Assessment of fat-mass loss during weight reduction in obese women

Methods for assessing body fat mass (FM) loss were compared in 32 obese (body mass index [BMI], 29 to 41 kg/m2) premenopausal women before and after a weight loss of 13.0 +/- 3.4 kg (mean +/- SD). A four-component (4C) model was used as the criterion. The other methods were as follows: three-component models (body density with total body water [3W] or bone minerals [3M]), underwater weighing, dual-energy x-ray absorptiometry ([DXA] XR-26, software 2.5.2; Norland, Ft Atkinson, WI), bioelectric impedance analysis (BIA) with an obese-specific equation [Segal et al), skinfolds (Durnin and Womersley), and an equation with BMI (Deurenberg et al). The 3W model (bias +/- SD, 0.5 +/- 0.4 kg), XR-26 (0.6 +/- 2.1 kg), and BMI equation (-0.3 +/- 2.1 kg) gave practically unbiased mean estimations of fat loss. All other methods underestimated fat loss by at least 1.6 kg (range of bias, -2.7 to -1.6 kg). The small bias (0.7 +/- 1.0 kg) between underwater weighing and model 4C before weight reduction indicates that the two-component assumptions were valid in premenopausal, weight-stable obese women. However, particularly the water fraction of the fat-free body component (4C model) was increased after weight reduction (before, 72.9% +/- 1.4%; after, 75.7% +/- 2.2%), making both underwater weighing and the 3M model uncertain for assessment of body composition changes. A general tendency for overestimating FM was seen before and more clearly after weight reduction. However, most methods underestimated fat loss, apparently because of unexpected changes in hydration of the fat-free body component.     

Effect of exercise intensity on glucose and insulin metabolism in obese individuals and obese NIDDM patients

OBJECTIVE: The primary purpose of this study was to evaluate the acute effect of exercise of differing intensity on plasma glucose and insulin responses to an oral glucose challenge. RESEARCH DESIGN AND METHODS: Six obese men and six obese men with NIDDM of similar age, weight, percentage body fat, and VO2peak participated in the study. Each subject underwent two 7-day exercise programs in a counterbalanced order at 2-week intervals. During each 7-day exercise period, the subjects cycled every day at a power output corresponding to 50% VO2peak for 70 min or 70% VO2peak for 50 min. Muscle glycogen utilization was estimated during exercise on day 7 using a [3H]glucose infusion technique in conjunction with indirect calorimetry. During the day before and after each 7-day exercise period, a 3-h oral glucose tolerance test (OGTT) was administered after a 12-h overnight fast. RESULTS: The average caloric expenditure did not differ between exercise at 50 and 70% VO2peak in both obese and obese NIDDM subjects. However, the carbohydrate oxidation was higher (P < 0.05) during exercise at 70 than 50% VO2peak in obese subjects (77 +/- 5 vs. 68 +/- 6 g) and obese NIDDM subjects (70 +/- 4 vs. 58 +/- 6 g). Muscle glycogen utilization was also higher (P < 0.05) during exercise at 70 than 50% VO2peak in obese subjects (59 +/- 9 vs. 30 +/- 7 g) and in obese NIDDM subjects (48 +/- 5 vs. 24 +/- 5 g). In obese subjects, plasma glucose response area during the OGTT did not change after 7 days of exercise at either 50 or 70% VO2peak. Plasma insulin response area during the OGTT also did not change after 7 days of exercise at 50% VO2peak. However, plasma insulin response area was reduced (P < 0.05) after 7 days of exercise at 70% VO2peak (9,644 +/- 1,783 vs 7,538 +/- 1,522 microU.ml-1.180 min-1). In obese NIDDM subjects, both plasma glucose and insulin response areas during the OGTT did not decrease after 7 days of exercise at either 50 or 70% VO2peak. CONCLUSIONS: It is concluded that the exercise-induced improvement in insulin sensitivity is influenced by exercise intensity in obese individuals. The improved insulin sensitivity after 7 days of exercise at 70% VO2peak in obese individuals may be related to greater muscle glycogen utilization during exercise. The lack of improvement in glucose tolerance and insulin sensitivity after 7 days of exercise at either 50 or 70% VO2peak in obese NIDDM patients may be due to the fact that the NIDDM patients selected in the present study were relatively hypoinsulinemic.     

