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PubMed1996

Banting Lecture 1995. A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm.

Special features of glucose metabolism in pancreatic beta-cells are central to an understanding of the physiological role of these cells in glucose homeostasis. Several of these characteristics are emphasized: a high-capacity system for glucose transport; glucose phosphorylation by the high-Km glucokinase (GK), which is rate-limiting for glucose metabolism and determines physiologically the glucose dependency curves of many processes in beta-cell intermediary and energy metabolism and of insulin release and is therefore viewed as glucose sensor; remarkably low activity of lactate dehydrogenase and the presence of effective hydrogen shuttles to allow virtually quantitative oxidation of glycolytic NADH; the near absence of glycogen and fatty acid synthesis and of gluconeogenesis, such that intermediary metabolism is primarily catabolic; a crucial role of mitochondrial processes, including the citric acid cycle, electron transport, and oxidative phosphorylation with FoF1 ATPase governing the glucose-dependent increase of the ATP mass-action ratio; a Ca(2+)-independent glucose-induced respiratory burst and increased ATP production in beta-cells as striking manifestations of crucial mitochondrial reactions; control of the membrane potential by the mass-action ratio of ATP and voltage-dependent Ca2+ influx as signal for insulin release; accumulation of malonyl-CoA, acyl-CoA, and diacylglycerol as essential or auxiliary metabolic coupling factors; and amplification of the adenine nucleotide, lipid-related, and Ca2+ signals to recruit many auxiliary processes to maximize insulin biosynthesis and release. The biochemical design also suggests certain candidate diabetes genes related to fuel metabolism: low-activity and low-stability GK mutants that explain in part the maturity-onset diabetes of the young (MODY) phenotype in humans and mitochondrial DNA mutations of FoF1 ATPase components thought to cause late-onset diabetes in BHEcdb rats. These two examples are chosen to illustrate that metabolic reactions with high control strength participating in beta-cell energy metabolism and generating coupling factors and intracellular signals are steps with great susceptibility to genetic, environmental, and pharmacological influences. Glucose metabolism of beta-cells also controls, in addition to insulin secretion and insulin biosynthesis, an adaptive response to excessive fuel loads and may increase the beta-cell mass by hypertrophy, hyperplasia, and neogenesis. It is probable that this adaptive response is compromised in diabetes because of the GK or ATPase mutants that are highlighted here. A comprehensive knowledge of beta-cell intermediary and energy metabolism is therefore the foundation for understanding the role of these cells in fuel homeostasis and in the pathogenesis of the most prevalent metabolic disease, diabetes.

Adenine Nucleotides↗
PubMed1998

Mutation P291fsinsC in the transcription factor hepatocyte nuclear factor-1alpha is dominant negative.

The type 3 form of maturity-onset diabetes of the young (MODY3) results from mutations in the gene encoding the transcription factor, hepatocyte nuclear factor-1alpha (HNF-1alpha). The mechanism by which mutations in only one allele of the HNF-1alpha gene impair pancreatic beta-cell function is unclear. The functional form of HNF-1alpha is a dimer--either a homodimer or a heterodimer with the structurally related protein HNF-1beta--that binds to and activates transcription of the genes whose expression it regulates. HNF-1alpha is composed of three functional domains: an amino-terminal dimerization domain (amino acids 1-32), a DNA-binding domain with POU-like and homeodomain-like motifs (amino acids 150-280), and a COOH-terminal transactivation domain (amino acids 281-631). Because the dimerization domain is intact in many of the mutant forms of HNF-1alpha found in MODY subjects, these mutant proteins may impair pancreatic beta-cell function by forming nonproductive dimers with wild-type protein, thereby inhibiting its activity; that is, they are dominant-negative mutations. This hypothesis was tested by comparing the functional properties of the frameshift mutation P291fsinsC, the most common mutation identified to date in MODY3 patients, and wild-type HNF-1alpha. P291fsinsC-HNF-1alpha showed no transcriptional transactivation activity in HeLa cells, which lack endogenous HNF-1alpha. Overexpression of P291fsinsC-HNF-1alpha in MIN6 cells, a mouse beta-cell line, resulted in an approximately 40% inhibition of the endogenous HNF-1alpha activity in a dosage-dependent manner. Furthermore, heterodimer formation between wild-type and P291fsinsC mutant proteins were observed by electrophoretic mobility shift assay. These data suggest that the P291fsinsC mutation in HNF-1alpha functions as a dominant-negative mutation. However, other mutations, such as those in the promoter region and dimerization domain, may represent loss of function mutations. Thus mutations in the HNF-1alpha gene may lead to beta-cell dysfunction by two different mechanisms.

