhibits antihyperglycaemic and antioxidant activity in STZ-induced diabetic rats.

Intravesicular administration of clotrimazole for treatment of candiduria in a cat with diabetes mellitus.

A 12-year-old spayed female domestic longhair cat developed fungal cystitis (Candida sp). The cat had a history of chronic diabetes mellitus, hyperadrenocorticism, and bacterial cystitis caused by Escherichia coli. Antifungal agents (itraconazole and fluconazole) were administered orally without noticeable effect on the candiduria. Because of the ineffectiveness of these treatments, intravesicular administration of 1% clotrimazole solution was performed weekly for 3 treatments. Complete resolution of urinary candidiasis was detected after the third infusion. Intravesicular administration of clotrimazole solution appears to be a safe and effective treatment of fungal cystitis in cats.

Treatment of feline diabetes mellitus using an alpha-glucosidase inhibitor and a low-carbohydrate diet.

The purpose of this study was to determine the effect of an alpha-glucosidase inhibitor (acarbose), combined with a low-carbohydrate diet on the treatment of naturally occurring diabetes mellitus in cats. Eighteen client-owned cats with naturally occurring diabetes mellitus were entered into the study. Dual-energy X-ray absorptiometry (DEXA) was performed prior to and 4 months after feeding the diet to determine total body composition, including lean body mass (LBM) and percent body fat. Each cat was fed a commercially available low-carbohydrate canned feline diet and received 12.5mg/cat acarbose orally every 12h with meals. All cats received subcutaneous insulin therapy except one cat in the study group that received glipizide (5mg BID PO). Monthly serum glucose and fructosamine concentrations were obtained, and were used to adjust insulin doses based on individual cat's requirements. Patients were later classified as responders (insulin was discontinued, n=11) and non-responders (continued to require insulin or glipizide, n=7). Responders were initially obese (>28% body fat) and non-responders had significantly less body fat than responders (<28% body fat). Serum fructosamine and glucose concentrations decreased significantly in both responder and non-responder groups over the course of 4 months of therapy. Better results were observed in responder cats, for which exogenous insulin therapy was discontinued, glycemic parameters improved, and body fat decreased. In non-responders, median insulin requirements decreased and glycemic parameters improved significantly, despite continued insulin dependence. The use of a low-carbohydrate diet with acarbose was an effective means of decreasing exogenous insulin dependence and improving glycemic control in a series of client-owned cats with naturally occurring diabetes mellitus.

Critical care monitoring considerations for the diabetic patient.

Diabetes mellitus (DM) is a common endocrine disease encountered in the emergency and critical care setting. The diabetic Ketoacidotic (DKA) animal represents an extreme of the DM patient with regard to hyperglycemia and acid-base and electrolyte derangements. Prompt diagnosis of DKA in a critical patient and rapid initiation of appropriate therapy are necessary for a positive outcome. The steps of treatment, in order of importance, include initiation of intravenous fluid therapy, insulin therapy, electrolyte replacement, and reversal of the metabolic acidosis. The main goals of therapy--including correction of dehydration, electrolyte abnormalities and acidosis via aggressive fluid therapy with electrolyte supplementation and correction of ketoacidosis and hyperglycemia via initiation of insulin therapy--can be achieved if these steps are followed. Because of the severity of metabolic alterations in the DKA animal, frequent and careful monitoring are paramount because they will allow the clinician to tailor treatment to each case.

Hypercalcemia due to latrogenic secondary hypoadrenocorticism and diabetes mellitus in a cat.

A 9-year-old, spayed female domestic shorthair cat presented for polyphagia, polydipsia, and polyuria following chronic methylprednisolone acetate therapy for pruritus. Initial diagnostics were consistent with uncomplicated diabetes mellitus. Serum calcium was within reference range. Within 12 hours the cat developed depression, anorexia, vomiting, and severe dehydration. Laboratory analysis indicated marked hypercalcemia as measured by both ionized and total calcium concentration. No underlying neoplastic or inflammatory process was identified. An adrenocorticotropic hormone stimulation test was indicative of adrenocortical insufficiency. The hypercalcemia resolved with glucocorticoid supplementation and correction of the dehydration. The diabetes mellitus and adrenal insufficiency both resolved within 9 weeks.

Biochemical evaluation of multiple herbal treatments in alloxan-induced diabetes in Wistar rats.

