Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1997-12-23
2001-12-04
Myers, Carla J. (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S007100, C536S023200, C536S023500
Reexamination Certificate
active
06326141
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to the genetic basis of diabetics.
Diabetes mellitus is among the most common of all metabolic disorders, affecting up to 11% of the population by age 70. Type I (insulin dependent diabetes mellitus or IDDM) diabetes represents about 5 to 10% of this group and is the result of a progressive autoimmune destruction of the pancreatic &bgr;-cells with subsequent insulin deficiency. Type II (non-insulin dependent diabetes mellitus or NIDDM) diabetes represents 90-95% of the affected population but is much less well understood from the point of view of primary pathogenesis. Type II diabetic patients exhibit elements of both insulin resistance and relative insulin deficiency.
Alterations in glucose homeostasis are the sine qua non of diabetes mellitus and occur in both the Type I and Type II forms of the disease. In the mildest forms of diabetes this alteration is detected only after challenge with a carbohydrate load, while in moderate to severe forms of disease hyperglycemia is present in both the fasting and postprandial states. The most important tissue involved in disposal of a glucose load following oral ingestion, i.e., in the absorptive state, is skeletal muscle. (Klip 1990
Diabetes Care
13:228-243; Caro et al. 1989
Diab. Metab. Rev
. 5:665-689; Bogardus 1989
Diab. Metab. Rev
. 5:527-528; Beck-Nielsen 1989
Diab. Metab. Rev
. 5:487-493) Skeletal muscle comprises 40% of the body mass, but has been estimated to account for between 80 and 95% of glucose disposal at high insulin concentration or following an oral glucose load. (Beck-Nielsen 1989; Baron et al. 1988
Am. J. Physiol
. 255:E769-74) In insulin-treated animals, about 25% of an intravenous glucose load enters muscle within 1 minute. (Daniel et al. 1975
J. Physiol
. (Lond) 247:273-288).
Skeletal muscle takes up glucose by facilitated diffusion in both an insulin-independent and insulin-dependent manner and has been shown to express relatively high levels of GLUT4 (the “insulin responsive” glucose transporter) and low levels of GLUT1 and GLUT3 (the transporters believed to be involved in basal glucose transport). (Mueckler 1990
Diabetes
39:6-11; Bell et al. 1990
Diabetes Care
13:198-208) Once inside the muscle, glucose is rapidly phosphorylated by hexokinase to form glucose 6-phosphate. Although the rate-limiting step for glucose uptake is at the level of transport, there is increasing evidence that the major control of carbohydrate metabolism is exerted after the glucose-6-phosphate step. (Mandarino 1989
Diab. Metab. Rev
. 5:474-486; Felbert et al. 1977
Diabetes
26:693-699) Depending on the hormonal milieu and metabolic state, the glucose 6-phosphate can enter either anabolic or catabolic pathways. The major anabolic pathway involves conversion of the glucose to glycogen. The rate-limiting enzyme of this reaction is glycogen synthase. The activity of glycogen synthase is regulated primarily by phosphorylation and dephosphorylation and the presence of the allosteric regulator glucose-6-phosphate, although the level of expression of the enzyme must also play a role. In catabolic states, glucose is metabolized through the glycolytic pathway to pyruvate which in turn is either converted to lactate (under anaerobic conditions) or is oxidized by CO
2
and acetyl-CoA. The latter reaction is catalyzed by the multienzyme complex pyruvate dehydrogenase (PDH). PDH activity is also regulated by the level of the enzyme, phosphorylation and dephosphorylation, and a number of allosteric modifiers. Most of the enzymes and proteins involved in glucose metabolism have been identified and purified, and over the past several years, several of these have been cloned at a molecular level.
The dominant hormone regulating glucose metabolism in muscle is insulin. Insulin exerts its actions through insulin, and to a lesser extent IGF-1, receptors, both of which are expressed in skeletal muscle. (Beguinot et al. 1989
Endocrinology
125:1599-1605; Sinha et al. 1987
J. Clin. Invest
. 79:1330-1337; Obermaier-Kusser et al. 1989
J. Biol. Chem
. 264:9497-9504; Arner et al. 1987
Diabetologia
30:437-440) Like insulin and IGF-1 receptors on other tissues, these receptors are protein tyrosine kinases which are stimulated upon insulin and IGF-1 binding. (White et al.