Animals↗
PubMed1998

Glucose utilization and production in patients with maturity-onset diabetes of the young caused by a mutation of the hepatocyte nuclear factor-1alpha gene.

Mutations of the hepatocyte nuclear factor (HNF)-1alpha gene cause impaired insulin secretion and hyperglycemia in patients with maturity-onset diabetes of the young (MODY)3. Whether these mutations also affect glucose metabolism in tissues other than the beta-cell has not yet been documented. We therefore assessed, in five MODY3 patients and a dozen healthy control subjects, insulin secretion, oxidative and nonoxidative glucose disposal, and glucose production during a two-step hyperglycemic clamp and a euglycemic hyperinsulinemic (0.4 mU x kg(-1) x min(-1)) clamp. Compared with healthy control subjects, MODY3 patients had higher fasting plasma glucose (+100%) but similar rates of fasting glucose production and oxidation. Both the early and late phases of insulin secretion were virtually abolished during the hyperglycemic clamp, and glucose production was suppressed by only 43% in MODY3 patients vs. 100% in healthy control subjects. The rate of glucose infusion required to produce a 5 mmol/l increase above basal glycemia was reduced by 30%, net nonoxidative glucose disposal (which is equal to net glycogen deposition) was inhibited by 39%, and net carbohydrate oxidation during hyperglycemia was 25% lower in MODY3 patients compared with control subjects. Insulin-stimulated glucose utilization and oxidation measured during the hyperinsulinemic clamp (at approximately 200 pmol/l insulin) were identical in MODY3 patients and in healthy control subjects, indicating that peripheral insulin sensitivity was not altered. Suppression of endogenous glucose production was, however, mildly impaired. It is concluded that MODY3 patients have severely depressed glucose-induced insulin secretion. The development of hyperglycemia in these patients appears to be caused by a decreased stimulation of glucose utilization, oxidation, and nonoxidative glucose disposal as well as by a blunted suppression of endogenous glucose output. These phenomena are essentially secondary to insulinopenia, whereas insulin sensitivity remains intact.

Adult↗
PubMed2000

Reduced pancreatic polypeptide response to hypoglycemia and amylin response to arginine in subjects with a mutation in the HNF-4alpha/MODY1 gene.

Subjects with the Q268X mutation in the hepatocyte nuclear factor (HNF)-4alpha gene (RW pedigree/maturity-onset diabetes of the young [MODY]-1) have diminished insulin and glucagon secretory responses to arginine. To determine if pancreatic polypeptide (PP) secretion is likewise involved, we studied PP responses to insulin-induced hypoglycemia in 17 RW pedigree members: 6 nondiabetic mutation-negative [ND(-)], 4 nondiabetic mutation-positive [ND(+)], and 7 diabetic mutation-positive [D(+)]. Subjects received 0.08 U/kg body wt human regular insulin as an intravenous bolus to produce moderate self-limited hypoglycemia. PP areas under the curve (PP-AUCs) were compared among groups. With hypoglycemia, the PP-AUC was lower in the D(+) group (14,907 +/- 6,444 pg/ml, P = 0.03) and the ND(+) group (14,622 +/- 6,015 pg/ml, P = 0.04) compared with the ND(-) group (21,120 +/- 4,158 pg/ml). In addition, to determine if the beta-cell secretory defect in response to arginine involves amylin in addition to insulin secretion, we analyzed samples from 17 previously studied RW pedigree subjects. We compared the AUCs during arginine infusions for the 3 groups both at euglycemia and hyperglycemia as well as their C-peptide-to-amylin ratios. The D(+) and ND(+) groups had decreased amylin AUCs during both arginine infusions compared with the ND(-) group, but had similar C-peptide-to-amylin ratios. These results suggest that the HNF-4alpha mutation in the RW/MODY1 pedigree confers a generalized defect in islet cell function involving PP cells in addition to beta- and alpha-cells, and beta-cell impairment involving proportional deficits in insulin and amylin secretion.

