It is difficult in clinical practice to differentiate patients with newly diagnosed diabetes and ketosis. The aim of this study was to investigate the effect of intensive insulin therapy on islet function in patients with new-onset diabetes and concomitant ketosis, and to determine the value of alternation in islet function in the typing of diabetes.
A total of 206 inpatients with new-onset diabetes and ketosis were recruited after intensive insulin therapy and followed for 36 months. Patients were divided into type 1 diabetes group (Group A) and type 2 diabetes group (Group B). Islet function was compared between the 2 groups before and after intensive insulin therapy, and the influence of islet function on the typing of diabetes and the selection of therapeutic strategies is discussed.
In group A, the AUCI, AUCC, HOMA-β cell and HOMA-IR were significantly lower than those in Group B before and after intensive insulin therapy. The sensitivity and accuracy of antibody test were at a low level in Group A. An insulin release test was done after intensive insulin therapy. Results showed that the peaks of insulin and C peptide appeared at 0.5–1 h after glucose administration in Group A, which was earlier than that before therapy, but the maximal levels were no more than 2 times those of baseline levels. In Group B, the peaks appeared at 2 h, and the maximal levels were about 10 times those of baseline levels.
Poor islet function, incomplete recovery of islet function after intensive insulin therapy, and a short “honeymoon” period are characteristics of type 1 diabetes. Detection of diabetes-related antibodies is not reliable.
diabetic ketosis; typing; islet function; honeymoon period
To investigate whether serum ischemia-modified albumin or C-reactive protein is reliable for predicting type 2 diabetic patients with ketosis.
One hundred and four diabetic patients, 48 with diabetic ketosis, and 33 controls were enrolled in the study. Serum ischemia-modified albumin and C-reactive protein were measured and evaluated for their ability to distinguish diabetic ketosis.
Compared to the controls, the ischemia-modified albumin and C-reactive protein levels were higher in patients with diabetic ketosis and type 2 diabetes at the baseline. The levels of ischemia-modified albumin were higher in patients with type 2 diabetes than in the controls. C-reactive protein and ischemia-modified albumin levels were reduced after insulin treatment. The level of ischemia-modified albumin was an independent risk marker for diabetic ketosis (OR = 1.085, P = 0.008, 95% CI: 1.022–1.152). Receiver operating characteristic curves revealed that the areas under the curve were 0.917 for the modified albumin and 0.357 for C-reactive protein.
This study indicates that ischemia-modified albumin was significantly associated with diabetic ketosis and was more sensitive than C-reactive protein in reflecting diabetic ketosis.
diabetic ketosis; ischemia-modified albumin; C-reactive protein; biomarker
Most patients with ketosis-prone type 2 diabetes (KPD) discontinue insulin therapy and remain in near-normoglycemic remission. The aim of this study was to determine the effect of glucotoxicity on β-cell function during remission in obese patients with KPD.
RESEARCH DESIGN AND METHODS
Age- and BMI-matched obese African Americans with a history of KPD (n = 8), severe hyperglycemia but without ketosis (ketosis-resistant type 2 diabetes, n = 7), and obese control subjects (n = 13) underwent intravenous infusion of 10% dextrose at a rate of 200 mg per m2/min for 20 h. β-Cell function was assessed by changes in insulin and C-peptide concentrations during dextrose infusion and by changes in acute insulin response (AIR) and first-phase insulin release (FPIR) to arginine stimulation before and after dextrose infusion.
The mean ± SD time to discontinue insulin therapy was 7.1 ± 1.7 weeks in KPD and 9.6 ± 2.3 weeks in ketosis-resistant type 2 diabetes (NS). During a 20-h dextrose infusion, changes in insulin, C-peptide, and the C-peptide–to–glucose ratio were similar among diabetic and control groups. During dextrose infusion, subjects with ketosis-resistant type 2 diabetes had greater areas under the curve for blood glucose than subjects with KPD and control subjects (P < 0.05). The AIR and FPIR to arginine stimulation as well as glucose potentiation to arginine assessed before and after dextrose infusion were not different among the study groups.
Near-normoglycemia remission in obese African American patients with KPD and ketosis-resistant type 2 diabetes is associated with a remarkable recovery in basal and stimulated insulin secretion. At near-normoglycemia remission, patients with KPD displayed a pattern of insulin secretion similar to that of patients with ketosis-resistant type 2 diabetes and obese nondiabetic subjects.