J. Clin. Invest
. 82:1151-1156) This initial insulin signal then acts through a cascade of events involving phosphorylation and dephosphorylation, as well as possible mediator generation to promote glucose uptake, stimulate metabolism and conversion of glucose to glycogen by activating glycogen synthase, and regulate a variety of intracellular enzymes involved in carbohydrate. (Yki-Jarvinen et al. 1987
J. Clin. Invest
. 80:95-100; Mandarino et al. 1987
J. Clin. Invest
. 80:655-663) In addition, insulin also acts at the level of muscle to modify lipid and protein metabolism through effects on membrane transport, enzyme activity and gene expression. (Kimball et al. 1988
Diab. Metab. Rev
. 4:773-787; Alexander et al. 1988
Proc. Natl. Acad. Sci. USA
85:5092-5096).
In both Type I and Type II diabetes there are major alterations in the ability of peripheral tissues to take up and metabolize glucose. (DeFronzo 1988
Diabetes
37:667-687; Olefsky et al. 1988
Am. J. Med
. 85:86-105; Reaven 1988
Diabetes
37:1595-1607; Nankervis et al. 1984
Diabetologia
27:497-503; Yki-Jarvinen et al. 1986
N. Engl. J. Med
. 315:224-230; Hother-Nielsen et al. 1987
Diabetologia
30:834-840) These alterations affect liver, fat and muscle, as well as other tissues. In Type I diabetes, the alterations in glucose metabolism are largely secondary to insulin deficiency which has both acute and chronic effects with regard to regulation of glucose uptake and intracellular disposition metabolism. (Nankervis 1984; Yki-Jarvinen 1986; Hother-Nielsen 1987) The exact basis for impaired metabolism in muscle of Type II diabetics is less clear, but probably involves a combination of factors including a significant level of insulin resistance (due to acquired or genetic factors), as well as some component of relative insulin deficiency.
In obesity and diabetes, there are a variety of alterations in the muscle glucose homeostasis. In obese individuals without diabetes the major alteration is in oxidative glucose metabolism. (Beck-Nielsen 1989; DeFronzo 1988; Olefsky 1988) There are reduced insulin-stimulated nonoxidative glucose metabolism, a reduction in both basal and insulin-stimulated glucose oxidation and a higher rate of lipid oxidation than in lean controls. (Felber et al. 1987
Diabetologia
26:1341-1350) Glycogen synthase activity is decreased in obese individuals and may contribute to the reduced nonoxidative glucose disposal. (Bogardus et al. 1984
J. Clin. Invest
. 73:1185-1190; Freymond et al. 1988
J. Clin. Invest
. 82:1503-1509) In obese diabetics both oxidative and nonoxidative pathways are altered, and the latter may play a more quantitatively important role. (Beck-Nielsen 1989) In both obesity and Type II diabetes there is also decreased insulin stimulated receptor phosphorylation (Caro 1987; Obermaier-Kusser 1989; Arner 1987) decreased insulin stimulated glucose transport (Caro 1987; Felber 1987) decreased insulin-stimulated pyruvate dehydrogenase activity (Mandarino 1989), and defective insulin-stimulated glycogen synthase. (Mandarino 1989; Freymond 1988; Thorburn et al. 1990
J. Clin. Invest
. 85:522-529) Untreated Type I diabetic humans and rodents show many of the same changes. (Nankervis 1984; Yki-Jarvinen 1986; Hother-Nielsen 1987; Wallberg 1989
Med. Sci. Sports. Exerc
. 21:356-361) In the latter group, these tend to reverse with proper therapy, although in most studies some reduction in insulin-stimulated glucose oxidation and insulin-stimulated PDH activity persist despite therapy. Factors mediating these alterations in glucose homeostasis in diabetes and obesity are multiple and include the altered hormonal milieu, altered substrate levels, and possibly even circulating insulin antagonists. (DeFronzo 1988; Sugden et al. 1990
J. Endocr
Kahn C. Ronald
Reynet Christine
Fish & Richardson P.C.
Johannsen Diana
Joslin Diabetes Center, Inc.
Myers Carla J.
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