Adult↗
PubMed2001

Developmental biology of the pancreas.

All pancreatic cell types (endocrine, exocrine, and ductal) are derived from the same endodermal dorsal and ventral anlage, which grow together to form the definitive pancreas. Golosow and Grobstein were pioneers in the field of pancreatic developmental research, as were Wessells and Cohen, who already in the 1960s performed classic embryological experiments describing the morphogenesis of the pancreas and the epithelio-mesenchymal interactions that are instrumental for proper pancreas development. Recent findings suggest that follistatin and fibroblast growth factors represent some of these key mesenchymal factors that actively promote at least pancreatic exocrine development. The true endodermal origin of the pancreatic endocrine cells became evident by experiments performed by the groups of LeDouarin and Rutter in the 1970s. The newly acquired insights regarding the specification of pancreatic endocrine cells as controlled by the notch signaling pathway (i.e., similar to the mechanisms by which neurons are specified during neurogenesis) have provided a novel understanding of the long acknowledged similarities between neurons and the pancreatic endocrine cells. Last, the identification of a number of distinct transcription factors operating at various levels of pancreatic development and in different cell types has provided useful information both on pancreas development and on various pancreatic disorders such as diabetes. Interestingly, four of the hitherto defined five different maturity-onset diabetes of the young (MODY) genes correspond to transcription factors, and, in addition, several transcription factors have also been linked to type 2 diabetes.

Animals↗
PubMed2002

Overexpression of dominant-negative mutant hepatocyte nuclear fctor-1 alpha in pancreatic beta-cells causes abnormal islet architecture with decreased expression of E-cadherin, reduced beta-cell proliferation, and diabetes.

One subtype of maturity-onset diabetes of the young (MODY)-3 results from mutations in the gene encoding hepatocyte nuclear factor (HNF)-1 alpha. We generated transgenic mice expressing a naturally occurring dominant-negative form of human HNF-1 alpha (P291fsinsC) in pancreatic beta-cells. A progressive hyperglycemia with age was seen in these transgenic mice, and the mice developed diabetes with impaired glucose-stimulated insulin secretion. The pancreatic islets exhibited abnormal architecture with reduced expression of glucose transporter (GLUT2) and E-cadherin. Blockade of E-cadherin-mediated cell adhesion in pancreatic islets abolished the glucose-stimulated increases in intracellular Ca(2+) levels and insulin secretion, suggesting that loss of E-cadherin in beta-cells is associated with impaired insulin secretion. There was also a reduction in beta-cell number (50%), proliferation rate (15%), and pancreatic insulin content (45%) in 2-day-old transgenic mice and a further reduction in 4-week-old animals. Our findings suggest various roles for HNF-1 alpha in normal glucose metabolism, including the regulation of glucose transport, beta-cell growth, and beta-cell-to-beta-cell communication.

Animals↗
PubMed2002

Decreased glibenclamide uptake in hepatocytes of hepatocyte nuclear factor-1alpha-deficient mice: a mechanism for hypersensitivity to sulfonylurea therapy in patients with maturity-onset diabetes of the young, type 3 (MODY3).

