A study on the types of diabetes mellitus in first degree relatives of diabetic patients.
D CheţaC DumitrescuM GeorgescuG CocioabăRadu LichiardopolM StamoranC Ionescu-TîrgovişteM Păunescu-GeorgescuI Mincu
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The genetic characteristics of the diabetic types have been assessed by following up their frequency in first degree relatives of some non-selected diabetic patients, registered at eight different centers of the country. Out of 1,003 non-diabetic controls only 46 (4.6%) had 52 diabetic relatives, 65.4% of type 2 (non-insulin-dependent). Comparatively, out of the 704 patients, 172 (24.4%) had 229 diabetic first degree relatives, 72.5 of type 2. Out of 231 type 1 (insulin-dependent) diabetic patients, 29 (12.6%) had 34 diabetic relatives, 55.9% of type 1. Out of 300 type 2 patients, 99 (33.0%) had 121 diabetic relatives, 84.0% of type 2. The other 173 diabetic patients presented an "intermediary" type of the disease (needing insulin many years after onset). Forty-four (25.4%) of them had 64 diabetic relatives, 67.2% of type 2, 20.3% of type 1 and 12.5% with "intermediary" diabetes. The five times higher frequency of diabetes in patients' relatives versus controls is pointed out. Type 2 diabetic relatives predominated. The proportion of probands with diabetic relatives increased from 4.6% in non-diabetics to 12.6% in type 1, to 25.4% in "intermediary" diabetes and to 33.0% in type 2. The heredity of type 1 prevailed in type 1 and that of type 2 in type 2 and in "intermediary" diabetes. The fact that "intermediary" diabetes tends towards type 1 (insulin-dependent) as therapy and towards type 2 (non-insulin-dependent) as heredity might be an argument supporting the controversy on the diabetic syndrome classification.Keywords:
First-degree relatives
Heredity
Proband
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The genetic characteristics of the diabetic types have been assessed by following up their frequency in first degree relatives of some non-selected diabetic patients, registered at eight different centers of the country. Out of 1,003 non-diabetic controls only 46 (4.6%) had 52 diabetic relatives, 65.4% of type 2 (non-insulin-dependent). Comparatively, out of the 704 patients, 172 (24.4%) had 229 diabetic first degree relatives, 72.5 of type 2. Out of 231 type 1 (insulin-dependent) diabetic patients, 29 (12.6%) had 34 diabetic relatives, 55.9% of type 1. Out of 300 type 2 patients, 99 (33.0%) had 121 diabetic relatives, 84.0% of type 2. The other 173 diabetic patients presented an "intermediary" type of the disease (needing insulin many years after onset). Forty-four (25.4%) of them had 64 diabetic relatives, 67.2% of type 2, 20.3% of type 1 and 12.5% with "intermediary" diabetes. The five times higher frequency of diabetes in patients' relatives versus controls is pointed out. Type 2 diabetic relatives predominated. The proportion of probands with diabetic relatives increased from 4.6% in non-diabetics to 12.6% in type 1, to 25.4% in "intermediary" diabetes and to 33.0% in type 2. The heredity of type 1 prevailed in type 1 and that of type 2 in type 2 and in "intermediary" diabetes. The fact that "intermediary" diabetes tends towards type 1 (insulin-dependent) as therapy and towards type 2 (non-insulin-dependent) as heredity might be an argument supporting the controversy on the diabetic syndrome classification.
First-degree relatives
Heredity
Proband
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Diabetes mellitus is the world's largest endocrine disorder resulting in multiple aetiologies, involving metabolic disorders of carbohydrate, fat and protein. All forms of diabetes are due to a decrease in the circulating concentration of insulin (insulin deficiency) and a decrease in the response of pe- ripheral tissues to insulin i.e., insulin resistance. According to the World Health Organization projections, the prevalence of diabetes is likely to increase by 35% by the year 2025. In this study, the streptozotocin (STZ)-induced diabetic rats, the activities of membrane-bound adenosine triphosphatases (ATPases) are altered in erythrocytes and in tissues such as liver and kidney. Albino Wistar rats were rendered diabetic by a single intraperitoneal injec- tion of STZ (40 mg/kg body weight). Diabetic rats exhibited significantly (p<0.05) increased levels of plasma glucose and decreased levels of plasma insulin. The activities of total ATPases, (Na + +K + )-ATPase, Ca 2+ -ATPase and Mg 2+ -ATPase were significantly (p<0.05) decreased in diabetic control rats. Control and diabetic rats were treated with camel milk (250 mL/day) for a period of 45 days. A group of diabetic rats were also treated with gliben- clamide (600 µg/kg body weight). After the treatment period, a significant (p<0.05) decrease in the levels of glucose and increase in the levels of plasma insulin and the activities of ATPases in erythrocytes and tissues were observed in diabetic rats treated with camel milk. A similar effect is also observed in the glibenclamide treated rats. But, control rats treated with camel milk did not show any significant (p<0.05) effect in any of the parameters studied. Our study shows that camel milk has the potential to restore the deranged activities of membrane-bound ATPases in STZ-diabetic rats. Further detailed investigation is necessary to find out its mechanism of action.