Alloxan-induced diabetic rats were treated with multiple herbal preparation besides a control group receiving distilled water. The levels of glucose and alkaline phosphatase (ALP) increased abnormally in the alloxan treated group and the same were normalized upon treatment with the herbal preparation. The levels of blood urea nitrogen (BUN), alanine aminotransferase (ALT), protein and albumin in all groups remained unaltered. However, weekly body weight gain which got significantly altered in the alloxan-treated group was normalized by treatment with the herbal preparation. On the whole, a profound hypoglycemic effect was observed by the multiple herbal treatment in the diabetic rats.

Nutrients and botanicals in the treatment of diabetes in veterinary practice.

Diabetes mellitus can be frustrating to treat in veterinary practice, but botanical and nutritional supplements may offer assistance in stabilizing difficult patients. While dogs are typically subject to type 1 diabetes, cats develop type 2 diabetes as much as 70 percent of the time. Whereas treatment adjuncts to insulin may address carbohydrate metabolism from glucose absorption to insulin receptor function, success may depend on the type of diabetes present in the patient.

Effect of the alpha-glucosidase inhibitor acarbose on control of glycemia in dogs with naturally acquired diabetes mellitus.

OBJECTIVE: To evaluate effect of acarbose on control of glycemia in dogs with diabetes mellitus. DESIGN: Prospective randomized crossover controlled trial. ANIMALS: 5 dogs with naturally acquired diabetes mellitus. PROCEDURE: Dogs were treated with acarbose and placebo for 2 months each: in 1 of 2 randomly assigned treatment sequences. Dogs that weighed < or = 10 kg (22 lb; n = 3) or > 10 kg (2) were given 25 or 50 mg of acarbose, respectively, at each meal for 2 weeks, then 50 or 100 mg of acarbose, respectively, at each meal for 6 weeks, with a 1-month interval between treatments. Caloric intake, type of insulin, and frequency of insulin administration were kept constant, and insulin dosage was adjusted as needed to maintain control of glycemia. Serum glucose concentrations, blood glycosylated hemoglobin concentration, and serum fructosamine concentration were determined. RESULTS: Significant differences in mean body weight and daily insulin dosage among dogs treated with acarbose and placebo were not found. Mean preprandial serum glucose concentration, 8-hour mean serum glucose concentration, and blood glycosylated hemoglobin concentration were significantly lower in dogs treated with insulin and acarbose, compared with insulin and placebo. Semisoft to watery feces developed in 3 dogs treated with acarbose. CONCLUSIONS AND CLINICAL RELEVANCE: Acarbose may be useful as an adjunctive treatment in diabetic dogs in which cause for poor glycemic control cannot be identified, and insulin treatment alone is ineffective.

Pretreatment clinical and laboratory evaluation of cats with diabetes mellitus: 104 cases (1992-1994).

OBJECTIVE: To assess pretreatment clinical and laboratory findings in cats with diabetes mellitus and to determine the influence of ketoacidosis on pretreatment findings. DESIGN: Retrospective case series. ANIMALS: 104 cats with diabetes mellitus, 38 of which had ketoacidosis. PROCEDURE: Medical records of cats with diabetes mellitus examined over a 20-month period were reviewed. Cats that had received previous treatment for diabetes mellitus, or for which medical records were incomplete, were excluded from this study. RESULTS: Cats ranged in age from 1 to 19 years (median, 11 years). Male cats were twice as likely to develop diabetes as females. The most common historical signs were polyuria, polydipsia, weight loss, and diminished activity. Anorexia or poor appetite was reported more commonly than polyphagia, especially in cats with ketoacidosis. Diminished activity, anorexia, weakness, and vomiting were all significantly more common in ketoacidotic cats than in nonketoacidotic cats. Forty-four cats were considered thin, and 34 were considered obese. All cats had hyperglycemia and most had hypercholesterolemia and high activities of 1 or more hepatic enzymes. Compared with nonketoacidotic cats, ketoacidotic cats were more likely to have had low serum electrolyte values. All cats had glucosuria and 42 (40.4%) had ketonuria. Baseline serum insulin concentrations were measured in 18 cats and were low or at the low end of the reference range in 14 (77.8%) cats. Serum fructosamine concentration, determined in 22 cats, was high in 20 (90.9%) cats. Twenty-three of the 104 (22.1%) cats had concurrent disease, the most common of which were hyperthyroidism, inflammatory bowel disease, and eosinophilic granuloma complex. CLINICAL IMPLICATIONS: In more than a third of cats, diabetes mellitus is complicated by development of ketoacidosis, which increases the severity of clinical and laboratory abnormalities. Diagnosis of diabetes mellitus is made on the basis of signalment (e.g., middle-aged to old male cats), owner complaints (e.g., polyuria, polydipsia, and weight loss), physical examination findings (e.g., lethargy or muscle wasting), and laboratory findings (e.g., hyperglycemia and glucosuria).