Diabetes in subjects with hepatocyte nuclear factor (HNF)-1alpha gene mutations (maturity-onset diabetes of the young [MODY]-3) is characterized by impaired insulin secretion. Surprisingly, MODY3 patients exhibit hypersensitivity to the hypoglycemic actions of sulfonylurea therapy. To study the pharmacogenetic mechanism(s), we have investigated glibenclamide-induced insulin secretion, glibenclamide clearance from the blood, and glibenclamide metabolism in wild-type and Hnf-1alpha-deficient mice. We show that despite a profound defect in glucose-stimulated insulin secretion, diabetic Hnf-1alpha(-/-) mice have a robust glibenclamide-induced insulin secretory response. We demonstrate that the half-life (t(1/2)) of glibenclamide in the blood is increased in Hnf-1alpha(-/-) mice compared with wild-type littermates (3.9 +/- 1.3 vs. 1.5 +/- 1.8 min, P <or= 0.05). The clearance of glibenclamide from the blood during the first hours after intravenous administration was reduced approximately fourfold in Hnf-1alpha(-/-) mice compared with Hnf-1alpha(+/+) littermates. Glibenclamide uptake into hepatocytes was dramatically decreased in vivo and in vitro. To study the metabolism of glibenclamide in Hnf-1alpha(-/-) animals, we analyzed liver extracts from [(3)H]glibenclamide-injected animals by reverse-phase chromatography. We found that the ratio of the concentrations of glibenclamide and its metabolites was moderately increased in livers of Hnf-1alpha(-/-) mice, suggesting that hepatic glibenclamide metabolism was not impaired in animals with Hnf-1alpha deficiency. Our data demonstrate that high serum glibenclamide concentrations and an increased t(1/2) of glibenclamide in the blood of Hnf-1alpha(-/-) mice are caused by a defect in hepatic uptake of glibenclamide. This suggests that hypersensitivity to sulfonylureas in MODY3 patients may be due to impaired hepatic clearance and elevated plasma concentrations of the drug.

Animals↗
PubMed2002

Thyroid hormone receptor interacting protein 3 (trip3) is a novel coactivator of hepatocyte nuclear factor-4alpha.

Mutations of the hepatocyte nuclear factor-4alpha (HNF-4alpha) gene are associated with a subtype of maturity-onset diabetes of the young (MODY1) that is characterized by impaired insulin secretion in response to a glucose load. HNF-4alpha, which is a transcription factor expressed in pancreatic beta-cells, plays an important role in regulating the expression of genes involved in glucose metabolism. Thus, cofactors that interact with HNF-4alpha and modify its transcriptional activity might also play an important role in regulating the metabolic pathways in pancreatic beta-cells, and the genes of such cofactors are plausible candidate genes for MODY. In the present study, we showed, using a yeast two-hybrid screening assay, that thyroid hormone receptor interacting protein 3 (Trip3) interacted with HNF-4alpha, and their interaction was confirmed by the glutathione S-transferase pull-down assay. Human Trip3 cDNA contained an open reading frame for a protein of 155 amino acids, and the gene was expressed in both pancreatic islets and MIN6 cells. Cotransfection experiments indicated that Trip3 could enhance (two- to threefold) the transcription activity of HNF-4alpha in COS-7 cells and MIN6 cells. These results suggest that Trip3 is a coactivator of HNF-4alpha. Mutation screening revealed that variation of the Trip3 gene is not a common cause of MODY/early-onset type 2 diabetes in Japanese individuals. Trip3 may play an important role in glucose metabolism by regulating the transcription activity of HNF-4alpha.

Animals↗
PubMed2002

Hepatocyte nuclear factor-1alpha recruits the transcriptional co-activator p300 on the GLUT2 gene promoter.

