Therapeutic role of low-carbohydrate ketogenic diet in diabetes

IntroductionChanges in dietary habits influence the glycemic level. Preliminary studies using the low-carbohydrate ketogenic diet (LCKD) were found to be quite promising in controlling diabetes mellitus. Therefore, the objectives of this study are to investigate the therapeutic effects of LCKD in experimental diabetic rats following the administration of streptozotocin (STZ).Materials and methodsAdult rats were divided into three groups: normal diet, LCKD, and high-carbohydrate diet. Each group was subdivided into normal, sham, and diabetic groups. Diabetes was induced by a single intraperitoneal injection of STZ (55 mg/kg). Specific diets were given to each group of animals for a period of 8 wk and then the animals were sacrificed. The rats were monitored daily for food and water intake, whereas body weight, urine output, and blood glucose levels were monitored weekly. The histology of the islets of Langerhans was studied by histochemical methods.ResultsThe results showed that LCKD was effective in bringing blood glucose level close to normal (P < 0.01). Food and water intake and urine output were increased in all groups except the LCKD group (P < 0.01). The body weight was significantly reduced in all diabetic animals except in the LCKD group (P < 0.01). Histologic studies showed significant decrease in the islet size and number of β cells in all the diabetic groups.ConclusionThis study indicates that LCKD has a significant beneficial effect in ameliorating the diabetic state and helping to stabilize hyperglycemia.     

Long-term effects of corticosterone on behavior,oxidative and energy metabolism of parietotemporal cerebral cortex and hippocampus of rats: comparison to intracerebroventricular streptozotocin

We studied the effect of long-term application of corticosterone (CORT) s.c. the equivalent of cortisol in rats, on behavior, oxidative and energy metabolism in brain parietotemporal cortex and hippocampus of 1-year-old male Wistar rats. The data were compared with results derived from long-term and low dose intracerebroventricular application of the diabetogenic drug streptozotocin (STZ) known to inhibit the function of the neuronal insulin receptor and generating an insulin resistant brain state. CORT reduced both working and reference memory increasingly with time and running parallel to the STZ-induced deficit. The effect of CORT on the activities of the glycolytic enzymes hexokinase, phosphofructokinase, pyruvate kinase, glyceraldehyde-3-phosphodehydrogenase, lactate dehydrogenase and, in tricarboxylic acid cycle, alpha-ketoglutarate dehydrogenase equaled in both experimental conditions and in both regions studied: significant decreases of all enzyme activities except lactate dehydrogenase which increased between three and fourfold of normal. The CORT- and STZ-induced marked fall in ATP was in the same range in the regions studied. Differences became obvious in the concentration of creatine phosphate in parietotemporal cerebral cortex showing no decrease after CORT obviously due to a different susceptibility of the CORT-receptor. It is discussed that both CORT and STZ may act on the neuronal insulin receptor in a similar way. However, further studies are needed on the gene expression of insulin and the insulin receptor and its protein levels to clarify the exact action of CORT on the neuronal insulin receptor function.     

Improvement of biochemical parameters in type 1 diabetic rats after the roots aqueous extract of yacon [Smallanthus sonchifolius (Poepp.& Endl.)] treatment

The aim of this study was to evaluate the effect of yacon (Smallanthus sonchifolius) (Poepp.& Endl.) on clinical parameters under diabetic conditions. The aqueous extract of yacon tuberous roots (YRAE; 0.76 g fructan kg⁻¹ body weight) was prepared at the moment of each administration. Thirty-two male rats were divided into four groups (n = 8): control group (C); group that received YRAE (Y); untreated diabetic group (DM1); and diabetic group treated with YRAE (Y-DM1). The diabetes mellitus was induced by streptozotocin (60 mg kg⁻¹ body weight). The animals from Y2 and Y-DM1 received YRAE by gavage, at 7-day intervals, for 30 days. The aqueous extract of yacon roots decreased (p < 0.05) the water and food intake in diabetic rats (Y-DM1). YRAE treatment reduced (p < 0.05) glycaemia, total cholesterol, VLDL-c, LDL-c and triacylglycerol levels in diabetic rats (YRAE). HDL, urea and creatinine levels did not differ (p > 0.05) between the Y and Y-DM1 groups. YRAE normalised alanine aminotransferase (ALT) activity, when comparing DM1 and Y-DM1 rats, but had no effect on lactate dehydrogenase activity (LDH). In conclusion, YRAE was sufficient for controlling water and food consumption, hyperglycaemia and dyslipidaemia, and promote the reduction of the ALT, suggesting a hepatoprotective effect in rats with STZ-induced DM1.     

