Control of blood glucose in type 2 diabetes without weight loss by modification of diet composition

BACKGROUND: Over the past several years our research group has taken a systematic, comprehensive approach to determining the effects on body function (hormonal and non-hormonal) of varying the amounts and types of proteins, carbohydrates and fats in the diet. We have been particularly interested in the dietary management of type 2 diabetes. Our objective has been to develop a diet for people with type 2 diabetes that does not require weight loss, oral agents, or insulin, but that still controls the blood glucose concentration. Our overall goal is to enable the person with type 2 diabetes to control their blood glucose by adjustment in the composition rather than the amount of food in their diet. METHODS: This paper is a brief summary and review of our recent diet-related research, and the rationale used in the development of diets that potentially are useful in the treatment of diabetes. RESULTS: We determined that, of the carbohydrates present in the diet, absorbed glucose is largely responsible for the food-induced increase in blood glucose concentration. We also determined that dietary protein increases insulin secretion and lowers blood glucose. Fat does not significantly affect blood glucose, but can affect insulin secretion and modify the absorption of carbohydrates. Based on these data, we tested the efficacy of diets with various protein:carbohydrate:fat ratios for 5 weeks on blood glucose control in people with untreated type 2 diabetes. The results were compared to those obtained in the same subjects after 5 weeks on a control diet with a protein:carbohydrate:fat ratio of 15:55:30. A 30:40:30 ratio diet resulted in a moderate but significant decrease in 24-hour integrated glucose area and % total glycohemoglobin (%tGHb). A 30:20:50 ratio diet resulted in a 38% decrease in 24-hour glucose area, a reduction in fasting glucose to near normal and a decrease in %tGHb from 9.8% to 7.6%. The response to a 30:30:40 ratio diet was similar. CONCLUSION: Altering the diet composition could be a patient-empowering method of improving the hyperglycemia of type 2 diabetes without weight loss or pharmacologic intervention

The catalytic subunit of the system L1 amino acid transporter (S<i>lc7a5</i>) facilitates nutrient signalling in mouse skeletal muscle

The System L1-type amino acid transporter mediates transport of large neutral amino acids (LNAA) in many mammalian cell-types. LNAA such as leucine are required for full activation of the mTOR-S6K signalling pathway promoting protein synthesis and cell growth. The SLC7A5 (LAT1) catalytic subunit of high-affinity System L1 functions as a glycoprotein-associated heterodimer with the multifunctional protein SLC3A2 (CD98). We generated a floxed Slc7a5 mouse strain which, when crossed with mice expressing Cre driven by a global promoter, produced Slc7a5 heterozygous knockout (Slc7a5+/-) animals with no overt phenotype, although homozygous global knockout of Slc7a5 was embryonically lethal. Muscle-specific (MCK Cre-mediated) Slc7a5 knockout (MS-Slc7a5-KO) mice were used to study the role of intracellular LNAA delivery by the SLC7A5 transporter for mTOR-S6K pathway activation in skeletal muscle. Activation of muscle mTOR-S6K (Thr389 phosphorylation) in vivo by intraperitoneal leucine injection was blunted in homozygous MS-Slc7a5-KO mice relative to wild-type animals. Dietary intake and growth rate were similar for MS-Slc7a5-KO mice and wild-type littermates fed for 10 weeks (to age 120 days) with diets containing 10%, 20% or 30% of protein. In MS-Slc7a5-KO mice, Leu and Ile concentrations in gastrocnemius muscle were reduced by ∼40% as dietary protein content was reduced from 30 to 10%. These changes were associated with >50% decrease in S6K Thr389 phosphorylation in muscles from MS-Slc7a5-KO mice, indicating reduced mTOR-S6K pathway activation, despite no significant differences in lean tissue mass between groups on the same diet. MS-Slc7a5-KO mice on 30% protein diet exhibited mild insulin resistance (e.g. reduced glucose clearance, larger gonadal adipose depots) relative to control animals. Thus, SLC7A5 modulates LNAA-dependent muscle mTOR-S6K signalling in mice, although it appears non-essential (or is sufficiently compensated by e.g. SLC7A8 (LAT2)) for maintenance of normal muscle mass

TEAD and YAP regulate the enhancer network of human embryonic pancreatic progenitors.

The genomic regulatory programmes that underlie human organogenesis are poorly understood. Pancreas development, in particular, has pivotal implications for pancreatic regeneration, cancer and diabetes. We have now characterized the regulatory landscape of embryonic multipotent progenitor cells that give rise to all pancreatic epithelial lineages. Using human embryonic pancreas and embryonic-stem-cell-derived progenitors we identify stage-specific transcripts and associated enhancers, many of which are co-occupied by transcription factors that are essential for pancreas development. We further show that TEAD1, a Hippo signalling effector, is an integral component of the transcription factor combinatorial code of pancreatic progenitor enhancers. TEAD and its coactivator YAP activate key pancreatic signalling mediators and transcription factors, and regulate the expansion of pancreatic progenitors. This work therefore uncovers a central role for TEAD and YAP as signal-responsive regulators of multipotent pancreatic progenitors, and provides a resource for the study of embryonic development of the human pancreas