Mutations in the hepatocyte nuclear factor (HNF)-1alpha gene have been linked to subtype 3 of maturity-onset diabetes of the young (MODY), a disease characterized by a primary defect in insulin secretion. Here we show that the human GLUT2 gene is closely regulated by HNF-1alpha via sequences downstream of the transcriptional start site by interaction with transcriptional co-activator p300. The promoter region of the human GLUT2 gene was subcloned into luciferase expression plasmids that were transfected together with HNF-1alpha expression plasmid into a pancreatic beta-cell line, HIT-T15, to evaluate transcriptional activities. HNF-1alpha enhanced human GLUT2 promoter activity sixfold. Site-direct mutagenesis and footprint analyses showed that the HNF-1alpha binding site (+200 to +218) is critical in human GLUT2 gene expression. Furthermore, mammalian two-hybrid and immunoprecipitation studies revealed the transactivation domain of HNF-1alpha (amino acids 391-540) to interact with both the NH(2)-terminal region (amino acids 180-662) and the COOH-terminal region (amino acids 1,818-2,079) of p300. These findings demonstrated that HNF-1alpha binds to the 5'-untranslated region of GLUT2 and that p300 acts as a transcriptional co-activator for HNF-1alpha. In addition, these results provided new insight into the regulatory function of HNF-1alpha by suggesting a molecular basis for human GLUT2 gene expression.

5' Untranslated Regions↗
PubMed2004

Mitochondrial diabetes: molecular mechanisms and clinical presentation.

Mutations in mitochondrial DNA (mtDNA) associate with various disease states. A few mtDNA mutations strongly associate with diabetes, with the most common mutation being the A3243G mutation in the mitochondrial DNA-encoded tRNA(Leu,UUR) gene. This article describes clinical characteristics of mitochondrial diabetes and its molecular diagnosis. Furthermore, it outlines recent developments in the pathophysiological and molecular mechanisms leading to a diabetic state. A gradual development of pancreatic beta-cell dysfunction upon aging, rather than insulin resistance, is the main mechanism in developing glucose intolerance. Carriers of the A3243G mutation show during a hyperglycemic clamp at 10 mmol/l glucose a marked reduction in first- and second-phase insulin secretion compared with noncarriers. The molecular mechanism by which the A3243G mutation affects insulin secretion may involve an attenuation of cytosolic ADP/ATP levels leading to a resetting of the glucose sensor in the pancreatic beta-cell, such as in maturity-onset diabetes of the young (MODY)-2 patients with mutations in glucokinase. Unlike in MODY2, which is a nonprogressive form of diabetes, mitochondrial diabetes does show a pronounced age-dependent deterioration of pancreatic function indicating involvement of additional processes. Furthermore, one would expect that all mtDNA mutations that affect ATP synthesis lead to diabetes. This is in contrast to clinical observations. The origin of the age-dependent deterioration of pancreatic function in carriers of the A3243G mutation and the contribution of ATP and other mitochondrion-derived factors such as reactive oxygen species to the development of diabetes is discussed.

Animals↗
PubMed2004

Genome-wide scans reveal quantitative trait Loci on 8p and 13q related to insulin action and glucose metabolism: the San Antonio Family Heart Study.

Type 2 diabetes is a complex disease that arises from physiological disruptions of the body's sensitivity to insulin and ability to metabolize glucose. Multipoint linkage analyses for insulin sensitivity phenotypes were conducted in 1,280 Mexican Americans from 41 families who participated in the San Antonio Family Heart Study. A significant linkage signal (logarithm of odds [LOD] = 2.98) affecting corrected insulin response to glucose was detected on chromosome 13q between D13787 and D13S252, in the region where the MODY-4 gene has previously been mapped. Another signal on chromosome 13 was observed at D13S285 (LOD = 1.86), where the insulin receptor substrate 2 gene resides. Significant linkage (LOD = 3.09) for insulin response to glucose was found on chromosome 8 between D8S1130 and D8S1106, near the lipoprotein lipase and macrophage scavenger receptor genes. Multipoint analysis of abdominal skinfold with an LOD of 2.68 showed signals in the same region. There was also suggestive evidence for linkage of quantitative insulin sensitivity check index and fasting glucose to a previously reported location at D9S301 (LOD = 2.19). These results indicate that chromosomal locations on 8p and 13q might harbor genes that affect a variety of insulin- and glucose-related phenotypes that contribute to the observed variations in these important risk factors for diabetes in Mexican Americans.