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The effects of impaired glucose metabolism on thyroid hormone turnover were studied in four patients with insulin-independent diabetes mellitus and four patients with insulin-dependent diabetes mellitus before and after insulin therapy. Seven normal subjects were included as controls. All subjects were given T4 (0.2 mg daily) by mouth 3 weeks before and throughout the study. T4 turnover results from the untreated and treated diabetic subjects and from the normal subjects overlapped. However, both the mean free T4 fraction and mean free T4 concentration were reduced in the diabetic patients after insulin therapy. The mean MCRs of T3 were normal in both the insulin-independent and the insulin-dependent diabetic patients and were unaffected by insulin therapy. However, the mean serum T3 concentration, T3 disposal rates, and T3 conversion rates were low in both groups of diabetic patients. After insulin therapy, these values all increased but remained significantly lower than in the normal subjects. The mean serum levels, MCRs and disposal rates of rT3 were within the normal range in the insulin-independent diabetic patients and did not change with insulin therapy. In the insulin-dependent diabetic patients, the mean rT3 serum concentration and disposal rate were elevated and mean rTsMCR was low. These values reverted toward control values after insulin therapy; however, the changes were not statistically significant. Our results suggest a significant impairment of T4 monodeiodination of both phenyl rings in patients with uncontrolled diabetes mellitus. Good diabetic control with diet and insulin therapy for 2 weeks improved but did not totally correct the abnormal iodothyronine monodeiodination in these patients.
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The molecular basis for the β-cell dysfunction that characterizes non-insulin-dependent diabetes mellitus (NIDDM) is unknown. The Zucker diabetic fatty (ZDF) male rat is a rodent model of NIDDM with a predictable progression from the prediabetic to the diabetic state. We are using this model to study β-cell function during the development of diabetes with the goal of identifying genes that play a key role in regulating insulin secretion and, thus, may be potential targets for therapeutic intervention aimed at preserving or improving β-cell function. As a first step, we have characterized morphology, insulin secretion, and pattern of gene expression in islets from prediabetic and diabetic ZDF rats. The development of diabetes was associated with changes in islet morphology, and the islets of diabetic animals were markedly hypertrophic with multiple irregular projections into the surrounding exocrine pancreas. In addition, there were multiple defects in the normal pattern of insulin secretion. The islets of prediabetic ZDF rats secreted significantly more insulin at each glucose concentration tested and showed a leftward shift in the dose-response curve relating glucose concentration and insulin secretion. Islets of prediabetic animals also demonstrated defects in the normal oscillatory pattern of insulin secretion, indicating the presence of impairment of the normal feedback control between glucose and insulin secretion. The islets from diabetic animals showed further impairment in the ability to respond to a glucose stimulus. Changes in gene expression were also evident in islets from prediabetic and diabetic ZDF rats compared with age-matched control animals. In prediabetic animals, there was no change in insulin mRNA levels. However, there was a significant 30–70% reduction in the levels of a large number of other islet mRNAs including glucokinase, mitochondrial glycerol-3-phosphate dehydrogenase, voltage-dependent Ca2+ and K+ channels, Ca2+-ATPase, and transcription factor Islet-1 mRNAs. In addition, there was a 40–50% increase in the levels of glucose-6-phosphatase and 12-lipoxygenase mRNAs. There were further changes in gene expression in the islets from diabetic ZDF rats, including a decrease in insulin mRNA levels that was associated with reduced islet insulin levels. Our results indicate that multiple defects in β-cell function can be detected in islets of prediabetic animals well before the development of hyperglycemia and suggest that changes in the normal pattern of gene expression contribute to the development of β-cell dysfunction.
