Metabolic Phenotypes and Step by Step Evolution of Type 2 Diabetes: A New Paradigm

Unlike bolus insulin secretion mechanisms, basal insulin secretion is poorly understood. It is essential to elucidate these mechanisms in non-hyperinsulinaemia healthy persons. This establishes a baseline for investigation into pathologies where these processes are dysregulated, such as in type 2 diabetes (T2DM), cardiovascular disease (CVD), certain cancers and dementias. Chronic hyperinsulinaemia enforces glucose fueling, depleting the NAD+ dependent antioxidant activity that increases mitochondrial reactive oxygen species (mtROS). Consequently, beta-cell mitochondria increase uncoupling protein expression, which decreases the mitochondrial ATP surge generation capacity, impairing bolus mediated insulin exocytosis. Excessive ROS increases the Drp1:Mfn2 ratio, increasing mitochondrial fission, which increases mtROS; endoplasmic reticulum-stress and impaired calcium homeostasis ensues. Healthy individuals in habitual ketosis have significantly lower glucagon and insulin levels than T2DM individuals. As beta-hydroxybutyrate rises, hepatic gluconeogenesis and glycogenolysis supply extra-hepatic glucose needs, and osteocalcin synthesis/release increases. We propose insulin’s primary role is regulating beta-hydroxybutyrate synthesis, while the role of bone regulates glucose uptake sensitivity via osteocalcin. Osteocalcin regulates the alpha-cell glucagon secretory profile via glucagon-like peptide-1 and serotonin, and beta-hydroxybutyrate synthesis via regulating basal insulin levels. Establishing metabolic phenotypes aids in resolving basal insulin secretion regulation, enabling elucidation of the pathological changes that occur and progress into chronic diseases associated with ageing.

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Effects of fatty acids and ketone bodies on basal insulin secretion in type 2 diabetes

Diabetes ◽

10.2337/diabetes.48.3.577 ◽

1999 ◽

Vol 48 (3) ◽

pp. 577-583 ◽

Cited By ~ 67

Author(s):

G. Boden ◽

X. Chen

Keyword(s):

Type 2 Diabetes ◽

Fatty Acids ◽

Insulin Secretion ◽

Basal Insulin ◽

Ketone Bodies ◽

Basal Insulin Secretion

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Elevated Basal Insulin Secretion in Type 2 Diabetes Caused by Reduced Plasma Membrane Cholesterol

Molecular Endocrinology ◽

10.1210/me.2016-1023 ◽

2016 ◽

Vol 30 (10) ◽

pp. 1059-1069 ◽

Cited By ~ 9

Author(s):

Vini Nagaraj ◽

Abdulla S. Kazim ◽

Johan Helgeson ◽

Clemens Lewold ◽

Satadal Barik ◽

...

Keyword(s):

Type 2 Diabetes ◽

Plasma Membrane ◽

Insulin Secretion ◽

Basal Insulin ◽

Membrane Cholesterol ◽

Basal Insulin Secretion ◽

Plasma Membrane Cholesterol

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The Acute Effects of Low-Dose TNF-αon Glucose Metabolism andβ-Cell Function in Humans

Mediators of Inflammation ◽

10.1155/2014/295478 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 9

Author(s):

Tobias Ibfelt ◽

Christian P. Fischer ◽

Peter Plomgaard ◽

Gerrit van Hall ◽

Bente Klarlund Pedersen

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Low Dose ◽

Cell Function ◽

Low Grade ◽

Intravenous Glucose ◽

Insulin Levels ◽

Basal Period

Type 2 diabetes is characterized by increased insulin resistance and impaired insulin secretion. Type 2 diabetes is also associated with low-grade inflammation and increased levels of proinflammatory cytokines such as TNF-α. TNF-αhas been shown to impair peripheral insulin signalingin vitroandin vivo. However, it is unclear whether TNF-αmay also affect endogenous glucose production (EGP) during fasting and glucose-stimulated insulin secretion (GSIS)in vivo. We hypothesized that low-dose TNF-αwould increase EGP and attenuate GSIS. Recombinant human TNF-αor placebo was infused in healthy, nondiabetic young men (n=10) during a 4-hour basal period followed by an intravenous glucose tolerance test (IVGTT). TNF-αlowered insulin levels by 12% during the basal period (P<0.05). In response to the IVGTT, insulin levels increased markedly in both trials, but there was no difference between trials. Compared to placebo, TNF-αdid not affect EGP during the basal period. Our results indicate that TNF-αacutely lowers basal plasma insulin levels but does not impair GSIS. The mechanisms behind this are unknown but we suggest that it may be due to TNF-αincreasing clearance of insulin from plasma without impairing beta-cell function or hepatic insulin sensitivity.