Ultradian pulsatility of plasma glucose and insulin secretion rate: circadian and sleep modulation

Insulin release is a complex oscillatory process with rapid pulses (10 min) superimposed on slower circhoral oscillations (50-100 min). The exact mechanism of the circhoral oscillations, which are probably in part the consequence of a negative feedback loop linking glucose and insulin secretion rate, remains unclear. Stimulatory effects of sleep on insulin secretion are achieved by an enhancement of the oscillation amplitude which could be partly mediated by GH. The different patterns observed after acute or chronic shift of sleep suggest however an interaction between sleep influence and circadian rhythmicity, as described for numerous pituitary hormones. The intra-sleep awakenings have a modulatory effect on glucose levels but no systematic relationship exists between glucose or insulin secretion rate oscillations and the REM-NREM sleep cycles. Irrespective of the mechanisms involved, sleep or GH stimulatory effects result from a modulation of the oscillation amplitude rather than of their frequency which is probably an important feature of insulin efficacy.     

Acute effects of laboratory stress on blood glucose in noninsulin-dependent diabetes

The acute effects of two psychological stressors (personally stressful imagery and threat of shock) on blood glucose (BG), heart rate, blood pressure, skin conductance, and subjective stress were studied in 22 noninsulin-dependent diabetic adults and nine healthy, nondiabetic subjects similar in age, weight, education and sex. The diabetic group's BG rose significantly after threat of shock (M change from rest = 18.4 mg/dL, p < .05), although the nondiabetic group's BG remained stable throughout the assessment. Significant increases in subjective stress ratings (p < .05) and skin conductance level (p < .05) paralleled the noninsulin-dependent diabetes mellitis (NIDDM) subjects' BG response to threat of shock. The findings suggest that some stressors can have hyperglycemic effects on individuals with NIDDM, although generalization of these findings to the natural environment remains to be demonstrated. The methodology used is contrasted with other studies that have failed to demonstrate stress effects on BG.     

Ref: Gallstone formation in obese subjects undergoing a weight reduction diet

The case of a giant-cell epulis as an initial feature of primary hyperparathyroidism is presented. A 58-year-old woman appeared for dental treatment with a buccal alveolar swelling that was confirmed by means of biopsies to be a multinucleated giant-cell lesion. High calcium levels warranted investigation for a parathyroid adenoma, which was located in an ectopic position and surgically removed. This case delineates the importance of referring patients with oral lesions of doubtful cause to specialists for further diagnostic workup.     

Dehydroepiandrosterone decreases serum tumor necrosis factor-alpha and restores insulin sensitivity: independent effect from secondary weight reduction in genetically obese Zucker fatty rats

Dehydroepiandrosterone (DHEA) and its sulfate ester are the most abundant circulating adrenal steroids in humans. Administration of DHEA has been reported to have beneficial effects on obesity, hyperlipidemia, diabetes, and atherosclerosis in obese rodents, although its effects on insulin resistance have not been fully elucidated. In this study, the effects of DHEA treatment on insulin sensitivity were investigated in genetically obese Zucker rats, an animal model of insulin resistance, using the euglycemic clamp technique. After 0.4% DHEA was administered for 10 days to female obese Zucker rats aged 16 weeks, body weight and plasma insulin decreased and glucose disposal rate (GDR), which was normally reduced in obese rats, rose significantly compared with age- and sex-matched control obese rats. On the other hand, although the pair-fed obese rats also showed levels of weight reduction similar to those of DHEA-treated rats, the increase in GDR of DHEA-treated rats was significantly greater than in pair-fed rats, suggesting a direct ameliorating effect of DHEA on insulin sensitivity of obese rats. Serum concentration of tumor necrosis factor (TNF)-alpha, one of cytokines causing insulin resistance, was also reduced significantly in DHEA-treated, but not in pair-fed obese rats. In conclusion, our results suggest that DHEA treatment reduces body weight and serum TNF-alpha independently, and that both may ameliorate insulin resistance in obese Zucker fatty rats.     