Over half of newly diagnosed obese African Americans with diabetic ketoacidosis (DKA) discontinue insulin therapy and go through a period of near-normoglycemia remission. This subtype of diabetes is known as ketosis-prone type 2 diabetes (KPDM).
RESEARCH DESIGN AND METHODS
To investigate the role of lipotoxicity on β-cell function, eight obese African Americans with KPDM, eight obese subjects with type 2 diabetes with severe hyperglycemia without ketosis (ketosis-resistant type 2 diabetes), and nine nondiabetic obese control subjects underwent intravenous infusion of 20% intralipid at 40 ml/h for 48 h. β-Cell function was assessed by changes in insulin and C-peptide concentration during infusions and by changes in acute insulin response to arginine stimulation (AIRarg) before and after lipid infusion.
The mean time to discontinue insulin therapy was 11.0 ± 8.0 weeks in KPDM and 9.6 ± 2.2 weeks in ketosis-resistant type 2 diabetes (P = NS). At remission, KPDM and ketosis-resistant type 2 diabetes had similar glucose (94 ± 14 vs. 109 ± 20 mg/dl), A1C (5.7 ± 0.4 vs. 6.3 ± 1.1%), and baseline AIRarg response (34.8 ± 30 vs. 64 ± 69 μU/ml). P = NS despite a fourfold increase in free fatty acid (FFA) levels (0.4 ± 0.3 to 1.8 ± 1.1 mmol/l, P < 0.01) during the 48-h intralipid infusion; the response to AIRarg stimulation, as well as changes in insulin and C-peptide levels, were similar among obese patients with KPDM, patients with ketosis-resistant type 2 diabetes, and nondiabetic control subjects.
Near-normoglycemia remission in obese African American patients with KPDM and ketosis-resistant type 2 diabetes is associated with a remarkable recovery in basal and stimulated insulin secretion. A high FFA level by intralipid infusion for 48 h was not associated with β-cell decompensation (lipotoxicity) in KPDM patients.
Non-insulin-dependent (type II) diabetes mellitus is an inherited metabolic disorder characterized by hyperglycemia with resistance to ketosis. The onset is usually after age 40 years. Patients are variably symptomatic and frequently obese, hyperlipidemic and hypertensive. Clinical, pathological and biochemical evidence suggests that the disease is caused by a combined defect of insulin secretion and insulin resistance. Goals in the treatment of hyperglycemia, dyslipidemia and hypertension should be appropriate to the patient's age, the status of diabetic complications and the safety of the regimen. Nonpharmacologic management includes meal planning to achieve a suitable weight, such that carbohydrates supply 50% to 60% of the daily energy intake, with limitation of saturated fats, cholesterol and salt when indicated, and physical activity appropriate to the patient's age and cardiovascular status. Follow-up should include regular visits with the physician, access to diabetes education, self-monitoring of the blood or urine glucose level and laboratory-based measurement of the plasma levels of glucose and glycated hemoglobin. If unacceptably high plasma glucose levels (e.g., 8 mmol/L or more before meals) persist the use of orally given hypoglycemic agents (a sulfonylurea agent or metformin or both) is indicated. Temporary insulin therapy may be needed during intercurrent illness, surgery or pregnancy. Long-term insulin therapy is recommended in patients with continuing symptoms or hyperglycemia despite treatment with diet modification and orally given hypoglycemic agents. The risk of pancreatitis may be reduced by treating severe hypertriglyceridemia (fasting serum level greater than 10 mmol/L) and atherosclerotic disease through dietary and, if necessary, pharmacologic management of dyslipidemia. Antihypertensive agents are available that have fewer adverse metabolic effects than thiazides and beta-adrenergic receptor blockers. New drugs are being developed that will enhance effective insulin secretion and action and inhibit the progress of complications.