Nutritional therapy for diabetes mellitus.

Dietary therapy affects diabetes management in the dog and cat directly through control of blood glucose and indirectly through control of obesity and lipid abnormalities. Caloric intake, the feeding schedule, food form, macronutrient composition of the diet, and the presence of any concurrent problems must all be considered when planning the dietary regime. Generally, the healthy diabetic dog or cat should be fed a diet with increased fiber and moderate carbohydrate in a quantity sufficient to attain and maintain optimal body weight; whenever possible, the daily food allotment should be divided into multiple small meals that are fed through the day and evening when the physiologic effects of administered insulin are present. Once established, the dietary regime should be kept constant from day to day. Following these guidelines will help minimize postprandial hyperglycemia and may lead to a decreased exogenous insulin requirement. However, if a concurrent disorder has dietary requirements that conflict with those for the diabetic pet, nutritional management of the other disorder should usually take precedence.

Hypophosphatemia. Causes and clinical consequences.

Severe hypophosphatemia (i.e., serum phosphorus concentration below 1 mg/dl) occurs infrequently in veterinary patients. It is most often associated with diabetic ketoacidosis in small animals. Phosphate is necessary for the production of 2,3 diphosphoglycerate (2,3-DPG) and adenosine triphosphate (ATP); both are important for normal cellular metabolism. Consequences of severe hypophosphatemia may include hemolytic anemia, seizures, altered mentation, cardiomyopathy, and skeletal muscle weakness. Parenteral phosphate therapy is necessary in most cases of severe hypophosphatemia.

Severe hypophosphatemia associated with diabetes mellitus in six dogs and one cat.

Severe hypophosphatemia was found in 6 diabetic dogs and in one diabetic cat. The cat suffered from hemolysis, and one dog had seizures, both apparently as a result of the severe hypophosphatemia. Clinical signs were not determined solely by the serum concentration of phosphorus, as seen in 5 other patients that did not have signs of disease despite similar serum phosphorus concentrations.

Diabetes mellitus: relationships of nonhuman primates and other animal models to human forms of diabetes.

Results from studies with M. nigra allow some conclusions and predictions about the etiology and development of diabetes relative to the islet lesion in monkeys and human beings. Some factor or factors must initiate the lesion; whether this is genetic, environmental, or a combination of both is not known. Amyloid is not the initiating factor to the islet lesion, but appears later as there is deterioration of cells. Sufficient evidence does not yet exist to choose from among the alternatives regarding the source of amyloid. With gradual deterioration of cells and replacement by amyloid, secretion of insulin is impaired and concentrations of glucagon increase. Sufficient circulating insulin is probably chronically available to the cells in this moderately impaired state, so that an acute decrease in delta IRI in response to glucose in an iv-administered GTT does not cause significant impairment in glucose clearance. The increase in circulating glucagon is probably due to a loss of controls on alpha-cell secretion or synthesis of glucagon. Fasting glucose levels increase but remain within the nondiabetic range. Eventually there is sufficient accretion of amyloid, usually greater than 50%, so that substantial beta-cell loss occurs and the monkey can no longer maintain fasting normoglycemia. The monkey then is hyperglycemic and hypoinsulinemic. Only at this time are the impairments detectable by the usual diagnostic clinical criterion of hyperglycemia. The ICAs arise in response to secretory cell deterioration and are present until there no longer are sufficient cells to elicit an immune response. Results from M. nigra can give insight into a similar condition that probably exists in a subpopulation of older diabetic humans. Humans probably pass through stages similar to those discerned in monkeys. Nondiabetic humans with sufficient beta cells to sustain adequate secretion of insulin, but with moderate amyloid infiltration, probably would be in a category equivalent to BD monkeys; since these people are not overtly hyperglycemic, they are not clinically recognizable as diabetic and would be classified retrospectively as nondiabetic. Continued loss of cells with concomitant amyloid deposition would eventually lead to hyperglycemia; if examined at autopsy, these people would have visible islet amyloid as well as a retrospective diagnosis of diabetes. Older type II diabetic humans with ICA usually proceed to insulin therapy more rapidly than do those who are ICA negative (Irvine et al., 1977; Del Prete et al., 1977; Gray et al., 1980).(ABSTRACT TRUNCATED AT 400 WORDS)