Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ketone bodies (KBs) D-3-hydroxybutyrate (D-3HB) and acetoacetate (AcAc) play a role in starvation and have been associated with insulin resistance. The dose-response relationship between insulin and KBs was demonstrated to be shifted to the right in type 2 diabetes patients. However, KB levels have also been reported to be decreased in obesity. We investigated the metabolic adaptation to fasting with respect to glucose and KB metabolism in lean and obese men without type 2 diabetes using stable glucose and D-3HB isotopes in a two-step pancreatic clamp after 38 h of fasting. We found that D-3HB fluxes in the basal state were higher in lean compared to obese men: 15.2 (10.7-27.1) vs. 7.0 (3.5-15.1) micromol/kg lean body mass (LBM) x min, respectively, P < 0.01. No differences were found in KB fluxes between lean and obese volunteers during the pancreatic clamp (step 1: 6.9 (1.8-12.0) vs. 7.4 (4.2-17.8) micromol/kg LBM x min, respectively; and step 2: 2.9 (0-7.2) vs. 3.4 (0.85-18.7) micromol/kg LBM x min, respectively), despite similar plasma insulin levels. Meanwhile, peripheral glucose uptake was higher in lean compared to obese men (step 1: 15.2 (12.3-25.6) vs. 14.7 (11.9-22.7) micromol/kg LBM x min, respectively, P < or = 0.05; and step 2: 12.5 (7.0-17.3) vs. 10.8 (5.2-15.0) micromol/kg LBM x min, respectively, P < or = 0.01). These data show that obese subjects who display insulin resistance on insulin-mediated peripheral glucose uptake have the same sensitivity for the insulin-mediated suppression of ketogenesis. This implies differential insulin sensitivity of intermediary metabolism in obesity.
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PMID:Effects of insulin on ketogenesis following fasting in lean and obese men. 1936 40

SH2B1 is a key regulator of body weight in mammals. Here, we identified dSH2B as the Drosophila homolog of SH2B1. dSH2B bound to Chico and directly promoted insulin-like signaling. Disruption of dSH2B decreased insulin-like signaling and somatic growth in flies. dSH2B deficiency also increased hemolymph carbohydrate levels, whole-body lipid levels, life span, and resistance to starvation and oxidative stress. Systemic overexpression of dSH2B resulted in opposite phenotypes. dSH2B overexpression in fat body decreased lipid and glucose levels, whereas neuron-specific overexpression of dSH2B decreased oxidative resistance and life span. Genetic deletion of SH2B1 also resulted in growth retardation, obesity, and type 2 diabetes in mice; surprisingly, life span and oxidative resistance were reduced in SH2B1 null mice. These data suggest that dSH2B regulation of insulin-like signaling, growth, and metabolism is conserved in SH2B1, whereas dSH2B regulation of oxidative stress and longevity may be conserved in other SH2B family members.
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PMID:SH2B regulation of growth, metabolism, and longevity in both insects and mammals. 2041 56

True euglycemic diabetic ketoacidosis is a rare complication of diabetes. We describe a case of diabetic ketoacidosis in a male with type 2 diabetes and Duchenne muscular dystrophy. He presented with normal plasma glucose as a consequence of starvation, reduced muscle mass and increased body fat.
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PMID:True euglycemic diabetic ketoacidosis in a person with type 2 diabetes and Duchenne muscular dystrophy. 2121 84

AMP-activated protein kinase (AMPK) is a cellular energy sensor that exists in almost all eukaryotes. Genetic studies in lower eukaryotes suggest that the ancestral role of AMPK was in response to starvation for a carbon source and that AMPK is involved in life-span extension in response to caloric restriction. In mammals, AMPK is activated by an increasing cellular AMP:ATP ratio (which signifies a decrease in energy) caused by metabolic stresses that interfere with ATP production (eg, hypoxia) or that accelerate ATP consumption (eg, muscle contraction). Because glucose deprivation can increase the AMP:ATP ratio, AMPK can also act as a glucose sensor. AMPK activation occurs by a dual mechanism that involves allosteric activation and phosphorylation by upstream kinases. Once activated, AMPK switches on catabolic pathways that generate ATP (eg, the uptake and oxidation of glucose and fatty acids and mitochondrial biogenesis) while switching off ATP-consuming, anabolic pathways (eg, the synthesis of lipids, glucose, glycogen, and proteins). In addition to the acute effects via direct phosphorylation of metabolic enzymes, AMPK has longer-term effects by regulating transcription. These features make AMPK an ideal drug target in the treatment of metabolic disorders such as insulin resistance and type 2 diabetes. The antidiabetic drug metformin (which is derived from an herbal remedy) works in part by activating AMPK, whereas many xenobiotics or "nutraceuticals," including resveratrol, quercetin, and berberine, are also AMPK activators. Most of these agents activate AMPK because they inhibit mitochondrial function.
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PMID:Sensing of energy and nutrients by AMP-activated protein kinase. 2132 38