During very low carbohydrate intake, the regulated and controlled production of ketone bodies causes a harmless physiological state known as dietary ketosis. Ketone bodies flow from the liver to extra-hepatic tissues (e.g., brain) for use as a fuel; this spares glucose metabolism via a mechanism similar to the sparing of glucose by oxidation of fatty acids as an alternative fuel. In comparison with glucose, the ketone bodies are actually a very good respiratory fuel. Indeed, there is no clear requirement for dietary carbohydrates for human adults. Interestingly, the effects of ketone body metabolism suggest that mild ketosis may offer therapeutic potential in a variety of different common and rare disease states. Also, the recent landmark study showed that a very-low-carbohydrate diet resulted in a significant reduction in fat mass and a concomitant increase in lean body mass in normal-weight men. Contrary to popular belief, insulin is not needed for glucose uptake and utilization in man. Finally, both muscle fat and carbohydrate burn in an amino acid flame.
low-carbohydrate diets; ketogenic diets; ketogenesis; ketosis; diabetic ketoacidosis; ketone bodies; gluconeogenesis; insulin; glucagon; carbohydrate recommendations; glucose utilization; glucose transporters; fatty acids
A slight but real acidosis, involving a temporary decrease in alkaline reserve and increase in urinary acidity, occurs after all inhalation anæsthesias. Ketonuria is also present in 20 to 80 per cent. of cases. Local anæsthetics also produce these conditions, but less severely and less frequently.
The acidosis seemed to depend on complex factors, but mainly on tissue anoxæmia produced by the upset of normal respiration and circulation during operative procedures. In the normal individual this acidosis is very slight, transient, causes no symptoms and is of no moment. It cannot be entirely prevented by previous administration of sodium bicarbonate, glucose and insulin, although high carbohydrate diet before operation minimizes the tendency to acidosis. Cases with acidosis before operation become worse afterwards and require treatment to prevent complications.
The pre- and post-operative treatment of acidosis and ketosis in normals and diabetics, especially in emergency conditions, is discussed.
Ingestion of tolbutamide (Orinase®) by nondiabetic humans brought about a maximum reduction in blood sugar within one to two hours. In diabetic persons taking large doses of insulin, or who needed insulin for control, hyperglycemia, ketosis, and increased excretion of glucose in the urine developed when tolbutamide was substituted for insulin or was used before insulin therapy was begun.
The only serious toxic manifestation observed was a skin rash in two patients.
Successful control of diabetes with tolbutamide was limited to cases in which the disease was of mild, stable type and the patient was 40 or more years of age, of normal weight, and with a previous insulin requirement of 5 to 30 units per day.
It was of benefit in 43.5 per cent of all diabetic patients in the series studied and in about 75 per cent of the group that might be referred to as selected. The duration of the disease and the duration of insulin therapy were unimportant in predicting effectiveness for tolbutamide therapy.
Diabetic ketoacidosis (DKA) has been considered a key clinical feature of Type 1 diabetes mellitus; however, increasing evidence indicates that DKA is also a common feature of Type 2 diabetes (T2DM). Many cases of DKA develop under stressful conditions such as trauma or infection but an increasing number of cases without precipitating cause have been reported in children and adults with T2DM. Such patients present with severe hyperglycemia and ketosis as in Type 1 diabetes mellitus but can discontinue insulin after a few months and maintain acceptable glycemic control on diet or oral agents. This subtype of diabetes has been referred to as ketosis-prone T2DM. In this article, we reviewed the literature on ketosis-prone T2DM and summarized the epidemiology, putative pathophysiology and approaches to management.
Low-carbohydrate ketogenic diets are commonly used as weight loss alternatives to low-fat diets, however the physiological and molecular adaptations to these diets are not completely understood. It is assumed that the metabolic phenotype of the ketogenic diet (KD) is caused by the absence of carbohydrate and high fat content, however in rodents the protein content of KD affects weight gain and ketosis. In this study we examined the role of methionine and choline in mediating the metabolic effects of KD. We have found that choline was more effective than methionine in decreasing the liver steatosis of KD-fed mice. On the other hand, methionine supplementation was more effective than choline in restoring weight gain and normalizing the expression of several fatty acid and inflammatory genes in the liver of KD-fed mice. Our results indicate that choline and methionine restriction rather than carbohydrate restriction underlies many of the metabolic effects of KD.