Increasing Protein at the Expense of Carbohydrate in the Diet Down-Regulates Glucose Utilization as Glucose Sparing Effect in Rats

High protein (HP) diet could serve as a good strategy against obesity, provoking the changes in energy metabolic pathways. However, those modifications differ during a dietary adaptation. To better understand the mechanisms involved in effect of high protein diet (HP) on limiting adiposity in rats we studied in parallel the gene expression of enzymes involved in protein and energy metabolism and the profiles of nutrients oxidation. Eighty male Wistar rats were fed a normal protein diet (NP, 14% of protein) for one week, then either maintained on NP diet or assigned to a HP diet (50% of protein) for 1, 3, 6 and 14 days. mRNA levels of genes involved in carbohydrate and lipid metabolism were measured in liver, adipose tissues, kidney and muscles by real time PCR. Energy expenditure (EE) and substrate oxidation were measured by indirect calorimetry. Liver glycogen and plasma glucose and hormones were assayed. In liver, HP feeding 1) decreased mRNA encoding glycolysis enzymes (GK, L-PK) and lipogenesis enzymes(ACC, FAS), 2) increased mRNA encoding gluconeogenesis enzymes (PEPCK), 3) first lowered, then restored mRNA encoding glycogen synthesis enzyme (GS), 4) did not change mRNA encoding β-oxidation enzymes (CPT1, ACOX1, βHAD). Few changes were seen in other organs. In parallel, indirect calorimetry confirmed that following HP feeding, glucose oxidation was reduced and fat oxidation was stable, except during the 1st day of adaptation where lipid oxidation was increased. Finally, this study showed that plasma insulin was lowered and hepatic glucose uptake was decreased. Taken together, these results demonstrate that following HP feeding, CHO utilization was increased above the increase in carbohydrate intake while lipogenesis was decreased thus giving a potential explanation for the fat lowering effect of HP diets

A low-carbohydrate diet may prevent end-stage renal failure in type 2 diabetes. A case report

An obese patient with type 2 diabetes whose diet was changed from the recommended high-carbohydrate, low-fat type to a low-carbohydrate diet showed a significant reduction in bodyweight, improved glycemic control and a reversal of a six year long decline of renal function. The reversal of the renal function was likely caused by both improved glycemic control and elimination of the patient's obesity. Insulin treatment in type 2 diabetes patients usually leads to weight increase which may cause further injury to the kidney. Although other unknown metabolic mechanisms cannot be excluded, it is likely that the obesity caused by the combination of high-carbohydrate diet and insulin in this case contributed to the patient's deteriorating kidney function. In such patients, where control of bodyweight and hyperglycemia is vital, a trial with a low-carbohydrate diet may be appropriate to avoid the risk of adding obesity-associated renal failure to already failing kidneys

Low-carbohydrate diet in type 2 diabetes: stable improvement of bodyweight and glycemic control during 44 months follow-up

<p>Abstract</p> <p>Background</p> <p>Low-carbohydrate diets, due to their potent antihyperglycemic effect, are an intuitively attractive approach to the management of obese patients with type 2 diabetes. We previously reported that a 20% carbohydrate diet was significantly superior to a 55–60% carbohydrate diet with regard to bodyweight and glycemic control in 2 groups of obese diabetes patients observed closely over 6 months (intervention group, n = 16; controls, n = 15) and we reported maintenance of these gains after 22 months. The present study documents the degree to which these changes were preserved in the low-carbohydrate group after 44 months observation time, without close follow-up. In addition, we assessed the performance of the two thirds of control patients from the high-carbohydrate diet group that had changed to a low-carbohydrate diet after the initial 6 month observation period. We report cardiovascular outcome for the low-carbohydrate group as well as the control patients who did not change to a low-carbohydrate diet.</p> <p>Method</p> <p>Retrospective follow-up of previously studied subjects on a low carbohydrate diet.</p> <p>Results</p> <p>The mean bodyweight at the start of the initial study was 100.6 ± 14.7 kg. At six months it was 89.2 ± 14.3 kg. From 6 to 22 months, mean bodyweight had increased by 2.7 ± 4.2 kg to an average of 92.0 ± 14.0 kg. At 44 months average weight has increased from baseline g to 93.1 ± 14.5 kg. Of the sixteen patients, five have retained or reduced bodyweight since the 22 month point and all but one have lower weight at 44 months than at start. The initial mean HbA1c was 8.0 ± 1.5%. After 6, 12 and 22 months, HbA1c was 6.1 ± 1.0%, 7.0 ± 1.3% and 6.9 ± 1.1% respectively. After 44 months mean HbA1c is 6.8 ± 1.3%.</p> <p>Of the 23 patients who have used a low-carbohydrate diet and for whom we have long-term data, two have suffered a cardiovascular event while four of the six controls who never changed diet have suffered several cardiovascular events.</p> <p>Conclusion</p> <p>Advice to obese patients with type 2 diabetes to follow a 20% carbohydrate diet with some caloric restriction has lasting effects on bodyweight and glycemic control.</p

Low-carbohydrate diet in type 2 diabetes. Stable improvement of bodyweight and glycemic control during 22 months follow-up