Chronic chlorpropamide therapy of noninsulin-dependent diabetes augments basal and stimulated insulin secretion by increasing islet sensitivity to glucose

To determine the effect of chronic sulfonylurea therapy on islet function in noninsulin-dependent diabetes mellitus (NIDDM), studies were performed in 18 untreated NIDDM patients before and after 12-16 weeks of chlorpropamide therapy. Fasting plasma glucose (FPG) fell with chlorpropamide therapy from 249 +/- 16 to 157 +/- 8 mg/dl (mean +/- SEM; P less than 0.001), and basal insulin increased from 17 +/- 2 to 24 +/- 3 microU/ml (P less than 0.001). The percent change in basal insulin correlated with the pretreatment FPG (r = 0.62; P less than 0.01) and inversely with the change in FPG during chlorpropamide (r = -0.57; P less than 0.025). Thus, patients with the highest pretreatment FPG showed the largest relative increase in basal insulin and the largest fall of FPG with chlorpropamide therapy. In nine patients, arginine-stimulated acute insulin responses (AIR) were studied at each of three plasma glucose (PG) levels both before and during chlorpropamide treatment. AIR at FPG was not different before and during treatment. However, when PG during treatment was matched by glucose infusion to the pretreatment FPG, the AIR was clearly increased during chlorpropamide therapy (176 +/- 65 vs. 49 +/- 11 microU/ml; P less than 0.02). When AIR is plotted against PG for each individual, the slope of the regression line generated (slope of glucose potentiation) is a measure of that patient's islet sensitivity to glucose. The logarithm of the slope of glucose potentiation correlated inversely with FPG (r = -0.92; P less than 0.001). Chlorpropamide treatment increased the slopes of potentiation from 0.26 +/- 0.11 to 1.47 +/- 0.70 (P less than 0.01). We conclude that chronic chlorpropamide therapy augments both basal and stimulated insulin secretion in NIDDM and that this may be an important mechanism of the drug's hypoglycemic effect. The data support the hypothesis that the hyperglycemia of NIDDM is related to islet insensitivity to glucose and that chlorpropamide treatment improves this impairment.     

Mechanism of glucose intolerance during fasting: differences between lean and obese subjects

Oral glucose tolerance tests were performed on 14 lean and 14 obese nondiabetic subjects before and after a 6-day fast. In addition, insulin tolerance tests were performed on 8 lean and 8 obese subjects before and after starvation. Both in lean and obese subjects glucose tolerance deteriorated during starvation, but much more so in the lean population. During fasting, insulin elevation after a glucose load was significantly delayed in lean subjects but not in the obese. Circulating levels of factors known to affect glucose tolerance, such as glucagon, growth hormone, free fatty acids, and ketone bodies were higher in fasting lean than in fasting obese individuals. In normals fasting resulted in a significant decrease of the blood glucose response to insulin injection, whereas in fasting obese subjects glucose response was unchanged. The results obtained suggest that the effect of fasting on insulin release and insulin sensitivity was more pronounced in lean than in obese subjects, which resulted in greater deterioration of glucose tolerance in the lean population.     