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Effect of exercise on basal insulin levels in normoglycaemic offspring of patients with Type 2 Diabetes mellitus

Annals of Health Research ◽

10.30442/ahr.0502-24-54 ◽

2019 ◽

Vol 5 (2) ◽

pp. 224-230

Author(s):

EO Taiwo ◽

OA Sofola ◽

AA Fasanmade ◽

G Onyemelukwe

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Basal Insulin ◽

Insulin Level ◽

Normal Weight ◽

Insulin Levels ◽

Sensitivity Pattern ◽

Graded Exercise

Background: Low basal insulin level is a risk factor for Type 2 Diabetes mellitus (T2DM) as a result of altered insulin sensitivity pattern. However, it is uncertain if exercise may influence the occurrence of T2DM in the offspring of diabetic parents. Objective: To assess the effect of exercise on basal insulin levels in the offspring of T2DM parents compared with the offspring of non-diabetic parents.Design: The participants were assigned into four groups using a convenience sampling method; 27 Normal-weight Offspring of Non-Diabetic Parents (NONDP), 21 Normal-weight Offspring of Diabetic Parents (NODP), 26 Overweight Offspring of Non-Diabetic Parents (OONDP) and 21 Overweight Offspring of Diabetic Parents (OODP). Each participant followed a protocol of graded exercise using ''tummy trimmer'' everyday spending 30-45 minutes daily for 24 weeks. Blood samples were obtained after overnight fasting for determination of insulin level using standard methods (immunoassay technique) at baseline, six weeks, 12 weeks, 18 weeks and 24 weeks respectively.Results: There were 23/42 males (54.8%) in the study groups and 34/51 females (64.2%) in the control groups. Thirty-one (58.7%) in the control group and 24 (57.1%) in the study group were aged 21-30 years. An increase in insulin levels was recorded at 12 weeks in all groups except in NONDP where the insulin levels decreased. The insulin level change was highest in the NODP (2.25ng/ml) group.Conclusions: Graded exercise improved insulin levels in all test groups. The clinical importance of graded exercise in the prevention of diabetes mellitus among the offspring of diabetic parents may be promising.

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Basal insulin secretion capacity predicts the initial response and maximum levels of beta‐hydroxybutyrate during therapy with the sodium‐glucose co‐transporter‐2 inhibitor tofogliflozin, in relation to weight loss

Diabetes Obesity and Metabolism ◽

10.1111/dom.13890 ◽

2019 ◽

Vol 22 (2) ◽

pp. 222-230 ◽

Cited By ~ 1

Author(s):

Yuichi Sato ◽

Kiyohide Nunoi ◽

Kohei Kaku ◽

Akihiro Yoshida ◽

Hideki Suganami

Keyword(s):

Weight Loss ◽

Insulin Secretion ◽

Basal Insulin ◽

Initial Response ◽

Basal Insulin Secretion ◽

Beta Hydroxybutyrate

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Type 2 diabetes-associated single nucleotide polymorphism in Sorcs1 gene results in alternative processing of the Sorcs1 protein in INS1 β-cells

Scientific Reports ◽

10.1038/s41598-019-55873-6 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Belinda Yau ◽

Zachary Blood ◽

Yousun An ◽

Zhiduan Su ◽

Melkam A. Kebede

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Allelic Variation ◽

Association Studies ◽

Mutant Form ◽

Genome Wide Association Studies ◽

Insulin Levels ◽

Alternative Processing ◽

Trait Locus

AbstractA threonine-to-Isoleucine (Thr52Ile) mutation within the pro-domain of the Sorcs1 gene was positionally cloned as the gene underlying a quantitative trait locus that affects fasting insulin levels in mice. In humans, genome-wide association studies and linkage studies have shown that SORCS1 is associated with diabetes and all of diabetes complications. We have recently shown that deletion of Sorcs1 in mice made obese with the leptinob mutation results in diabetes and an insulin granule stability defect. This present study investigates the functional consequence of the Sorcs1 Thr52Ile mutation in the rat INS1 β-cell line expressing either the wildtype or mutant Sorcs1 allele. We find that Sorcs1 Thr52Ile mutation is associated with increased basal insulin secretion, reduced glucose-stimulated insulin secretion and decreased insulin content in INS1 cells. Moreover, expression of Thr52Ile causes differential processing of the Sorcs1 protein resulting in the formation of an additional 90 kDa mutant form of the protein. The mutant form of the protein is localised to the ER, retains its pro-domain, and concurrently reduces expression of the functional mature 130 kDa Sorcs1 protein. These findings provide a mechanistic clue to why this specific allelic variation in Sorcs1 was associated with reduced insulin levels and type 2 diabetes.