Ketogenic diet; Weight loss; Fatty acid oxidation; Methionine metabolism; Methylation
Type 2 diabetes mellitus is a chronic progressive disease. During the course of the disease intensive treatment is often necessary resulting in multiple interventions including administration of insulin. Although dietary intervention is highly recommended, the clinical results of the widely prescribed diets with low fat content and high carbohydrates are disappointing. In this proof-of-concept study, we tested the effect of dietary carbohydrate-restriction in conjunction with metformin and liraglutide on metabolic control in patients with type 2 diabetes.
Forty patients with type 2 diabetes already being treated with two oral anti-diabetic drugs or insulin treatment and who showed deterioration of their glucose metabolism (i.e. HbA1c >7.5), were treated. A carbohydrate-restricted diet and a combination of metformin and liraglutide were instituted, after stopping either insulin or oral anti-diabetic drugs (excluding metformin). After enrollment, the study patients were scheduled for follow-up visits at one, two, three and six months. Primary outcome was glycemic control, measured by HbA1c at six months. Secondary outcomes were body weight, lipid-profile and treatment satisfaction.
Thirty-five (88%) participants completed the study. Nearly all participating patients experienced a drop in HbA1c and body weight during the first three months, an effect which was maintained until the end of the study at six months. Seventy-one percent of the patients reached HbA1c values below 7.0%. The range of body weight at enrollment was extreme, reaching 165 kg as the highest initial value. The average weight loss after 6 months was 10%. Most patients were satisfied with this treatment. During the intervention no significant change of lipids was observed. Most patients who were on insulin could maintain the treatment without insulin with far better metabolic control.
Carbohydrate restriction in conjunction with metformin and liraglutide is an effective treatment option for patients with advanced diabetes who are candidates for instituting insulin or who are in need of intensified insulin treatment. This proof-of-principle study showed a significant treatment effect on metabolic control.
Objective. To compare clinical characteristics, immunological markers, and β-cell functions of 4 subgroups (“Aβ” classification system) of ketosis-onset diabetes and ketosis prone diabetes patients without known diabetes, presenting with ketosis or diabetic ketoacidosis (DKA) and admitted to our department from March 2011 to December 2011 in China, with 50 healthy persons as control group. Results. β-cell functional reserve was preserved in 63.52% of patients. In almost each subgroup (except A− β− subgroup of ketosis prone group), male patients were more than female ones. The age of the majority of patients in ketosis prone group was older than that of ketosis-onset group, except A− β− subgroup of ketosis prone group. The durations from the patient first time ketosis or DKA onset to admitting to the hospital have significant difference, which were much longer for the ketosis prone group except the A+ β+ subgroup. BMI has no significant difference among subgroups. FPG of ketosis prone group was lower than that of A− β+ subgroup and A+ β+ subgroup in ketosis-onset group. A− β− subgroup and A+ β+ subgroup of ketosis prone group have lower HbA1c than ketosis-onset group. Conclusions. Ketosis-onset diabetes and ketosis prone diabetes do not absolutely have the same clinical characteristics. Each subgroup shows different specialty.
Forty-one diabetic patients on insulin were given 100mg. of phenformin daily for six weeks, either before or after a period of six weeks of inert capsules, in a double-blind cross-over trial. Eleven patients while on phenformin noticed hypoglycaemic effects and reduced their insulin on average by almost 20% without resultant rise in blood sugar levels. Twenty-eight patients felt no untoward effects and maintained their usual insulin dose. Phenformin led to improved control of the diabetes, with a significant decrease in blood sugar levels and a significant reduction in the variability of the weekly blood sugar readings. There was no increased ketosis, no change in cholesterol, and no significant loss of weight.
Salient aspects of prolonged metabolic studies on seven excessively labile diabetic patients and a review of the literature concerning causation and therapy of brittle diabetes are presented. Brittleness is redefined as “a syndrome of excessive insulin-sensitivity and ketosis-proneness manifested by extreme and unexplainable short-term and long-term fluctuations in the parameters of the disease”. Evidence on the causation of hyperlability points to dysfunction of plasma-protein transport and of hepatic and peripheral tissue metabolism of insulin. No objectively demonstrable complete and lasting stabilization was possible by means of any antidiabetic or adjunctive therapeutic measures. However, achievement of quantitative improvement in the accuracy of regulation of diabetes and moderation in deviations from the acceptable range of parameters were feasible. To this end, therapy recommended for everyday use incorporates the following principles found to be most helpful in following the oscillations of the disease on the research ward: flexibility in the plan of therapy; accuracy, especially in timing of therapeutic events; and employment of an insulin program best suited to the patient's needs and comfort.