Adverse effects of recombinant human insulin-like growth factor I in obese insulin-resistant type II diabetic patients

Data from studies in diabetic rodents and evidence from clinical situations of severe resistance to insulin suggest that insulin-like growth factor I (IGF-I) is able to at least partly overcome insulin resistance. To assess the efficacy of recombinant human IGF-I in subjects with the most common form of insulin resistance, e.g., obese, type II diabetic patients, we administered recombinant human IGF-I (rhIGF) in doses of 120 and 160 micrograms/kg twice daily for 4-52 days to seven such individuals who had been treated previously with high doses of insulin (> 0.7 U.kg-1 x day-1). Four patients exhibited comparable or enhanced, whereas three had diminished, blood glucose control on rhIGF-I relative to that while on twice daily NPH insulin during the six-week control period. The occurrence of adverse effects in all patients compelled us to discontinue rhIGF-I administration before completing the 8-week treatment period. These adverse effects included edema primarily on the face and hands, mild weight gain, occasional dyspnea, bilateral jaw tenderness, arthralgias and myalgias, fatigue, tachycardia, flushing, orthostatic hypotension, and local burning at the injection site. We conclude that the frequency and severity of side effects associated with administering high-dose subcutaneous rhIGF-I to obese insulin-resistant diabetic patients make it an unacceptable therapeutic agent for these patients despite its ability to produce reasonable blood glucose control in approximately 50% of them.     

Insulin sensitivity, insulin action, and fibrinolysis activity in nondiabetic and diabetic obese subjects

Because inconsistencies occur with regard to the relative contribution of insulin to the hypofibrinolysis characteristic of obesity and diabetes, we explored the relationship between insulin and fibrinolysis, assessing both insulin sensitivity and insulin action. Seventeen markedly obese subjects (body mass index [BMI], 34.0+/-1.6 kg/m2; 12 nondiabetic and five diabetic) were studied using the three-step euglycemic-hyperinsulinemic clamp technique. Since the circadian rhythm of the fibrinolytic system may obscure a true effect of insulin, variations in fibrinolysis parameters observed during the glucose clamp were compared with those occurring spontaneously because of the circadian rhythm. Compared with six normal-weight subjects (BMI, 21.0+/-0.9 kg/m2), all obese subjects exhibited basal hyperinsulinism (fasting plasma insulin, 16.0+/-1.4 v 9.8+/-1.3 microU/microL, P < .001; fasting plasma C-peptide, 1.4+/-0.2 v 0.5+/-0.2 ng/mL, P < .001), hypofibrinolysis (euglobulin lysis time [ELT], 378+/-29 v 222+/-31 minutes, P=.01; tissue plasminogen activator [tPA] antigen, 7.8+/-0.9 v 4.2+/-0.5 ng/mL, P=.04; plasminogen activator inhibitor type 1 [PAI-1] activity, 22.2+/-2.5 v3.9+/-0.6 AU/mL, P=.004), and marked insulin resistance (M value, ie, the maximal glucose disposal rate, 9.1+/-0.6 v 18.6+/-0.8 mg/(kg x min), P < .001). The M value correlated inversely with tPA antigen (r=-.46, P=.05). During insulin infusion, values for fibrinolysis parameters decreased, but were not different compared with variations due to the circadian rhythm. In conclusion, our findings together with previously reported data reinforce the idea that chronic hyperinsulinism is linked to hypofibrinolysis, but insulin does not seem to acutely regulate the fibrinolysis system.     

Tumor necrosis factor-alpha in sera of obese patients: fall with weight loss

In view of the recent demonstration that obesity in animals and humans is associated with an increase in tumor necrosis factor-alpha (TNFalpha) expression, that this expression falls with weight loss, and that TNFalpha may specifically inhibit insulin action, the possibility that TNFalpha may be a mediator of insulin resistance has been raised. We have undertaken this study to investigate whether serum TNFalpha concentrations are elevated in obese subjects, whether they fall after weight loss, and whether this fall parallels the fall in insulin release after glucose challenge. Obese patients (age range: 25-54, weight mean +/- SD: 96.4 +/- 13.8 kg, body mass index: 35.7 +/- 5.6 kg/m2) were started on a diet program. The mean weight fell to 84.5 +/- 11.3 (P < 0.0001) and body mass index to 31.3 +/- 4.9 (P < 0.0001). Plasma TNFalpha concentrations were markedly elevated in the obese (3.45 +/- 0.16 pg/mL), when compared with controls (0.72 +/- 0.28 pg/mL), and fell significantly (2.63 +/- 1.40 pg/mL) after weight loss (P < 0.02). The magnitude of insulin release after glucose (75 g) challenge (area under the curve) also fell significantly (P < 0.01) after weight loss. The magnitude of weight loss and fall in TNFalpha were related to basal body weight (r = 0.57, P < 0.001) and basal TNFalpha (r = 0.55, P < 0.001) concentrations, respectively, but not to each other or to the glucose-induced insulin release (area under the curve). We conclude that obesity is associated with increased plasma TNFalpha concentrations, which fall with weight loss. Because circulating TNFalpha may mediate insulin resistance in the obese, a fall in TNFalpha concentrations may contribute to the restoration of insulin resistance after weight loss, Thus, TNFalpha may be an important circulating cytokine, which may provide a potentially reversible mechanism for mediating insulin resistance.     

