Permanent neonatal diabetes mellitus (PNDM) is a rare disorder usually presenting within 6 months of birth.Although several genes have been linked to this disorder, in almost half the cases documented in Italy, the genetic cause remains unknown. Because the Akita mouse bearing a mutation in the Ins2 gene exhibits PNDM associated with pancreatic β cell apoptosis, we sequenced the human insulin gene in PNDM subjects with unidentified mutations. We discovered 7 heterozygous mutations in 10 unrelated probands. In 8 of these patients, insulin secretion was detectable at diabetes onset, but rapidly declined over time. When these mutant proinsulins were expressed in HEK293 cells, we observed defects in insulin protein folding and secretion. In these experiments, expression of the mutant proinsulins was also associated with increased Grp78 protein expression and XBP1 mRNA splicing, 2 markers of endoplasmic reticulum stress, and with increased apoptosis. Similarly transfected INS-1E insulinoma cells had diminished viability compared with those expressing WT proinsulin. In conclusion, we find that mutations in the insulin gene that promote proinsulin misfolding may cause PNDM.
We studied the effects of genetic background on the phenotype of ob/ob mice, a model of severe obesity, insulin resistance, and diabetes caused by leptin deficiency. Despite a comparable degree of obesity and hyperinsulinemia, C57BL/6J ob/ob mice had much milder hyperglycemia and, surprisingly, normal circulating adiponectin levels despite still-prominent signs of insulin resistance. Hyperinsulinemic-euglycemic clamp revealed relatively less whole-body and muscle insulin resistance in C57BL/6J ob/ob mice, whereas liver insulin resistance tended to be more severe than in FVB/N ob/ob mice. C57BL/6J ob/ob mice had also more rapid clearance of circulating triglycerides and more severe hepatic steatosis. We suggest that strain-related distinction in lipid handling is the most important player in the differences in diabetic phenotype and insulin sensitivity, whereas the impact of circulating adiponectin levels on the overall phenotype of ob/ob mice is less important.
Mutations in the pancreatic ATP-sensitive K؉ channel (K ATP channel) cause permanent neonatal diabetes mellitus (PNDM) in humans. All of the K ATP channel mutations examined result in decreased ATP inhibition, which in turn is predicted to suppress insulin secretion. Here we describe a patient with severe PNDM, which includes developmental delay and epilepsy, in addition to neonatal diabetes (developmental delay, epilepsy, and neonatal diabetes [DEND]), due to a G334D mutation in the Kir6.2 subunit of K ATP channel. The patient was wholly unresponsive to sulfonylurea therapy (up to 1.14 mg ⅐ kg ؊1 ⅐ day ؊1 ) and remained insulin dependent. Consistent with the putative role of G334 as an ATP-binding residue, reconstituted homomeric and mixed WT؉G334D channels exhibit absent or reduced ATP sensitivity but normal gating behavior in the absence of ATP. In disagreement with the sulfonylurea insensitivity of the affected patient, the G334D mutation has no effect on the sulfonylurea inhibition of reconstituted channels in excised patches. However, in macroscopic rubidium-efflux assays in intact cells, reconstituted mutant channels do exhibit a decreased, but still present, sulfonylurea response. The results demonstrate that ATP-binding site mutations can indeed cause DEND and suggest the possibility that sulfonylurea insensitivity of such patients may be a secondary reflection of the presence of DEND rather than a simple reflection of the underlying molecular basis.
Until early 2000, permanent and transient neonatal diabetes mellitus (NDM), defined as diabetes with onset within 6 weeks from birth that requires insulin therapy for at least 2 weeks, were considered exceedingly rare conditions, with a global incidence of 1:500,000–1:400,000 live births. The new definition of NDM recently adopted, that includes patients with diabetes onset within 6 months of age, has prompted studies that have set the incidence of the permanent form alone between 1:210,000 and 1:260,000 live births. Aim of the present work was to ascertain the incidence of NDM (i.e. permanent + transient form) in Italy for years 2005–2010. Patients referred to the Italian reference laboratory for NDM between years 2005 and 2010 and screened for mutations in common NDM genes (KCNJ11, ABCC8, and INS) and for uniparental isodisomy of chromosome 6 (UDP6) were reviewed. A questionnaire aimed at identifying NDM cases investigated in other laboratories was sent to 54 Italian reference centers for pediatric diabetes. Twenty-seven patients with NDM born between 2005 and 2010 were referred to the reference laboratory. In this group, a mutation of either KCNJ11, ABCC8 or INS was found in 18 patients, and a case with UDP6 was identified. Questionnaires revealed 4 additional cases with transient neonatal diabetes due to UDP6. Incidence of NDM was calculated at 1:90,000 (CI: 1:63,000–1:132,000) live births. Thus, with the definition currently in use, about 6 new cases with NDM are expected to be born in Italy each year.