Since its discovery, many physiologic functions have been ascribed to ghrelin, a gut derived hormone. The presence of a median fatty acid side chain on the ghrelin peptide is required for the binding and activation of the classical ghrelin receptor, the growth hormone secretagogue receptor (GHSR)-1a. Ghrelin O-acyl transferase (GOAT) was recently discovered as the enzyme responsible for this acylation process. GOAT is expressed in all tissues that have been found to express ghrelin and has demonstrated actions on several complex endocrine organ systems such as the hypothalamus-pituitary-gonadal, insular and adrenal axis as well as the gastrointestinal (GI) tract, bone and gustatory system. Ghrelin acylation is dependent on the function of GOAT and the availability of substrates such as proghrelin and short- to medium-chain fatty acids (MCFAs). This process is governed by GOAT activity and has been shown to be modified by dietary lipids. In this review, we provided evidence that support an important role of GOAT in the regulation of energy homeostasis and glucose metabolism by modulating acyl ghrelin (AG) production. The relevance of GOAT and AG during periods of starvation remains to be defined. In addition, we summarized the recent literature on the metabolic effects of GOAT specific inhibitors and shared our view on the potential of targeting GOAT for the treatment of metabolic disorders such as obesity and type 2 diabetes.
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PMID:Ghrelin acylation and metabolic control. 2189 40

THE BARKER HYPOTHESIS: Is an excellent explanation of the process where human and animal foetuses exposed to malnutrition, either by maternal malnutrition or placental insufficiency, are metabolically programmed, with selective stunting of cell differentiation and organ growth. With the postnatal excess of nutrition observed in developed countries, this irreversible programming causes metabolic syndrome, including obesity, type 2 diabetes, and hypertension. Metabolic programming involves epigenetic changes including imprinting which might be transmitted through more than one generation rather than being completely re-set or erased during reproduction. The Barker hypothesis was supported by epidemiological data that recognised no excess fetal or postnatal mortality when pregnant women were starved during the Dutch famine in World War II. This argued against the "thrifty genotype" theory introduced in 1962, which proposed that starvation selected against members of the population with less "thrifty" genes, but the survivors who had "thrifty" genes developed metabolic syndrome if they were subsequently over-nourished. EMBRYONIC/FETAL SELECTION: Embryos or early foetuses could be selected very early in pregnancy on the basis of their genotype, by maternal malnutrition, hypertension, obesity or other causes of placental insufficiency. The genotype that allows embryos, or cells within them, to survive a less hospitable environment in the decidua after implantation might contribute to the later development of metabolic syndrome. This article hypothesises that an adverse intrauterine environment, caused by maternal malnutrition or placental insufficiency, kills a proportion of embryos and selects a surviving population of early embryos whose growth in utero is retarded by their genotype, their environment or a combination of both. The metabolic syndrome follows if the offspring is over-nourished later in life. The embryonic selection hypothesis presented here could be tested by using single nucleotide polymorphism (SNP) microarrays to study adults who had a history of intrauterine growth retardation (IUGR) and subsequent metabolic syndrome. Their SNP array could be compared with their parents and unaffected unrelated or related controls. If there were no selection based on a "thrifty genotype", all parental sequences would be expected to appear in their surviving children, whether or not they had IUGR or developed metabolic syndrome. SNP sequences present in parents or controls but missing from adult offspring with metabolic syndrome who had IUGR, could be associated with or linked to genes that influence susceptibility to metabolic syndrome. This hypothesis proposes that missing genotypes would be lost if the embryos that inherited them died very early in pregnancy.
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PMID:Genetic selection of embryos that later develop the metabolic syndrome. 2234 93