Hyperinsulinemia and hypofibrinolysis: effects of short-term optimized glycemic control with continuous insulin infusion in type II diabetic patients

A defect in the fibrinolytic system results from an increase in type 1 plasminogen activator inhibitor (PAI-1) in diabetes. It can be considered an independent risk factor for the development of cardiovascular disease. In obese and type II diabetic patients, plasma PAI-1 level correlates with fasting insulinemia. However, during the euglycemic clamp, acute hyperinsulinemia does not increase PAI-1 production. The present study was undertaken to investigate the effect of optimized glycemic control by continuous subcutaneous insulin infusion (CSII) on the hypofibrinolytic state for 14 days in 16 type II diabetic patients with poor metabolic control despite maximal oral antidiabetic treatment. Plasma PAI-1 activity levels decreased from 13.38 +/- 2.85 IU/mL to 6.77 +/- 1.81 IU/mL (P = .002) during CSII, along with a concurrent improvement in insulin sensitivity (index obtained by basal glycemia-nadir glycemia/basal glycemia) during the insulin sensitivity test (0.121 +/- 0.03 v 0.057 +/- 0.02, P = .02). These results suggest that insulin resistance rather than hyperinsulinism may be involved in the hypofibrinolytic state in type II diabetic patients. The positive correlation between the changes in triglycerides and in PAI-1 activity (r = .589, P = .026) strongly suggests a role for triglycerides in the impairment of fibrinolysis, which could be a link between insulin resistance and hypofibrinolysis.     

Age-related reduction in glucose elimination is accompanied by reduced glucose effectiveness and increased hepatic insulin extraction in man

This study examined whether insulin secretion, insulin sensitivity, glucose effectiveness (SG), and hepatic extraction (HE) of insulin are altered by age when glucose tolerance is normal. A frequently sampled i.v. glucose tolerance test was performed in 20 elderly (E, 10/10 male/female, all 63 yr old) and in 20 young subjects (Y, 10/10 male/female, all 27 yr old), who were similar in body mass index and 2-h blood glucose during oral glucose tolerance test. E exhibited impaired glucose elimination (i.v. tolerance index, 1.31 +/- 0.10 vs. 1.70 +/- 0.12% min-1; P = 0.019). First-phase insulin secretion and SI did not differ between the groups, whereas E had lower glucose sensitivity of second-phase insulin secretion (0.40 +/- 0.07 vs. 0.70 +/- 0.08 (pmol/L)min-2/(mmol/L), P = 0.026), lower SG, 0.017 +/- 0.002 vs. 0.025 +/- 0.002 min-1, P = 0.004), and higher HE (81.3 +/- 2.4 vs. 73.2 +/- 2.1%, P = 0.013). Across both groups, SG correlated positively with glucose tolerance index (r = 0.58, P < 0.001) and negatively with HE (r = -0.54, P < 0.001). Plasma leptin and glucagon did not change by age, whereas plasma pancreatic polypeptide (PP) was higher in E (122 +/- 18 vs. 66 +/- 6 pg/mL, P = 0.004). PP did not, however, correlate to any other parameter. We conclude that E subjects with normal oral glucose tolerance have reduced SG, impaired second-phase insulin secretion, and increased HE, whereas SI and first-phase insulin secretion seem normal. SG seems most related to age-dependent impairment of glucose elimination, whereas leptin, glucagon, and PP do not seem to contribute.     