Of a group of 32 patients with diabetes, 26 had a favorable modification of the disease in response to administration of butyl-sulfonyl-urea. All but one of the patients who had good response were past the age of 38. All diabetic patients included in this group were those with little or no tendency to ketosis after cessation of insulin administration. No toxic manifestations were noted except for a slight decrease in leukocytes in one case.
The patient, a woman, aged 40, had five normal pregnancies before, and six abnormal pregnancies after, the onset of diabetic symptoms. The case differed from typical diabetes in the following respects. In spite of severe thirst and polyuria, lasting untreated for six years, the patient became very fat, and the condition did not progress in the usual way. At the termination of the last pregnancy the glycosuria disappeared and the blood-sugar became almost normal, although the diet was very little restricted and all insulin was omitted. Insulin had only a small hypoglycæmic effect and the blood-sugar curves after glucose were atypical. The fasting level was raised, but the blood-sugar returned to the initial figure in two hours, suggesting that sugar was being well tolerated in spite of the hyperglycæmia. A very severe ketosis and a lowered threshold for glucose were present during the last three months of the pregnancy and disappeared immediately after labour. At labour, extreme hydramnios was obvious, and a very large fœtus weighing 12 lb. 6 oz. was stillborn. On the fourth day after the labour 10 units of pituitary extract (1 c.c. pituitrin) produced an epileptiform attack and nearly killed the patient. There was a temporary return of the glycosuria, without hyperglycæmia, and a transient ketosis. The belief that the pituitary is or was involved is supported by the patient's history that her head had grown larger, and by the definite constriction of the temporal fields of vision in both eyes.
It therefore seems reasonable to conclude that the disturbance of carbohydrate metabolism was not due to disease of the pancreas causing a deficient production of endogenous insulin, but to the antagonistic influence of a hyperactive pituitary gland associated with repeated pregnancies.
The prevalence of type 2 diabetes is increasing worldwide, accounting for 85-95% of all diagnosed cases of diabetes. Clinical trials provide evidence of benefits of low-carbohydrate ketogenic diets in terms of clinical outcomes on type 2 diabetes patients. However, the molecular events responsible for these improvements still remain unclear in spite of the high amount of knowledge on the primary mechanisms of both the diabetes and the metabolic state of ketosis. Molecular network analysis of conditions, diseases and treatments might provide new insights and help build a better understanding of clinical, metabolic and molecular relationships among physiological conditions. Accordingly, our aim is to reveal such a relationship between a ketogenic diet and type 2 diabetes through systems biology approaches.
Our systemic approach is based on the creation and analyses of the cell networks representing the metabolic state in a very-low-carbohydrate low-fat ketogenic diet. This global view might help identify unnoticed relationships often overlooked in molecule or process-centered studies.
A strong relationship between the insulin resistance pathway and the ketosis main pathway was identified, providing a possible explanation for the improvement observed in clinical trials. Moreover, the map analyses permit the formulation of some hypothesis on functional relationships between the molecules involved in type 2 diabetes and induced ketosis, suggesting, for instance, a direct implication of glucose transporters or inflammatory processes. The molecular network analysis performed in the ketogenic-diet map, from the diabetes perspective, has provided insights on the potential mechanism of action, but also has opened new possibilities to study the applications of the ketogenic diet in other situations such as CNS or other metabolic dysfunctions.