BACKGROUND: Low-carbohydrate diets in the management of obese patients with type 2 diabetes seem intuitively attractive due to their potent antihyperglycemic effect. We previously reported that a 20 % carbohydrate diet was significantly superior to a 55–60 % carbohydrate diet with regard to bodyweight and glycemic control in 2 non-randomised groups of obese diabetes patients observed closely over 6 months. The effect beyond 6 months of reduced carbohydrate has not been previously reported. The objective of the present study, therefore, was to determine to what degree the changes among the 16 patients in the low-carbohydrate diet group at 6-months were preserved or changed 22 months after start, even without close follow-up. In addition, we report that, after the 6 month observation period, two thirds of the patients in the high-carbohydrate changed their diet. This group also showed improvement in bodyweight and glycemic control. METHOD: Retrospective follow-up of previously studied subjects on a low carbohydrate diet. RESULTS: The mean bodyweight at the start of the initial study was 100.6 ± 14.7 kg. At six months it was 89.2 ± 14.3 kg. From 6 to 22 months, mean bodyweight had increased by 2.7 ± 4.2 kg to an average of 92.0 ± 14.0 kg. Seven of the 16 patients (44%) retained the same bodyweight from 6 to 22 months or reduced it further; all but one had lower weight at 22 months than at the beginning. Initial mean HbA1c was 8.0 ± 1.5 %. After 6 and 12 months it was 6.6 ± 1.0 % and 7.0 ± 1.3 %, respectively. At 22 months, it was still 6.9 ± 1.1 %. CONCLUSION: Advice on a 20 % carbohydrate diet with some caloric restriction to obese patients with type 2 diabetes has lasting effect on bodyweight and glycemic control

A Small Mammal Community in a Forest Fragment, Vegetation Corridor and Coffee Matrix System in the Brazilian Atlantic Forest

The objective of our work was to verify the value of the vegetation corridor in the conservation of small mammals in fragmented tropical landscapes, using a model system in the southeastern Minas Gerais. We evaluated and compared the composition and structure of small mammals in a vegetation corridor, forest fragments and a coffee matrix. A total of 15 species were recorded, and the highest species richness was observed in the vegetation corridor (13 species), followed by the forest fragments (10) and the coffee matrix (6). The absolute abundance was similar between the vegetation corridor and fragments (F = 22.94; p = 0.064), and the greatest differences occurred between the vegetation corridor and the matrix (F = 22.94; p = 0.001) and the forest fragments and the matrix (F = 22.94; p = 0.007). Six species showed significant habitat preference possibly related to the sensitivity of the species to the forest disturbance. Marmosops incanus was the species most sensitive to disturbance; Akodon montensis, Cerradomys subflavus, Gracilinanus microtarsus and Rhipidomys sp. displayed little sensitivity to disturbance, with a high relative abundance in the vegetation corridor. Calomys sp. was the species least affected by habitat disturbance, displaying a high relative abundance in the coffee matrix. Although the vegetation corridors are narrow (4 m width), our results support the hypothesis in which they work as a forest extension, share most species with the forest fragment and support species richness and abundance closer to forest fragments than to the coffee matrix. Our work highlights the importance and cost-effectiveness of these corridors to biodiversity management in the fragmented Atlantic Forest landscapes and at the regional level

Skp2B Overexpression Alters a Prohibitin-p53 Axis and the Transcription of PAPP-A, the Protease of Insulin-Like Growth Factor Binding Protein 4

We previously reported that the degradation of prohibitin by the SCF(Skp2B) ubiquitin ligase results in a defect in the activity of p53. We also reported that MMTV-Skp2B transgenic mice develop mammary gland tumors that are characterized by an increased proteolytic cleavage of the insulin-like growth factor binding protein 4 (IGFBP-4), an inhibitor of IGF signaling. However, whether a link exists between a defect in p53 activity and proteolysis of IGFBP-4 was not established.We analyzed the levels of pregnancy-associated plasma protein A (PAPP-A), the protease of IGFBP-4, in MMTV-Skp2B transgenic mice and found that PAPP-A levels are elevated. Further, we found a p53 binding site in intron 1 of the PAPP-A gene and that both wild type and mutant p53 bind to this site. However, binding of wild type p53 results in the transcriptional repression of PAPP-A, while binding of mutant p53 results in the transcriptional activation of PAPP-A. Since MMTV-Skp2B mice express wild type p53 and yet show elevated levels of PAPP-A, at first, these observations appeared contradictory. However, further analysis revealed that the defect in p53 activity in Skp2B overexpressing cells does not only abolish the activity of wild type of p53 but actually mimics that of mutant p53. Our results suggest that in absence of prohibitin, the half-life of p53 is increased and like mutant p53, the conformation of p53 is denatured.These observations revealed a novel function of prohibitin as a chaperone of p53. Further, they suggest that binding of denatured p53 in intron 1 causes an enhancer effect and increases the transcription of PAPP-A. Therefore, these findings indicate that the defect in p53 function and the increased proteolysis of IGFBP-4, we had observed, represent two components of the same pathway, which contributes to the oncogenic function of Skp2B