Adult↗
PubMed2004

Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation.

Glucokinase (GK) is a glycolytic key enzyme that functions as a glucose sensor in the pancreatic beta-cell, where it governs glucose-stimulated insulin secretion (GSIS). Heterozygous inactivating mutations in the glucokinase gene (GCK) cause a mild form of diabetes (maturity-onset diabetes of the young [MODY]2), and activating mutations have been associated with a mild form of familial hyperinsulinemic hypoglycemia. We describe the first case of severe persistent hyperinsulinemic hypoglycemia due to a "de novo" mutation in GCK (Y214C). A baby girl presented with hypoglycemic seizures since the first postnatal day as well as with inappropriate hyperinsulinemia. Severe hypoglycemia persisted even after treatment with diazoxide and subtotal pancreatectomy, leading to irreversible brain damage. Pancreatic histology revealed abnormally large and hyperfunctional islets. The mutation is located in the putative allosteric activator domain of the protein. Functional studies of purified recombinant glutathionyl S-transferase fusion protein of GK-Y214C showed a sixfold increase in its affinity for glucose, a lowered cooperativity, and increased kcat. The relative activity index of GK-Y214C was 130, and the threshold for GSIS predicted by mathematical modeling was 0.8 mmol/l, compared with 5 mmol/l in the wild-type enzyme. In conclusion, we have identified a de novo GCK activating mutation that causes hyperinsulinemic hypoglycemia of exceptional severity. These findings demonstrate that the range of the clinical phenotype caused by GCK mutations varies from complete insulin deficiency to extreme hyperinsulinemia.

Amino Acid Substitution↗
PubMed2006

Contrasting insulin sensitivity of endogenous glucose production rate in subjects with hepatocyte nuclear factor-1beta and -1alpha mutations.

Heterozygous mutations in the transcription factors hepatocyte nuclear factor (HNF)-1alpha and -1beta result in MODY (maturity-onset diabetes of the young). Despite structural similarity between HNF-1alpha and -1beta, HNF-1beta mutation carriers have hyperinsulinemia, whereas HNF-1alpha mutation carriers have normal or reduced insulin concentrations. We examined whether HNF-1beta mutation carriers are insulin resistant. The endogenous glucose production rate and rate of glucose uptake were measured with a two-step, low-dose (0.3 mU . kg(-1) . min(-1)) and high-dose (1.5 mU . kg(-1) . min(-1)) hyperinsulinemic-euglycemic clamp, with an infusion of [6,6-(2)H(2)]glucose, in six subjects with HNF-1alpha mutations, six subjects with HNF-1beta mutations, and six control subjects, matched for age, sex, and BMI. Endogenous glucose production rate was not suppressed by low-dose insulin in HNF-1beta subjects but was suppressed by 89% in HNF-1alpha subjects (P = 0.004) and 80% in control subjects (P < 0.001). Insulin-stimulated glucose uptake and suppression of lipolysis were similar in all groups at low- and high-dose insulin. Subjects with HNF-1beta mutations have reduced insulin sensitivity of endogenous glucose production but normal peripheral insulin sensitivity. This is likely to reflect reduced action of HNF-1beta in the liver and possibly the kidney. This may be mediated through regulation by HNF-1beta of the key gluconeogenic enzymes glucose-6-phosphatase or PEPCK.

Adult↗
PubMedDate not supplied

Standardization of definition, classification, and reporting in diabetes-related epidemiologic studies.