The objective of this study is to induce experimental diabetes mellitus by Streptozotocin in normal adult Wistar rats via comparison of changes in body weight, consumption of food and water, volume of urine and levels of glucose, insulin and C-peptide in serum, between normal and diabetic rats. Intra-venous injection of 60mg/kg dose of Streptozotocin in adult wistar rats, makes pancreas swell and at last causes degeneration in Langerhans islet beta cells and induces experimental diabetes mellitus in the 2–4 days. Induction of experimental diabetes mellitus is indeed the first step in the plan of purification of pancreatic Langerhans islet cells of normal rats for transplanting under the testis subcutaneous of experimentally induced diabetic rats. Streptozotocin induces one type of diabetes which is similar to diabetes mellitus with non-ketosis hyperglycemia in some animal species. For induction of experimental diabetes in male adult rats weighted 250–300 grams (75–90 days), 60mg/kg of Streptozotocin was injected intravenously. Three days after degeneration of beta cells, diabetes was induced in all animals. The diabetic and normal animals were kept in the metabolic cages separately and their body weight, consumption of food and water, urine volume, the levels of serum glucose, insulin and C-peptide quantities in all animals were measured and then these quantities were compared. For a microscopic study of degeneration of Langerhans islet beta cells of diabetic rats, sampling from pancreas tissue of diabetic and normal rats, staining and comparison between them, were done. Induction of diabetes with Streptozotocin decreases Nicotinamide-adenine dinucleotide (NAD) in pancreas islet beta cells and causes histopathological effects in beta cells which probably intermediates induction of diabetes. In this study, we used Streptozotocin for our experiments in induction of experimental diabetes mellitus. After Induction of diabetes, consumption of food and water, volume of urine and glucose increased in the diabetic animals in comparison with normal animals, but the weight of body and the volume of insulin and C-peptide decreased in the diabetic animals. Sampling and staining of pancreas tissue of diabetic and normal rats showed that the Langerhans islet beta cells of diabetic rats have been clearly degenerated. In three days, Streptozotocin makes pancreas swell and at last causes degeneration in Langerhans islet beta cells and induces experimental diabetes. It also changes normal metabolism in diabetic rats in comparison with normal rats. Consumption of water and food, volume of urine, serum glucose increases in diabetic animals in comparison with normal rats but the levels of serum insulin, C-peptide and body weight decreases.
Diabetes Induction; Streptozotocin; Islet cells
The features of carotid atherosclerosis in ketosis-onset diabetes have not been investigated. Our aim was to evaluate the prevalence and clinical characteristics of carotid atherosclerosis in newly diagnosed Chinese diabetic patients with ketosis but without islet-associated autoantibodies.
In total, 423 newly diagnosed Chinese patients with diabetes including 208 ketosis-onset diabetics without islet-associated autoantibodies, 215 non-ketotic type 2 diabetics and 79 control subjects without diabetes were studied. Carotid atherosclerosis was defined as the presence of atherosclerotic plaques in any of the carotid vessel segments. Carotid intima-media thickness (CIMT), carotid atherosclerotic plaque formation and stenosis were assessed and compared among the three groups based on Doppler ultrasound examination. The clinical features of carotid atherosclerotic lesions were analysed, and the risk factors associated with carotid atherosclerosis were evaluated using binary logistic regression in patients with diabetes.
The prevalence of carotid atherosclerosis was significantly higher in the ketosis-onset diabetic group (30.80%) than in the control group (15.2%, p=0.020) after adjusting for age- and sex-related differences, but no significant difference was observed in comparison to the non-ketotic diabetic group (35.8%, p=0.487). The mean CIMT of the ketosis-onset diabetics (0.70±0.20 mm) was markedly higher than that of the control subjects (0.57±0.08 mm, p<0.001), but no significant difference was found compared with the non-ketotic type 2 diabetics (0.73±0.19 mm, p=0.582) after controlling for differences in age and sex. In both the ketosis-onset and the non-ketotic diabetes, the prevalence of carotid atherosclerosis was markedly increased with age (both p<0.001) after controlling for sex, but no sex difference was observed (p=0.479 and p=0.707, respectively) after controlling for age. In the ketosis-onset diabetics, the presence of carotid atherosclerosis was significantly associated with age, hypertension, low-density lipoprotein cholesterol and mean CIMT.
The prevalence and risk of carotid atherosclerosis were significantly higher in the ketosis-onset diabetics than in the control subjects but similar to that in the non-ketotic type 2 diabetics. The characteristics of carotid atherosclerotic lesions in the ketosis-onset diabetics resembled those in the non-ketotic type 2 diabetics. Our findings support the classification of ketosis-onset diabetes as a subtype of type 2 diabetes.
