Maternally inherited diabetes and deafness: a new diabetes subtype

Maassen, J. A.; Kadowaki, Takuya

doi:10.1007/s001250050456

Cited by 46 publications

(68 citation statements)

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“…The monogenic forms of diabetes account for approximately 5% of cases and are caused by mutations in genes encoding insulin 3 , the insulin receptor 4 , the glycolytic enzyme glucokinase 5 , and the transcription factors hepatocyte nuclear factor-1α (HNF-1α), HNF-1β, HNF-4α, insulin promoter factor-1 and NeuroD1/BETA2 (refs [6][7][8][9][10]. Mutations in maternally inherited mitochondrial genes can also cause diabetes, often in association with hearing loss 11 . Type 1 and type 2 diabetes are multifactorial disorders.…”

Section: Introductionmentioning

confidence: 99%

Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus

et al. 2000

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Type 2 or non-insulin-dependent diabetes mellitus (NIDDM) is the most common form of diabetes worldwide, affecting approximately 4% of the world's adult population. It is multifactorial in origin with both genetic and environmental factors contributing to its development. A genome-wide screen for type 2 diabetes genes carried out in Mexican Americans localized a susceptibility gene, designated NIDDM1, to chromosome 2. Here we describe the positional cloning of a gene located in the NIDDM1 region that shows association with type 2 diabetes in Mexican Americans and a Northern European population from the Botnia region of Finland. This putative diabetes-susceptibility gene encodes a ubiquitously expressed member of the calpain-like cysteine protease family, calpain-10 (CAPN10). This finding suggests a novel pathway that may contribute to the development of type 2 diabetes.

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Section: Introductionmentioning

confidence: 99%

Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus

et al. 2000

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“…Maternally-inherited diabetes with deafness (MIDD) results from a mutation at position 3243 of the mitochondrial DNA, which encodes a leucine transfer RNA [142]. It seems likely that the failure of insulin secretion in MIDD patients results because glucose metabolism is impaired and fails to cause closure of the K ATP channel.…”

Section: Diseases Of K Atp Channel Regulationmentioning

confidence: 99%

ATP-sensitive K + channels and insulin secretion: their role in health and disease

Ashcroft

Gribble²

1999

Diabetologia

408

279

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IntroductionSulphonylureas have been used for over 50 years to enhance insulin secretion in patients with Type II (non-insulin-dependent) diabetes mellitus but their therapeutic target was not discovered until 1985 and we are only just beginning to address their molecular mechanism of action. The sulphonylurea drugs were discovered serendipitously by Marcel Janbon in 1942, when he observed a high incidence of hypoglycaemic symptoms in typhoid patients treated with the bacteriostatic agent p-aminobenzenesulphamidoisopropylthiodiazole (2254RP) [1]. This observation was extended by Auguste Loubatires, who showed that 2254RP induced hypoglycaemia in dogs by stimulating insulin secretion [2]. Subsequently, it was discovered that another sulphonamide drug being tested for bacteriostatic effects, carbutamide, also caused hypoglycaemia in man [3]. Clinical studies followed and led to the development of tolbutamide for the treatment of Type II diabetes. The full story of these pioneering experiments has been vividly recounted in an earlier review by Henquin [4]. Numerous sulphonylureas and related compounds have now been synthesized, with different potencies and time-courses of action and many millions of Type II diabetic patients are now routinely treated with these drugs.The first clues to the mechanism of action of sulphonylureas on insulin secretion came with the discovery that these drugs depolarize the pancreatic beta cell and stimulate electrical activity [5] and the finding that this depolarization was due to a decrease in the potassium permeability of the beta-cell membrane [6]. Patch-clamp studies subsequently showed that sulphonylureas interact specifically with the ATP-sensitive potassium (K ATP ) channel in the betacell membrane and bring about its closure [7]. The activity of the K ATP channel sets the resting membrane potential of the unstimulated beta cell and its closure decreases the membrane K + permeability, producing membrane depolarization and insulin secretion [8]. Radioligand binding studies established the presence of both low-affinity and high-affinity sulphonylurea binding sites in the beta-cell membrane [9, 10] and led to considerable speculation about whether the high-affinity sulphonylurea receptor and the K ATP channel were the same or different proteins. The purification and subsequent cloning of a high-affinity sulphonylurea receptor from insulinoma cells [11] resolved this issue by showing that this receptor is an integral component of the K ATP channel [12,13].In this article, we review the role of the K ATP channel in insulin secretion in health and disease. We also summarise current knowledge of how sulphonylureas act on the different types of K ATP channel found in beta cells and in extra-pancreatic tissues, and discuss the implications of these findings for the use of sulphonylureas as therapeutic agents to stimulate insulin secretion in humans. Finally, we consider the evidence for additional targets for sulphonylureas, both within the beta cell and in extra-pancreatic tissues.Funct...

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“…Production of ATP is coupled to mitochondrial metabolism of glucose. The importance of mitochondrial function is underscored by the severe effects on glucose-induced insulin secretion by mutations in mitochondrial DNA (encoding genes important for respiration) in humans [11] or by experimentally induced inhibition of mitochondrial gene transcription [12]. Also, the shuttling to mitochondria of nicotinamide adenine dinucleotide (NADH) formed in the cytoplasm by glycolysis is important for efficient ATP production [13].…”

Section: Normal Regulation Of Insulin Secretionmentioning

confidence: 99%

Dysfunctional insulin secretion in type 2 diabetes: role of metabolic abnormalities

Grill¹,

Björklund

2000

CMLS, Cell. Mol. Life Sci.

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Insulin secretion is finely tuned to the requirements of tissues by tight coupling to prevailing blood glucose levels. The normal regulation of insulin secretion is coupled to glucose metabolism in the pancreatic B cell, a major but not exclusive signal for secretion being closure of K+ ATP (adenosine' triphosphate)-dependent channels in the cell membrane through an increase in cytosolic ATP/adenosine diphosphate. Insulin secretion in type 2 diabetes is abnormal in several respects due to genetic causes but also due to the metabolic environment of the pancreatic B cells. This environment may be particularly important for the deterioration of insulin secretion which occurs with increasing duration of diabetes. Factors in the environment with potential importance include overstimulation, a negative effect of hyperglycemia per se ('glucotoxicity') as well as adverse effects of elevated fatty acids ('lipotoxicity'). Elucidating the mechanisms behind these factors as well as their clinical importance will pave the way for treatment which could preserve B-cell function in type 2 diabetic patients.

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Maternally inherited diabetes and deafness: a new diabetes subtype

Cited by 46 publications

References 0 publications

Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus

Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus

ATP-sensitive K + channels and insulin secretion: their role in health and disease

Dysfunctional insulin secretion in type 2 diabetes: role of metabolic abnormalities

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