Body weight reduction, sympathetic nerve traffic, and arterial baroreflex in obese normotensive humans

BACKGROUND: Previous studies have shown that sympathetic cardiovascular outflow is increased in obese normotensive subjects and that this increase is associated with a baroreflex impairment. The purpose of this study was to determine whether these abnormalities are irreversible or can be favorably affected by body weight reduction. METHODS AND RESULTS: In 20 obese normotensive subjects (age, 31.3+/-1.7 years; body mass index, 37.6+/-0.9 kg/m2, mean+/-SEM), we measured beat-to-beat arterial blood pressure (Finapres technique), heart rate (ECG), postganglionic muscle sympathetic nerve activity (microneurography at a peroneal nerve), and venous plasma norepinephrine (high-performance liquid chromatography) at rest and during baroreceptor stimulation and deactivation induced by increases and reductions of blood pressure via stepwise intravenous infusions of phenylephrine and nitroprusside. Measurements were repeated in 10 subjects after a 16-week hypocaloric diet with normal sodium content (4600 to 5000 J and 210 mmol NaCl/d) and in the remaining 10 subjects after a 16-week observation period without any reduction in the caloric intake. The hypocaloric diet significantly reduced body mass index, slightly reduced blood pressure, and caused a significant and marked decrease in both muscle sympathetic nerve activity (from 50.0+/-5.1 to 32.9+/-4.6 bursts per 100 heart beats, P<.01) and plasma norepinephrine (from 356.2+/-43 to 258.4+/-29 pg/mL, P<.05). This was associated with a significant improvement in the sensitivity of the baroreceptor heart rate (+71.5 +/- 11%, P<.01) and muscle sympathetic nerve activity (+124.5 +/- 22%, P<.001) reflex. Total body glucose uptake also increased significantly (+60.8 +/- 12.0%, P<.05), indicating an increase in insulin sensitivity. All variables remained unchanged in subjects not undergoing caloric restriction. CONCLUSIONS: In obese normotensive subjects, a reduction in body weight induced by a hypocaloric diet with normal sodium content exerts a marked reduction in sympathetic activity owing to central sympathoinhibition. This can be due to the consequences of an increased insulin sensitivity but also to a restoration of the baroreflex control of the cardiovascular system with weight loss.     

Comparative effects of lisinopril and losartan on insulin sensitivity in the treatment of non diabetic hypertensive patients

There are many researchers engaged in qualitative research who look to experts in this mode of inquiry to validate their findings. But can any outsider, even an "expert" in qualitative research, do this? Such an expert is unlikely to know the data as well or to be as fully immersed in the project as the researcher. There are different kinds of expertise that may be required for different phases and purposes of research, and to satisfy different epistemological and ethical concerns. Moreover, new modes of participatory research have complicated the role of expert and the idea of expertise. Researchers must be judicious in their claims to expert validation, and experts must move researchers away from a preoccupation with validation toward craftsmanship and accountability to diverse communities.     

Transdermal iontophoresis of insulin: effect of penetration enhancers on blood glucose level in diabetic rats

The effects of many usual penetration enhancers such as azone (AZ), oleic acid (OA), poloxamer 188 (POL 188) and propylene glycol (PG) on the blood glucose level in diabetic rats after transdermal iontophoresis of insulin were studied. The change of blood glucose level (D%), defined as the percent ratio of the concentration of blood glucose in rats after the iontophoretic application of insulin to that before administration of insulin, was used to present the data. The results showed that following iontophoretic application of insulin for 3 h, the D% in diabetic rats treated with 100% AZ and 5% AZ/PG was 38.58% and 25.28% respectively, and the D% in diabetic rats untreated with enhancers was 45.48%. The D% in diabetic rats treated with 100% OA, 10%-OA/PG, 10% POL 188/PG and 100% PG was 66.28%, 60.47%, 76.75% and 57.93% respectively. So, AZ showed a synergistic effect on the ability of iontophoresis to promote skin permeation of insulin, and PG further increased this effect. The combination of AZ, PG and iontophoresis increased the permeation of insulin significantly. OA, POL 188 and PG did not display synergistic effect on iontophoresis enhancement. The combination of iontophoresis and some enhancers provided a novel idea and possibility for the administration of polypeptide drugs.     