This working paper reviews some advantages and disadvantages of various alternative definitions and classification schemes. Certain of these alternatives were discussed by an international group of experts on the epidemiology of diabetes. It was recommended by the conferees that the following terms not be used as standard descriptors in epidemiologic reports: juvenile diabetes, juvenile-type diabetes, maturity-onset diabetes of youth (MODY), latent diabetes, subclinical diabetes, clinical diabetes, chemical diabetes, and J-type (Jamaica) diabetes. Alternative ways of describing these conditions were offered. Some, but not all, conferees favored abandonment or modification of the terms "secondary diabetes" and "pancreatic diabetes." Two alternate approaches are described in classification. One is designed to classify all types of cases in a single scheme. In this system each case is described by indices that include etiology and special etiologic concomitants, fatness, severity, type of treatment, and, if present, special or peculiar manifestations, and morbidity. This system makes it possible to classify all cases by mutually exclusive categories. A disadvantage of this scheme is that the number of combinations of classifying indices and subindices is great. Another approach is to classify cases by syndromes, using in each class a mixture of indices (e.g., etiology, severity, fatness, etc.). The conferees failed to reach a consensus in the specifics of this approach. There was considerable disagreement on how certain terms should be defined, whether they should be used, and on the degree of need for specific definitions. These designations included the terms "insulin-dependent," "idiopathic," "insulin-requiring," and "ketosis-prone." The conferees agreed that in either of the two approaches to classification, the prime indices should be those that can be ascertained by ordinary clinical methods. Much progress could be accomplished, even in the absence of international standardized definitions and classification systems, provided that authors keep in mind the need to describe the major characteristics of their cases and define the sense in which they use terms such as insulin-dependent, ketosis-prone, obese, etc.

Diabetes Mellitus↗
PubMed1997

The role of late-onset autoimmune diabetes in white familial NIDDM pedigrees.

OBJECTIVE: To determine whether autoimmunity is a prominent feature of NIDDM among diabetic members in families with a strong history of NIDDM or in families with a mixture of NIDDM and IDDM. RESEARCH DESIGN AND METHODS: We determined GAD and islet cell (ICA512) autoantibodies from 215 NIDDM individuals and from 14 individuals with impaired glucose tolerance (IGT) of 68 families, including 1 family with maturity-onset diabetes of the young (MODY) and 3 families ascertained specifically for a mixture of NIDDM and IDDM. We tested 2 control populations: 50 unrelated spouses form Utah families, including 29 spouses with either IGT or NIDDM and 198 random nondiabetic white individuals from Colorado. RESULTS: We detected either GAD or ICA512 autoantibodies in 11 members of seven families and in one spouse used as a control subject. In two families, two affected individuals showed evidence of autoimmunity, but NIDDM individuals in each of the seven families showed no evidence of autoimmunity. Among the five families with both IDDM and NIDDM individuals (three families ascertained for a mixture and two families ascertained with an incidental IDDM child), antibodies were detected in members of only one family. Antibody-positive individuals were significantly younger at diabetes onset and had low waist-to-hip ratios, but were not more likely to be insulin treated. CONCLUSIONS: Autoimmunity is an important cause of apparent NIDDM, even among families with a strong history of NIDDM. However, autoimmunity among affected family members appeared to be a chance event and not the manifestation of a different genetic cause of diabetes.

Adult↗
PubMed2002

Intrauterine hyperglycemia is associated with an earlier diagnosis of diabetes in HNF-1alpha gene mutation carriers.