Severe adipose tissue deficiency (lipoatrophy) causes insulin-resistant diabetes, elevated serum triglyceride and fatty acid levels, and massive triglyceride deposition in the liver. In lipoatrophic A-ZIP/F-1 mice, transplantation of normal adipose tissue greatly improved these parameters, whereas 1 week of leptin infusion had more modest effects. In contrast, leptin infusion was strikingly more effective in the aP2-n sterol response element binding protein 1 lipoatrophic mouse. Here we show that a longer duration of leptin infusion further improves the metabolic status of the A-ZIP/F-1 mice and that genetic background does not make a major contribution to the effect of leptin on glucose and insulin levels. Adipose transplantation using leptin-deficient ob/ob fat had no effect on the phenotype of the A-ZIP/ F-1 mice. Moreover, the presence of ob/ob adipose tissue did not enhance the effects of leptin infusion. Serum adiponectin levels were 2% of control levels in the A-ZIP/F-1 mouse and increased only twofold with adipose transplantation and not at all after leptin infusion, suggesting that adiponectin deficiency is not a major contributor to the diabetic phenotype. Taken together, these results suggest that sequestration of triglycerides into fat may not be enough to restore a nondiabetic phenotype and that leptin deficiency plays a major role in causing the metabolic complications of lipoatrophy.
Context: Mutations in the Kir6.2 subunit (KCNJ11) of the ATP-sensitive potassium channel (K ATP ) underlie neonatal diabetes mellitus. In severe cases, Kir6.2 mutations underlie developmental delay, epilepsy, and neonatal diabetes (DEND). All Kir6.2 mutations examined decrease the ATP inhibition of K ATP , which is predicted to suppress electrical activity in neurons (peripheral and central), muscle, and pancreas. Inhibitory sulfonylureas (SUs) have been used successfully to treat diabetes in patients with activating Kir6.2 mutations. There are two reports of improved neurological features in SU-treated DEND patients but no report of such improvement in adulthood.Objective: The objective of the study was to determine the molecular basis of intermediate DEND in a 27-yr-old patient with a KCNJ11 mutation (G53D) and the patient's response to SU therapy. Design:The G53D patient was transferred from insulin to gliclazide and then to glibenclamide over a 160-d period. Motor function was assessed throughout. Electrophysiology assessed the effect of the G53D mutation on K ATP activity. Results:The G53D patient demonstrated improved glycemic control and motor coordination with SU treatment, although glibenclamide was more effective than gliclazide. Reconstituted G53D channels exhibit reduced ATP sensitivity, which is predicted to suppress electrical activity in vivo. G53D channels coexpressed with SUR1 (the pancreatic and neuronal isoform) exhibit high-affinity block by gliclazide but are insensitive to block when coexpressed with SUR2A (the skeletal muscle isoform). High-affinity block by glibenclamide is present in G53D channels coexpressed with either SUR1 or SUR2A. tion from the pancreatic -cell by coupling changes in metabolism (represented by the concentration ratio of ATP to ADP) with changes in electrical activity. At low blood glucose levels, K ATP channels provide the dominant membrane conductance in the pancreatic -cell and maintain the cell in a hyperpolarized, nonsecreting state. However, as blood glucose levels rise, the intracellular ATP to ADP ratio increases, causing in succession, Conclusion
OBJECTIVE—Heterozygous, gain-of-function mutations of the insulin gene can cause permanent diabetes with onset ranging from the neonatal period through adulthood. The aim of our study was to screen for the insulin gene in patients who had been clinically classified as type 1 diabetic but who tested negative for type 1 diabetes autoantibodies. RESEARCH DESIGN AND METHODS—We reviewed the clinical records of 326 patients with the diagnosis of type 1 diabetes and identified seven probands who had diabetes in isolation and were negative for five type 1 diabetes autoantibodies. We sequenced the INS gene in these seven patients. RESULTS—In two patients whose diabetes onset had been at 2 years 10 months of age and at 6 years 8 months of age, respectively, we identified the mutation GB8S and a novel mutation in the preproinsulin signal peptide (ASignal23S). CONCLUSIONS—Insulin gene mutations are rare in absolute terms in patients classified as type 1 diabetic (0.6%) but can be identified after a thorough screening of type 1 diabetes autoantibodies.
Aims/hypothesisThe aim of this study was to investigate the genetic aetiology of permanent diabetes mellitus with onset in the first 12 months of age.MethodsWe studied 46 probands with permanent, insulin-requiring diabetes with onset within the first 6 months of life (permanent neonatal diabetes mellitus [PNDM]/monogenic diabetes of infancy [MDI]) (group 1) and eight participants with diabetes diagnosed between 7 and 12 months of age (group 2). KCNJ11, INS and ABCC8 genes were sequentially sequenced in all patients. For those who were negative in the initial screening, we examined ERN1, CHGA, CHGB and NKX6-1 genes and, in selected probands, CACNA1C, GCK, FOXP3, NEUROG3 and CDK4. The incidence rate for PNDM/MDI was calculated using a database of Italian patients collected from 1995 to 2009.ResultsIn group 1 we found mutations in KCNJ11, INS and ABCC8 genes in 23 (50%), 9 (19.5%) and 4 (8.6%) patients respectively, and a single homozygous mutation in GCK (2.1%). In group 2, we identified one incidence of a KCNJ11 mutation. No genetic defects were detected in other loci. The incidence rate of PNDM/MDI in Italy is estimated to be 1:210,287.Conclusions/interpretationGenetic mutations were identified in ~75% of non-consanguineous probands with PNDM/MDI, using sequential screening of KCNJ11, INS and ABCC8 genes in infants diagnosed within the first 6 months of age. This percentage decreased to 12% in those with diabetes diagnosed between 7 and 12 months. Patients belonging to the latter group may either carry mutations in genes different from those commonly found in PNDM/MDI or have developed an early-onset form of autoimmune diabetes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-011-2094-8) contains supplementary material, which is available to authorised users.
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