Alcohol with a meal has no adverse effects on postprandial glucose homeostasis in diabetic patients

OBJECTIVE: To examine the effect of moderate alcohol intake with a meal on glucose homeostasis in diabetic patients. RESEARCH DESIGN AND METHODS: Alcohol (1 g/kg, an aperitif before, wine during, and a drink after a meal) or an equal amount of mineral water was given during a dinner. Blood glucose and insulin concentrations were measured before, during, and after the meal until the next morning. This study was conducted at the Helsinki University Hospital Metabolic Ward and the Finnish Diabetes Association Education Center. The participants in the study included 10 type I diabetic patients treated with insulin and 16 type II diabetic patients treated with diet alone or with diet and oral drugs. In each subject, we examined hypoglycemic episodes or differences in blood glucose or serum insulin concentrations between alcohol and the control study. RESULTS: In type I diabetic patients, blood glucose and insulin concentrations were virtually identical in both studies. In type II diabetic patients, alcohol slightly enhanced the meal-induced insulin secretion resulting in lower blood glucose concentrations next morning. No hypoglycemic glucose concentrations were observed in either group after alcohol ingestion. CONCLUSIONS: Moderate alcohol intake with a meal does not lead to hypo- or hyperglycemia in diabetic patients.     

Natural estrous cycle in normal and diabetic bitches in relation to glucose and insulin tests

The influence of spontaneous "sex seasons" on blood sugar (BS) and serum insulin levels was studied in bitches with natural diabetes mellitus (DM) and normal controls, in the basal condition and during glucose and insulin tests, was studied. DM increased basal BS, reduced glucose tolerance, distribution space (DS) and clearance from blood, and induced resistance to insulin hypoglycemic action. In normals occurrence of "seasons", inconsistently modified basal BS, increased glucose tolerance and DS; during estrogenic phase (EP), these variables were above those during luteal phase (LP). In diabetics at LP, BS found in lasting condition and during glucose test were higher than in diabetic bitches at EP (respective values at anestrous (A) in between) and glucose DS was smaller. Rate of glucose clearance from blood remained unaffected by "seasons" in both dog groups. Basal serum IRI was not modified by DM or "seasons". In normals, serum IRI response to glucose load was nonsignificant during A and increased during the "seasons"; either insulin DS or the rate of insulin clearance from blood stream remained unchanged under the circumstances, the increase being mediated by insulin secretion. During EP, the increase was particularly intense and mean insulinogenic index (MII) rose. During LP, MII returned to A value, whereby diabetic states might be manifest. Serum IRI profiles during insulin test were not modified by "seasons" in normal bitches; such response in diabetic bitches was intense during A, then decreased (EP) or was later abolished (LP). Either in normal or diabetic bitches, the sensitivity to exogenous insulin hypoglycemic action remained unchanged in spite of "seasons". In diabetic bitches at A, serum IRI after glucose challenge peaked higher than in respective normal controls (insulin clearance and insulin DS were similar): they exhibited relative insulin shortage and resistance to insulin hypoglycemic action partly compensated by promoted insulin secretion. Along with "season", abolished serum IRI response to glucose load in diabetics was observed. During EP, extrapancreatic factors regulating serum IRI concentration and MII did not change in respect to A, whereby abolishment appears mediated by depressed insulin secretion. During LP, insulin antagonism in conjunction with 1) absolute insulin deficiency and 2) intense decrease in MII appears as a powerful factor exposing diabetic bitches to a severe or fatal derangement in diabetic disease.