Indy encodes the fly homolog of a mammalian transporter of di and tricarboxylate components of the Krebs cycle. Reduced expression of fly Indy or two of the C. elegans Indy homologs leads to an increase in life span. Fly and worm tissues that play key roles in intermediary metabolism are also the places where Indy genes are expressed. One of the mouse homologs of Indy (mIndy) is mainly expressed in the liver. It has been hypothesized that decreased INDY activity creates a state similar to caloric restriction (CR). This hypothesis is supported by the physiological similarities between Indy mutant flies on high calorie food and control flies on CR, such as increased physical activity and decreases in weight, egg production, triglyceride levels, starvation resistance, and insulin signaling. In addition, Indy mutant flies undergo changes in mitochondrial biogenesis also observed in CR animals. Recent findings with mIndy knockout mice support and extend the findings from flies. mIndy(-/-) mice display an increase in hepatic mitochondrial biogenesis, lipid oxidation, and decreased hepatic lipogenesis. When mIndy(-/-) mice are fed high calorie food they are protected from adiposity and insulin resistance. These findings point to INDY as a potential drug target for the treatment of metabolic syndrome, type 2 diabetes, and obesity.
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PMID:Indy mutants: live long and prosper. 2236 40

All living organisms maintain a high ATP:ADP ratio to drive energy-requiring processes. They therefore need mechanisms to maintain energy balance at the cellular level. In addition, multicellular eukaryotes have assigned the task of storing energy to specialized cells such as adipocytes, and therefore also need a means of intercellular communication to signal the needs of individual tissues and to maintain overall energy balance at the whole body level. Such signaling allows animals to survive periods of fasting or starvation when food is not available and is mainly achieved by hormonal and nervous communication. Insulin, adipokines, epinephrine, and other agonists thus stimulate pathways that regulate the activities of key enzymes involved in control of metabolism to integrate organismal carbohydrate and lipid metabolism. Overnutrition can dysregulate these pathways and have damaging consequences, causing insulin resistance and type 2 diabetes.
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PMID:Organismal carbohydrate and lipid homeostasis. 2255 Feb 28

Food insecurity is defined as limited or uncertain ability to acquire nutritionally adequate and safe foods in socially acceptable ways. The United States Department of Agriculture (USDA) has divided food insecurity into two categories: low food security and very low food security. Low food security is characterized by irregular access to food, binge eating when food is available, overconsumption of energy-dense foods, obesity, and even type 2 diabetes. This type of food insecurity occurs in impoverished urban areas of high-income countries such as the United States. In contrast, very low food security is distinctly different from low food security and can lead to undernutrition and frank starvation. Very low food security is found in developing countries in both rural areas and urban slums. In these countries, food insecurity is often exacerbated by natural disasters and climate changes that compromise food availability. With a focus on the social, economic, and behavioral factors that promote obesity and cardiometabolic disease in food insecure households in the United States, this review will first define the key terms and concepts associated with food insecurity. Then, the characteristics of food insecure households and the relationship to cardiometabolic disease will be discussed. Finally, the cardiac consequences of food insecurity in developing countries will be briefly described.
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PMID:Inconsistent Access to Food and Cardiometabolic Disease: The Effect of Food Insecurity. 2262 73

Insulin resistance is perceived as deleterious, associated with conditions as the metabolic syndrome, type 2 diabetes mellitus and critical illness. However, insulin resistance is evolutionarily well preserved and its persistence suggests that it benefits survival. Insulin resistance is important in various states such as starvation, immune activation, growth and cancer, to spare glucose for different biosynthetic purposes such as the production of NADPH, nucleotides in the pentose phosphate pathway and oxaloacetate for anaplerosis. In these conditions, total glucose oxidation by the tricarboxylic acid cycle is actually low and energy demands are largely met by fatty acid and ketone body oxidation. This beneficial role of insulin resistance has consequences for treatment and research. Insulin resistance should be investigated at the cellular, tissue and whole organism level. The metabolic pathways discussed here, should be integrated in the accepted and valid mechanistic events of insulin resistance before interfering with them to promote insulin sensitivity at any cost.
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PMID:The evolutionary benefit of insulin resistance. 2268 85


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