OBJECTIVE: In animals, experimentally induced maternal hyperglycemia during pregnancy results in hyperglycemic offspring. Similarly, Pima Indian offspring with mothers who are diabetic at the time of pregnancy have increased risk of early-onset diabetes. We hypothesized that exposure to hyperglycemia in utero would decrease the age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY) due to a mutation in the hepatocyte nuclear factor 1alpha (HNF-1alpha) gene. RESEARCH DESIGN AND METHODS: We analyzed the affect of maternal diabetes on age at diagnosis of diabetes in 150 HNF-1alpha gene mutation carriers from 55 families. RESULTS: Age at diagnosis in HNF-1alpha mutation carriers was younger when the mother was diagnosed before pregnancy compared with when the mother was diagnosed after pregnancy (15.5 +/- 5.4 vs. 27.5 +/- 13.1 years, P < 0.0001). This is unlikely to represent a generalized familial decrease in age at diagnosis due to a more severe mutation, because no difference was seen in age of the offspring at diagnosis of diabetes when the father was diagnosed at a young age, and a similar trend was seen when only the single common mutation, P291fsinsC, was analyzed. CONCLUSIONS: We conclude that maternal hyperglycemia during pregnancy probably increases the penetrance of HNF-1alpha mutations. The potential role of exposure to hyperglycemia in utero in a monogenic diabetic subgroup warrants prospective study.

Adult↗
PubMed2004

Adult-onset atypical (type 1) diabetes: additional insights and differences with type 1A diabetes in a European Mediterranean population.

OBJECTIVE: In 1997, the American Diabetes Association proposed two subcategories for type 1 diabetes: type 1A or immunomediated diabetes and type 1B or idiopathic diabetes characterized by negative beta-cell autoimmunity markers, lack of association with HLA, and fluctuating insulinopenia. The aim of this study was to examine clinical characteristics, beta-cell function, HLA typing, and mutations in maturity-onset diabetes of the young (MODY) genes in patients with atypical type 1 diabetes (type 1 diabetes diagnosed at onset, without pancreatic autoantibodies and fluctuating insulinopenia). RESEARCH DESIGN AND METHODS: Eight patients with atypical type 1 diabetes (all men, 30.7 +/- 7.6 years) and 16 newly diagnosed age- and sex-matched patients with type 1A diabetes were studied retrospectively. Islet cell, GAD, tyrosine phosphatase and insulin antibodies, and basal and stimulated plasma C-peptide were measured at onset and after 1 year. HLA-DRB1-DQA1-DQB1 typing and screening for mutations in the HNF-1alpha and HNF-4alpha genes were performed from genomic DNA. RESULTS: Atypical patients displayed significantly higher BMI and better beta-cell function at onset and after 12 months. Three patients carried protective or neutral type 1 diabetes haplotypes, five patients displayed heterozygosity for susceptible and protective haplotypes, and seven patients showed Asp(beta57). We found a nondescribed variant Pro436Ser in exon 10 of the HNF-4alpha gene in one atypical patient without susceptible haplotypes. CONCLUSIONS: In our population, there are atypical forms of young adult-onset ketosis-prone diabetes initially diagnosed as type 1 diabetes, differing from type 1 diabetes in the absence of beta-cell autoimmunity, persistent beta-cell function capacity, fluctuating insulin requirements and ketosis-prone episodes, as well as clinical features of type 2 diabetes. Only one subgroup could be strictly classified as having type 1B diabetes. Additional information is still needed to improve our understanding of the mechanisms that finally lead to the disease.

Adult↗
PubMed2006

Hyperinsulinemic hypoglycemia due to adult nesidioblastosis in insulin-dependent diabetes.

In neonates, persistent hyperinsulinemic hypoglycemia (PHH) is associated with nesidioblastosis. In adults, PHH is usually caused by solitary benign insulinomas. We report on an adult patient who suffered from insulin-dependent diabetes mellitus, and subsequently developed PHH caused by diffuse nesidioblastosis. Mutations of the MEN1 and Mody (2/3) genes were ruled out. Preoperative diagnostic procedures, the histopathological criteria and the surgical treatment options of adult nesidioblastosis are discussed. So far only one similar case of adult nesidioblastosis subsequent to diabetes mellitus II has been reported in the literature. In case of conversion of diabetes into hyperinsulinemic hypoglycemia syndrome, nesidioblastosis in addition to insulinoma should be considered.

Adult↗