Ketosis-prone diabetes; Type 2 diabetes; Atherosclerosis; Carotid arteries; Epidemiology
DKA is a severe metabolic derangement characterized by dehydration, loss of electrolytes, hyperglycemia, hyperketonemia, acidosis and progressive loss of consciousness that results from severe insulin deficiency combined with the effects of increased levels of counterregulatory hormones (catecholamines, glucagon, cortisol, growth hormone). The biochemical criteria for diagnosis are: blood glucose > 200 mg/dl, venous pH <7.3 or bicarbonate <15 mEq/L, ketonemia >3 mmol/L and presence of ketonuria. A patient with DKA must be managed in an emergency ward by an experienced staff or in an intensive care unit (ICU), in order to provide an intensive monitoring of the vital and neurological signs, and of the patient's clinical and biochemical response to treatment. DKA treatment guidelines include: restoration of circulating volume and electrolyte replacement; correction of insulin deficiency aiming at the resolution of metabolic acidosis and ketosis; reduction of risk of cerebral edema; avoidance of other complications of therapy (hypoglycemia, hypokalemia, hyperkalemia, hyperchloremic acidosis); identification and treatment of precipitating events. In Brazil, there are few pediatric ICU beds in public hospitals, so an alternative protocol was designed to abbreviate the time on intravenous infusion lines in order to facilitate DKA management in general emergency wards. The main differences between this protocol and the international guidelines are: intravenous fluid will be stopped when oral fluids are well tolerated and total deficit will be replaced orally; if potassium analysis still indicate need for replacement, it will be given orally; subcutaneous rapid-acting insulin analog is administered at 0.15 U/kg dose every 2-3 hours until resolution of metabolic acidosis; approximately 12 hours after treatment initiation, intermediate-acting (NPH) insulin is initiated at the dose of 0.6-1 U/kg/day, and it will be lowered to 0.4-0.7 U/kg/day at discharge from hospital.
Albert Renold strived to gain insight into the abnormalities
of human diabetes by defining the pathophysiology
of the disease peculiar to a given animal.
He investigated the Israeli desert-derived spiny mice
(Acomys cahirinus), which became obese on fat-rich
seed diet. After a few months hyperplasia and hypertrophy
of β-cells occurred leading to a sudden rupture,
insulin loss and ketosis. Spiny mice were low
insulin responders, which is probably a characteristic
of certain desert animals, protecting against insulin
oversecretion when placed on an abundant
diet. We have compared the response to overstimulation
of several mutant diabetic species and nutritionally
induced nonmutant animals when placed on
affluent diet. Some endowed with resilient β-cells
sustain long-lasting oversecretion, compensating for
the insulin resistance, without lapsing into overt diabetes.
Some with labile beta cells exhibit apoptosis
and lose their capacity of coping with insulin resistance
after a relatively short period. The wide
spectrum of response to insulin resistance among
different diabetes prone species seems to represent
the varying response of human beta cells among the
populations. In search for the molecular background
of insulin resistance resulting from overnutrition we
have studied the Israeli desert gerbil Psammomys
obesus (sand rat), which progresses through hyperinsulinemia,
followed by hyperglycemia and irreversible
beta cell loss. Insulin resistance was found
to be the outcome of reduced activation of muscle insulin
receptor tyrosine kinase by insulin, in association
with diminished GLUT4 protein and DNA
content and overexpression of PKC isoenzymes, notably
of PKCε. This overexpression and translocation
to the membrane was discernible even prior to hyperinsulinemia
and may reflect the propensity to diabetes
in nondiabetic species and represent a marker
for preventive action. By promoting the phosphorylation
of serine/threonine residues on certain proteins
of the insulin signaling pathway, PKCε exerts a
negative feedback on insulin action. PKCε was also
found to attenuate the activity of PKB and to promote
the degradation of insulin receptor, as determined
by co-incubation in HEK 293 cells. PKCε
overexpression was related to the rise in muscle diacylglycerol
and lipid content, which are prevalent
on lascivious nutrition especially if fat-rich. Thus,
Psammomys illustrates the probable antecedents of
the development of worldwide diabetes epidemic in
human populations emerging from food scarcity to
nutritional affluence, inappriopriate to their metabolic
To investigate the effect of aqueous solution of Biophytum sensitivum leaf extract (BSEt) on normal and streptozotocin (STZ)-nicotinamide-induced diabetic rats.