Effects of dietary saturated,monounsaturated and polyunsaturated fats on plasma lipids and lipoproteins in diabetic rats*

The effects of altering the type of dietary fat on plasma lipid and lipoprotein levels were investigated in streptozotocin‐diabetic rats fed non‐purified diets containing corn oil, olive oil, cod‐liver oil, sheep tallow and lard. After 32 days of experimental feeding, plasma levels of glucose, triglycerides, total cholesterol, low density and high density lipoprotein cholesterol were determined. Body weights and food intake were also measured. In neither animal group did the type of fat in the diet affect significantly the plasma levels of lipids and lipoproteins and their calculated ratios, and plasma glucose, body weight change or accumulative food intakes. In all studied diabetic rats, significant correlations were observed between body weight change and the following plasma variables: total cholesterol level (r = —0.37, P < 0.03), low density lipoprotein cholesterol level (r = —0.38, P<0.03) and triglycéride concentration (r = —0.36, P < 0.04). A significant positive correlation (r = 0.60, P < 0.0003) was also found between plasma levels of glucose and triglycérides. No significant correlations were noticed between accumulative food intakes and any of the studied variables. It is concluded that, in uncontrolled hyperglycemia in diabetes, the type of fat in the diet exerts little or no influence on plasma lipid and lipoprotein concentrations.     

Problems of the management of insulinomas. Review of 132 cases treated with medical measures

Summary A collective review of 132 cases of insulin-secreting tumors of the pancreas treated by medical measures is reported. The most widely used drugs were diazoxide, corticoids and streptozotocin which have been effective in controlling hypoglycemia respectively in 48 out of 88 cases, in 15 out of 43 cases and in 10 out of 18 cases. Other drugs were of benefit only in a few cases, or were not sufficiently investigated. Results of treatment, evaluation of toxicity and incidence of side-effects suggest that the drug of choice in the treatment of insulinomas is diazoxide. Streptozotocin must be employed only in patients with malignant disease. The role and indications of medical management in patients with insulinomas are discussed.     

对链脲佐菌素诱导的糖尿病大鼠壁细胞和G细胞的体视学研究

采用ＨＥ染色和免疫组化方法结合生物体视学技术，对链脲佐菌素诱导的糖尿病大鼠在胃底腺的壁细胞和幽门部胃粘膜的Ｇ细胞进行立体计量研究。结果显示：糖尿病状态的早期，壁细胞和Ｇ细胞的体积均明显增大，数量却显著减少。根据正常情况下壁细胞和Ｇ细胞的细胞动力学变化、胃泌素的生物学作用和上述实验结果，认为大鼠胃底腺峡部的干细胞向壁细胞分化成熟的功能及Ｇ细胞的分裂增殖活动，在胰岛素缺乏的情况下受到一定程度的抑制，而这种功能的抑制是糖尿病状态下易出现胃粘膜萎缩、胃酸分泌减少和胃轻瘫的重要原因之一。     

B‐1 cells produce insulin and abrogate experimental streptozotocin‐induced diabetes

The participation of B‐1 cells in a murine model of spontaneous diabetes has been recently reported. Here, we describe the role of B‐1 cells in streptozotocin (STZ) induced diabetes in mice. We demonstrated that XID (B‐1 cell‐deficient) mice are more susceptible to STZ treatment than WT mice, as evidenced by their higher blood glucose level in response to STZ. Unexpectedly, the XID mice that were i.p. transferred with purified B‐1 cells, either before or after the STZ treatment, did not develop diabetes. These cell transfers provided long‐lasting protection for the XID mice against STZ‐induced diabetes, suggesting that B‐1 cells play an important role in the experimental diabetes pathobiology. We also showed that B‐1 cell culture supernatants were able to regulate the blood glucose level of the diabetic XID mice, and we identified insulin‐producing cells when B‐1 cells were differentiated in B‐1 cell‐derived phagocyte in vitro. These findings provide a novel role for B‐1 cells in metabolic processes, presenting a new mechanism to explain the pathogenesis of diabetes and a possible therapeutical target.     