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Uncoupling protein-2 polymorphisms in type 2 diabetes, obesity, and insulin secretion

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00231.2003 ◽

2004 ◽

Vol 286 (1) ◽

pp. E1-E7 ◽

Cited By ~ 92

Author(s):

Hua Wang ◽

Winston S. Chu ◽

Tong Lu ◽

Sandra J. Hasstedt ◽

Philip A. Kern ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Uncoupling Protein ◽

Uncoupling Protein 2 ◽

Mrna Levels ◽

Metabolic Study ◽

Β Cell ◽

Family Based ◽

Ucp2 Mrna

The onset of type 2 diabetes (T2DM) is preceded by obesity, insulin resistance, and impaired β-cell function. Uncoupling protein-2 (UCP2) is a widely expressed inner mitochondrial membrane protein. Common polymorphisms of the UCP2 gene have been implicated in diabetes, in obesity, and with changes in UCP2 mRNA levels. We tested the hypothesis that common UCP2 variants influence T2DM susceptibility in four parallel studies of separate populations. We typed the -866 promoter (G/A) variant, a nonsynonymous (Ala55Val or A55V) single-nucleotide polymorphism in exon 4, and a 45-nt insertion in the 3′-untranslated (3′UTR) region. Study populations included a case-control population study, a family-based association study, and a metabolic study of individuals who had been characterized for insulin sensitivity and secretion. To evaluate UCP2 mRNA levels, we examined a fourth population of subjects, who had undergone subcutaneous fat biopsy. All three variants showed a trend to an association with T2DM ( P = 0.05 to 0.07) in the population but not the family-based association study. The 3′ insertion/deletion (3′UTR I/D) variant was associated with body mass index (BMI, P = 0.035) among nondiabetic family members. Haplotype combinations were significantly associated with BMI ( P = 0.028), triglyceride levels ( P = 0.026), and fasting insulin ( P = 0.029); highest values for the three traits were observed in individuals with the heterozygous combination GVI/AVD. In the metabolic study, all three variants were associated with an index of β-cell compensation for insulin sensitivity (disposition index), particularly in interaction with family membership ( P < 0.000001). Individuals homozygous for the -866 A allele had decreased adipose mRNA levels relative to GG homozygous individuals ( P = 0.009), but the 3′UTR I/D variant had no impact on mRNA levels. We confirm modest effects of UCP2 variants on BMI and T2DM and show significant effects on insulin secretion in interaction with family-specific factors. However, the associated allele and the effects on gene expression are opposite to those reported previously.

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Short Course of Insulin Treatment versus Metformin in Newly Diagnosed Patients with Type 2 Diabetes

Journal of Clinical Medicine ◽

10.3390/jcm7090235 ◽

2018 ◽

Vol 7 (9) ◽

pp. 235 ◽

Cited By ~ 2

Author(s):

Marta Seghieri ◽

Eleni Rebelos ◽

Andrea Mari ◽

Luigi Sciangula ◽

Carlo Giorda ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Insulin Sensitivity ◽

Basal Insulin ◽

Insulin Treatment ◽

Oral Glucose ◽

Newly Diagnosed ◽

Insulin Group ◽

Short Course

The ß-cell dysfunction of type 2 diabetes is partly reversible. The optimal time window to induce glycemic remission is uncertain; short courses of insulin treatment have been tested as a strategy to induce remission. In a pilot study in 38 newly-diagnosed patients, we assessed the time-course of insulin sensitivity and ß-cell function (by repeat oral glucose tolerance tests) following a 6-week basal insulin treatment compared to metformin monotherapy in equipoised glycemic control. At 6 weeks, insulin secretion and sensitivity were increased in both groups whilst ß-cell glucose sensitivity was unchanged. From this time onwards, in the insulin group glycemia started to rise at 3 months, and was no longer different from baseline at 1 year. The initial improvement in insulin secretion and sensitivity dissipated. In the metformin group, fasting plasma glucose and HbA1c levels reached a nadir at 8 months, at which time insulin secretion, glucose and insulin sensitivity were significantly better than at baseline and higher than in the insulin group. A short course of basal insulin in newly-diagnosed patients does not appear to offer clinical advantage over recommended initiation with metformin.

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