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Rats with diabetes induced by streptozotocin (STZ) and nicotinamide (NA) are often used in animal studies concerning various aspects of diabetes. In this experimental model, the severity of diabetes is different depending on doses of STZ and NA. Moreover, diabetic changes in rats with STZ-NA-induced diabetes are not fully characterized. In our present study, metabolic changes and insulin secretion were investigated in rats with diabetes induced by administration of 60 mg of STZ and 90 mg of NA per kg body weight. Four to six weeks after diabetes induction, insulin, glucagon and some metabolic parameters were determined to evaluate the severity of diabetes. Moreover, insulin secretory capacity of pancreatic islets isolated from control and diabetic rats was compared. It was demonstrated that administration of 60 mg of STZ and 90 mg of NA per kg body weight induced relatively mild diabetes, since insulin, glucagon and other analyzed parameters were only slightly affected in diabetic rats compared with control animals. In vitro studies revealed that insulin secretory response was preserved in pancreatic islets of diabetic rats, however, was lower than in islets of control animals. This effect was observed in the presence of different stimuli. Insulin secretion induced by 6.7 and 16.7 mmol/l glucose was moderately reduced in islets of diabetic rats compared with control islets. In the presence of leucine with glutamine, insulin secretion appeared to be also decreased in islets of rats with STZ-NA-induced diabetes. Insulinotropic action of 6.7 mmol/l glucose with forskolin was also deteriorated in diabetic islets. Moreover, it was demonstrated that at a non-stimulatory glucose, pharmacological depolarization of plasma membrane with a concomitant activation of protein kinase C evoked significant rise in insulin release in islets of control and diabetic rats. However, in diabetic islets, this effect was attenuated. These results indicate that impairment in insulin secretion in pancreatic islets of rats with mild diabetes induced by STZ and NA results from both metabolic and nonmetabolic disturbances in these islets.
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To examine whether glucagon-like peptide-1 (GLP-1), which has been suggested as a new therapeutic agent in type 2 diabetes, affects circulating islet amyloid polypeptide (IAPP), a B-cell peptide of potential importance for diabetes pathophysiology.GLP-1 was administered in a buccal tablet (400 micrograms) to seven healthy subjects and nine subjects with type 2 diabetes. Serum IAPP and insulin levels were measured before and after GLP-1 administration.In the fasting state, serum IAPP was 4.1 +/- 0.3 pmol/l in the controls vs 9.8 +/- 0.9 pmol/l in the subjects with type 2 diabetes (P < 0.001). IAPP correlated with insulin only in controls (r = 0.74, P = 0.002) but not in type 2 diabetes (r = 0.26, NS). At 15 min after GLP-1, circulating IAPP increased to (6.0 +/- 0.5 pmol/l in controls P = 0.009) and to 13.8 +/- 1.2 pmol/l in type 2 diabetes (P = 0.021). In both groups, serum insulin increased and blood glucose decreased compared with placebo. In controls serum IAPP increased in parallel with insulin (r = 0.79, P = 0.032), whereas in type 2 diabetes the increase in IAPP did not correlate with the increase in insulin.Type 2 diabetes is associated with elevated circulating IAPP; GLP-1stimulates IAPP secretion both in healthy human subjects and in type 2 diabetes; IAPP secretion correlates with insulin secretion only in healthy subjects and not in type 2 diabetes.
Amyloid (mycology)
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Basal and maximal Ca2+ ATPase activity was studied in erythrocytes of 29 healthy controls, 15 patients with insulin-dependent diabetes mellitus (IDDM) and 22 patients with non-insulin-dependent diabetes mellitus (NIDDM). Basal and maximal Ca2+ ATPase activity was significantly decreased in insulin-dependent diabetes mellitus (8.4±0.5 and 22.5±1.1 pmol/106 RBC/min) and non-insulin-dependent diabetes mellitus (7.3±1.0 and 18.6±1.8 pmol/106 RBC/min) compared to healthy controls (9.3±1.0 and 24.6±1.1 pmol/106 RBC/min). Maximal Ca2+ ATPase activity showed a significant correlation to systolic blood pressure in both insulin-dependent diabetes mellitus and non-insulin-dependent diabetes mellitus. There was no significant correlation of maximal Ca2+ ATPase activity to fasting serum glucose concentration and to HbA1 levels. Maximal Ca2+ ATPase activity was significantly correlated to creatinine clearance in non-insulin-dependent diabetes mellitus, but not in insulin-dependent diabetes mellitus. It is concluded that a decreased cellular Ca2+ ATPase activity may predispose to the development of hypertension in diabetes mellitus.
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