Diabetes was induced in adult male Wistar rats by the administration of STZ-nicotinamide (40, 110 mg/kg b.w., respectively) intraperitoneally. BSEt (200 mg/kg) was administered to diabetic rats for 28 days. The effect of extract on blood glucose, plasma insulin, total haemoglobin, glycosylated haemoglobin, liver glycogen and carbohydrate metabolism regulating enzymes of liver was studied in diabetic rats.
BSEt significantly reduced the blood glucose and glycosylated haemoglobin levels and significantly increased the total haemoglobin, plasma insulin and liver glycogen levels in diabetic rats. It also increased the hexokinase activity and decreased glucose-6-phosphatase, fructose-1, 6-bisphosphatase activities in diabetic rats.
The results of our study suggest that BSEt possesses a promising effect on STZ-nicotinamide-induced diabetes.
Biophytum sensitivum; Carbohydrate metabolism; Diabetes mellitus; Streptozotocin-nicotinamide
Though widely employed for clinical intervention in obesity, metabolic syndrome, seizure disorders and other neurodegenerative diseases, the mechanisms through which low carbohydrate ketogenic diets exert their ameliorative effects still remain to be elucidated. Rodent models have been used to identify the metabolic and physiologic alterations provoked by ketogenic diets. A commonly used rodent ketogenic diet (Bio-Serv F3666) that is very high in fat (~94% kcal), very low in carbohydrate (~1% kcal), low in protein (~5% kcal), and choline restricted (~300 mg/kg) provokes robust ketosis and weight loss in mice, but through unknown mechanisms, also causes significant hepatic steatosis, inflammation, and cellular injury. To understand the independent and synergistic roles of protein restriction and choline deficiency on the pleiotropic effects of rodent ketogenic diets, we studied four custom diets that differ only in protein (5% kcal vs. 10% kcal) and choline contents (300 mg/kg vs. 5 g/kg). C57BL/6J mice maintained on the two 5% kcal protein diets induced the most significant ketoses, which was only partially diminished by choline replacement. Choline restriction in the setting of 10% kcal protein also caused moderate ketosis and hepatic fat accumulation, which were again attenuated when choline was replete. Key effects of the 5% kcal protein diet – weight loss, hepatic fat accumulation, and mitochondrial ultrastructural disarray and bioenergetic dysfunction – were mitigated by choline repletion. These studies indicate that synergistic effects of protein restriction and choline deficiency influence integrated metabolism and hepatic pathology in mice when nutritional fat content is very high, and support the consideration of dietary choline content in ketogenic diet studies in rodents to limit hepatic mitochondrial dysfunction and fat accumulation.
The transition period is a severe challenge to dairy cows. Glucose supply cannot meet demand and body fat is mobilized, potentially leading to negative energy balance (NEB), ketosis, or fatty liver. Propionate produces glucose by gluconeogenesis, which depends heavily on the number and species of microbes. In the present study, we analyzed the rumen microbiome composition of cows in the transition period, cows with ketosis, and nonperinatal cows by terminal restriction fragment length polymorphism (TRFLP) analysis of 16S rRNA genes and quantitative PCR. TRFLP analysis indicated that the quantity of Veillonellaceae organisms was reduced and that of Streptococcaceae organisms was increased in rumen samples from the transition period and ketosis groups, with the number of Lactobacillaceae organisms increased after calving. Quantitative PCR data suggested that the numbers of the main propionate-producing microbes, Megasphaera elsdenii and Selenomonas ruminantium, were decreased, while numbers of the main lactate-producing bacterium, Streptococcus bovis, were increased in the rumen of cows from the transition period and ketosis groups, with the number of Lactobacillus sp. organisms increased after calving. Volatile fatty acid (VFA) and glucose concentrations were decreased, but the lactic acid concentration was increased, in rumen samples from the transition period and ketosis groups. Our results indicate that the VFA concentration is significantly related to the numbers of Selenomonas ruminantium and Megasphaera elsdenii organisms in the rumen.
The concentrations of immunoreactive gastrin in serum from portal and peripheral venous blood were determined in 10 patients with indwelling portal catheters before and after feeding. No significant differences were found between the gastrin concentrations in portal and peripheral serum. Gel filtration studies of serum did not reveal any differences between the gastrin components of portal and peripheral venous serum. Since neither the concentrations of immunoreactive gastrin nor the four gastrin components differed between portal and peripheral serum it is suggested that the liver is without effect on gastrin metabolism.