Impact of an autologous oxygenating matrix culture system on rat islet transplantation outcome

Disruption of the pancreatic islet environment combined with the decrease in oxygen supply that occurs during isolation leads to poor islet survival. The aim of this study was to validate the benefit of using a plasma-based scaffold supplemented with perfluorodecalin to improve islet transplantation outcome.Rat islets were cultured in three conditions: i) control group, ii) plasma based-matrix (P-matrix), and iii) P-matrix supplemented with emulsified perfluorodecalin. After 24 h culture, matrix/cell contacts (Integrinβ1, p-FAK/FAK, p-Akt/Akt), survival (caspase 3, TUNEL, FDA/PI), function, and HIF-1α translocation were assessed. Afterwards, P-matrices were dissolved and the islets were intraportally transplanted. Graft function was monitored for 31 days with glycaemia and C-peptide follow up. Inflammation was assessed by histology (macrophage and granulocyte staining) and thrombin/anti-thrombin complex measurement.Islet survival correlated with an increase in integrin, FAK, and Akt activation in P-matrices and function was maintained. Perfluorodecalin supplementation decreased translocation of HIF-1α in the nucleus and post-transplantation islet structure was better preserved in P-matrices, but a quicker activation of IBMIR resulted in early loss of graft function.“Oxygenating” P-matrices provided a real benefit to islet survival and resistance in vivo. However, intraportal transplantation is not suitable for this kind of culture due to IBMIR; thus, alternative sites must be explored.     

Spontaneous glucose intolerance in the progeny of low dose streptozotocin-induced diabetic mice

Summary Multiple low doses of streptozotocin (LDS) induce low-incidence diabetes mellitus in Balb/cHan and high-incidence diabetes in CD-1 mice. We studied offspring of diabetic parents in both strains. Group 1 consisted of litters from control mice with no streptozotocin treatment. Group 2 litters had an LDS diabetic mother and a control father, group 3 litters had control mother with LDS diabetic father, and group 4 litters had both, LDS diabetic mother and father. Diabetes was induced by 5×40 mg streptozotocin per kg on five consecutive days. Progeny of diabetic mothers showed a state of reduced glucose tolerance associated with reduced glucose disappearance during intravenous glucose tolerance test and increased insulin secretion of isolated islets of Langerhans. These metabolic abnormalities predominated in the male litters of both strains of mice. Amniotic insulin was increased in diabetic mothers during pregnancy. No histologic abnormalities were observed in group 2 progeny. Pancreases in male offspring of LDS diabetic CD-1 fathers (group 3) were studied for insulitis. Insulitis was found in 40% of mice with normal glucose tolerance. A single subdiabetogenic dose of streptozotocin (40 mg/kg) induced insulitis in 90% of pancreases accompanied by reduced insulin release of isolated islets. By contrast, male Balb/cHan progeny of diabetic fathers failed to develop insulitis. In conclusion, we found (1) parental LDS diabetes was transmitted more often to male offspring, (2) maternal LDS diabetes was associated with hyperinsulin secretion and glucose intolerance in the offspring and (3) paternal LDS diabetes was accompanied by insulitis and insulin secretion deficiency in CD-1 progeny.     

Effects of a high protein diet on the evolution of diabetes in streptozotocin-induced and spontaneously diabetic “BB” wistar rats

Summary Recently, we demonstrated a reduction in the diabetogenic action of streptozotocin (STZ) in rats previously adapted to a high protein (HP) diet. These data suggested that amelioration of diabetes resulted from the combination of two effects of the HP diet: initial protection against the diabetogenic action of the drug at the time of exposure and subsequent improvement of the induced diabetic condition. The present study evaluated the effects of a HP diet on the evolution of the metabolic condition in rats with STZ-induced or spontaneous diabetes (BB Wistar rats). Two days after STZ injection, the animals were given isocaloric HP (70% protein, 8% fat) or control (66% carbohydrate, 16% protein, 8% fat) diets for 15 days. After 13 days, the STZ-treated rats fed HP diet showed an impressive decrease in severity of diabetes, as judged by rate of body weight change, plasma glucose, urine volume and glycosuria, serum and pancreatic insulin. The BB Wistar rats, already diabetic for 5 weeks before being transferred to the HP or control diet, were treated with daily injections of insulin. After 31 days on the HP diet, the BB rats showed reduced insulin requirement, reduced blood and urinary glucose levels, but no difference in body weight gain or pancreatic insulin content. The data show that short-term use of HP diets can greatly improve the diabetic condition in STZ-treated animals, but that the beneficial effects of the diet are much less marked in rats with chronic spontaneous diabetes. These data suggest that the ameliorating effect of HP diet is fully manifested only when the diabetic rats have a sufficient number of residual functioning B-cells.